The rules governing medicinal productsin the European UnionVolume 4Good manufacturingpracticesMedicinal products for human andveterinary use1998 EditionEUROPEAN COMMISSIONDirectorate General III — IndustryPharmaceuticals and cosmetics
THE RULES GOVERNING MEDICINAL PRODUCTS INTHE EUROPEAN UNIONVolume 1Pharmaceutical legislationMedicinal products for human useVolume 2Notice to applicantsMedicinal products for human useVolume 3GuidelinesMedicinal products for human useVolume 4Good manufacturing practicesMedicinal products for human and veterinary useVolume 5Pharmaceutical legislationVeterinary medicinal productsVolume 6Notice to applicantsVeterinary medicinal productsVolume 7GuidelinesVeterinary medicinal productsVolume 8Maximum residue limitsVeterinary medicinal productsVolume 9PharmacovigilanceMedicinal products for human and veterinary use
FOREWORDThe Pharmaceutical Industry of the European Community maintains high standards of QualityAssurance in the development, manufacture and control of medicinal products. A system ofMarketing Authorisations ensures that all medicinal products are assessed by a CompetentAuthority to ensure compliance with contemporary requirements of safety, quality and system of Manufacturing Authorisations ensures that all products authorised on the Europeanmarket are manufactured only by authorised manufacturers, whose activities are regularlyinspected by the Competent Authorities. Manufacturing Authorisations are required by allpharmaceutical manufacturers in the European Community whether the products are sold withinor outside of the directives laying down principles and guidelines of good manufacturing practice (GMP) formedicinal products were adopted by the Commission in 1991, the first for medicinal products forhuman use (Directive 91/356/EEC), the second one for veterinary use (Directive 91/412/EEC).Detailed guidelines in accordance with those principles are published in the Guide to GoodManufacturing Practice which will be used in assessing applications for Manufacturingauthorisations and as a basis for inspection of manufacturers of medicinal principles of GMP and the detailed guidelines are applicable to all operations which requirethe authorisation referred to in Article 16 of Directive 75/319/EEC and in Article 24 of Directive81/851/EEC as modified. They are also relevant for all other large scale pharmaceuticalmanufacturing processes, such as that undertaken in hospitals, and for the preparation ofproducts for use in clinical Member States and the Industry itself are agreed that the GMP requirements applicable tothe manufacture of veterinary medicinal products are the same as those applicable to themanufacture of medicinal products for human use. Certain detailed adjustments to the GMPguidelines are set out in two annexes specific to veterinary medicinal products and toimmunological veterinary medicinal Guide is presented in chapters, each headed by a principle. Chapter 1 on QualityManagement outlines the fundamental concept of Quality Assurance as applied to themanufacture of medicinal products. Thereafter each chapter has a principle outlining the QualityAssurance objectives of that chapter and a text which provides sufficient detail for manufacturersto be made aware of the essential matters to be considered when implementing the addition to the general matters of Good Manufacturing Practice outlined in the 9 chapters ofthis guide, a series of annexes providing detail about specific areas of activity is included. Forsome manufacturing processes, different annexes will apply simultaneously (. annex on sterilepreparations and on radiopharmaceuticals and/or on biological medicinal products).iii
A glossary of some terms used in the Guide has been incorporated after the first edition of the Guide was published in 1989, including an annex on the manufacture ofsterile medicinal second edition was published in January 1992; including the Commission Directives 91/356of 13 June 1991 and 91/412 of 23 July 1991 laying down the principles and guidelines on goodmanufacturing practice for medicinal products for human use as well as for veterinary medicinalproducts. The second edition also included 12 additional basic requirements in the main guide have not been modified. 14 annexes on themanufacture of medicinal products have been included in this third 1 on the manufacture of sterile medicinal products has been modified. Annex 13 on themanufacture of investigational medicinal products, which was not included in the second editionof the Guide, has been modified and included in this version. Annex 14 on the manufacture ofproducts derived from human blood or human plasma, which was not included in the secondedition of the Guide, has been included in this version and a revision is scheduled for Guide is not intended to cover security aspects for the personnel engaged in may be particularly important in the manufacture of certain medicinal products such ashighly active, biological and radioactive medicinal products, but they are governed by otherprovisions of Community or national the Guide it is assumed that the requirements of the Marketing Authorisationrelating to the safety, quality and efficacy of the products, are systematically incorporated into allthe manufacturing, control and release for sale arrangements of the holder of the manufacture of medicinal products has for many years taken place in accordance withguidelines for Good Manufacturing Practice and the manufacture of medicinal products is notgoverned by CEN/ISO standards. Harmonised standards as adopted by the Europeanstandardisation organisations CEN/ISO may be used at industry’s discretion as a tool forimplementing a quality system in the pharmaceutical sector. The CEN/ISO standards have beenconsidered but the terminology of these standards has not been implemented in this third editionof the is recognised that there are acceptable methods, other than those described in the Guide, whichare capable of achieving the principles of Quality Assurance. The Guide is not intended to placeany restraint upon the development of any new concepts or new technologies which have beenvalidated and which provide a level of Quality Assurance at least equivalent to those set out inthis will be regularly
TABLE OF CONTENTSForeword........................................................................................................................................iiiDIRECTIVES.....................................................................................................................1Commission Directive 91/356/EEC of 13 June 1991 laying down the principles andguidelines of good manufacturing practice for medicinal products for human use ..................3Commission Directive 91/412/EEC of 23 July 1991 laying down the principles andguidelines of good manufacturing practice for veterinary medicinal products..........................11GOOD MANUFACTURING PRACTICES.........................................................................19BASIC REQUIREMENTS.................................................................................................21CHAPTER 1: QUALITY MANAGEMENT ..................................................................................23Principle ...................................................................................................................................23Quality Assurance ...................................................................................................................23Good Manufacturing Practice for Medicinal Products...........................................................24Quality Control ........................................................................................................................25CHAPTER 2: PERSONNEL ........................................................................................................27Principle ...................................................................................................................................27General .....................................................................................................................................27Key Personnel ..........................................................................................................................27Training....................................................................................................................................29Personnel Hygiene ...................................................................................................................29CHAPTER 3: PREMISES AND EQUIPMENT ..........................................................................31Principle ...................................................................................................................................31Premises ...................................................................................................................................31General ..............................................................................................................................31Production Area .................................................................................................................31Storage Area ......................................................................................................................32Quality Control Area .........................................................................................................33Ancillary Areas...................................................................................................................33Equipment ................................................................................................................................34CHAPTER 4: DOCUMENTATION .............................................................................................35Principle ...................................................................................................................................35General .....................................................................................................................................35Documents Required ...............................................................................................................36Specifications ....................................................................................................................36Specifications for starting and packaging materials ................................................36Specifications for Intermediate and Bulk Products ..................................................36v
Specifications for Finished Products ..........................................................................36Manufacturing Formulae and Processing Instructions ........................................................37Packaging Instructions ...........................................................................................................37Batch Processing Records ........................................................................................................38Batch Packaging Records ........................................................................................................39Procedures and Records ..........................................................................................................39Receipt ...............................................................................................................................39Sampling ............................................................................................................................40Testing ...............................................................................................................................40Other ..................................................................................................................................40CHAPTER 5: PRODUCTION ......................................................................................................43Principle ...................................................................................................................................43General......................................................................................................................................43Prevention of Cross-contamination in Production .................................................................44Validation .................................................................................................................................45Starting Materials ...................................................................................................................45Processing Operations: Intermediate and Bulk Products .....................................................46Packaging Materials ...............................................................................................................46Packaging Operations .............................................................................................................46Finished Products ....................................................................................................................48Rejected, Recovered and Returned Materials ........................................................................48CHAPTER 6: QUALITY CONTROL ...........................................................................................49Principle ...................................................................................................................................49General .....................................................................................................................................49Good Quality Control Laboratory Practice .............................................................................49Documentation ........................................................................................................................50Sampling ..................................................................................................................................50Testing .....................................................................................................................................51CHAPTER 7: CONTRACT MANUFACTURE AND ANALYSIS ...............................................53Principle ...................................................................................................................................53General .....................................................................................................................................53The Contract Giver ..................................................................................................................53The Contract Acceptor .............................................................................................................54The Contract ............................................................................................................................54CHAPTER 8: COMPLAINTS AND PRODUCT RECALL .........................................................55Principle ...................................................................................................................................55Complaints ...............................................................................................................................55Recalls ......................................................................................................................................55CHAPTER 9: SELF INSPECTION .............................................................................................57Principle ...................................................................................................................................57vi
ANNEXES.........................................................................................................................59Annex 1Manufacture of sterile medicinal products..............................................................61Principel....................................................................................................................................61General......................................................................................................................................61Isolator technology...................................................................................................................64Blow/fill/seal technology...........................................................................................................64Terminally sterilised products.................................................................................................65Aseptic preparation..................................................................................................................65Personnel..................................................................................................................................65Premises....................................................................................................................................67Equipment................................................................................................................................68Sanitation.................................................................................................................................68Processing.................................................................................................................................68Sterilisation..............................................................................................................................70Sterilisation by heat.................................................................................................................70Moist heat.................................................................................................................................71Dry heat....................................................................................................................................71Sterilisation by radiation.........................................................................................................71Sterilisation with ethylene oxide.............................................................................................72Filtration of medicinal products which cannot be sterilised in their final container...........73Finishing of sterile products....................................................................................................73Quality control..........................................................................................................................74Annex 2Manufacture of biological medicinal products for human use................................75Scope..........................................................................................................................................75Principle....................................................................................................................................75Personnel..................................................................................................................................76Premises and equipment..........................................................................................................77Animal quarters and care........................................................................................................78Documentation.........................................................................................................................78Production.................................................................................................................................78Starting materials..............................................................................................................78Seed lot and cell bank system...........................................................................................79Operating principles..........................................................................................................79Quality control..........................................................................................................................80Annex 3Manufacture of radiopharmaceuticals ....................................................................81Principle....................................................................................................................................81Personnel..................................................................................................................................81Premises and equipment..........................................................................................................81Production.................................................................................................................................82Quality control..........................................................................................................................82Distribution and recalls...........................................................................................................82Annex 4Manufacture of veterinary medicinal products other than immunologicals ........83Manufacture of premixes for medicated and feedingstuffs....................................................83Manufacture of ectoparasiticides.............................................................................................84Manufacture of veterinary medicinal products......................................................................84Retention of samples................................................................................................................84vii
Sterile veterinary medicinal products.....................................................................................84Annex 5Manufacture of immunological veterinary medicinal products .............................85Principle....................................................................................................................................85Personnel...................................................................................................................................85Premises....................................................................................................................................86Equipment................................................................................................................................88Animals and animal houses.....................................................................................................90Disinfection – Waste disposal..................................................................................................90Production.................................................................................................................................90Starting materials....................................................................................................................90Quality control..........................................................................................................................93Annex 6Manufacture of medicinal gases ..............................................................................95Principle....................................................................................................................................95Personnel...................................................................................................................................95Premises and equipment..........................................................................................................95Production and quality control................................................................................................96Labelling...................................................................................................................................98Storage – Release......................................................................................................................98Annex 7Manufacture of herbal medicinal products .............................................................99Principle....................................................................................................................................99Premises....................................................................................................................................99Storage areas......................................................................................................................99Production area..................................................................................................................99Documentation..........................................................................................................................99Specifications for starting materials.................................................................................99Processing instructions......................................................................................................100Sampling...................................................................................................................................100Quality control..........................................................................................................................100Annex 8Sampling of starting and packaging materials .......................................................103Principle....................................................................................................................................103Personnel...................................................................................................................................103Starting materials....................................................................................................................103Packaging material..................................................................................................................104Annex 9Manufacture of liquids, creams and ointments ......................................................105Principle....................................................................................................................................105Premises and equipment..........................................................................................................105Production.................................................................................................................................105Annex 10Manufacture of pressurised metered dose aerosol preparations for inhalation ...107Principle....................................................................................................................................107General......................................................................................................................................107Premises and equipment..........................................................................................................107Production and quality control................................................................................................107viii
Annex 11..............................................................................Computerised systems 109Principle....................................................................................................................................109Personnel..................................................................................................................................109Validation.................................................................................................................................109System.......................................................................................................................................109Annex 12Use of ionising radiation in the manufacture of medicinal products ....................113Introduction..............................................................................................................................113Responsibilities.........................................................................................................................113Dosimetry..................................................................................................................................114Validation of the process..........................................................................................................114Commissioning of the plant.....................................................................................................115General...............................................................................................................................115Gamma irradiators.............................................................................................................115Electron beam irradiators.................................................................................................116Re-commissioning..............................................................................................................117Premises....................................................................................................................................117Processing ................................................................................................................................117Gamma irradiators.............................................................................................................117Electron beam irradiators.................................................................................................118Documentation.........................................................................................................................118Microbiological monitoring......................................................................................................118Annex 13Manufacture of investigational medicinal products ...............................................119Introduction..............................................................................................................................119Glossary....................................................................................................................................120Quality management................................................................................................................121Personnel..................................................................................................................................121Premises and equipment..........................................................................................................121Documentation.........................................................................................................................122Order...................................................................................................................................122Product Specification File..................................................................................................122Manufacturing Formulae and Processing Instructions...................................................122Packaging instructions......................................................................................................123Labelling Instructions........................................................................................................123Manufacturing and packaging batch records...................................................................124Production.................................................................................................................................124Starting materials..............................................................................................................124Manufacturing operations.................................................................................................124Principles applicable to comparator product....................................................................125Randomisation code...........................................................................................................125Quality control..........................................................................................................................125Release of batches....................................................................................................................126Free movement.........................................................................................................................126Contract manufacture and contract analysis..........................................................................126Complaints................................................................................................................................126Recalls and returns..................................................................................................................127Shipping – Returns – Destruction...........................................................................................127Shipping.............................................................................................................................127ix
Returns............................................................................................................................... 127Destruction......................................................................................................................... 128Annex 14 Manufacture of products derived from human blood or human plasma................ 129Principle.................................................................................................................................... 129Quality management................................................................................................................ 130Premises and equipment.......................................................................................................... 130Blood collection......................................................................................................................... 130Production and quality control................................................................................................ 131Fractionation/purification procedures..................................................................................... 132a) Precipitation methods................................................................................................ 132b) Solid phase and filtration methods........................................................................... 133Retention of samples................................................................................................................ 133Cellular products and whole blood.......................................................................................... 133GLOSSARY .................................................................................................................... 137x
DIRECTIVES
DIRECTIVE 91/356/EECCommission Directive 91/356/EEC of 13 June 1991 laying downthe principles and guidelines of good manufacturing practicefor medicinal products for human use(OJ No L 193 of 17. 7. 1991, p. 30)THE COMMISSION OF THE EUROPEAN COMMUNITIES,Having regard to the Treaty establishing the European Economic Community,Having regard to Council Directive 75/319/EEC of 20 May 1975 on the approximation ofprovisions laid down by law, regulation or administrative action relating to proprietary medicinal12products (), as last amended by Directive 89/381/EEC (), and in particular Article 19a thereof,Whereas all medicinal products for human use manufactured or imported into the Community,including medicinal products intended for export, should be manufactured in accordance with theprinciples and guidelines of good manufacturing practice;Whereas, in accordance with national legislation, Member States may require compliance withthese principles of good manufacturing practice during the manufacture of products intended foruse in clinical trials;Whereas the detailed guidelines mentioned in Article 19a of Directive 75/319/EEC have beenpublished by the Commission after consultation with the pharmaceutical inspection services ofthe Member States in the form of a ‘Guide to good manufacturing practice for medicinal products’;Whereas it is necessary that all manufacturers should operate an effective quality managementof their manufacturing operations, and that this requires the implementation of a pharmaceuticalquality assurance system;Whereas officials representing the competent authorities should report on whether themanufacturer complies with good manufacturing practice and that these reports should becommunicated upon reasoned request to the competent authorities of another Member State;Whereas the principles and guidelines of good manufacturing practice should primarily concernpersonnel, premises and equipment, documentation, production, quality control, contracting out,complaints and product recall, and self inspection; (1)OJ No L 147 of 9. 6. 1975, p. ()OJ No L 181 of 28. 6. 1989, p.
Whereas the principles and guidelines envisaged by this Directive are in accordance with theopinion of the Committee for the Adaptation to Technical Progress of the Directives on theRemoval of Technical Barriers to Trade in the Proprietary Medicinal Products Sector set up byArticle 2b of Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws ofMember States relating to analytical, pharmaco-toxicological and clinical standards and protocols1in respect of the testing of proprietary medicinal products (), as last amended by Directive289/341/EEC (),HAS ADOPTED THIS DIRECTIVE:CHAPTER IGeneral ProvisionsArticle 1This Directive lays down the principles and guidelines of good manufacturing practice formedicinal products for human use whose manufacture requires the authorization referred to inArticle 16 of Directive 75/319/ 2For the purposes of this Directive, the definition of medicinal products set out in Article 1 (2) of3Council Directive 65/65/EEC (), shall addition,—manufacturer shall mean any holder of the authorization referred to in Article 16 ofDirective 75/319/EEC,—qualified person shall mean the person referred to in Article 21 of Directive 75/319/EEC,—pharmaceutical quality assurance shall mean the sum total of the organized arrangementsmade with the object of ensuring that medicinal products are of the quality required fortheir intended use,—good manufacturing practice shall mean the part of quality assurance which ensures thatproducts are consistently produced and controlled to the quality standards appropriate totheir intended 3By means of the repeated inspections referred to in Article 26 of Directive 75/319/EEC, theMember States shall ensure that manufacturers respect the principles and guidelines of goodmanufacturing practice laid down by this Directive. 1()OJ No L 147 of 9. 6. 1975, p. ()OJ No L 142 of 25. 5. 1989, p. ()OJ No 22 of 9. 2. 1965, p. 369/
For the interpretation of these principles and guidelines of good manufacturing practice, themanufacturers and the agents of the competent authorities shall refer to the detailed guidelinesreferred to in Article 19a of Directive 75/319/EEC. These detailed guidelines are published by theCommission in the Guide to good manufacturing practice for medicinal products and in itsAnnexes (Office for Official Publications of the European Communities, The rules governingmedicinal products in the European Community, Volume IV).Article 4The manufacturer shall ensure that the manufacturing operations are carried out in accordancewith good manufacturing practice and with the manufacturing medicinal products imported from third countries, the importer shall ensure that themedicinal products have been manufactured by manufacturers duly authorized and conforming togood manufacturing practice standards, at least equivalent to those laid down by the 5The manufacturer shall ensure that all manufacturing operations subject to an authorization formarketing are carried out in accordance with the information given in the application formarketing authorization as accepted by the competent manufacturer shall regularly review their manufacturing methods in the light of scientificand technical progress. When a modification to the marketing authorization dossier is necessary,the application for modification must be submitted to the competent IIPrinciples and Guidelines of Good Manufacturing PracticeArticle 6Quality managementThe manufacturer shall establish and implement an effective pharmaceutical quality assurancesystem, involving the active participation of the management and personnel of the differentservices each manufacturing site, the manufacturer shall have competent and appropriatelyqualified personnel at his disposal in sufficient number to achieve the pharmaceutical qualityassurance
duties of managerial and supervisory staff, including the qualified person(s),responsible for implementing and operating good manufacturing practice shall be defined in jobdescriptions. Their hierarchical relationships shall be defined in an organization charts and job descriptions shall be approved in accordance with the manufacturer’sinternal referred to in paragraph 2 shall be given sufficient authority to discharge theirresponsibilities shall receive initial and continuing training including the theory and applicationof the concept of quality assurance and good manufacturing programmes adapted to the activities to be carried out shall be established andobserved. These programmes include procedures relating to health, hygiene and clothing 8Premises and and manufacturing equipment shall be located, designed, constructed, adaptedand maintained to suit the intended out, design and operation must aim to minimize the risk of errors and permit effectivecleaning and maintenance in order to avoid contamination, cross contamination and, in general,any adverse effect on the quality of the and equipment intended to be used for manufacturing operations which arecritical for the quality of the products shall be subjected to appropriate manufacturer shall have a system of documentation based upon specifications,manufacturing formulae and processing and packaging instructions, procedures and recordscovering the various manufacturing operations that they perform. Documents shall be clear, freefrom errors and kept up to date. Pre-established procedures for general manufacturing operationsand conditions shall be available, together with specific documents for the manufacture of eachbatch. This set of documents shall make it possible to trace the history of the manufacture of eachbatch. The batch documentation shall be retained for at least one year after the expiry date of thebatches to which it relates or at least five years after the certification referred to in Article 22 (2)of Directive 75/319/EEC whichever is the electronic, photographic or other data processing systems are used instead of writtendocuments, the manufacturer shall have validated the systems by proving that the data will beappropriately stored during the anticipated period of storage. Data stored by these systems shallbe made readily available in legible form. The electronically stored data shall be protected againstloss or damage of data (. by duplication or back-up and transfer onto another storage system).6
Article 10ProductionThe different production operations shall be carried out according to pre-established instructionsand procedures and in accordance with good manufacturing practice. Adequate and sufficientresources shall be made available for the in-process technical and/or organizational measures shall be taken to avoid cross contaminationand new manufacture or important modification of a manufacturing process shall be phases of manufacturing processes shall be regularly 11Quality manufacturer shall establish and maintain a quality control department. Thisdepartment shall be placed under the authority of a person having the required qualifications andshall be independent of the other quality control department shall have at its disposal one or more quality controllaboratories appropriately staffed and equipped to carry out the necessary examination andtesting of starting materials, packaging materials and intermediate and finished productstesting. Resorting to outside laboratories may be authorized in accordance with Article 12 of thisDirective after the authorization referred to in Article 5b of Directive 75/319/EEC has the final control of finished products before their release for sale or distribution, inaddition to analytical results, the quality control department shall take into account essentialinformation such as the production conditions, the results of in-process controls, the examinationof the manufacturing documents and the conformity of the products to their specifications(including the final finished pack). of each batch of finished products shall be retained for at least one year after theexpiry date. Unless in the Member States of manufacture a longer period is required, samples ofstarting materials (other than solvents, gases and water) used shall be retained for at least twoyears after the release of the product. This period may be shortened if their stability, asmentioned in the relevant specification, is shorter. All these samples shall be maintained at thedisposal of the competent certain medicinal products manufactured individually or in small quantities, or when theirstorage could raise special problems, other sampling and retaining conditions may be defined inagreement with the competent
Article 12Work contracted manufacturing operation or operation linked with the manufacture which is carriedout under contract, shall be the subject of a written contract between the contract giver and thecontract contract shall clearly define the responsibilities of each party and in particular theobservance of good manufacturing practice by the contract acceptor and the manner in which thequalified person responsible for releasing each batch shall undertake his full contract acceptor shall not subcontract any of the work entrusted to him by thecontract giver without the written authorization of the contract contract acceptor shall respect the principles and guidelines of good manufacturingpractice and shall submit to inspections carried out by the competent authorities as provided forby Article 26 of Directive 75/319/ 13Complaints and product recallThe manufacturer shall implement a system for recording and reviewing complaints togetherwith an effective system for recalling promptly and at any time the medicinal products in thedistribution network. Any complaint concerning a defect shall be recorded and investigated by themanufacturer. The competent authority shall be informed by the manufacturer of any defect thatcould result in a recall or abnormal restriction on the supply. In so far as possible, the countries ofdestination shall also be indicated. Any recall shall be made in accordance with the requirementsreferred to in Article 33 of Directive 75/319/ 14Self-inspectionThe manufacturer shall conduct repeated self-inspections as part of the quality assurance systemin order to monitor the implementation and respect of good manufacturing practice and topropose any necessary corrective measures. Records of such self-inspections and any subsequentcorrective action shall be
CHAPTER IIIFinal ProvisionsArticle 15Member States shall bring into force the laws, regulations and administrative provisionsnecessary to comply with this Directive not later than 1 January 1992. They shall forthwithinform the Commission Member States adopt these provisions, these shall contain a reference to this Directive orshall be accompanied by such reference at the time of their official publication. The procedure forsuch reference shall be adopted by Member 16This Directive is addressed to the Member at Brussels, 13 June the CommissionMartin BANGEMANNVice-President9
DIRECTIVE 91/412/EECCommission Directive 91/412/EEC of 23 July 1991 laying downthe principles and guidelines of good manufacturing practicefor veterinary medicinal products(OJ No L 228 of 17. 8. 1991, p. 70)THE COMMISSION OF THE EUROPEAN COMMUNITIES,Having regard to the Treaty establishing the European Economic Community,Having regard to Council Directive 81/851/EEC of 28 September 1981 concerning the1approximation of the laws of the Member States relating to veterinary medicinal products (), as2last amended by Directive 90/676/EEC (), and in particular Article 27a,Having regard to Council Directive 90/677/EEC of 13 December 1990 extending the scope ofDirective 81/851/EEC on the approximation of the laws of the Member States relating toveterinary medicinal products and laying down additional provisions for immunological3veterinary medicinal products (),Whereas all veterinary medicinal products manufactured or imported into the Community,including medicinal products intended for export should be manufactured in accordance with theprinciples and guidelines of good manufacturing practice;Whereas, in accordance with national legislation, Member States may require compliance withthese principles of good manufacturing practice during the manufacture of products intended foruse in clinical trials;Whereas the detailed guidelines mentioned in Article 27a of Directive 81/851/EEC have beenpublished by the Commission after consultation with the pharmaceutical inspection services ofthe Member States in the form of a Guide to good manufacturing practice for medicinal products;Whereas it is necessary that all manufacturers should operate an effective quality managementof their manufacturing operations, and that this requires the implementation of a pharmaceuticalquality assurance system;Whereas officials representing the competent authorities should report on whether themanufacturer complies with good manufacturing practice and that these reports should becommunicated upon reasoned request to the competent authorities of another Member State;Whereas the principles and guidelines of good manufacturing practice should primarily concernpersonnel, premises and equipment, documentation, production, quality control, contracting out,complaints and product recall, and self inspection; 1()OJ No L 317 of 6. 11. 1981, p. ()OJ No L 373 of 31. 12. 1990, p. ()OJ No L 373 of 31. 12. 1990, p.
Whereas the principles and guidelines envisaged by this Directive are in conformity with theopinion of the Committee for Adaptation to Technical Progress of the Directives on the Removalof Technical Barriers to Trade in the Veterinary Medicinal Products Sector created by Article 2bof Directive 81/852/EEC of 28 September 1981 concerning the approximation of the laws ofMember States relating to analytical, pharmaco-toxicological and clinical standards and protocols1in respect of the testing of veterinary medicinal products (), as last amended by Directive287/20/EEC (),HAS ADOPTED THIS DIRECTIVE:CHAPTER IGENERAL PROVISIONSArticle 1This Directive lays down the principles and guidelines of good manufacturing practice forveterinary medicinal products whose manufacture requires the authorization referred to inArticle 24 of Directive 81/851/ 2For the purposes of this Directive, the definition of medicinal products set out in Article 1 (2) of3Council Directive 65/65/EEC ,() and the definition of veterinary medicinal products set out inArticle 1 (2) of Directive 81/851/EEC, shall addition,—manufacturer shall mean any holder of the authorization referred to in Article 24 ofDirective 81/851/EEC;—qualified person shall mean the person referred to in Article 29 of Directive 81/851/EEC;—pharmaceutical quality assurance shall mean the sum total of the organized arrangementsmade with the object of ensuring that veterinary medicinal products are of the qualityrequired for their intended use;—good manufacturing practice shall mean the part of quality assurance which ensures thatproducts are consistently produced and controlled to the quality standards appropriate totheir intended 3By means of the repeated inspections referred to in Article 34 of Directive 81/851/EEC, theMember States shall ensure that manufacturers respect the principles and guidelines of goodmanufacturing practice laid down by this Directive. 1()OJ No L 317 of 6. 11. 1981, p. ()OJ No L 15 of 17. 1. 1987, p. ()OJ No 22 of 9. 2. 1965, p. 369/
For the interpretation of these principles and guidelines of good manufacturing practice, themanufacturers and the agents of the competent authorities refer to the detailed guidelinesreferred to in Article 27a of Directive 81/851/EEC. These detailed guidelines are published by theCommission in the Guide to good manufacturing practice for medicinal products and in itsannexes (Office for Official Publications of the European Communities, The Rules GoverningMedicinal Products in the European Community, Volume IV).Article 4The manufacturers shall ensure that the manufacturing operations are carried out in accordancewith good manufacturing practice and with the manufacturing veterinary medicinal products imported from third countries, the importer shall ensure thatthe veterinary medicinal products have been manufactured by manufacturers duly authorizedand conforming to good manufacturing practice standards, at least equivalent to those laid downby the 5The manufacturer shall ensure that all manufacturing operations subject to an authorization formarketing are carried out in accordance with the information given in the application formarketing authorization as accepted by the competent manufacturers shall regularly review their manufacturing methods in the light of scientificand technical progress. When a modification to the marketing authorization dossier is necessary,the application for modification must be submitted to the competent IIPRINCIPLES AND GUIDELINES OF GOOD MANUFACTURINGPRACTICEArticle 6Quality managementThe manufacturer shall establish and implement an effective pharmaceutical quality assurancesystem, involving the active participation of the management and personnel of the differentservices each manufacturing site, the manufacturer shall have competent and appropriatelyqualified personnel at his disposal in sufficient number to achieve the pharmaceutical qualityassurance
duties of managerial and supervisory staff, including the qualified person(s),responsible for implementing and operating good manufacturing practice shall be defined in jobdescriptions. Their hierarchical relationships shall be defined in an organizational charts and job descriptions shall be approved in accordance with themanufacturer’s internal referred to in paragraph 2 shall be given sufficient authority to carry out theirresponsibilities shall receive initial and continuing training including the theory and applicationof the concept of quality assurance and good manufacturing programmes adapted to the activities to be carried out shall be established andobserved. These programmes include procedures relating to health, hygiene and clothing 8Premises and and manufacturing equipment shall be located, designed, constructed, adaptedand maintained to suit the intended out, design and operation must aim to minimize the risk of errors and permit effectivecleaning and maintenance in order to avoid contamination, cross contamination and, in general,any adverse effect on the quality of the and equipment intended to be used for manufacturing operations which arecritical for the quality of the products shall be subjected to appropriate manufacturer shall have a system of documentation based upon specifications,manufacturing formulae and processing and packaging instructions, procedures and recordscovering the different manufacturing operations that they perform. Documents shall be clear, freefrom errors and kept up to-date. Pre-established procedures for general manufacturing operationsand conditions shall be available, together with specific documents for the manufacture of eachbatch. This set of documents shall make it possible to trace the history of the manufacture of eachbatch. The batch documentation shall be retained for at least one year after the expiry date of thebatches to which it relates, or at least five years after the certification referred to in Article 30 (2)of Directive 81/851/EEC, whichever is the
electronic, photographic or other data processing systems are used instead of writtendocuments, the manufacturer shall have validated the system by proving that the data will beappropriately stored during the anticipated period of storage. Data stored by these systems shallbe made readily available in legible form. The electronically stored data shall be protected againstloss or damage of data (. by duplication or back-up and transfer onto another storage system).Article 10ProductionThe different production operations shall be carried out according to pre-established instructionsand procedures and in accordance with good manufacturing practice. Adequate and sufficientresources shall be made available for the in-process technical and/or organizational measures shall be taken to avoid cross contaminationand new manufacture or important modification of a manufacturing process shall be phases of manufacturing process shall be regularly 11Quality manufacturer shall establish and maintain a quality control department. Thisdepartment shall be placed under the authority of a person having the required qualifications andshall be independent of the other quality control department shall have at its disposal one or more quality controllaboratories appropriately staffed and equipped to carry out the necessary examination andtesting of starting materials, packaging materials and intermediate and finished productstesting. Resorting to outside laboratories is authorized in accordance with Article 12 of thisDirective and after the authorization referred to in Article 10 (2) of Directive 81/851/EEC hasbeen the final control of finished products before their release for the sale or distribution,in addition to analytical results, the quality control department shall take into account essentialinformation such as the production conditions, the results of in-process controls, the examinationof the manufacturing documents and the conformity of the products to their specifications(including the final finished pack). of each batch of finished products shall be retained for at least one year after theexpiry date. Unless in the Member State of manufacture a longer period is required, samples ofstarting materials (other than solvents, gases and water) used shall be retained for at least twoyears after the release of the product. This period may be shortened if their stability, asmentioned in the relevant specification, is shorter. All these samples shall be maintained at thedisposal of the competent
For certain veterinary medicinal products manufactured individually or in small quantities, orwhen their storage could raise special problems, other sampling and retaining conditions may bedefined in agreement with the competent 12Work contracted manufacturing operation or operation linked with the manufacture which is carriedout under contract, shall be the subject of a written contract between the contract giver and thecontract contract shall clearly define the responsibilities of each party and in particular theobservance of good manufacturing practice by the contract acceptor and the manner in which thequalified person responsible for releasing each batch shall undertake his full contract acceptor shall not further sub-contract any of the work entrusted to him bythe contract giver without the written authorization of the contract contract acceptor shall respect the principles and guidelines of good manufacturingpractice and shall submit to inspections carried out by the competent authorities as provided forby Article 34 of Directive 81/851/ 13Complaints and product recallThe manufacturer shall implement a system for recording and reviewing complaints togetherwith an effective system for recalling promptly and at any time the veterinary medicinal productsin the distribution network. Any complaint concerning a quality defect shall be recorded andinvestigated by the manufacturer. The competent authority shall be informed by themanufacturer of any quality defect that could result in a recall or abnormal restriction on thesupply. In so far as possible, the countries of destination shall also be indicated. Any recall shallbe made in accordance with the requirements referred to in Article 42 of Directive 81/851/ 14Self-inspectionThe manufacturer shall conduct repeated self-inspections as part of the quality assurance systemin order to monitor the implementation and respect of good manufacturing practice and topropose any necessary corrective measures. Records of such self-inspections and any furthercorrective action shall be
CHAPTER IIIFINAL PROVISIONSArticle 15Member States shall bring into force the laws, regulations and administrative provisionsnecessary to comply with this Directive before 23 July 1993. They shall forthwith inform theCommission Member States adopt these provisions, these shall contain a reference to this Directive orshall be accompanied by such reference at the time of their official publication. The procedure forsuch reference shall be adopted by Member 16This Directive is addressed to the Member at Brussels, 23 July the CommissionMartin BANGEMANNVice-President17
GUIDE TO GOOD MANUFACTURINGPRACTICE FOR MEDICINAL PRODUCTS
BASIC REQUIREMENTS
CHAPTER 1 QUALITY MANAGEMENTPrincipleThe holder of a Manufacturing Authorisation must manufacture medicinal products so asto ensure that they are fit for their intended use, comply with the requirements of theMarketing Authorisation and do not place patients at risk due to inadequate safety, qualityor efficacy. The attainment of this quality objective is the responsibility of seniormanagement and requires the participation and commitment by staff in many differentdepartments and at all levels within the company, by the company’s suppliers and by thedistributors. To achieve the quality objective reliably there must be a comprehensivelydesigned and correctly implemented system of Quality Assurance incorporating GoodManufacturing Practice and thus Quality Control. It should be fully documented and itseffectiveness monitored. All parts of the Quality Assurance system should be adequatelyresourced with competent personnel, and suitable and sufficient premises, equipment andfacilities. There are additional legal responsibilities for the holder of the ManufacturingAuthorisation and for the Qualified Person(s). basic concepts of Quality Assurance, Good Manufacturing Practice and Quality Controlare inter-related. They are described here in order to emphasise their relationships andtheir fundamental importance to the production and control of medicinal Assurance is a wide ranging concept which covers all matters which individually orcollectively influence the quality of a product. It is the sum total of the organisedarrangements made with the object of ensuring that medicinal products are of the qualityrequired for their intended use. Quality Assurance therefore incorporates GoodManufacturing Practice plus other factors outside the scope of this system of Quality Assurance appropriate for the manufacture of medicinal productsshould ensure that: products are designed and developed in a way that takes account of therequirements of Good Manufacturing Practice and Good Laboratory Practice; and control operations are clearly specified and Good ManufacturingPractice adopted;iiimanagerial responsibilities are clearly specified; are made for the manufacture, supply and use of the correct startingand packaging materials; necessary controls on intermediate products, and any other in-process controlsand validations are carried out; finished product is correctly processed and checked, according to the definedprocedures;23
products are not sold or supplied before a Qualified Person has certifiedthat each production batch has been produced and controlled in accordance with therequirements of the Marketing Authorisation and any other regulations relevant tothe production, control and release of medicinal products; arrangements exist to ensure, as far as possible, that the medicinalproducts are stored, distributed and subsequently handled so that quality ismaintained throughout their shelf life; is a procedure for Self-Inspection and/or quality audit which regularlyappraises the effectiveness and applicability of the Quality Assurance Manufacturing Practice for Medicinal Products(GMP) Manufacturing Practice is that part of Quality Assurance which ensures thatproducts are consistently produced and controlled to the quality standards appropriate totheir intended use and as required by the Marketing Authorisation or product Manufacturing Practice is concerned with both production and quality control. Thebasic requirements of GMP are that: manufacturing processes are clearly defined, systematically reviewed in the lightof experience and shown to be capable of consistently manufacturing medicinalproducts of the required quality and complying with their specifications; steps of manufacturing processes and significant changes to the process arevalidated; necessary facilities for GMP are provided including: qualified and trained personnel; premises and space; equipment and services; materials, containers and labels; procedures and instructions; storage and transport; and procedures are written in an instructional form in clear andunambiguous language, specifically applicable to the facilities provided; are trained to carry out procedures correctly; are made, manually and/or by recording instruments, during manufacturewhich demonstrate that all the steps required by the defined procedures andinstructions were in fact taken and that the quantity and quality of the product wasas expected. Any significant deviations are fully recorded and investigated; of manufacture including distribution which enable the complete history of abatch to be traced, are retained in a comprehensible and accessible form; distribution (wholesaling) of the products minimises any risk to their quality;24
system is available to recall any batch of product, from sale or supply; about marketed products are examined, the causes of quality defectsinvestigated and appropriate measures taken in respect of the defective products andto prevent Control is that part of Good Manufacturing Practice which is concerned withsampling, specifications and testing, and with the organisation, documentation and releaseprocedures which ensure that the necessary and relevant tests are actually carried out andthat materials are not released for use, nor products released for sale or supply, until theirquality has been judged to be basic requirements of Quality Control are that: facilities, trained personnel and approved procedures are available forsampling, inspecting and testing starting materials, packaging materials,intermediate, bulk, and finished products, and where appropriate for monitoringenvironmental conditions for GMP purposes; of starting materials, packaging materials, intermediate products, bulkproducts and finished products are taken by personnel and by methods approved byQuality Control; methods are validated; are made, manually and/or by recording instruments, which demonstratethat all the required sampling, inspecting and testing procedures were actuallycarried out. Any deviations are fully recorded and investigated; finished products contain active ingredients complying with the qualitative andquantitative composition of the Marketing Authorisation, are of the purity required,and are enclosed within their proper containers and correctly labelled; are made of the results of inspection and that testing of materials,intermediate, bulk, and finished products is formally assessed against assessment includes a review and evaluation of relevant productiondocumentation and an assessment of deviations from specified procedures; batch of product is released for sale or supply prior to certification by a QualifiedPerson that it is in accordance with the requirements of the MarketingAuthorisation;viii. sufficient reference samples of starting materials and products are retained to permitfuture examination of the product if necessary and that the product is retained in itsfinal pack unless exceptionally large packs are
CHAPTER 2 PERSONNELPrincipleThe establishment and maintenance of a satisfactory system of quality assurance and thecorrect manufacture of medicinal products relies upon people. For this reason there must besufficient qualified personnel to carry out all the tasks which are the responsibility of themanufacturer. Individual responsibilities should be clearly understood by the individualsand recorded. All personnel should be aware of the principles of Good ManufacturingPractice that affect them and receive initial and continuing training, including hygieneinstructions, relevant to their manufacturer should have an adequate number of personnel with the necessaryqualifications and practical experience. The responsibilities placed on any one individualshould not be so extensive as to present any risk to manufacturer must have an organisation chart. People in responsible positions shouldhave specific duties recorded in written job descriptions and adequate authority to carry outtheir responsibilities. Their duties may be delegated to designated deputies of a satisfactoryqualification level. There should be no gaps or unexplained overlaps in the responsibilitiesof those personnel concerned with the application of Good Manufacturing Personnel include the head of Production, the head of Quality Control, and if at leastone of these persons is not responsible for the duties described in Article 22 of Directive75/319/EEC, the Qualified Person(s) designated for the purpose. Normally key posts shouldbe occupied by full-time personnel. The heads of Production and Quality Control must beindependent from each other. In large organisations, it may be necessary to delegate someof the functions listed in , and duties of the Qualified Person(s) are fully described in Article 22 of Directive75/319/EEC, and can be summarised as follows:a)for medicinal products manufactured within the European Community, a QualifiedPerson must ensure that each batch has been produced and tested/checked in1accordance with the directives and the marketing authorisation ();(b)for medicinal products manufactured outside the European Community, a QualifiedPerson must ensure that each imported batch has undergone, in the importingcountry, the testing specified in paragraph 1 (b) of Article 22; 1()According to Directive 75/319/EEC and the Ruling (Case 247/81) of the Court of Justice of the EuropeanCommununities, medicinal products which have been properly controlled in the EU by a Qualified Person do nothave to be recontrolled or rechecked in any other Member State of the
(c)a Qualified Person must certify in a register or equivalent document, as operationsare carried out and before any release, that each production batch satisfies theprovisions of Article persons responsible for these duties must meet the qualification requirements laiddown in Article 23 of the same Directive, they shall be permanently and continuously at thedisposal of the holder of the Manufacturing Authorisation to carry out their responsibilities may be delegated, but only to other Qualified Person(s). head of the Production Department generally has the following responsibilities: ensure that products are produced and stored according to the appropriatedocumentation in order to obtain the required quality; approve the instructions relating to production operations and to ensure theirstrict implementation; ensure that the production records are evaluated and signed by an authorisedperson before they are sent to the Quality Control Department; check the maintenance of his department, premises and equipment; ensure that the appropriate validations are done; ensure that the required initial and continuing training of his departmentpersonnel is carried out and adapted according to head of the Quality Control Department generally has the following responsibilities: approve or reject, as he sees fit, starting materials, packaging materials, andintermediate, bulk and finished products; evaluate batch records; ensure that all necessary testing is carried out; approve specifications, sampling instructions, test methods and other QualityControl procedures; approve and monitor any contract analysts; check the maintenance of his department, premises and equipment; ensure that the appropriate validations are done; ensure that the required initial and continuing training of his departmentpersonnel is carried out and adapted according to duties of the Quality Control Department are summarised in Chapter heads of Production and Quality Control generally have some shared, or jointlyexercised, responsibilities relating to quality. These may include, subject to any nationalregulations:—the authorisation of written procedures and other documents, includingamendments;—the monitoring and control of the manufacturing environment;—plant hygiene;—process validation;28
—training;—the approval and monitoring of suppliers of materials;—the approval and monitoring of contract manufacturers;—the designation and monitoring of storage conditions for materials and products;—the retention of records;—the monitoring of compliance with the requirements of Good Manufacturing Practice;—the inspection, investigation, and taking of samples, in order to monitor factors whichmay affect product manufacturer should provide training for all the personnel whose duties take them intoproduction areas or into control laboratories (including the technical, maintenance andcleaning personnel), and for other personnel whose activities could affect the quality of the basic training on the theory and practice of Good Manufacturing Practice,newly recruited personnel should receive training appropriate to the duties assigned tothem. Continuing training should also be given, and its practical effectiveness should beperiodically assessed. Training programmes should be available, approved by either thehead of Production or the head of Quality Control, as appropriate. Training records shouldbe working in areas where contamination is a hazard, . clean areas or areaswhere highly active, toxic, infectious or sensitising materials are handled, should be givenspecific or untrained personnel should, preferably, not be taken into the production andquality control areas. If this is unavoidable, they should be given information in advance,particularly about personal hygiene and the prescribed protective clothing. They should beclosely concept of Quality Assurance and all the measures capable of improving itsunderstanding and implementation should be fully discussed during the training hygiene programmes should be established and adapted to the different needswithin the factory. They should include procedures relating to the health, hygiene practicesand clothing of personnel. These procedures should be understood and followed in a verystrict way by every person whose duties take him into the production and control programmes should be promoted by management and widely discussed duringtraining personnel should receive medical examination upon recruitment. It must be themanufacturer’s responsibility that there are instructions ensuring that health conditionsthat can be of relevance to the quality of products come to the manufacturer’s
After the first medical examination, examinations should be carried out when necessary forthe work and personal should be taken to ensure as far as is practicable that no person affected by aninfectious disease or having open lesions on the exposed surface of the body is engaged inthe manufacture of medicinal person entering the manufacturing areas should wear protective garmentsappropriate to the operations to be carried , drinking, chewing or smoking, or the storage of food, drink, smoking materials orpersonal medication in the production and storage areas should be prohibited. In general,any unhygienic practice within the manufacturing areas or in any other area where theproduct might be adversely affected, should be contact should be avoided between the operator’s hands and the exposed product aswell as with any part of the equipment that comes into contact with the should be instructed to use the hand-washing specific requirements for the manufacture of special groups of products, for examplesterile preparations, are covered in the
CHAPTER 3 PREMISES AND EQUIPMENTPrinciplePremises and equipment must be located, designed, constructed, adapted and maintainedto suit the operations to be carried out. Their layout and design must aim to minimise therisk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality should be situated in an environment which, when considered together withmeasures to protect the manufacture, presents minimal risk of causing contamination ofmaterials or should be carefully maintained, ensuring that repair and maintenance operationsdo not present any hazard to the quality of products. They should be cleaned and, whereapplicable, disinfected according to detailed written , temperature, humidity and ventilation should be appropriate and such that theydo not adversely affect, directly or indirectly, either the medicinal products during theirmanufacture and storage, or the accurate functioning of should be designed and equipped so as to afford maximum protection against theentry of insects or other should be taken in order to prevent the entry of unauthorised people. Production,storage and quality control areas should not be used as a right of way by personnel who donot work in order to minimise the risk of a serious medical hazard due to cross-contamination,dedicated and self contained facilities must be available for the production of particularmedicinal products, such as highly sensitising materials (. penicillins) or biologicalpreparations (. from live micro-organisms). The production of certain additionalproducts, such as certain antibiotics, certain hormones, certain cytotoxics, certain highlyactive drugs and non-medicinal products should not be conducted in the same facilities. Forthose products, in exceptional cases, the principle of campaign working in the samefacilities can be accepted provided that specific precautions are taken and the necessaryvalidations are made. The manufacture of technical poisons, such as pesticides andherbicides, should not be allowed in premises used for the manufacture of
should preferably be laid out in such a way as to allow the production to takeplace in areas connected in a logical order corresponding to the sequence of the operationsand to the requisite cleanliness adequacy of the working and in-process storage space should permit the orderly andlogical positioning of equipment and materials so as to minimise the risk of confusionbetween different medicinal products or their components, to avoid cross-contaminationand to minimise the risk of omission or wrong application of any of the manufacturing orcontrol starting and primary packaging materials, intermediate or bulk products areexposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth,free from cracks and open joints, and should not shed particulate matter and should permiteasy and effective cleaning and, if necessary, , light fittings, ventilation points and other services should be designed and sitedto avoid the creation of recesses which are difficult to clean. As far as possible, formaintenance purposes, they should be accessible from outside the manufacturing should be of adequate size, and have trapped gullies. Open channels should beavoided where possible, but if necessary, they should be shallow to facilitate cleaning areas should be effectively ventilated, with air control facilities (includingtemperature and, where necessary, humidity and filtration) appropriate both to theproducts handled, to the operations undertaken within them and to the of starting materials usually should be carried out in a separate weighing roomdesigned for that cases where dust is generated (. during sampling, weighing, mixing and processingoperations, packaging of dry products), specific provisions should be taken to avoid cross-contamination and facilitate for the packaging of medicinal products should be specifically designed and laidout so as to avoid mix-ups or areas should be well lit, particularly where visual on-line controls are -process controls may be carried out within the production area provided they do notcarry any risk for the areas should be of sufficient capacity to allow orderly storage of the variouscategories of materials and products: starting and packaging materials, intermediate, bulkand finished products, products in quarantine, released, rejected, returned or areas should be designed or adapted to ensure good storage conditions. Inparticular, they should be clean and dry and maintained within acceptable temperaturelimits. Where special storage conditions are required (. temperature, humidity) theseshould be provided, checked and
and dispatch bays should protect materials and products from the areas should be designed and equipped to allow containers of incoming materialsto be cleaned where necessary before quarantine status is ensured by storage in separate areas, these areas must beclearly marked and their access restricted to authorised personnel. Any system replacingthe physical quarantine should give equivalent should normally be a separate sampling area for starting materials. If sampling isperformed in the storage area, it should be conducted in such a way as to preventcontamination or areas should be provided for the storage of rejected, recalled or returnedmaterials or active materials or products should be stored in safe and secure packaging materials are considered critical to the conformity of the medicinalproduct and special attention should be paid to the safe and secure storage of Control , Quality Control laboratories should be separated from production areas. This isparticularly important for laboratories for the control of biologicals, microbiologicals andradioisotopes, which should also be separated from each laboratories should be designed to suit the operations to be carried out in space should be given to avoid mix-ups and cross-contamination. There should beadequate suitable storage space for samples and rooms may be necessary to protect sensitive instruments from vibration, electricalinterference, humidity, requirements are needed in laboratories handling particular substances, such asbiological or radioactive and refreshment rooms should be separate from other for changing clothes, and for washing and toilet purposes should be easilyaccessible and appropriate for the number of users. Toilets should not directly communicatewith production or storage workshops should as far as possible be separated from production parts and tools are stored in the production area, they should be kept in rooms orlockers reserved for that houses should be well isolated from other areas, with separate entrance (animalaccess) and air handling
equipment should be designed, located and maintained to suit its and maintenance operations should not present any hazard to the quality of equipment should be designed so that it can be easily and thoroughlycleaned. It should be cleaned according to detailed and written procedures and stored onlyin a clean and dry and cleaning equipment should be chosen and used in order not to be a source should be installed in such a way as to prevent any risk of error or equipment should not present any hazard to the products. The parts of theproduction equipment that come into contact with the product must not be reactive,additive or absorptive to such an extent that it will affect the quality of the product andthus present any and measuring equipment of an appropriate range and precision should beavailable for production and control , weighing, recording and control equipment should be calibrated and checked atdefined intervals by appropriate methods. Adequate records of such tests should pipework should be clearly labelled to indicate the contents and, where applicable,the direction of , deionized and, where appropriate, other water pipes should be sanitised accordingto written procedures that detail the action limits for microbiological contamination and themeasures to be equipment should, if possible, be removed from production and quality controlareas, or at least be clearly labelled as
CHAPTER 4 DOCUMENTATIONPrincipleGood documentation constitutes an essential part of the quality assurance system. Clearlywritten documentation prevents errors from spoken communication and permits tracing ofbatch history. Specifications, Manufacturing Formulae and instructions, procedures, andrecords must be free from errors and available in writing. The legibility of documents is ofparamount describe in detail the requirements with which the products or materialsused or obtained during manufacture have to conform. They serve as a basis for Formulae, Processing and Packaging Instructions state all the startingmaterials used and lay down all processing and packaging give directions for performing certain operations . cleaning, clothing,environmental control, sampling, testing, equipment provide a history of each batch of product, including its distribution, and also of allother relevant circumstances pertinent to the quality of the final should be designed, prepared, reviewed and distributed with care. They shouldcomply with the relevant parts of the manufacturing and marketing authorisation should be approved, signed and dated by appropriate and authorised should have unambiguous contents; title, nature and purpose should be clearlystated. They should be laid out in an orderly fashion and be easy to check. Reproduceddocuments should be clear and legible. The reproduction of working documents from masterdocuments must not allow any error to be introduced through the reproduction should be regularly reviewed and kept up-to-date. When a document has beenrevised, systems should be operated to prevent inadvertent use of superseded should not be handwritten; although, where documents require the entry ofdata, these entries may be made in clear, legible, indelible handwriting. Sufficient spaceshould be provided for such alteration made to the entry on a document should be signed and dated; the alterationshould permit the reading of the original information. Where appropriate, the reason forthe alteration should be records should be made or completed at the time each action is taken and in such away that all significant activities concerning the manufacture of medicinal products aretraceable. They should be retained for at least one year after the expiry date of the
may be recorded by electronic data processing systems, photographic or other reliablemeans, but detailed procedures relating to the system in use should be available and theaccuracy of the records should be checked. If documentation is handled by electronic dataprocessing methods, only authorised persons should be able to enter or modify data in thecomputer and there should be a record of changes and deletions; access should be restrictedby passwords or other means and the result of entry of critical data should beindependently checked. Batch records electronically stored should be protected by back-uptransfer on magnetic tape, microfilm, paper or other means. It is particularly importantthat the data are readily available throughout the period of should be appropriately authorised and dated specifications for starting andpackaging materials, and finished products; where appropriate, they should be alsoavailable for intermediate or bulk for starting and packaging for starting and primary or printed packaging materials should include, ifapplicable:a)a description of the materials, including:—the designated name and the internal code reference;—the reference, if any, to a pharmacopoeial monograph;—the approved suppliers and, if possible, the original producer of the products;—a specimen of printed materials;b)directions for sampling and testing or reference to procedures;c)qualitative and quantitative requirements with acceptance limits;d)storage conditions and precautions;e)the maximum period of storage before for intermediate and bulk for intermediate and bulk products should be available if these arepurchased or dispatched, or if data obtained from intermediate products are used for theevaluation of the finished product. The specifications should be similar to specifications forstarting materials or for finished products, as for finished for finished products should include:a)the designated name of the product and the code reference where applicable;b)the formula or a reference to;36
c)a description of the pharmaceutical form and package details;d)directions for sampling and testing or a reference to procedures;e)the qualitative and quantitative requirements, with the acceptance limits;f)the storage conditions and any special handling precautions, where applicable;g)the Formula and Processing InstructionsFormally authorised Manufacturing Formula and Processing Instructions should exist foreach product and batch size to be manufactured. They are often combined in one Manufacturing Formula should include:a)the name of the product, with a product reference code relating to its specification;b)a description of the pharmaceutical form, strength of the product and batch size;c)a list of all starting materials to be used, with the amount of each, described usingthe designated name and a reference which is unique to that material; mentionshould be made of any substance that may disappear in the course of processing;d)a statement of the expected final yield with the acceptable limits, and of relevantintermediate yields, where Processing Instructions should include:a)a statement of the processing location and the principal equipment to be used;b)the methods, or reference to the methods, to be used for preparing the criticalequipment (. cleaning, assembling, calibrating, sterilising);c)detailed stepwise processing instructions (. checks on materials, pre-treatments,sequence for adding materials, mixing times, temperatures);d)the instructions for any in-process controls with their limits;e)where necessary, the requirements for bulk storage of the products; including thecontainer, labelling and special storage conditions where applicable;f)any special precautions to be should be formally authorised Packaging Instructions for each product, pack size andtype. These should normally include, or have a reference to, the following:a)name of the product;b)description of its pharmaceutical form, and strength where applicable;c)the pack size expressed in terms of the number, weight or volume of the product inthe final container;37
d)a complete list of all the packaging materials required for a standard batch size,including quantities, sizes and types, with the code or reference number relating tothe specifications of each packaging material;e)where appropriate, an example or reproduction of the relevant printed packagingmaterials, and specimens indicating where to apply batch number references, andshelf life of the product;f)special precautions to be observed, including a careful examination of the area andequipment in order to ascertain the line clearance before operations begin;g)a description of the packaging operation, including any significant subsidiaryoperations, and equipment to be used;h)details of in-process controls with instructions for sampling and acceptance Processing Batch Processing Record should be kept for each batch processed. It should be based onthe relevant parts of the currently approved Manufacturing Formula and ProcessingInstructions. The method of preparation of such records should be designed to avoidtranscription errors. The record should carry the number of the batch being any processing begins, there should be recorded checks that the equipment and workstation are clear of previous products, documents or materials not required for the plannedprocess, and that equipment is clean and suitable for processing, the following information should be recorded at the time each action istaken and, after completion, the record should be dated and signed in agreement by theperson responsible for the processing operations:a)the name of the product;b)dates and times of commencement, of significant intermediate stages and ofcompletion of production;c)name of the person responsible for each stage of production;d)initials of the operator of different significant steps of production and, whereappropriate, of the person who checked each of these operations (. weighing);e)the batch number and/or analytical control number as well as the quantities of eachstarting material actually weighed (including the batch number and amount of anyrecovered or reprocessed material added);f)any relevant processing operation or event and major equipment used;g)a record of the in-process controls and the initials of the person(s) carrying them out,and the results obtained;h)the product yield obtained at different and pertinent stages of manufacture;i)notes on special problems including details, with signed authorisation for anydeviation from the Manufacturing Formula and Processing
Batch Packaging Batch Packaging Record should be kept for each batch or part batch processed. It shouldbe based on the relevant parts of the Packaging Instructions and the method of preparationof such records should be designed to avoid transcription errors. The record should carrythe batch number and the quantity of bulk product to be packed, as well as the batchnumber and the planned quantity of finished product that will be any packaging operation begins, there should be recorded checks that the equipmentand work station are clear of previous products, documents or materials not required forthe planned packaging operations, and that equipment is clean and suitable for following information should be entered at the time each action is taken and, aftercompletion, the record should be dated and signed in agreement by the person(s)responsible for the packaging operations:a)the name of the product;b)the date(s) and times of the packaging operations;c)the name of the responsible person carrying out the packaging operation;d)the initials of the operators of the different significant steps;e)records of checks for identity and conformity with the packaging instructionsincluding the results of in-process controls;f)details of the packaging operations carried out, including references to equipmentand the packaging lines used;g)whenever possible, samples of printed packaging materials used, includingspecimens of the batch coding, expiry dating and any additional overprinting;h)notes on any special problems or unusual events including details, with signedauthorisation for any deviation from the Manufacturing Formula and ProcessingInstructions;i)the quantities and reference number or identification of all printed packagingmaterials and bulk product issued, used, destroyed or returned to stock and thequantities of obtained product, in order to provide for an adequate and should be written procedures and records for the receipt of each delivery of eachstarting and primary and printed packaging records of the receipts should include:a)the name of the material on the delivery note and the containers;b)the "in-house" name and/or code of material (if different from a);c)date of receipt;d)supplier’s name and, if possible, manufacturer’s name;39
e)manufacturer’s batch or reference number;f)total quantity, and number of containers received;g)the batch number assigned after receipt;h)any relevant comment (. state of the containers). should be written procedures for the internal labelling, quarantine and storage ofstarting materials, packaging materials and other materials, as should be written procedures for sampling, which include the person(s) authorised totake samples, the methods and equipment to be used, the amounts to be taken and anyprecautions to be observed to avoid contamination of the material or any deterioration in itsquality (see Chapter 6, item 13). should be written procedures for testing materials and products at different stages ofmanufacture, describing the methods and equipment to be used. The tests performedshould be recorded (see Chapter 6, item 17). release and rejection procedures should be available for materials and products,and in particular for the release for sale of the finished product by the Qualified Person(s)in accordance with the requirements of Article 22 of Directive 75/319/ should be maintained of the distribution of each batch of a product in order tofacilitate the recall of the batch if necessary (see Chapter 8). should be written procedures and the associated records of actions taken orconclusions reached, where appropriate, for:—validation;—equipment assembly and calibration;—maintenance, cleaning and sanitation;—personnel matters including training, clothing, hygiene;—environmental monitoring;—pest control;—complaints;—recalls;— operating procedures should be available for major items of manufacturing and
books should be kept for major or critical equipment recording, as appropriate, anyvalidations, calibrations, maintenance, cleaning or repair operations, including the datesand identity of people who carried these operations books should also record in chronological order the use of major or critical equipmentand the areas where the products have been
CHAPTER 5 PRODUCTIONPrincipleProduction operations must follow clearly defined procedures; they must comply with theprinciples of Good Manufacturing Practice in order to obtain products of the requisitequality and be in accordance with the relevant manufacturing and should be performed and supervised by competent handling of materials and products, such as receipt and quarantine, sampling, storage,labelling, dispensing, processing, packaging and distribution should be done in accordancewith written procedures or instructions and, where necessary, incoming materials should be checked to ensure that the consignment corresponds tothe order. Containers should be cleaned where necessary and labelled with the to containers and any other problem which might adversely affect the quality of amaterial should be investigated, recorded and reported to the Quality Control materials and finished products should be physically or administrativelyquarantined immediately after receipt or processing, until they have been released for useor and bulk products purchased as such should be handled on receipt as thoughthey were starting materials and products should be stored under the appropriate conditions establishedby the manufacturer and in an orderly fashion to permit batch segregation and on yields, and reconciliation of quantities, should be carried out as necessary toensure that there are no discrepancies outside acceptable on different products should not be carried out simultaneously or consecutivelyin the same room unless there is no risk of mix-up or every stage of processing, products and materials should be protected from microbial andother working with dry materials and products, special precautions should be taken toprevent the generation and dissemination of dust. This applies particularly to the handlingof highly active or sensitising all times during processing, all materials, bulk containers, major items of equipmentand where appropriate rooms used should be labelled or otherwise identified with anindication of the product or material being processed, its strength (where applicable) andbatch number. Where applicable, this indication should also mention the stage
applied to containers, equipment or premises should be clear, unambiguous and inthe company’s agreed format. It is often helpful in addition to the wording on the labels touse colours to indicate status (for example, quarantined, accepted, rejected, clean, ...). should be carried out to ensure that pipelines and other pieces of equipment usedfor the transportation of products from one area to another are connected in a deviation from instructions or procedures should be avoided as far as possible. If adeviation occurs, it should be approved in writing by a competent person, with theinvolvement of the Quality Control Department when to production premises should be restricted to authorised , the production of non-medicinal products should be avoided in areas and withthe equipment destined for the production of medicinal of cross-contamination in of a starting material or of a product by another material or product mustbe avoided. This risk of accidental cross-contamination arises from the uncontrolled releaseof dust, gases, vapours, sprays or organisms from materials and products in process, fromresidues on equipment, and from operators’ clothing. The significance of this risk varieswith the type of contaminant and of product being contaminated. Amongst the mosthazardous contaminants are highly sensitising materials, biological preparationscontaining living organisms, certain hormones, cytotoxics, and other highly activematerials. Products in which contamination is likely to be most significant are thoseadministered by injection, those given in large doses and/or over a long -contamination should be avoided by appropriate technical or organisationalmeasures, for example:a)production in segregated areas (required for products such as penicillins, livevaccines, live bacterial preparations and some other biologicals), or by campaign(separation in time) followed by appropriate cleaning;b)providing appropriate air-locks and air extraction;c)minimising the risk of contamination caused by recirculation or re-entry of untreatedor insufficiently treated air;d)keeping protective clothing inside areas where products with special risk of cross-contamination are processed;e)using cleaning and decontamination procedures of known effectiveness, as ineffectivecleaning of equipment is a common source of cross-contamination;f)using “closed systems” of production;g)testing for residues and use of cleaning status labels on to prevent cross-contamination and their effectiveness should be checkedperiodically according to set
studies should reinforce Good Manufacturing Practice and be conducted inaccordance with defined procedures. Results and conclusions should be any new manufacturing formula or method of preparation is adopted, steps should betaken to demonstrate its suitability for routine processing. The defined process, using thematerials and equipment specified, should be shown to yield a product consistently of therequired amendments to the manufacturing process, including any change in equipmentor materials, which may affect product quality and/or the reproducibility of the processshould be and procedures should undergo periodic critical re-validation to ensure that theyremain capable of achieving the intended purchase of starting materials is an important operation which should involve staffwho have a particular and thorough knowledge of the materials should only be purchased from approved suppliers named in therelevant specification and, where possible, directly from the producer. It is recommendedthat the specifications established by the manufacturer for the starting materials bediscussed with the suppliers. It is of benefit that all aspects of the production and control ofthe starting material in question, including handling, labelling and packagingrequirements, as well as complaints and rejection procedures are discussed with themanufacturer and the each delivery, the containers should be checked for integrity of package and seal andfor correspondence between the delivery note and the supplier’s one material delivery is made up of different batches, each batch must be considered asseparate for sampling, testing and materials in the storage area should be appropriately labelled (see Chapter 5,item 13). Labels should bear at least the following information:—the designated name of the product and the internal code reference where applicable;—a batch number given at receipt;—where appropriate, the status of the contents (. in quarantine, on test, released,rejected);—where appropriate, an expiry date or a date beyond which retesting is fully computerised storage systems are used, all the above information need notnecessarily be in a legible form on the should be appropriate procedures or measures to assure the identity of the contentsof each container of starting material. Bulk containers from which samples have beendrawn should be identified (see Chapter 6, item 13).45
starting materials which have been released by the Quality Control Department andwhich are within their shelf life should be materials should only be dispensed by designated persons, following a writtenprocedure, to ensure that the correct materials are accurately weighed or measured intoclean and properly labelled dispensed material and its weight or volume should be independently checked and thecheck dispensed for each batch should be kept together and conspicuously labelled operations: intermediate and bulk any processing operation is started, steps should be taken to ensure that the workarea and equipment are clean and free from any starting materials, products, productresidues or documents not required for the current and bulk products should be kept under appropriate processes should be validated (see "VALIDATION" in this Chapter). necessary in-process controls and environmental controls should be carried out significant deviation from the expected yield should be recorded and purchase, handling and control of primary and printed packaging materials shall beaccorded attention similar to that given to starting attention should be paid to printed materials. They should be stored inadequately secure conditions such as to exclude unauthorised access. Cut labels and otherloose printed materials should be stored and transported in separate closed containers so asto avoid mix-ups. Packaging materials should be issued for use only by authorisedpersonnel following an approved and documented delivery or batch of printed or primary packaging material should be given a specificreference number or identification or obsolete primary packaging material or printed packaging material should bedestroyed and this disposal setting up a programme for the packaging operations, particular attention should begiven to minimising the risk of cross-contamination, mix-ups or substitutions. Differentproducts should not be packaged in close proximity unless there is physical
packaging operations are begun, steps should be taken to ensure that the work area,packaging lines, printing machines and other equipment are clean and free from anyproducts, materials or documents previously used, if these are not required for the currentoperation. The line-clearance should be performed according to an appropriate name and batch number of the product being handled should be displayed at eachpackaging station or products and packaging materials to be used should be checked on delivery to thepackaging department for quantity, identity and conformity with the for filling should be clean before filling. Attention should be given to avoidingand removing any contaminants such as glass fragments and metal , filling and sealing should be followed as quickly as possible by labelling. If it isnot the case, appropriate procedures should be applied to ensure that no mix-ups ormislabelling can correct performance of any printing operation (for example code numbers, expiry dates)to be done separately or in the course of the packaging should be checked and should be paid to printing by hand which should be re-checked at care should be taken when using cut-labels and when over-printing is carried outoff-line. Roll-feed labels are normally preferable to cut-labels, in helping to avoid should be made to ensure that any electronic code readers, label counters or similardevices are operating and embossed information on packaging materials should be distinct and resistantto fading or -line control of the product during packaging should include at least checking thefollowing:a)general appearance of the packages;b)whether the packages are complete;c)whether the correct products and packaging materials are used;d)whether any over-printing is correct;e)correct functioning of line taken away from the packaging line should not be which have been involved in an unusual event should only be reintroduced intothe process after special inspection, investigation and approval by authorised record should be kept of this significant or unusual discrepancy observed during reconciliation of the amount of bulkproduct and printed packaging materials and the number of units produced should beinvestigated and satisfactorily accounted for before completion of a packaging operation, any unused batch-coded packaging materialsshould be destroyed and the destruction recorded. A documented procedure should befollowed if uncoded printed materials are returned to
Finished products should be held in quarantine until their final release under conditionsestablished by the evaluation of finished products and documentation which is necessary before release ofproduct for sale are described in Chapter 6 (Quality Control). release, finished products should be stored as usable stock under conditionsestablished by the , recovered and returned materials and products should be clearly marked as such and stored separately inrestricted areas. They should either be returned to the suppliers or, where appropriate,reprocessed or destroyed. Whatever action is taken should be approved and recorded byauthorised reprocessing of rejected products should be exceptional. It is only permitted if thequality of the final product is not affected, if the specifications are met and if it is done inaccordance with a defined and authorised procedure after evaluation of the risks should be kept of the recovery of all or part of earlier batches which conform to the required quality byincorporation into a batch of the same product at a defined stage of manufacture should beauthorised beforehand. This recovery should be carried out in accordance with a definedprocedure after evaluation of the risks involved, including any possible effect on shelf recovery should be need for additional testing of any finished product which has been reprocessed, or intowhich a recovered product has been incorporated, should be considered by the QualityControl returned from the market and which have left the control of the manufacturershould be destroyed unless without doubt their quality is satisfactory; they may beconsidered for re-sale, re-labelling or recovery in a subsequent batch only after they havebeen critically assessed by the Quality Control Department in accordance with a writtenprocedure. The nature of the product, any special storage conditions it requires, itscondition and history, and the time elapsed since it was issued should all be taken intoaccount in this assessment. Where any doubt arises over the quality of the product, itshould not be considered suitable for re-issue or re-use, although basic chemical re-processing to recover active ingredient may be possible. Any action taken should beappropriately
CHAPTER 6 QUALITY CONTROLPrincipleQuality Control is concerned with sampling, specifications and testing as well as theorganisation, documentation and release procedures which ensure that the necessary andrelevant tests are carried out, and that materials are not released for use, nor productsreleased for sale or supply, until their quality has been judged satisfactory. Quality Controlis not confined to laboratory operations, but must be involved in all decisions which mayconcern the quality of the product. The independence of Quality Control from Production isconsidered fundamental to the satisfactory operation of Quality Control.(see also Chapter 1). holder of a manufacturing authorisation should have a Quality Control department should be independent from other departments, and under the authorityof a person with appropriate qualifications and experience, who has one or several controllaboratories at his disposal. Adequate resources must be available to ensure that all theQuality Control arrangements are effectively and reliably carried principal duties of the head of Quality Control are summarised in Chapter 2. TheQuality Control Department as a whole will also have other duties, such as to establish,validate and implement all quality control procedures, keep the reference samples ofmaterials and products, ensure the correct labelling of containers of materials andproducts, ensure the monitoring of the stability of the products, participate in theinvestigation of complaints related to the quality of the product, etc. All these operationsshould be carried out in accordance with written procedures and, where necessary, product assessment should embrace all relevant factors, including productionconditions, results of in-process testing, a review of manufacturing (including packaging)documentation, compliance with Finished Product Specification and examination of thefinal finished Control personnel should have access to production areas for sampling andinvestigation as Quality Control Laboratory laboratory premises and equipment should meet the general and specificrequirements for Quality Control areas given in Chapter
personnel, premises, and equipment in the laboratories should be appropriate to thetasks imposed by the nature and the scale of the manufacturing operations. The use ofoutside laboratories, in conformity with the principles detailed in Chapter 7, ContractAnalysis, can be accepted for particular reasons, but this should be stated in the QualityControl documentation should follow the principles given in Chapter 4. An importantpart of this documentation deals with Quality Control and the following details should bereadily available to the Quality Control Department:—specifications;—sampling procedures;—testing procedures and records (including analytical worksheets and/or laboratorynotebooks);—analytical reports and/or certificates;—data from environmental monitoring, where required;—validation records of test methods, where applicable;—procedures for and records of the calibration of instruments and maintenance Quality Control documentation relating to a batch record should be retained for oneyear after the expiry date of the batch and at least 5 years after the certification referred toin article of Directive 75/319/ some kinds of data (. analytical tests results, yields, environmental controls,...) it isrecommended that records be kept in a manner permitting trend addition to the information which is part of the batch record, other original data such aslaboratory notebooks and/or records should be retained and readily sample taking should be done in accordance with approved written procedures thatdescribe:—the method of sampling;—the equipment to be used;—the amount of the sample to be taken;—instructions for any required sub-division of the sample;—the type and condition of the sample container to be used;—the identification of containers sampled;—any special precautions to be observed, especially with regard to the sampling ofsterile or noxious materials;50
—the storage conditions;—instructions for the cleaning and storage of sampling samples should be representative of the batch of materials or products fromwhich they are taken. Other samples may also be taken to monitor the most stressed partof a process (. beginning or end of a process). containers should bear a label indicating the contents, with the batch number, thedate of sampling and the containers from which samples have been samples from each batch of finished products should be retained till one yearafter the expiry date. Finished products should usually be kept in their final packaging andstored under the recommended conditions. Samples of starting materials (other than1solvents, gases and water) should be retained for at least two years () after the release ofthe product if their stability allows. This period may be shortened if their stability, asmentioned in the relevant specification, is shorter. Reference samples of materials andproducts should be of a size sufficient to permit at least a full methods should be validated. All testing operations described in the marketingauthorisation should be carried out according to the approved results obtained should be recorded and checked to make sure that they are consistentwith each other. Any calculations should be critically tests performed should be recorded and the records should include at least thefollowing data:a)name of the material or product and, where applicable, dosage form;b)batch number and, where appropriate, the manufacturer and/or supplier;c)references to the relevant specifications and testing procedures;d)test results, including observations and calculations, and reference to any certificatesof analysis;e)dates of testing;f)initials of the persons who performed the testing;g)initials of the persons who verified the testing and the calculations, whereappropriate;h)a clear statement of release or rejection (or other status decision) and the datedsignature of the designated responsible the in-process controls, including those made in the production area by productionpersonnel, should be performed according to methods approved by Quality Control and theresults recorded. 1()In Federal Republic of Germany, France, Belgium and Greece, samples of starting materials should be retained foras long as the corresponding finished
attention should be given to the quality of laboratory reagents, volumetricglassware and solutions, reference standards and culture media. They should be preparedin accordance with written reagents intended for prolonged use should be marked with the preparationdate and the signature of the person who prepared them. The expiry date of unstablereagents and culture media should be indicated on the label, together with specific storageconditions. In addition, for volumetric solutions, the last date of standardisation and thelast current factor should be necessary, the date of receipt of any substance used for testing operations ( and reference standards) should be indicated on the container. Instructions for useand storage should be followed. In certain cases it may be necessary to carry out anidentification test and/or other testing of reagent materials upon receipt or before used for testing components, materials or products, should, where appropriate, bequarantined before use. They should be maintained and controlled in a manner thatassures their suitability for the intended use. They should be identified, and adequaterecords should be maintained, showing the history of their
CHAPTER 7 CONTRACT MANUFACTURE ANDANALYSISPrincipleContract manufacture and analysis must be correctly defined, agreed and controlled inorder to avoid misunderstandings which could result in a product or work of unsatisfactoryquality. There must be a written contract between the Contract Giver and the ContractAcceptor which clearly establishes the duties of each party. The contract must clearly statethe way in which the Qualified Person releasing each batch of product for sale exercises hisfull :This Chapter deals with the responsibilities of manufacturers towards theCompetent Authorities of the Member States with respect to the granting ofmarketing and manufacturing authorisations. It is not intended in any way toaffect the respective liability of contract acceptors and contract givers to consumers;this is governed by other provisions of Community and national should be a written contract covering the manufacture and/or analysis arrangedunder contract and any technical arrangements made in connection with arrangements for contract manufacture and analysis including any proposed changes intechnical or other arrangements should be in accordance with the marketing authorisationfor the product Contract Contract Giver is responsible for assessing the competence of the Contract Acceptor tocarry out successfully the work required and for ensuring by means of the contract that theprinciples and guidelines of GMP as interpreted in this Guide are Contract Giver should provide the Contract Acceptor with all the informationnecessary to carry out the contracted operations correctly in accordance with the marketingauthorisation and any other legal requirements. The Contract Giver should ensure that theContract Acceptor is fully aware of any problems associated with the product or the workwhich might pose a hazard to his premises, equipment, personnel, other materials or Contract Giver should ensure that all processed products and materials delivered tohim by the Contract Acceptor comply with their specifications or that the products havebeen released by a Qualified
The Contract Contract Acceptor must have adequate premises and equipment, knowledge andexperience, and competent personnel to carry out satisfactorily the work ordered by theContract Giver. Contract manufacture may be undertaken only by a manufacturer who isthe holder of a manufacturing Contract Acceptor should ensure that all products or materials delivered to him aresuitable for their intended Contract Acceptor should not pass to a third party any of the work entrusted to himunder the contract without the Contract Giver’s prior evaluation and approval of thearrangements. Arrangements made between the Contract Acceptor and any third partyshould ensure that the manufacturing and analytical information is made available in thesame way as between the original Contract Giver and Contract Contract Acceptor should refrain from any activity which may adversely affect thequality of the product manufactured and/or analysed for the Contract contract should be drawn up between the Contract Giver and the Contract Acceptorwhich specifies their respective responsibilities relating to the manufacture and control ofthe product. Technical aspects of the contract should be drawn up by competent personssuitably knowledgeable in pharmaceutical technology, analysis and Good ManufacturingPractice. All arrangements for manufacture and analysis must be in accordance with themarketing authorisation and agreed by both contract should specify the way in which the Qualified Person releasing the batch forsale ensures that each batch has been manufactured and checked for compliance with therequirements of Marketing contract should describe clearly who is responsible for purchasing materials, testingand releasing materials, undertaking production and quality controls, including in-processcontrols, and who has responsibility for sampling and analysis. In the case of contractanalysis, the contract should state whether or not the Contract Acceptor should takesamples at the premises of the , analytical and distribution records, and reference samples should be keptby, or be available to, the Contract Giver. Any records relevant to assessing the quality of aproduct in the event of complaints or a suspected defect must be accessible and specified inthe defect/recall procedures of the Contract contract should permit the Contract Giver to visit the facilities of the the case of contract analysis, the Contract Acceptor should understand that he is subjectto Inspection by the competent
CHAPTER 8 COMPLAINTS AND PRODUCT RECALLPrincipleAll complaints and other information concerning potentially defective products must bereviewed carefully according to written procedures. In order to provide for all contingencies,and in accordance with Article 28 of Directive 75/319/EEC, a system should be designed torecall, if necessary, promptly and effectively products known or suspected to be defectivefrom the person should be designated responsible for handling the complaints and deciding themeasures to be taken together with sufficient supporting staff to assist him. If this personis not the Qualified Person, the latter should be made aware of any complaint, investigationor should be written procedures describing the action to be taken, including the need toconsider a recall, in the case of a complaint concerning a possible product complaint concerning a product defect should be recorded with all the original detailsand thoroughly investigated. The person responsible for Quality Control should normally beinvolved in the study of such a product defect is discovered or suspected in a batch, consideration should be given tochecking other batches in order to determine whether they are also affected. In particular,other batches which may contain reworks of the defective batch should be the decisions and measures taken as a result of a complaint should be recorded andreferenced to the corresponding batch records should be reviewed regularly for any indication of specific or recurringproblems requiring attention and possibly the recall of marketed Competent Authorities should be informed if a manufacturer is considering actionfollowing possibly faulty manufacture, product deterioration, or any other serious qualityproblems with a person should be designated as responsible for execution and co-ordination of recalls andshould be supported by sufficient staff to handle all the aspects of the recalls with theappropriate degree of urgency. This responsible person should normally be independent ofthe sales and marketing organisation. If this person is not the Qualified Person, the lattershould be made aware of any recall should be established written procedures, regularly checked and updated whennecessary, in order to organise any recall
operations should be capable of being initiated promptly and at any Competent Authorities of all countries to which products may have been distributedshould be informed promptly if products are intended to be recalled because they are, or aresuspected of being distribution records should be readily available to the person(s) responsible for recalls,and should contain sufficient information on wholesalers and directly supplied customers(with addresses, phone and/or fax numbers inside and outside working hours, batches andamounts delivered), including those for exported products and medical products should be identified and stored separately in a secure area whileawaiting a decision on their progress of the recall process should be recorded and a final report issued, including areconciliation between the delivered and recovered quantities of the effectiveness of the arrangements for recalls should be evaluated from time to
CHAPTER 9 SELF INSPECTIONPrincipleSelf inspections should be conducted in order to monitor the implementation andcompliance with Good Manufacturing Practice principles and to propose necessarycorrective matters, premises, equipment, documentation, production, quality control,distribution of the medicinal products, arrangements for dealing with complaints andrecalls, and self inspection, should be examined at intervals following a pre-arrangedprogramme in order to verify their conformity with the principles of Quality inspections should be conducted in an independent and detailed way by designatedcompetent person(s) from the company. Independent audits by external experts may also self inspections should be recorded. Reports should contain all the observations madeduring the inspections and, where applicable, proposals for corrective on the actions subsequently taken should also be
ANNEXES
ANNEX 1MANUFACTURE OF STERILE MEDICINAL PRODUCTSPrincipleThe manufacture of sterile products is subject to special requirements in order to minimiserisks of microbiological contamination, and of particulate and pyrogen contamination. Muchdepends on the skill, training and attitudes of the personnel involved. Quality Assurance isparticularly important, and this type of manufacture must strictly follow carefullyestablished and validated methods of preparation and procedure. Sole reliance for sterilityor other quality aspects must not be placed on any terminal process or finished :The present guidance does not lay down detailed methods for determining themicrobiological and particulate cleanliness of air, surfaces etc. Reference is made to othercompendia such as the CEN/ISO manufacture of sterile products should be carried out in clean areas entry to whichshould be through airlocks for personnel and/or for equipment and materials. Clean areasshould be maintained to an appropriate cleanliness standard and supplied with air whichhas passed through filters of an appropriate various operations of component preparation, product preparation and filling should becarried out in separate areas within the clean operations are divided into two categories; firstly those where the product isterminally sterilised, and secondly those which are conducted aseptically at some or areas for the manufacture of sterile products are classified according to the requiredcharacteristics of the environment. Each manufacturing operation requires an appropriateenvironmental cleanliness level in the operational state in order to minimise the risks ofparticulate or microbial contamination of the product or materials being order to meet “in operation” conditions these areas should be designed to reach certainspecified air-cleanliness levels in the “at rest” occupancy state. The “at-rest” state is thecondition where the installation is installed and operating, complete with productionequipment but with no operating personnel present. The “in operation” state is thecondition where the installation is functioning in the defined operating mode with thespecified number of personnel
For the manufacture of sterile medicinal products there are normally 4 grades of cleanareas. G r ade A : The local zone for high risk operations, . filling zone, stopper bowls, openampoules and vials, making aseptic connections. Normally such conditions are provided bya laminar air flow work station. Laminar air flow systems should provide a homogeneousair speed of m/s ± 20 % (guidance value) at the working position. G rade B : For aseptic preparation and filling, this is the background environment for gradeA zone. G rade C and D : Clean areas for carrying out less critical stages in the manufacture ofsterile airborne particulate classification for these grades is given in the following rest (b)in operation3Grademaximum permitted number of particles/m equal to or µ5µ µ5 µmA3 50003 5000B (a)3 5000350 0002 000C (a)350 0002 0003 500 00020000D (a)3 500 00020 000not defined (c)not defined (c)Notes(a)In order to reach the B, C and D air grades, the number of air changes should berelated to the size of the room and the equipment and personnel present in the air system should be provided with appropriate filters such as HEPA forgrades A, B and C.(b)The guidance given for the maximum permitted number of particles in the "at rest"condition corresponds approximately to the US Federal Standard 209 E and theISO classifications as follows: grades A and B correspond with class 100, M ,ISO 5; grade C with class , M , ISO 7 and grade D with class , , ISO 8.(c)The requirement and limit for this area will depend on the nature of the operationscarried of operations to be carried out in the various grades are given in the table below.(see also par. 11 and 12)GradeExamples of operations for terminally sterilised products. (see par. 11)AFilling of products, when unusually at of solutions, when unusually at risk. Filling of productsDPreparation of solutions and components for subsequent
GradeExamples of operations for aseptic preparations. (see par. 12)AAseptic preparation and of solutions to be of components after particulate conditions given in the table for the "at rest" state should be achieved in theunmanned state after a short "clean up" period of 15-20 minutes (guidance value), aftercompletion of operations. The particulate conditions for grade A in operation given in thetable should be maintained in the zone immediately surrounding the product whenever theproduct or open container is exposed to the environment. It is accepted that it may notalways be possible to demonstrate conformity with particulate standards at the point of fillwhen filling is in progress, due to the generation of particles or droplets from the areas should be monitored during operation, in order to control the particulatecleanliness of the various aseptic operations are performed monitoring should be frequent using methods suchas settle plates, volumetric air and surface sampling (. swabs and contact plates).Sampling methods used in operation should not interfere with zone protection. Resultsfrom monitoring should be considered when reviewing batch documentation for finishedproduct release. Surfaces and personnel should be monitored after critical microbiological monitoring is also required outside production operations, validation of systems, cleaning and limits for microbiological monitoring of clean areas during limits for microbial contamination (a)Gradesettle platescontact platesair sampleglove print(diam. 9 0 mm),(diam. 55 mm),3cfu/m5 fingers cfu/glovecfu/4 hours (b)cfu/plateA< 1< 1< 1< 1B0555C1005025–D20010050–Notes(a)These are average values.(b)Individual settle plates may be exposed for less than 4
alert and action limits should be set for the results of particulate andmicrobiological monitoring. If these limits are exceeded operating procedures shouldprescribe corrective utilisation of isolator technology to minimise human interventions in processing areasmay result in a significant decrease in the risk of microbiological contamination ofaseptically manufactured products from the environment. There are many possible designsof isolators and transfer devices. The isolator and the background environment should bedesigned so that the required air quality for the respective zones can be realised. Isolatorsare constructed of various materials more or less prone to puncture and leakage. Transferdevices may vary from a single door to double door designs to fully sealed systemsincorporating sterilisation transfer of materials into and out of the unit is one of the greatest potential sources ofcontamination. In general the area inside the isolator is the local zone for high riskmanipulations, although it is recognised that laminar air flow may not exist in the workingzone of all such devices. The air classification required for the background environmentdepends on the design of the isolator and its application. It should be controlled and foraseptic processing it should be at least grade should be introduced only after appropriate validation. Validation should takeinto account all critical factors of isolator technology, for example the quality of the airinside and outside (background) the isolator, sanitisation of the isolator, the transferprocess and isolator should be carried out routinely and should include frequent leak testing of theisolator and glove/sleeve units are purpose built machines in which, in one continuous operation,containers are formed from a thermoplastic granulate, filled and then sealed, all by the oneautomatic machine. Blow/fill/seal equipment used for aseptic production which is fittedwith an effective grade A air shower may be installed in at least a grade C environment,provided that grade A/B clothing is used. The environment should comply with the viableand non viable limits at rest and the viable limit only when in operation. Blow/fill/sealequipment used for the production of products which are terminally sterilised should beinstalled in at least a grade D of this special technology particular attention should be paid to, at least thefollowing: equipment design and qualification, validation and reproducibility of cleaning-in-place and sterilisation-in-place, background cleanroom environment in which theequipment is located, operator training and clothing, and interventions in the critical zoneof the equipment including any aseptic assembly prior to the commencement of
Terminally sterilised of components and most products should be done in at least a grade Denvironment in order to give low risk of microbial and particulate contamination, suitablefor filtration and sterilisation. Where the product is at a high or unusual risk of microbialcontamination, (for example, because the product actively supports microbial growth ormust be held for a long period before sterilisation or is necessarily processed not mainly inclosed vessels), then preparation should be carried out in a grade C of products for terminal sterilisation should be carried out in at least a grade the product is at unusual risk of contamination from the environment, for examplebecause the filling operation is slow or the containers are wide-necked or are necessarilyexposed for more than a few seconds before sealing, the filling should be done in a grade Azone with at least a grade C background. Preparation and filling of ointments, creams,suspensions and emulsions should generally be carried out in a grade C environment beforeterminal after washing should be handled in at least a grade D environment. Handlingof sterile starting materials and components, unless subjected to sterilisation or filtrationthrough a micro-organism-retaining filter later in the process, should be done in a grade Aenvironment with grade B of solutions which are to be sterile filtered during the process should be done ina grade C environment; if not filtered, the preparation of materials and products should bedone in a grade A environment with a grade B and filling of aseptically prepared products should be done in a grade Aenvironment with a grade B to the completion of stoppering, transfer of partially closed containers, as used infreeze drying should be done either in a grade A environment with grade B background orin sealed transfer trays in a grade B and filling of sterile ointments, creams, suspensions and emulsions should bedone in a grade A environment, with a grade B background, when the product is exposedand is not subsequently the minimum number of personnel required should be present in clean areas; this isparticularly important during aseptic processing. Inspections and controls should beconducted outside the clean areas as far as personnel (including those concerned with cleaning and maintenance) employed in suchareas should receive regular training in disciplines relevant to the correct manufacture ofsterile products. This training should include reference to hygiene and to the basic elementsof microbiology. When outside staff who have not received such training (. building or65
maintenance contractors) need to be brought in, particular care should be taken over theirinstruction and who have been engaged in the processing of animal tissue materials or of cultures ofmicro-organisms other than those used in the current manufacturing process should notenter sterile-product areas unless rigorous and clearly defined entry procedures have standards of personal hygiene and cleanliness are essential. Personnel involved in themanufacture of sterile preparations should be instructed to report any condition which maycause the shedding of abnormal numbers or types of contaminants; periodic health checksfor such conditions are desirable. Actions to be taken about personnel who could beintroducing undue microbiological hazard should be decided by a designated and washing should follow a written procedure designed to minimisecontamination of clean area clothing or carry-through of contaminants to the clean , make-up and jewellery should not be worn in clean clothing and its quality should be appropriate for the process and the grade of theworking area. It should be worn in such a way as to protect the product description of clothing required for each grade is given below: G r ade D : Hair and, where relevant, beard should be covered. A general protective suit andappropriate shoes or overshoes should be worn. Appropriate measures should be taken toavoid any contamination coming from outside the clean area. G r ade C : Hair and where relevant beard and moustache should be covered. A single or two-piece trouser suit, gathered at the wrists and with high neck and appropriate shoes orovershoes should be worn. They should shed virtually no fibres or particulate matter. G rade A/B : Headgear should totally enclose hair and, where relevant, beard andmoustache; it should be tucked into the neck of the suit; a face mask should be worn toprevent the shedding of droplets. Appropriate sterilised, non-powdered rubber or plasticgloves and sterilised or disinfected footwear should be worn. Trouser-legs should be tuckedinside the footwear and garment sleeves into the gloves. The protective clothing shouldshed virtually no fibres or particulate matter and retain particles shed by the clothing should not be brought into changing rooms leading to grade B and Crooms. For every worker in a grade A/B area, clean sterile (sterilised or adequatelysanitised) protective garments should be provided at each work session, or at least once aday if monitoring results justify this. Gloves should be regularly disinfected duringoperations. Masks and gloves should be changed at least at every working area clothing should be cleaned and handled in such a way that it does not gatheradditional contaminants which can later be shed. These operations should follow writtenprocedures. Separate laundry facilities for such clothing are desirable. Inappropriatetreatment of clothing will damage fibres and may increase the risk of shedding of
clean areas, all exposed surfaces should be smooth, impervious and unbroken in order tominimise the shedding or accumulation of particles or micro-organisms and to permit therepeated application of cleaning agents, and disinfectants where reduce accumulation of dust and to facilitate cleaning there should be no uncleanablerecesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doorsshould be designed to avoid those uncleanable recesses; sliding doors may be undesirablefor this ceilings should be sealed to prevent contamination from the space above and ducts and other utilities should be installed so that they do not create recesses,unsealed openings and surfaces which are difficult to and drains should be prohibited in grade A/B areas used for aseptic manufacture. Inother areas air breaks should be fitted between the machine or sink and the drains. Floordrains in lower grade clean rooms should be fitted with traps or water seals to rooms should be designed as airlocks and used to provide physical separation ofthe different stages of changing and so minimise microbial and particulate contamination ofprotective clothing. They should be flushed effectively with filtered air. The final stage ofthe changing room should, in the at-rest state, be the same grade as the area into which itleads. The use of separate changing rooms for entering and leaving clean areas issometimes desirable. In general hand washing facilities should be provided only in the firststage of the changing airlock doors should not be opened simultaneously. An interlocking system or a visualand/or audible warning system should be operated to prevent the opening of more than onedoor at a filtered air supply should maintain a positive pressure and an air flow relative tosurrounding areas of a lower grade under all operational conditions and should flush thearea effectively. Adjacent rooms of different grades should have a pressure differential of 10- 15 pascals (guidance values). Particular attention should be paid to the protection of thezone of greatest risk, that is, the immediate environment to which a product and cleanedcomponents which contact the product are exposed. The various recommendationsregarding air supplies and pressure differentials may need to be modified where it becomesnecessary to contain some materials, . pathogenic, highly toxic, radioactive or live viralor bacterial materials or products. Decontamination of facilities and treatment of airleaving a clean area may be necessary for some should be demonstrated that air-flow patterns do not present a contamination risk, should be taken to ensure that air flows do not distribute particles from a particle-generating person, operation or machine to a zone of higher product warning system should be provided to indicate failure in the air supply. Indicators ofpressure differences should be fitted between areas where these differences are pressure differences should be recorded regularly or otherwise
conveyor belt should not pass through a partition between a grade A or B area and aprocessing area of lower air cleanliness, unless the belt itself is continually sterilised (. ina sterilising tunnel). far as practicable equipment, fittings and services should be designed and installed sothat operations, maintenance and repairs can be carried out outside the clean area. Ifsterilisation is required, it should be carried out, wherever possible, after equipment maintenance has been carried out within the clean area, the area shouldbe cleaned, disinfected and/or sterilised where appropriate, before processing recommencesif the required standards of cleanliness and/or asepsis have not been maintained during treatment plants and distribution systems should be designed, constructed andmaintained so as to ensure a reliable source of water of an appropriate quality. They shouldnot be operated beyond their designed capacity. Water for injections should be produced,stored and distributed in a manner which prevents microbial growth, for example byconstant circulation at a temperature above 70° equipment such as sterilisers, air handling and filtration systems, air vent and gasfilters, water treatment, generation, storage and distribution systems should be subject tovalidation and planned maintenance; their return to use should be sanitation of clean areas is particularly important. They should be cleaned thoroughlyin accordance with a written programme. Where disinfectants are used, more than one typeshould be employed. Monitoring should be undertaken regularly in order to detect thedevelopment of resistant and detergents should be monitored for microbial contamination; dilutionsshould be kept in previously cleaned containers and should only be stored for definedperiods unless sterilised. Disinfectants and detergents used in Grades A and B areas shouldbe sterile prior to of clean areas may be useful for reducing microbiological contamination ininaccessible to minimise contamination should be taken during all processing stagesincluding the stages before of microbiological origin should not be made or filled in areas used for theprocessing of other medicinal products; however, vaccines of dead organisms or of bacterialextracts may be filled, after inactivation, in the same premises as other sterile
of aseptic processing should include simulating the process using a nutrientmedium. The form of the nutrient medium used should generally be equivalent to thedosage form of the product. The process simulation test should imitate, as closely aspossible the routine aseptic manufacturing process and include all the critical subsequentmanufacturing steps. Process simulation should be repeated at defined intervals and afterany significant modification to the equipment and process. The number of containers usedfor a medium fill should be sufficient to enable a valid evaluation. For small batches, thenumber of containers for the medium fill should at least equal the size of the product contamination rate should be less than % with 95% confidence should be taken that any validation does not compromise the sources, water treatment equipment and treated water should be monitoredregularly for chemical and biological contamination and, as appropriate, for should be maintained of the results of the monitoring and of any action in clean areas and especially when aseptic operations are in progress should bekept to a minimum and movement of personnel should be controlled and methodical, toavoid excessive shedding of particles and organisms due to over-vigorous activity. Theambient temperature and humidity should not be uncomfortably high because of the natureof the garments contamination of starting materials should be minimal. Specificationsshould include requirements for microbiological quality when the need for this has beenindicated by and materials liable to generate fibres should be minimised in clean appropriate, measures should be taken to minimise the particulate contamination ofthe end , containers and equipment should be handled after the final cleaning processin such a way that they are not interval between the washing and drying and the sterilisation of components,containers and equipment as well as between their sterilisation and use should beminimised and subject to a time-limit appropriate to the storage time between the start of the preparation of a solution and its sterilisation or filtrationthrough a micro-organism-retaining filter should be minimised. There should be a setmaximum permissible time for each product that takes into account its composition and theprescribed method of bioburden should be monitored before sterilisation. There should be working limits oncontamination immediately before sterilisation which are related to the efficiency of themethod to be used. Where appropriate the absence of pyrogens should be monitored. Allsolutions, in particular large volume infusion fluids, should be passed through a micro-organism-retaining filter, if possible sited immediately before , containers, equipment and any other article required in a clean area whereaseptic work takes place should be sterilised and passed into the area through double-ended sterilisers sealed into the wall, or by a procedure which achieves the same objectiveof not introducing contamination. Non-combustible gases should be passed through micro-organism retentive
efficacy of any new procedure should be validated, and the validation verified atscheduled intervals based on performance history or when any significant change is madein the process or sterilisation processes should be validated. Particular attention should be given whenthe adopted sterilisation method is not described in the current edition of the EuropeanPharmacopoeia, or when it is used for a product which is not a simple aqueous or oilysolution. Where possible, heat sterilisation is the method of choice. In any case, thesterilisation process must be in accordance with the marketing and any sterilisation process is adopted its suitability for the product and its efficacy inachieving the desired sterilising conditions in all parts of each type of load to be processedshould be demonstrated by physical measurements and by biological indicators whereappropriate. The validity of the process should be verified at scheduled intervals, at leastannually, and whenever significant modifications have been made to the should be kept of the effective sterilisation the whole of the material must be subjected to the requiredtreatment and the process should be designed to ensure that this is loading patterns should be established for all sterilisation processes . indicators should be considered as an additional method for monitoring thesterilisation. They should be stored and used according to the manufacturers instructions,and their quality checked by positive biological indicators are used, strict precautions should be taken to avoid transferringmicrobial contamination from should be a clear means of differentiating products which have not been sterilisedfrom those which have. Each basket, tray or other carrier of products or components shouldbe clearly labelled with the material name, its batch number and an indication of whetheror not it has been sterilised. Indicators such as autoclave tape may be used, whereappropriate, to indicate whether or not a batch (or sub-batch) has passed through asterilisation process, but they do not give a reliable indication that the lot is, in fact, records should be available for each sterilisation run. They should be approvedas part of the batch release by heat sterilisation cycle should be recorded on a time/temperature chart with asufficiently large scale or by other appropriate equipment with suitable accuracy andprecision. The position of the temperature probes used for controlling and/or recordingshould have been determined during the validation, and where applicable also checkedagainst a second independent temperature probe located at the same
or biological indicators may also be used, but should not take the place of time must be allowed for the whole of the load to reach the required temperaturebefore measurement of the sterilising time-period is commenced. This time must bedetermined for each type of load to be the high temperature phase of a heat sterilisation cycle, precautions should be takenagainst contamination of a sterilised load during cooling. Any cooling fluid or gas in contactwith the product should be sterilised unless it can be shown that any leaking containerwould not be approved for temperature and pressure should be used to monitor the process. Controlinstrumentation should normally be independent of monitoring instrumentation andrecording charts. Where automated control and monitoring systems are used for theseapplications they should be validated to ensure that critical process requirements are and cycle faults should be registered by the system and observed by the reading of the independent temperature indicator should be routinely checked againstthe chart recorder during the sterilisation period. For sterilisers fitted with a drain at thebottom of the chamber, it may also be necessary to record the temperature at this position,throughout the sterilisation period. There should be frequent leak tests on the chamberwhen a vacuum phase is part of the items to be sterilised, other than products in sealed containers, should be wrapped in amaterial which allows removal of air and penetration of steam but which preventsrecontamination after sterilisation. All parts of the load should be in contact with thesterilising agent at the required temperature for the required should be taken to ensure that steam used for sterilisation is of suitable quality anddoes not contain additives at a level which could cause contamination of product process used should include air circulation within the chamber and the maintenance ofa positive pressure to prevent the entry of non-sterile air. Any air admitted should bepassed through a HEPA filter. Where this process is also intended to remove pyrogens,challenge tests using endotoxins should be used as part of the by sterilisation is used mainly for the sterilisation of heat sensitive materials andproducts. Many medicinal products and some packaging materials are radiation-sensitive,so this method is permissible only when the absence of deleterious effects on the producthas been confirmed experimentally. Ultraviolet irradiation is not normally an acceptablemethod of
the sterilisation procedure the radiation dose should be measured. For this purpose,dosimetry indicators which are independent of dose rate should be used, giving aquantitative measurement of the dose received by the product itself. Dosimeters should beinserted in the load in sufficient number and close enough together to ensure that there isalways a dosimeter in the irradiator . Where plastic dosimeters are used they should beused within the time-limit of their calibration. Dosimeter absorbances should be readwithin a short period after exposure to indicators may be used as an additional procedures should ensure that the effects of variations in density of thepackages are handling procedures should prevent mix-up between irradiated and non-irradiated materials. Radiation sensitive colour disks should also be used on each packageto differentiate between packages which have been subjected to irradiation and those whichhave total radiation dose should be administered within a predetermined time with ethylene method should only be used when no other method is practicable. During processvalidation it should be shown that there is no damaging effect on the product and that theconditions and time allowed for degassing are such as to reduce any residual gas andreaction products to defined acceptable limits for the type of product or contact between gas and microbial cells is essential; precautions should be taken toavoid the presence of organisms likely to be enclosed in material such as crystals or driedprotein. The nature and quantity of packaging materials can significantly affect exposure to the gas, materials should be brought into equilibrium with the humidityand temperature required by the process. The time required for this should be balancedagainst the opposing need to minimise the time before sterilisation cycle should be monitored with suitable biological indicators, using theappropriate number of test pieces distributed throughout the load. The information soobtained should form part of the batch each sterilisation cycle, records should be made of the time taken to complete the cycle,of the pressure, temperature and humidity within the chamber during the process and ofthe gas concentration and of the total amount of gas used. The pressure and temperatureshould be recorded throughout the cycle on a chart. The record(s) should form part of thebatch sterilisation, the load should be stored in a controlled manner under ventilatedconditions to allow residual gas and reaction products to reduce to the defined level. Thisprocess should be
Filtration of medicinal products which cannot besterilised in their final alone is not considered sufficient when sterilisation in the final container ispossible. With regard to methods currently available, steam sterilisation is to be the product cannot be sterilised in the final container, solutions or liquids can be filteredthrough a sterile filter of nominal pore size of micron (or less), or with at leastequivalent micro-organism retaining properties, into a previously sterilised container. Suchfilters can remove most bacteria and moulds, but not all viruses or should be given to complementing the filtration process with some degree ofheat to the potential additional risks of the filtration method as compared with othersterilisation processes, a second filtration via a further sterilised micro-organism retainingfilter, immediately prior to filling, may be advisable. The final sterile filtration should becarried out as close as possible to the filling shedding characteristics of filters should be integrity of the sterilised filter should be verified before use and should be confirmedimmediately after use by an appropriate method such as a bubble point, diffusive flow orpressure hold test. The time taken to filter a known volume of bulk solution and thepressure difference to be used across the filter should be determined during validation andany significant differences from this during routine manufacturing, should be noted andinvestigated. Results of these checks should be included in the batch record. The integrityof critical gas and air vent filters should be confirmed after use. The integrity of otherfilters should be confirmed at appropriate same filter should not be used for more than one working day unless such use has filter should not affect the product by removal of ingredients from it or by release ofsubstances into of sterile products88Containers should be closed by appropriately validated methods. Containers closed byfusion, . glass or plastic ampoules should be subject to 100% integrity testing. Samples ofother containers should be checked for integrity according to appropriate sealed under vacuum should be tested for maintenance of that vacuum after anappropriate, pre-determined containers of parenteral products should be inspected individually for extraneouscontamination or other defects. When inspection is done visually, it should be done undersuitable and controlled conditions of illumination and background. Operators doing theinspection should pass regular eye-sight checks, with spectacles if worn, and be allowedfrequent breaks from inspection. Where other methods of inspection are used, the processshould be validated and the performance of the equipment checked at intervals. Resultsshould be
Quality sterility test applied to the finished product should only be regarded as the last in aseries of control measures by which sterility is assured. The test should be validated for theproduct(s) those cases where parametric release has been authorised, special attention should bepaid to the validation and the monitoring of the entire manufacturing taken for sterility testing should be representative of the whole of the batch, butshould in particular include samples taken from parts of the batch considered to be most atrisk of contamination, .: products which have been filled aseptically, samples should include containersfilled at the beginning and end of the batch and after any significant intervention, products which have been heat sterilised in their final containers, considerationshould be given to taking samples from the potentially coolest part of the
ANNEX 2MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FORHUMAN USEScopeThe methods employed in the manufacture of biological medicinal products are a criticalfactor in shaping the appropriate regulatory control. Biological medicinal products can bedefined therefore largely by reference to their method of manufacture. Biological medicinalproducts prepared by the following methods of manufacture will fall under the scope of this1annex (). Biological medicinal products manufactured by these methods include: vaccines,immunosera, antigens, hormones, cytokines, enzymes and other products of fermentation(including monoclonal antibodies and products derived from r-DNA).a)Microbial cultures, excluding those resulting from r-DNA techniques;b)Microbial and cell cultures, including those resulting from recombinant DNA orhybridoma techniques;c)Extraction from biological tissuesd)Propagation of live agents in embryos or animals(Not all of the aspects of this annex may necessarily apply to products in category a).NoteIn drawing up this guidance, due consideration has been given to the general requirementsfor manufacturing establishments and control laboratories proposed by the present guidance does not lay down detailed requirements for specific classes ofbiological products, and attention is therefore directed to other guidelines issued by theCommittee for Proprietary Medicinal Products (CPMP), for example the note for guidance onmonoclonal antibodies and the note for guidance on products of recombinant DNAtechnology (“The rules governing medicinal product in the European Community”,Volume 3).PrincipleThe manufacture of biological medicinal products involves certain specific considerationsarising from the nature of the products and the processes. The way in which biologicalmedicinal products are produced, controlled and administered make some particularprecautions necessary. 1()Biological medicinal products manufactured by these methods include: vaccines, immunosera, antigens, hormones,cytokines, enzymes and other products of fermentation (including monoclonal antibodies and products derived fromr-DNA).75
Unlike conventional medicinal products, which are reproduced using chemical and physicaltechniques capable of a high degree of consistency, the production of biological medicinalproducts involves biological processes and materials, such as cultivation of cells orextraction of material from living organisms. These biological processes may displayinherent variability, so that the range and nature of by-products are variable. Moreover,the materials used in these cultivation processes provide good substrates for growth ofmicrobial of biological medicinal products usually involves biological analytical techniqueswhich have a greater variability than physico-chemical determinations. In-process controlstherefore take on a great importance in the manufacture of biological medicinal personnel (including those concerned with cleaning, maintenance or quality control)employed in areas where biological medicinal products are manufactured should receiveadditional training specific to the products manufactured and to their work. Personnelshould be given relevant information and training in hygiene and responsible for production and quality control should have an adequatebackground in relevant scientific disciplines, such as bacteriology, biology, biometry,chemistry, medicine, pharmacy, pharmacology, virology, immunology and veterinarymedicine, together with sufficient practical experience to enable them to exercise theirmanagement function for the process immunological status of personnel may have to be taken into consideration for productsafety. All personnel engaged in production, maintenance, testing and animal care (andinspectors) should be vaccinated where necessary with appropriate specific vaccines andhave regular health checks. Apart from the obvious problem of exposure of staff toinfectious agents, potent toxins or allergens, it is necessary to avoid the risk ofcontamination of a production batch with infectious agents. Visitors should generally beexcluded from production changes in the immunological status of personnel which could adversely affect thequality of the product should preclude work in the production area. Production of BCGvaccine and tuberculin products should be restricted to staff who are carefully monitored byregular checks of immunological status or chest the course of a working day, personnel should not pass from areas where exposure to liveorganisms or animals is possible to areas where other products or different organisms arehandled. If such passage is unavoidable, clearly defined decontamination measures,including change of clothing and shoes and, where necessary, showering should be followedby staff involved in any such
Premises and degree of environmental control of particulate and microbial contamination of theproduction premises should be adapted to the product and the production step, bearing inmind the level of contamination of the starting materials and the risk to the risk of cross-contamination between biological medicinal products, especially duringthose stages of the manufacturing process in which live organisms are used, may requireadditional precautions with respect to facilities and equipment, such as the use of dedicatedfacilities and equipment, production on a campaign basis and the use of closed systems. Thenature of the product as well as the equipment used will determine the level of segregationneeded to avoid principle, dedicated facilities should be used for the production of BCG vaccine and forthe handling of live organisms used in production of tuberculin facilities should be used for the handling of Bacillus anthracis, of Clostridiumbotulinum and of Clostridium tetani until the inactivation process is on a campaign basis may be acceptable for other spore forming organismsprovided that the facilities are dedicated to this group of products and not more than oneproduct is processed at any one production in the same area using closed systems of biofermenters may beacceptable for products such as monoclonal antibodies and products prepared by steps after harvesting may be carried out simultaneously in the sameproduction area provided that adequate precautions are taken to prevent crosscontamination. For killed vaccines and toxoids, such parallel processing should only beperformed after inactivation of the culture or after pressure areas should be used to process sterile products but negative pressure inspecific areas at point of exposure of pathogens is acceptable for containment negative pressure areas or safety cabinets are used for aseptic processing ofpathogens, they should be surrounded by a positive pressure sterile filtration units should be specific to the processing area concerned and recirculation ofair should not occur from areas handling live pathogenic layout and design of production areas and equipment should permit effective cleaningand decontamination (. by fumigation). The adequacy of cleaning and decontaminationprocedures should be used during handling of live organisms should be designed to maintain culturesin a pure state and uncontaminated by external sources during systems, valves and vent filters should be properly designed to facilitate cleaningand sterilisation. The use of ‘clean in place’ and ‘sterilise in place’ systems should beencouraged. Valves on fermentation vessels should be completely steam sterilisable. Airvent filters should be hydrophobic and validated for their scheduled life containment should be designed and tested to demonstrate freedom from
which may contain pathogenic micro-organisms should be to the variability of biological products or processes, some additives or ingredients haveto be measured or weighed during the production process (. buffers). In these cases,small stocks of these substances may be kept in the production quarters and are used for the manufacture of a number of biological products, for example poliovaccine (monkeys), snake antivenoms (horses and goats), rabies vaccine (rabbits, mice andhamsters) and serum gonadotropin (horses). In addition, animals may also be used in thequality control of most sera and vaccines, . pertussis vaccine (mice), pyrogenicity(rabbits), BCG vaccine (guinea-pigs). requirements for animal quarters, care and quarantine are laid down in Directive86/609/EEC. Quarters for animals used in production and control of biological productsshould be separated from production and control areas. The health status of animals fromwhich some starting materials are derived and of those used for quality control and safetytesting should be monitored and recorded. Staff employed in such areas must be providedwith special clothing and changing facilities. Where monkeys are used for the production orquality control of biological medicinal products, special consideration is required as laiddown in the current WHO Requirements for Biological Substances n° for biological starting materials may need additional documentation on thesource, origin, method of manufacture and controls applied, particularly are routinely required for intermediate and bulk biological source, origin and suitability of starting materials should be clearly defined. Where thenecessary tests take a long time, it may be permissible to process starting materials beforethe results of the tests are available. In such cases, release of a finished product isconditional on satisfactory results of these sterilisation of starting materials is required, it should be carried out where possibleby heat. Where necessary, other appropriate methods may also be used for inactivation ofbiological materials (. irradiation).78
Seed lot and cell bank order to prevent the unwanted drift of properties which might ensue from repeatedsubcultures or multiple generations, the production of biological medicinal productsobtained by microbial culture, cell culture or propagation in embryos and animals should bebased on a system of master and working seed lots and/or cell number of generations (doublings, passages) between the seed lot or cell bank and thefinished product should be consistent with the marketing authorisation dossier. Scaling upof the process should not change this fundamental lots and cell banks should be adequately characterised and tested for suitability for use should be further demonstrated by the consistency of thecharacteristics and quality of the successive batches of product. Seed lots and cell banksshould be established, stored and used in such a way as to minimise the risks ofcontamination or of the seed lot and cell bank should be performed in a suitably controlledenvironment to protect the seed lot and the cell bank and, if applicable, the personnelhandling it. During the establishment of the seed lot and cell bank, no other living orinfectious material (. virus, cell lines or cell strains) should be handled simultaneously inthe same area or by the same of the stability and recovery of the seeds and banks should be containers should be hermetically sealed, clearly labelled and kept at anappropriate temperature. An inventory should be meticulously kept. Storage temperatureshould be recorded continuously for freezers and properly monitored for liquid deviation from set limits and any corrective action taken should be authorised personnel should be allowed to handle the material and this handlingshould be done under the supervision of a responsible person. Access to stored materialshould be controlled. Different seed lots or cell banks should be stored in such a way toavoid confusion or cross-contamination. It is desirable to split the seed lots and cell banksand to store the parts at different locations so as to minimise the risks of total containers of master or working cell banks and seed lots should be treated identicallyduring storage. Once removed from storage, the containers should not be returned to growth promoting properties of culture media should be of materials or cultures to fermenters and other vessels and the taking of samplesshould be carried out under carefully controlled conditions to ensure that absence ofcontamination is maintained. Care should be taken to ensure that vessels are correctlyconnected when addition or sampling take and blending of products can lead to aerosol formation, and containment ofsuch activities to prevent transfer of live micro-organisms is possible, media should be sterilised in situ. In-line sterilising filters for routine additionof gases, media, acids or alkalis, defoaming agents etc. to fermenters should be used
consideration should be given to the validation of any necessary virus removal orinactivation undertaken (see CPMP notes for guidance). cases where a virus inactivation or removal process is performed during manufacture,measures should be taken to avoid the risk of recontamination of treated products by non-treated wide variety of equipment is used for chromatography, and in general such equipmentshould be dedicated to the purification of one product and should be sterilised or sanitisedbetween batches. The use of the same equipment at different stages of processing should bediscouraged. Acceptance criteria, life span and sanitation or sterilisation method of columnsshould be -process controls play a specially important role in ensuring the consistency of the qualityof biological medicinal products. Those controls which are crucial for quality (. virusremoval) but which cannot be carried out on the finished product, should be performed atan appropriate stage of may be necessary to retain samples of intermediate products in sufficient quantities andunder appropriate storage conditions to allow the repetition or confirmation of a monitoring of certain production processes is necessary, for examplefermentation. Such data should form part of the batch continuous culture is used, special consideration should be given to the qualitycontrol requirements arising from this type of production
ANNEX 3MANUFACTURE OF RADIOPHARMACEUTICALSPrincipleThe manufacturing and handling of radiopharmaceuticals is potentially hazardous. Thelevel of risk depends in particular upon the types of radiation emitted and the half-lives ofthe radioactive isotopes. Particular attention must be paid to the prevention of cross-contamination, to the retention of radionuclide contaminants, and to waste consideration may be necessary with reference to the small batch sizes madefrequently for many radiopharmaceuticals. Due to their short half-life, someradiopharmaceuticals are released before completion of certain Quality Control tests. Inthis case, the continuous assessment of the effectiveness of the Quality Assurance systembecomes very must comply with the requirements of EURATOM Directives laying down thebasic standards for the health protection of the general public and workers against thedangers of ionising radiation, as well as complying with other relevant personnel (including those concerned with cleaning and maintenance) employed inareas where radioactive products are manufactured should receive additional trainingspecific to this class of products. In particular, they should be given detailed informationand appropriate training on radiation and products should be stored, processed, packaged and controlled in dedicated andself-contained facilities. The equipment used for manufacturing operations should bereserved exclusively for order to contain the radioactive particles, it may be necessary for the air pressure to belower where products are exposed than in surrounding areas. However, it is still necessaryto protect the product from environmental sterile products the working zone where products or containers may be exposed shouldcomply with the environmental requirements described in the Supplement on SterileProducts. This may be achieved by the provision within the work station of a laminar flowof HEPA-filtered air and by fitting air-locks to entry ports. Total containment work stationsmay provide these requirements. They should be in an environment conforming to at leastgrade
extracted from areas where radioactive products are handled should not be recirculated; air outlets should be designed to avoid possible environmental contamination byradioactive particles and should be a system to prevent air entering the clean area through extract ducts the extract fan is not of different radioactive products in the same work stations and at the same timeshould be avoided in order to minimise the risk of cross-contamination or validation, in-process controls and monitoring of process parameters andenvironment, assume particular importance in cases where it is necessary to take thedecision to release or reject a batch or a product before all tests are products have to be dispatched before all tests are completed, this does not obviatethe need for a formal recorded decision to be taken by the Qualified Person on theconformity of the batch. In this case there should be a written procedure detailing allproduction and Quality Control data which should be considered before the batch isdispatched. A procedure should also describe the measures to be taken by the QualifiedPerson if unsatisfactory test results are obtained after otherwise specified in the marketing authorisation, reference samples of every batchshould be and distribution records should be maintained and there should be procedures whichdescribe the measures to be taken for stopping the use of defective operations should be shown to be operable within a very short
ANNEX 4MANUFACTURE OF VETERINARY MEDICINAL PRODUCTSOTHER THAN IMMUNOLOGICAL VETERINARY MEDICINALPRODUCTSNoteThis annex applies to all veterinary medicinal products falling within the scope of Directive81/851/EEC other than immunological veterinary medicinal products, which are thesubject of a separate of premixes for medicated feedingstuffsFor the purposes of these paragraphs,—a medicated feedingstuff is any mixture of a veterinary medicinal product or products andfeed or feeds which is ready prepared for marketing and intended to be fed to animalswithout further processing because of its curative or preventative properties or otherproperties as a medicinal product covered by Article 1(2) of Directive 65/65/EEC;—a pre-mix for medicated feedingstuffs is any veterinary medicinal product prepared inadvance with a view to the subsequent manufacture of medicated manufacture of premixes for medicated feedingstuffs requires the use of largequantities of vegetable matter which is likely to attract insects and rodents. Premisesshould be designed, equipped and operated to minimise this risk (point .) and should alsobe subject to a regular pest control of the large volume of dust generated during the production of bulk material forpremixes, specific attention should be given to the need to avoid cross contamination andfacilitate cleaning (point ), for example through the installation of sealed transportsystems and dust extraction, whenever possible. The installation of such systems does not,however, eliminate the need for regular cleaning of production of the process likely to have a significant adverse influence on the stability of theactive ingredient(s) (. use of steam in pellet manufacture) should be carried out in anuniform manner from batch to should be given to undertake the manufacture of premixes in dedicated areaswhich, if at all possible, do not form part of a main manufacturing plant. Alternatively,such dedicated areas should be surrounded by a buffer zone in order to minimise the risk ofcontamination of other manufacturing
veterinary medicinal products_______________________________________________Manufacture of derogation from point , ectoparasiticides for external application to animals, whichare veterinary medicinal products, and subject to marketing authorisation, may beproduced and filled on a campaign basis in pesticide specific areas. However othercategories of veterinary medicinal products should not be produced in such validated cleaning procedures should be employed to prevent crosscontamination, and steps should be taken to ensure the secure storage of the veterinarymedicinal product in accordance with the of veterinary medicinal products use of penicillins in veterinary medicine does not present the same risks ofhypersensitivity in animals as in humans. Although incidents of hypersensitivity have beenrecorded in horses and dogs, there are other materials which are toxic to certain species,. the ionophore antibiotics in horses. Although desirable, the requirements that suchproducts be manufactured in dedicated, self-contained facilities (point ) may bedispensed with in the case of facilities dedicated to the manufacture of veterinary medicinalproducts only. However, all necessary measures should be taken to avoid crosscontamination and any risk to operator safety in accordance with the guide. In suchcircumstances, penicillin-containing products should be manufactured on a campaign basisand should be followed by appropriate, validated decontamination and cleaning of samples (point viii and point ) is recognised that because of the large volume of certain veterinary medicinal products intheir final packaging, in particular premixes, it may not be feasible for manufacturers toretain samples from each batch in its final packaging. However, manufacturers shouldensure that sufficient representative samples of each batch are retained and stored inaccordance with the all cases, the container used for storage should be composed of the same material as themarket primary container in which the product is veterinary medicinal this has been accepted by the competent authorities, terminally sterilised veterinarymedicinal products may be manufactured in a clean area of a lower grade than the graderequired in the annex on “Sterile preparations”, but at least in a grade D
ANNEX 5MANUFACTURE OF IMMUNOLOGICAL VETERINARYMEDICINAL PRODUCTSPrincipleThe manufacture of immunological veterinary medicinal products has special characteristicswhich should be taken into consideration when implementing and assessing the qualityassurance to the large number of animal species and related pathogenic agents, the variety of productsmanufactured is very wide and the volume of manufacture is often low; hence, work on acampaign basis is common. Moreover, because of the very nature of this manufacture (cultivationsteps, lack of terminal sterilisation, etc.), the products must be particularly well-protected againstcontamination and cross-contamination. The environment also must be protected especially whenthe manufacture involves the use of pathogenic or exotic biological agents and the worker must beparticularly well-protected when the manufacture involves the use of biological agents pathogenicto factors, together with the inherent variability of immunological products and the relativeinefficiency in particular of final product quality control tests in providing adequate informationabout products, means that the role of the quality assurance system is of the utmost need to maintain control over all of the following aspects of GMP, as well as those outlined inthis Guide, cannot be overemphasised. In particular, it is important that the data generated bythe monitoring of the various aspects of GMP (equipment, premises, product etc.) are rigorouslyassessed and informed decisions, leading to appropriate action, are made and personnel (including those concerned with cleaning and maintenance) employed inareas where immunological products are manufactured should be given training in andinformation on hygiene and microbiology. They should receive additional training specific tothe products with which they personnel should be formally trained in some or all of the following fields:bacteriology, biology, biometry, chemistry, immunology, medicine, parasitology, pharmacy,pharmacology, virology and veterinary medicine and should also have an adequateknowledge of environmental protection should be protected against possible infection with the biological agents used inmanufacture. In the case of biological agents known to cause disease in humans, adequatemeasures should be taken to prevent infection of personnel working with the agent or withexperimental relevant, the personnel should be vaccinated and subject to medical
measures should be taken to prevent biological agents being taken outside themanufacturing plant by personnel acting as a carrier. Dependent on the type of biologicalagent, such measures may include complete change of clothes and compulsory showeringbefore leaving the production immunological products, the risk of contamination or cross-contamination by personnelis particularly of contamination by personnel should be achieved by a set of measures andprocedures to ensure that appropriate protective clothing is used during the differentstages of the production of cross-contamination by personnel involved in production should be achievedby a set of measures and procedures to ensure that they do not pass from one area toanother unless they have taken appropriate measures to eliminate the risk ofcontamination. In the course of a working day, personnel should not pass from areas wherecontamination with live micro-organisms is likely or where animals are housed to premiseswhere other products or organisms are handled. If such passage is unavoidable, clearlydefined decontamination procedures, including change of clothing and shoes, and, wherenecessary, showering, should be followed by staff involved in any such entering a contained area where organisms had not been handled in open circuitoperations in the previous twelve hours to check on cultures in sealed, surfacedecontaminated flasks would not be regarded as being at risk of contamination, unless theorganism involved was an should be designed in such a way as to control both the risk to the product and tothe can be achieved by the use of containment, clean, clean/contained or controlled biological agents should be handled in contained areas. The level of containmentshould depend on the pathogenicity of the micro-organism and whether it has beenclassified as exotic. (Other relevant legislation, such as Directives 90/219/EEC and90/220/EEC, also applies). biological agents should be handled in clean areas. Clean areas should also beused when handling non-infected cells isolated from multicellular organisms and, in somecases, filtration-sterilised circuit operations involving products or components not subsequently sterilisedshould be carried out within a laminar air flow work station (grade A) in a grade B operations where live biological agents are handled (quality control, research anddiagnostic services, etc.) should be appropriately contained and separated if productionoperations are carried out in the same building. The level of containment should depend onthe pathogenicity of the biological agent and whether they have been classified as diagnostic activities are carried out, there is the risk of introducing highlypathogenic organisms. Therefore, the level of containment should be adequate to cope withall such risks. Containment may also be required if quality control or other activities arecarried out in buildings in close proximity to those used for
premises should be easily disinfected and should have the followingcharacteristics:a)the absence of direct venting to the outside;b)a ventilation with air at negative pressure. Air should be extracted through HEPAfilters and not be re circulated except to the same area, and provided further HEPAfiltration is used (normally this condition would be met by routing the re circulatedair through the normal supply HEPAs for that area). However, recycling of airbetween areas may be permissible provided that it passes through two exhaustHEPAs, the first of which is continuously monitored for integrity, and there areadequate measures for safe venting of exhaust air should this filter fail;c)air from manufacturing areas used for the handling of exotic organisms should bevented through 2 sets of HEPA filters in series, and that from production areas notre-circulated;d)a system for the collection and disinfection of liquid effluents including contaminatedcondensate from sterilizers, biogenerators, etc. Solid wastes, including animalcarcasses, should be disinfected, sterilized or incinerated as filters should be removed using a safe method;e)changing rooms designed and used as air locks, and equipped with washing andshowering facilities if appropriate. Air pressure differentials should be such thatthere is no flow of air between the work area and the external environment or risk ofcontamination of outer clothing worn outside the area;f)an air lock system for the passage of equipment, which is constructed so that there isno flow of contaminated air between the work area and the external environment orrisk of contamination of equipment within the lock. The air lock should be of a sizewhich enables the effective surface decontamination of materials being passedthrough it. Consideration should be given to having a timing device on the doorinterlock to allow sufficient time for the decontamination process to be )in many instances, a barrier double-door autoclave for the secure removal of wastematerials and introduction of sterile passes and changing rooms should have an interlock mechanism or otherappropriate system to prevent the opening of more than one door at a time. Changingrooms should be supplied with air filtered to the same standard as that for the work area,and equipped with air extraction facilities to produce an adequate air circulationindependent of that of the work area. Equipment passes should normally be ventilated inthe same way, but unventilated passes, or those equipped with supply air only, may operations such as cell maintenance, media preparation, virus culture, to cause contamination should be performed in separate areas. Animals and animalproducts should be handled with appropriate areas where biological agents particularly resistant to disinfection (. spore-forming bacteria) are handled should be separated and dedicated to that particular purposeuntil the biological agents have been the exception of blending and subsequent filling operations, one biological agent onlyshould be handled at a time within an
areas should be designed to permit disinfection between campaigns, usingvalidated of biological agents may take place in controlled areas provided it is carried outin totally enclosed and heat sterilised equipment, all connections being also heat sterilisedafter making and before breaking. It may be acceptable for connections to be made underlocal laminar air flow provided these are few in number and proper aseptic techniques areused and there is no risk of leakage. The sterilisation parameters used before breaking theconnections must be validated for the organisms being used. Different products may beplaced in different biogenerators, within the same area, provided that there is no risk ofaccidental cross-contamination. However, organisms generally subject to specialrequirements for containment should be in areas dedicated to such houses where animals intended or used for production are accommodated, shouldbe provided with the appropriate containment and/or clean area measures, and should beseparate from other animal houses where animals used for quality control, involving the use of pathogenicbiological agents, are accommodated, should be adequately to manufacturing areas should be restricted to authorised personnel. Clear andconcise written procedures should be posted as relating to the premises should be readily available in a plant master manufacturing site and buildings should be described in sufficient detail (by means ofplans and written explanations) so that the designation and conditions of use of all therooms are correctly identified as well as the biological agents which are handled in flow of people and product should also be clearly animal species accommodated in the animal houses or otherwise on the site should activities carried out in the vicinity of the site should also be of contained and/or clean area premises, should describe the ventilation systemindicating inlets and outlets, filters and their specifications, the number of air changes perhour, and pressure gradients. They should indicate which pressure gradients are monitoredby pressure equipment used should be designed and constructed so that it meets the particularrequirements for the manufacture of each being put into operation the equipment should be qualified and validated andsubsequently be regularly maintained and appropriate, the equipment should ensure satisfactory primary containment of thebiological appropriate, the equipment should be designed and constructed as to allow easy andeffective decontamination and/or
equipment used for the primary containment of the biological agents should bedesigned and constructed as to prevent any leakage or the formation of droplets and outlets for gases should be protected so as to achieve adequate containment the use of sterilising hydrophobic introduction or removal of material should take place using a sterilisable closedsystem, or possibly in an appropriate laminar air where necessary should be properly sterilised before use, preferably bypressurised dry steam. Other methods can be accepted if steam sterilisation cannot be usedbecause of the nature of the equipment. It is important not to overlook such individualitems as bench centrifuges and water used for purification, separation or concentration should be sterilised ordisinfected at least between use for different products. The effect of the sterilisationmethods on the effectiveness and validity of the equipment should be studied in order todetermine the life span of the sterilisation procedures should be should be designed so as to prevent any mix-up between different organisms orproducts. Pipes, valves and filters should be identified as to their incubators should be used for infected and non infected containers and alsogenerally for different organisms or cells. Incubators containing more than one organism orcell type will only be acceptable if adequate steps are taken to seal, surface decontaminateand segregate the containers. Culture vessels, etc. should be individually labelled. Thecleaning and disinfection of the items can be particularly difficult and should receivespecial used for the storage of biological agents or products should be designed andused in such a manner as to prevent any possible mix-up. All stored items should be clearlyand unambiguously labelled and in leak-proof containers. Items such as cells andorganisms seed stock should be stored in dedicated equipment, such as that requiring temperature control, should be fitted withrecording and/or alarm avoid breakdowns, a system of preventive maintenance, together with trend analysis ofrecorded data, should be loading of freeze dryers requires an appropriate clean/contained freeze dryers contaminates the immediate environment. Therefore, for single-ended freeze dryers, the clean room should be decontaminated before a furthermanufacturing batch is introduced into the area, unless this contains the same organisms,and double door freeze dryers should be sterilised after each cycle unless opened in a of freeze dryers should be done in accordance with item 24. In case ofcampaign working, they should at least be sterilised after each
Animals and animal requirements for animal quarters, care and quarantine are laid down in Directive86/609/ houses should be separated from the other production premises and sanitary status of the animals used for production should be defined, monitored, andrecorded. Some animals should be handled as defined in specific monographs (. SpecificPathogens Free flocks)., biological agents, and tests carried out should be the subject of an identificationsystem so as to prevent any risk of confusion and to control all possible – Waste and/or wastes and effluents disposal may be particularly important in the caseof manufacture of immunological products. Careful consideration should therefore be givento procedures and equipment aiming at avoiding environmental contamination as well as totheir validation or of the wide variety of products, the frequently large number of stages involved inthe manufacture of immunological veterinary medicinal products and the nature of thebiological processes, careful attention must be paid to adherence to validated operatingprocedures, to the constant monitoring of production at all stages and to in-process , special consideration should be given to starting materials, media and the useof a seed lot suitability of starting materials should be clearly defined in written should include details of the supplier, the method of manufacture, the geographicalorigin and the animal species from which the materials are derived. The controls to beapplied to starting materials must be included. Microbiological controls are results of tests on starting materials must comply with the specifications. Where thetests take a long time (. eggs from SPF flocks) it may be necessary to process startingmaterials before the results of analytical controls are available. In such cases, the release ofa finished product is conditional upon satisfactory results of the tests on starting attention should be paid to a knowledge of the supplier’s quality assurance systemin assessing the suitability of a source and the extent of quality control testing
possible, heat is the preferred method for sterilising starting materials. If necessary,other validated methods, such as irradiation, may be ability of media to support the desired growth should be properly validated in should preferably be sterilised in situ or in line. Heat is the preferred method. Gases,media, acids, alkalis, defoaming agents and other materials introduced into sterilebiogenerators should themselves be lot and cell bank order to prevent the unwanted drift of properties which might ensue from repeatedsubcultures or multiple generations, the production of immunological veterinary medicinalproducts obtained by microbial, cell or tissue culture, or propagation in embryos andanimals, should be based on a system of seed lots or cell number of generations (doublings, passages) between the seed lot or cell bank and thefinished product should be consistent with the dossier of authorisation for lots and cell banks should be adequately characterised and tested for criteria for new seed lots should be established. Seed lots and cell banks shallbe established, stored and used in such a way as to minimise the risks of contamination, orany alteration. During the establishment of the seed lot and cell bank, no other living orinfectious material (. virus or cell lines) shall be handled simultaneously in the samearea or by the same of the seed lot and cell bank should be performed in a suitable environmentto protect the seed lot and the cell bank and, if applicable, the personnel handling it and theexternal origin, form and storage conditions of seed material should be described in of the stability and recovery of the seeds and cells should be provided. Storagecontainers should be hermetically sealed, clearly labelled and stored at an appropriatetemperature. Storage conditions shall be properly monitored. An inventory should be keptand each container accounted authorised personnel should be allowed to handle the material and this handlingshould be done under the supervision of a responsible person. Different seed lots or cellbanks shall be stored in such a way to avoid confusion or cross-contamination errors. It isdesirable to split the seed lots and cell banks and to store the parts at different locations soas to minimise the risk of total formation of droplets and the production of foam should be avoided or minimisedduring manufacturing processes. Centrifugation and blending procedures which can lead todroplet formation should be carried out in appropriate contained or clean/contained areas toprevent transfer of live
spillages, especially of live organisms, must be dealt with quickly and decontamination measures should be available for each organism. Wheredifferent strains of single bacteria species or very similar viruses are involved, the processneed be validated against only one of them, unless there is reason to believe that they mayvary significantly in their resistance to the agent(s) involving the transfer of materials such as sterile media, cultures or productshould be carried out in pre-sterilised closed systems wherever possible. Where this is notpossible, transfer operations must be protected by laminar airflow work of media or cultures to biogenerators and other vessels should be carried outunder carefully controlled conditions to ensure that contamination is not introduced. Caremust be taken to ensure that vessels are correctly connected when addition of culturestakes necessary, for instance when two or more fermenters are within a single area,sampling and addition ports, and connectors (after connection, before the flow of product,and again before disconnection) should be sterilised with steam. In other circumstances,chemical disinfection of ports and laminar air flow protection of connections may , glassware, the external surfaces of product containers and other such materialsmust be disinfected before transfer from a contained area using a validated method (see 47above). Batch documentation can be a particular problem. Only the absolute minimumrequired to allow operations to GMP standards should enter and leave the area. Ifobviously contaminated, such as by spills or aerosols, or if the organism involved is anexotic, the paperwork must be adequately disinfected through an equipment pass, or theinformation transferred out by such means as photocopy or or solid wastes such as the debris after harvesting eggs, disposable culture bottles,unwanted cultures or biological agents, are best sterilised or disinfected before transferfrom a contained area. However, alternatives such as sealed containers or piping may beappropriate in some and materials, including documentation, entering a production room should becarefully controlled to ensure that only articles and materials concerned with productionare introduced. There should be a system which ensures that articles and materialsentering a room are reconciled with those leaving so that their accumulation within theroom does not stable articles and materials entering a clean area or clean/contained area should doso through a double-ended autoclave or oven. Heat labile articles and materials shouldenter through an air-lock with interlocked doors where they are disinfected. Sterilisation ofarticles and materials elsewhere is acceptable provided that they are double wrapped andenter through an airlock with the appropriate must be taken to avoid contamination or confusion during incubation. Thereshould be a cleaning and disinfection procedure for incubators. Containers in incubatorsshould be carefully and clearly the exception of blending and subsequent filling operations (or when totally enclosedsystems are used) only one live biological agent may be handled within a production roomat any given time. Production rooms must be effectively disinfected between the handling ofdifferent live biological
should be inactivated by the addition of inactivant accompanied by sufficientagitation. The mixture should then be transferred to a second sterile vessel, unless thecontainer is of such a size and shape as to be easily inverted and shaken so as to wet allinternal surfaces with the final culture/inactivant containing inactivated products should not be opened or sampled in areascontaining live biological agents. All subsequent processing of inactivated products shouldtake place in clean areas grade A-B or enclosed equipment dedicated to consideration should be given to the validation of methods for sterilisation,disinfection, virus removal and should be carried out as soon as possible following production. Containers of bulkproduct prior to filling should be sealed, appropriately labelled and stored under specifiedconditions of should be a system to assure the integrity and closure of containers after capping of vials containing live biological agents must be performed in such a way thatensures that contamination of other products or escape of the live agents into other areas orthe external environment does not various reasons there may be a delay between the filling of final containers and theirlabelling and packaging. Procedures should be specified for the storage of unlabelledcontainers in order to prevent confusion and to ensure satisfactory storage attention should be paid to the storage of heat labile or photosensitive temperatures should be each stage of production, the yield of product should be reconciled with that expectedfrom that process. Any significant discrepancies should be -process controls play a specially important role in ensuring the consistency of the qualityof biological medicinal products. Those controls which are crucial for the quality (. virusremoval) but which cannot be carried out on the finished product, should be performed atan appropriate stage of may be necessary to retain samples of intermediate products in sufficient amount andunder appropriate storage conditions to allow repetition or confirmation of a batch may be a requirement for the continuous monitoring of data during a productionprocess, for example monitoring of physical parameters during culture of biological products is a common practice and special considerationneeds to be given to the quality control requirements arising from this type of
ANNEX 6MANUFACTURE OF MEDICINAL GASESPrincipleBecause the manufacture of medicinal gases is a specialised industrial process not normallyundertaken by pharmaceutical companies, manufacturers of these gases are not alwaysfamiliar with the regulatory provisions governing the pharmaceutical industry. Medicinalgases are nevertheless classified as medicinal products, and their manufacture shouldcomply with good manufacturing qualified person responsible for releasing batches should have a thorough knowledge ofthe production and control of medicinal gases including practical experience. All personnelshould know the GMP relevant to medicinal gases and should be aware of the criticallyimportant aspects and potential hazards for patients from medicinal products in the form and manufacture of medicinal gases is generally carried out in closed , environmental contamination of the product is minimal. However, there is arisk of cross-contamination with other should provide sufficient space for manufacturing, filling and testing operationsto avoid the risk of mix-up. Premises should be clean and tidy to encourage areas should be of sufficient size and have an orderly layout to provide:a)separate marked areas for different gases and different cylinder sizes;b)clearly identifiable segregation of empty cylinders from full cylinders;c)clear distinction of the stage reached by given cylinders (. "awaiting filling","filled", "awaiting test", "released").The method used to achieve these various levels of segregation will depend on the nature,extent and complexity of the overall operation, but marked-out floor areas, partitions,barriers, labels and signs should be used as is necessary to ensure that the correct gas is put into the correct container. There shouldbe no interconnections between pipelines carrying different gases. The manifolds should beequipped with fill connections that correspond only to the valve for that particular gas ormixture of gases so that the wrong containers cannot be attached to the manifold. (The useof manifold and container valve connections may be subject to national or internationalrules.)95
and maintenance operations should not present any hazard to the quality of themedicinal gases should be filled in a separate area from non medicinal gases and thereshould be no exchange of cylinders between these may be acceptable to fill non medicinal and medicinal gases cylinders (concurrently) onthe same line but in different areas, provided that the gas used for non medicinal purposesis at least equal to the quality of the medicinal gas, and the cylinders have been prepared inaccordance with specific requirements referred to in this supplementary guide. Thereshould be a non return valve in the line supplying the filling area for non medicinal gases toprevent for medicinal gases should have appropriate technical characteristics. The outletsof cylinders should be equipped with tamper-evident refrigerated medicinal gas may be transported in the same tankers as the samenon medicinal gas provided that the latter is at least equal quality to the medicinal and quality production should be continuously monitored for quality and impurity the transfer operations of liquefied refrigerated medicinal gases from primary storageshould be in accordance with a written procedure designed to avoid any of gas may be added to bulk storage tanks containing the same gas from previousdeliveries. In this case, either:—a sample must be tested and found acceptable before the delivery is added; or—when the finished product is a single gas the sample may be taken either from themixed delivery in the bulk storage tank or from the first cylinder filled, provided thatthe filling line has been purged after the new shipment has been added to the bulktank;—when the finished product is a mixture of gases, each component should be medicinal gases manifold should be dedicated to a single gas or to a given mixture and purging of filling equipment and pipelines should follow written procedures,and checks for the absence of cleaning agents or other contaminants should be carried outbefore the line is released for cylinders and cylinders returned to use after any pressure test should be subject to aninternal visual to be performed before filling should include:—visual external inspection of each valve and container for dents, arc burns, otherdamage and oil or grease;—a check of each cylinder or cryogenic vessel valve connection to determine that it isthe proper type for the particular medicinal gas involved;96
—a check to determine that the hydrostatic test has been conducted as required. Eachcylinder should be coded to show the date of the last hydrostatic test;—a check to determine that each container is colour-coded and which have been returned for refilling should be prepared as follows: any gasremaining in the cylinders should be removed by blowing down each container, followed bya purge (partial pressurisation then blowing down) or evacuation of the container [at least25 inches of mercury – . absolute pressure below 150 mbar]. As an alternative, fullanalysis of the remaining gas should be carried out for each individual should also be given to inversion of the container while blowing down toassist with the removal of any liquid should be appropriate checks to ensure that containers have been the case of a single medicinal gas filled via a multi-cylinder manifold, at least onecylinder of product from each manifold filling should be tested for identity and purity eachtime the cylinders are changed on the the case of a single medicinal gas put into cylinders one at a time by individual fillingoperations, at least one cylinder of each uninterrupted filling cycle should be tested foridentity and assay. An example of an uninterrupted filling operation cycle is one shift’sproduction using the same personnel, equipment, and batch of bulk the case of a finished product gas produced by mixing two different gases in a cylinder,every cylinder should be tested for the identity and assay of one of the gases, and at leastone cylinder from each manifold filling should be tested for identity of the other gas in the case of a finished medicinal gas produced by mixing three different gases in acylinder, every cylinder should be tested for the identity and assay of two of the gases andat least one cylinder from each manifold filling should be tested for the identity of the thirdgas in the gases are mixed in-line before filling (. nitrous oxide/oxygen mixture) continuousanalysis of the mixture being filled is a cylinder is filled with more than one gas, the filling process must ensure that thegases are correctly mixed in every cylinder and are fully filled cylinder should be tested for leaks using an appropriate method, such as a leakdetection solution applied to the valve the case of cryogenic liquefied gas filled into cryogenic vessels for delivery to users, eachvessel should be tested for identity and vessels which are retained by customers and refilled in place from mobiledelivery tanks need not be sampled after filling provided the filling company delivers acertificate of analysis for a sample taken from their samples are not required, unless otherwise
cylinder should be labelled and colour-coded. The batch number may be on a – filling, all cylinders should be held in quarantine until released by the cylinders should be stored under cover and not be subjected to extremes oftemperature. Storage areas should be clean, dry, well ventilated and free of arrangements should permit segregation of different gases and of full/emptycylinders and permit rotation of
ANNEX 7MANUFACTURE OF HERBAL MEDICINAL PRODUCTSPrincipleBecause of their often complex and variable nature, and the number and small quantity ofdefined active ingredients, control of starting materials, storage and processing assumeparticular importance in the manufacture of herbal medicinal (. unprocessed) plants should be stored in separate areas. The storage area shouldbe well ventilated and be equipped in such a way as to give protection against the entry ofinsects or other animals, especially rodents. Effective measures should be taken to preventthe spread of any such animals and micro-organisms brought in with the crude plant and toprevent cross-contamination. Containers should be located in such a way as to allow freeair attention should be paid to the cleanliness and good maintenance of the storageareas particularly when dust is of plants, extracts, tinctures and other preparations may require special conditionsof humidity, temperature or light protection; these conditions should be provided provisions should be taken during sampling, weighing, mixing and processingoperations of crude plants whenever dust is generated, to facilitate cleaning and to avoidcross-contamination, as for example, dust extraction, dedicated premises, for starting from the data described in General Guide (chapter 4, point ), specifications formedicinal crude plants should include, as far as possible:—the botanical name (with, if appropriate, the name of the originator of theclassification, . Linnaeus);—the details of the source of the plant (country or region of origin, and whereapplicable, cultivation, time of harvesting, collection procedures, possible pesticidesused, etc.);99
—whether the whole plant or only a part is used;—when a dried plant is purchased, the drying system should be specified;—the description of the plant and its macro and microscopical examination;—the suitable identification tests including, where appropriate, identification tests forknown active ingredients, or markers. A reference authentic specimen should beavailable for identification purposes;—the assay, where appropriate, of constituents of known therapeutic activity or ofmarkers;—the methods suitable to determine possible pesticide contamination and limitsaccepted;—the tests to determine fungal and/or microbial contamination, including aflatoxinsand pest-infestations, and limits accepted;—the tests for toxic metals and for likely contaminants and adulterants;—the tests for foreign treatment used to reduce fungal/microbial contamination or other infestation should bedocumented. Specifications for such procedures should be available and should includedetails of process, tests and limits for processing instructions should describe the different operations carried out upon thecrude plant such as drying, crushing and sifting, and include drying time andtemperatures, and methods used to control fragment or particle size. It should also describesecurity sieving or other methods of removing foreign the production of a vegetable drug preparation, instructions should include details ofbase or solvent, time and temperatures of extraction, details of any concentration stagesand methods used (see also the note for guidance “Quality of herbal remedies”, Volume IIIof “The rules governing medicinal products in the European Union”). to the fact that crude drugs are an aggregate of individual plants and contain anelement of heterogeneity, their sampling has to be carried out with special care bypersonnel with particular expertise. Each batch should be identified by its Control personnel should have particular expertise in herbal medicinal products inorder to be able to carry out identification tests and recognise adulteration, the presence offungal growth, infestations, non-uniformity within a delivery of crude plants,
identity and quality of vegetable drug preparations and of finished product should betested as described in the note for guidance “Quality of herbal remedies”.101
ANNEX 8SAMPLING OF STARTING AND PACKAGING MATERIALSPrincipleSampling is an important operation in which only a small fraction of a batch is taken. Validconclusions on the whole cannot be based on tests which have been carried out on non-representative samples. Correct sampling is thus an essential part of a system of is dealt with in Chapter 6 of the Guide, items . to . This annex givesadditional guidance on the sampling of starting and packaging who take samples should receive initial and on-going regular training in thedisciplines relevant to correct sampling. This training should include:—sampling plans,—written sampling procedures,—the techniques and equipment for sampling,—the risks of cross-contamination,—the precautions to be taken with regard to unstable and/or sterile substances,—the importance of considering the visual appearance of materials, containers andlabels,—the importance of recording any unexpected or unusual identity of a complete batch of starting materials can normally only be ensured ifindividual samples are taken from all the containers and an identity test performed on eachsample. It is permissible to sample only a proportion of the containers where a validatedprocedure has been established to ensure that no single container of starting material hasbeen incorrectly validation should take account of at least the following aspects:—the nature and status of the manufacturer and of the supplier and theirunderstanding of the GMP requirements of the Pharmaceutical Industry;—the Quality Assurance system of the manufacturer of the starting material;103
—the manufacturing conditions under which the starting material is produced andcontrolled;—the nature of the starting material and the medicinal products in which it will such a system, it is possible that a validated procedure exempting identity testing ofeach incoming container of starting material could be accepted for:—starting materials coming from a single product manufacturer or plant;—starting materials coming directly from a manufacturer or in the manufacturer’ssealed container where there is a history of reliability and regular audits of themanufacturer’s Quality Assurance system are conducted by the purchaser (themanufacturer of the medicinal product) or by an officially accredited is improbable that a procedure could be satisfactorily validated for:—starting materials supplied by intermediaries such as brokers where the source ofmanufacture is unknown or not audited;—starting materials for use in parenteral quality of a batch of starting materials may be assessed by taking and testing arepresentative sample. The samples taken for identity testing could be used for thispurpose. The number of samples taken for the preparation of a representative sampleshould be determined statistically and specified in a sampling plan. The number ofindividual samples which may be blended to form a composite sample should also bedefined, taking into account the nature of the material, knowledge of the supplier and thehomogeneity of the composite sampling plan for packaging materials should take account of at least the following:the quantity received, the quality required, the nature of the material (. primarypackaging materials and/or printed packaging materials), the production methods, andwhat is known of the Quality Assurance system of the packaging materials manufacturerbased on audits. The number of samples taken should be determined statistically andspecified in a sampling
ANNEX 9MANUFACTURE OF LIQUIDS, CREAMS AND OINTMENTSPrincipleLiquids, creams and ointments may be particularly susceptible to microbial and othercontamination during manufacture. Therefore special measures must be taken to preventany and use of closed systems for processing and transfer is recommended in order to protectthe product from contamination. Production areas where the products or open cleancontainers are exposed should normally be effectively ventilated with filtered , containers, pipework and pumps should be designed and installed so that they maybe readily cleaned and if necessary sanitised. In particular, equipment design shouldinclude a minimum of dead-legs or sites where residues can accumulate and promotemicrobial use of glass apparatus should be avoided wherever possible. High quality stainlesssteel is often the material of choice for parts coming into contact with chemical and microbiological quality of water used in production should be specifiedand monitored. Care should be taken in the maintenance of water systems in order to avoidthe risk of microbial proliferation. After any chemical sanitisation of the water systems, avalidated flushing procedure should be followed to ensure that the sanitising agent hasbeen effectively quality of materials received in bulk tankers should be checked before they aretransferred to bulk storage should be taken when transferring materials via pipelines to ensure that they aredelivered to their correct likely to shed fibres or other contaminants, like cardboard or wooden pallets,should not enter the areas where products or clean containers are should be taken to maintain the homogeneity of mixtures, suspensions, etc. duringfilling. Mixing and filling processes should be validated. Special care should be taken at thebeginning of a filling process, after stoppages and at the end of the process to ensure thathomogeneity is the finished product is not immediately packaged, the maximum period of storageand the storage conditions should be specified and adhered
ANNEX 10MANUFACTURE OF PRESSURISED METERED DOSEAEROSOL PREPARATIONS FOR INHALATIONPrincipleThe manufacture of pressurised aerosol products for inhalation with metering valvesrequires special consideration because of the particular nature of this form of product. Itshould be done under conditions which minimise microbial and particulate of the quality of the valve components and, in the case of suspensions, ofuniformity is also of particular are presently two common manufacturing and filling methods as follows:-shot system (pressure filling). The active ingredient is suspended in a highboiling point propellant, the dose is put into the container, the valve is crimped onand the lower boiling point propellant is injected through the valve stem to make upthe finished product. The suspension of active ingredient in propellant is kept cool toreduce evaporation -shot process (cold filling). The active ingredient is suspended in a mixture ofpropellants and held either under high pressure or at a low temperature, or suspension is then filled directly into the container in one and and filling should be carried out as far as possible in a closed products or clean components are exposed, the area should be fed with filtered air,should comply with the requirements of at least a Grade D environment and should beentered through and quality valves for aerosols are more complex pieces of engineering than most items usedin pharmaceutical production. Their specifications, sampling and testing should recognisethis. Auditing the Quality Assurance system of the valve manufacturer is of fluids (. liquid or gaseous propellants) should be filtered to remove particles greaterthan micron. An additional filtration where possible immediately before filling
and valves should be cleaned using a validated procedure appropriate to the useof the product to ensure the absence of any contaminants such as fabrication aids () or undue microbiological contaminants. After cleaning, valves should be kept inclean, closed containers and precautions taken not to introduce contamination duringsubsequent handling, . taking samples. Containers should be fed to the filling line in aclean condition or cleaned on line immediately before should be taken to ensure uniformity of suspensions at the point of fillthroughout the filling a two-shot filling process is used, it is necessary to ensure that both shots are of thecorrect weight in order to achieve the correct composition. For this purpose, 100% weightchecking at each stage is often after filling should ensure the absence of undue leakage. Any leakage test shouldbe performed in a way which avoids microbial contamination or residual
ANNEX 11COMPUTERISED SYSTEMSPrincipleThe introduction of computerised systems into systems of manufacturing, includingstorage, distribution and quality control does not alter the need to observe the relevantprinciples given elsewhere in the Guide. Where a computerised system replaces a manualoperation, there should be no resultant decrease in product quality or quality should be given to the risk of losing aspects of the previous system whichcould result from reducing the involvement of is essential that there is the closest co-operation between key personnel and thoseinvolved with computer systems. Persons in responsible positions should have theappropriate training for the management and use of systems within their field ofresponsibility which utilises computers. This should include ensuring that appropriateexpertise is available and used to provide advice on aspects of design, validation,installation and operation of computerised extent of validation necessary will depend on a number of factors including the use towhich the system is to be put, whether the validation is to be prospective or retrospectiveand whether or not novel elements are incorporated. Validation should be considered aspart of the complete life cycle of a computer system. This cycle includes the stages ofplanning, specification, programming, testing, commissioning, documentation, operation,monitoring and should be paid to the siting of equipment in suitable conditions where extraneousfactors cannot interfere with the written detailed description of the system should be produced (including diagrams asappropriate) and kept up to date. It should describe the principles, objectives, securitymeasures and scope of the system and the main features of the way in which the computeris used and how it interacts with other systems and software is a critical component of a computerised system. The user of such softwareshould take all reasonable steps to ensure that it has been produced in accordance with asystem of Quality
system should include, where appropriate, built-in checks of the correct entry andprocessing of a system using a computer is brought into use, it should be thoroughly tested andconfirmed as being capable of achieving the desired results. If a manual system is beingreplaced, the two should be run in parallel for a time, as a part of this testing should only be entered or amended by persons authorised to do so. Suitable methodsof deterring unauthorised entry of data include the use of keys, pass cards, personal codesand restricted access to computer terminals. There should be a defined procedure for theissue, cancellation, and alteration of authorisation to enter and amend data, including thechanging of personal passwords. Consideration should be given to systems allowing forrecording of attempts to access by unauthorised critical data are being entered manually (for example the weight and batch numberof an ingredient during dispensing), there should be an additional check on the accuracy ofthe record which is made. This check may be done by a second operator or by validatedelectronic system should record the identity of operators entering or confirming critical to amend entered data should be restricted to nominated persons. Any alterationto an entry of critical data should be authorised and recorded with the reason for thechange. Consideration should be given to building into the system the creation of acomplete record of all entries and amendments (an "audit trail"). to a system or to a computer program should only be made in accordance with adefined procedure which should include provision for validating, checking, approving andimplementing the change. Such an alteration should only be implemented with theagreement of the person responsible for the part of the system concerned, and thealteration should be recorded. Every significant modification should be quality auditing purposes, it should be possible to obtain clear printed copies ofelectronically stored should be secured by physical or electronic means against wilful or accidentaldamage, in accordance with item of the Guide. Stored data should be checked foraccessibility, durability and accuracy. If changes are proposed to the computer equipmentor its programs, the above mentioned checks should be performed at a frequencyappropriate to the storage medium being should be protected by backing-up at regular intervals. Back-up data should be storedas long as necessary at a separate and secure should be available adequate alternative arrangements for systems which need to beoperated in the event of a breakdown. The time required to bring the alternativearrangements into use should be related to the possible urgency of the need to use example, information required to effect a recall must be available at short procedures to be followed if the system fails or breaks down should be defined andvalidated. Any failures and remedial action taken should be procedure should be established to record and analyse errors and to enable correctiveaction to be
outside agencies are used to provide a computer service, there should be a formalagreement including a clear statement of the responsibilities of that outside agency (seeChapter 7). the release of batches for sale or supply is carried out using a computerised system,the system should allow for only a Qualified Person to release the batches and it shouldclearly identify and record the person releasing the
ANNEX 12USE OF IONISING RADIATION IN THE MANUFACTURE OFMEDICINAL PRODUCTSNoteThe holder of, or applicant for, a marketing authorisation for a product which includesirradiation as part of its processing should also refer to the note produced by the Committeefor Proprietary Medicinal Products giving guidance on “Ionising radiation in themanufacture of medicinal products”.IntroductionIonising radiation may be used during the manufacturing process for various purposesincluding the reduction of bioburden and the sterilisation of starting materials, packagingcomponents or products and the treatment of blood are two types of irradiation process: Gamma Irradiation from a radioactive sourceand high energy Electron Irradiation (Beta radiation) from an Irradiation: two different processing modes may be employed:(i)Batch mode: the product is arranged at fixed locations around the radiation sourceand cannot be loaded or unloaded while the radiation source is exposed.(ii)Continuous mode: an automatic system conveys the products into the radiation cell,past the exposed radiation source along a defined path and at an appropriate speed,and out of the Irradiation: the product is conveyed past a continuous or pulsed beam of highenergy electrons (Beta radiation) which is scanned back and forth across the by irradiation may be carried out by the pharmaceutical manufacturer or by anoperator of a radiation facility under contract (a “contract manufacturer”), both of whommust hold an appropriate manufacturing pharmaceutical manufacturer bears responsibility for the quality of the productincluding the attainment of the objective of irradiation. The contract operator of theradiation facility bears responsibility for ensuring that the dose of radiation required by themanufacturer is delivered to the irradiation container (. the outermost container in whichthe products are irradiated). required dose including justified limits will be stated in the marketing authorisationfor the
is defined as the measurement of the absorbed dose by the use of understanding and correct use of the technique is essential for the validation,commissioning and control of the calibration of each batch of routine dosimeters should be traceable to a national orinternational standard. The period of validity of the calibration should be stated, justifiedand adhered same instrument should normally be used to establish the calibration curve of theroutine dosimeters and to measure the change in their absorbance after irradiation. If adifferent instrument is used, the absolute absorbance of each instrument should on the type of dosimeter used, due account should be taken of possible causes ofinaccuracy including the change in moisture content, change in temperature, time elapsedbetween irradiation and measurement, and the dose wavelength of the instrument used to measure the change in absorbance of dosimetersand the instrument used to measure their thickness should be subject to regular checks ofcalibration at intervals established on the basis of stability, purpose and of the is the action of proving that the process, . the delivery of the intendedabsorbed dose to the product, will achieve the expected results. The requirements forvalidation are given more fully in the note for guidance on “the use of ionising radiation inthe manufacture of medicinal products”. should include dose mapping to establish the distribution of absorbed dosewithin the irradiation container when packed with product in a defined irradiation process specification should include at least the following: of the packaging of the product; loading pattern(s) of product within the irradiation container. Particular careneeds to be taken, when a mixture of products is allowed in the irradiation container,that there is no underdosing of dense product or shadowing of other products bydense product. Each mixed product arrangement must be specified and validated; loading pattern of irradiation containers around the source (batch mode) or thepathway through the cell (continuous mode); and minimum limits of absorbed dose to the product [and associatedroutine dosimetry]; and minimum limits of absorbed dose to the irradiation container andassociated routine dosimetry to monitor this absorbed dose; process parameters, including dose rate, maximum time of exposure, number ofexposures, irradiation is supplied under contract at least parts (d) and (e) of the irradiationprocess specification should form part of that
Commissioning of the is the exercise of obtaining and documenting evidence that the irradiationplant will perform consistently within predetermined limits when operated according to theprocess specification. In the context of this annex, predetermined limits are the maximumand minimum doses designed to be absorbed by the irradiation container. It must not bepossible for variations to occur in the operation of the plant which give a dose to thecontainer outside these limits without the knowledge of the should include the following elements:a)Design;b)Dose mapping;c)Documentation;d)Requirement for absorbed dose received by a particular part of an irradiation container at any specificpoint in the irradiator depends primarily on the following factors:a)the activity and geometry of the source;b)the distance from source to container;c)The duration of irradiation controlled by the timer setting or conveyor speed;d)The composition and density of material, including other products, between thesource and the particular part of the total absorbed dose will in addition depend on the path of containers through acontinuous irradiator or the loading pattern in a batch irradiator, and on the number ofexposure a continuous irradiator with a fixed path or a batch irradiator with a fixed loadingpattern, and with a given source strength and type of product, the key plant parametercontrolled by the operator is conveyor speed or timer the dose mapping procedure, the irradiator should be filled with irradiation containerspacked with dummy products or a representative product of uniform density. Dosimetersshould be placed throughout a minimum of three loaded irradiation containers which arepassed through the irradiator, surrounded by similar containers or dummy products. If theproduct is not uniformly packed, dosimeters should be placed in a larger number positioning of dosimeters will depend on the size of the irradiation container. Forexample, for containers up to 1 x 1 x m, a three-dimensional 20 cm grid throughout thecontainer including the outside surfaces might be suitable. If the expected positions of theminimum and maximum dose are known from a previous irradiator performance115
characterisation, some dosimeters could be removed from regions of average dose andreplaced to form a 10 cm grid in the regions of extreme results of this procedure will give minimum and maximum absorbed doses in theproduct and on the container surface for a given set of plant parameters, product densityand loading , reference dosimeters should be used for the dose mapping exercise because of theirgreater precision. Routine dosimeters are permissible but it is advisable to place referencedosimeters beside them at the expected positions of minimum and maximum dose and atthe routine monitoring position in each of the replicate irradiation containers. The observedvalues of dose will have an associated random uncertainty which can be estimated from thevariations in replicate minimum observed dose, as measured by the routine dosimeters, necessary to ensurethat all irradiation containers receive the minimum required dose will be set in theknowledge of the random variability of the routine dosimeters parameters should be kept constant, monitored and recorded during dosemapping. The records, together with the dosimetry results and all other records generated,should be beam absorbed dose received by a particular portion of an irradiated product dependsprimarily on the following factors:a)the characteristics of the beam, which are: electron energy, average beam current,scan width and scan uniformity;b)the conveyor speed;c)the product composition and density;d)the composition, density and thickness of material between the output window andthe particular portion of product;e)the output window to container parameters controlled by the operator are the characteristics of the beam and theconveyor the dose mapping procedure, dosimeters should be placed between layers ofhomogeneous absorber sheets making up a dummy product, or between layers ofrepresentative products of uniform density, such that at least ten measurements can bemade within the maximum range of the electrons. Reference should also be made tosections 18 to parameters should be kept constant, monitored and recorded during dosemapping. The records, together with the dosimetry results and all other records generated,should be
should be repeated if there is a change to the process or the irradiatorwhich could affect the dose distribution to the irradiation container (. change of sourcepencils). The extent to re-commissioning depends on the extent of the change in theirradiator or the load that has taken place. If in doubt, should be designed and operated to segregate irradiated from non-irradiatedcontainers to avoid their cross-contamination. Where materials are handled within closedirradiation containers, it may not be necessary to segregate pharmaceutical from non-pharmaceutical materials, provided there is no risk of the former being contaminated bythe possibility of contamination of the products by radionuclide from the source must containers should be packed in accordance with the specified loading pattern(s)established during the process, the radiation dose to the irradiation containers should be monitoredusing validated dosimetry procedures. The relationship between this dose and the doseabsorbed by the product inside the container must have been established during processvalidation and plant indicators should be used as an aid to differentiating irradiated from non-irradiated containers. They should not be used as the sole means of differentiation or as anindication of satisfactory of mixed loads of containers within the irradiation cell should only be done whenit is known from commissioning trials or other evidence that the radiation dose received byindividual containers remains within the limits the required radiation dose is by design given during more than one exposure orpassage through the plant, this should be with the agreement of the holder of themarketing authorisation and occur within a predetermined time period. Unplannedinterruptions during irradiation should be notified to the holder of the marketingauthorisation if this extends the irradiation process beyond a previously agreed -irradiated products must be segregated from irradiated products at all times. Methodsof doing this include the use of radiation indicators (31.) and appropriate design of premises(28.).Gamma continuous processing modes, dosimeters should be placed so that at least two areexposed in the irradiation at all
batch modes, at least two dosimeters should be exposed in positions related to theminimum dose continuous process modes, there should be a positive indication of the correct position ofthe source and an interlock between source position and conveyor movement. Conveyorspeed should be monitored continuously and batch process modes source movement and exposure times for each batch should bemonitored and a given desired dose, the timer setting or conveyor speed requires adjustment for sourcedecay and source additions. The period of validity of the setting or speed should be recordedand adhered Beam dosimeter should be placed on every should be continuous recording of average beam current, electron energy, scan-widthand conveyor speed. These variables, other than conveyor speed, need to be controlledwithin the defined limits established during commissioning since they are liable toinstantaneous numbers of containers received, irradiated and dispatched should be reconciled witheach other and with the associated documentation. Any discrepancy should be reported irradiation plant operator should certify in writing the range of doses received by eachirradiated container within a batch or and control records for each irradiation batch should be checked and signed by anominated responsible person and retained. The method and place of retention should beagreed between the plant operator and the holder of the marketing documentation associated with the validation and commissioning of the plant shouldbe retained for one year after the expiry date or at least five years after the release of thelast product processed by the plant, whichever is the monitoring is the responsibility of the pharmaceutical manufacturer. It mayinclude environmental monitoring where product is manufactured and pre-irradiationmonitoring of the product as specified in the marketing
ANNEX 13MANUFACTURE OF INVESTIGATIONAL MEDICINALPRODUCTSIntroductionMedicinal products intended for research and development trials are not at present subjecteither to marketing or manufacturing Community , when adopting Directive 91/356/EEC on GMP for medicinal products for humanuse, it was agreed to include a “whereas” stating that Member States may requirecompliance with the principles of GMP during the manufacture of products intended for usein clinical trials. It was also suggested in a EC Discussion Paper (III/3044/91) in January1991 that it is illogical for experimental products not to be subject to the controls whichwould apply to the formulations of which they are the prototypes and most of the commentsreceived from interested parties were in line with this it was agreed to prepare this annex to the Community Guide to GoodManufacturing Practice so that both those Member States instituting controls voluntarilyand manufacturers of investigational products would have a reference point to enablecommon standards to evolve in all Member Commission is currently preparing a draft directive on clinical trials and this firstrevision of the annex will be reviewed when veterinary investigational medicinal products should also be prepared underappropriate GMP conditions, most aspects of this annex derive from human GCP and arethus specific to investigational medicinal products for human principles and many of the detailed guidelines of Good Manufacturing Practice forMedicinal Products (Volume IV of the series “The rules governing medicinal products in theEuropean Union”) as well as some other guidelines published by the European Commission(. validation of virus inactivation/removal) are relevant to the preparation of products foruse in clinical annex specifically addresses those practices which may be different for investigationalproducts, which are usually not manufactured under a set routine, and with possiblyincomplete characterisation of the product at initial stages of clinical development. It alsoincludes guidance on ordering, shipping, and returning clinical supplies, which is at theinterface with the Guideline on Good Clinical Practice (revised 1 January 1997).119
GlossaryBLINDINGA procedure in which one or more parties to the trial are kept unaware of the treatmentassignment(s). Single-blinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, dataanalyst(s) being unaware of the treatment assignment(s).CLINICAL TRIALAny investigation in human subjects intended to discover or verify the clinical,pharmacological and/or other pharmacodynamic effects of an investigational product(s)and/or to identify any adverse reactions to an investigational product(s), and /or to studyabsorption, distribution, metabolism, and excretion of an investigational product(s) withthe object of ascertaining its safety and/or PRODUCTAn investigational or marketed product (., active control), or placebo, used as a referencein clinical MEDICINAL PRODUCTA pharmaceutical form of an active ingredient or placebo being tested or used as a referencein a clinical trial, including a product with a marketing authorisation when used orassembled (formulated or packaged) in a way different from the approved form, or whenused for an unapproved indication, or when used to gain further information about anapproved person responsible for the conduct of the clinical trial at a trial site. If a trial is conductedby a team of individuals at a trial site, the investigator is the responsible leader of the teamand may be called the principal to process, package and/or ship a certain number of units of Specification FileReference file containing all the information necessary to draft the detailed writteninstructions on processing, packaging, quality control testing, batch release and operation of packaging for shipment, and sending of ordered medicinal products forclinical
SPONSORAn individual, company, institution or organisation which takes responsibility for theinitiation, management and/or financing of a clinical of the production processes of investigational medicinal products which have nomarketing authorisation may not be validated to the extent necessary for a routineproduction. For sterile products, the validation of sterilising processes should be of thesame standard as for products authorised for marketing. The product specifications andmanufacturing instructions may vary during development. This increased complexity inmanufacturing operations requires a highly effective system of Quality Quality Assurance System, designed, set up and verified by the manufacturer, shouldbe described in written procedures maintained by the sponsor, taking into account the GMPprinciples applied to investigational medicinal and labelling operations are often performed after the release of the bulkproduct and in accordance with specific requirements of different trials. These operationsare of paramount importance for the integrity of clinical trials. In this respect, selfinspection or independent audits, as referred to in the Community Guideline on GoodClinical Practice and in . of the Guide to GMP are an integral part of the QualityAssurance it is likely that the number of staff involved will be small, there should beseparate people responsible for production and quality control. All production operationsshould be carried out under control of a clearly identified responsible person. Personnelinvolved in release of investigational medicinal products should be appropriately trained inquality systems, GMP and regulatory requirements specific to these types of products. Theymust be independent of the staff responsible for and manufacture of investigational medicinal products, it may be that differentproducts are handled in the same premises and at the same time, and this reinforces theneed to minimise all risks of contamination, including cross-contamination and product mixup, by using appropriate the production of the particular products referred to in paragraph of the Guide toGMP, campaign working may be acceptable in place of dedicated and self-containedfacilities. Because the toxicity of the materials may not be fully known, cleaning is ofparticular importance; account should be taken of the solubility of the product and ofexcipients in various cleaning
of aseptic processes presents special problems when the batch size is small; inthese cases the number of units filled may be the maximum number filled in and sealing is often a hand operation presenting great challenges to sterility soenhanced attention should be given to environmental (for starting materials, primary packaging materials, intermediate and bulkproducts and finished products), manufacturing formulae and processing and packaginginstructions may be changed as development of the product progresses. Each new versionshould take into account the latest data, current technology used and the regulatory andpharmacopoeial requirements, and should refer to the previous version to allow traceabilityto the previous document. Rationales for changes should be may not be necessary to produce Master Formula and Processing Instructions, but forevery manufacturing operation or supply there should be clear and adequate writteninstructions and written records. Records are particularly important for the preparation ofthe final version of the documents to be used in routine manufacturing records should be retained for at least two years after completion ofthe clinical trial or at least 2 years after formal discontinuation or in conformance with theapplicable regulatory requirement(s). order may request the processing and/or packaging of a certain number or units and/ortheir shipping. It may only be given by the sponsor to the manufacturer of aninvestigational medicinal product. It should be in writing (though it may be transmitted byelectronic means), and precise enough to avoid any ambiguity. It should be formallyauthorised and it should refer to the approved Product Specification Specification the information necessary to draft the detailed written instructions on processing,packaging, quality control testing, batch release, storage conditions and/or shipping shouldbe referenced in a Product Specification File. This Product Specification File should becontinually updated, ensuring appropriate traceability to the previous Formulae and Processing changes should be carried out according to a written procedure which should addressany implications for stability and bioequivalence. Changes should be authorised by aresponsible person and be clearly
Packaging and labelling of investigational medicinal products are likely to be more complexand more liable to errors (which are also harder to detect) than of marketed products when“blinded” labels are used. Supervision procedures such as label reconciliation, lineclearance, etc. and the independent checks by quality control staff should accordingly medicinal products must be packed in an individual way for each patientincluded in the clinical trial. Packaging instructions are based on the order. Contrary towhat happens with large-scale manufacturing of licensed medicinal products, batches ofinvestigational medicinal products may be subdivided into different packaging batches andpackaged in several operations over a period of number of units to package should be specified prior to the start of the packagingoperations, considering also the number of units necessary for carrying out quality controlsand the number of samples to be kept. A reconciliation should take place at the end of thepackaging and labelling should include:a)name of the sponsor;b)pharmaceutical dosage form, route of administration, quantity of dosage units (andname/identifier of the product and strength/potency in case of open trial);c)the batch and/or code number to identify the contents and packaging operation;d)the trial subject identification number, where applicable;e)directions for use;f)“for clinical trial use only”;g)the name of the investigator (if not included as a code in the trial reference code);h)a trial reference code allowing identification of the trial site and investigator;i)the storage conditions;j)the period of use (use-by date, expiry date or re-test date as applicable), inmonth/year);k)“keep out of reach of children” except when the product is for use only in hospital;The outer packaging may include symbols or pictograms to clarify certain information,mentioned above and the request “return empty packaging and unused products”.Additional information for example any warnings and handling instructions, whereapplicable may be displayed according to the order. A copy of each type of label should bekept in the batch the immediate packaging when the outer packaging carries the particulars mentionedin paragraph 17, a-k, the particulars mentioned in paragraph 17, a-f, shall be
the outer packaging carries the particulars mentioned in paragraph 18, a-k and theimmediate packaging takes the form of blister packs or small immediate packaging unitssuch as ampoules on which the particulars mentioned in paragraph 17, a-f can not bedisplayed, the particulars mentioned in paragraph 17, a, c and d as well as route ofadministration in case of ampoules, shall at least appear on the immediate case of use date extension, an additional label should be affixed to the investigationalmedicinal product. This additional label should include the new use date and repeat thebatch number. It may be superposed on the old use date, but, for quality control reasons,not on the original batch number. This operation may be performed on site by the clinicaltrial monitor(s) or the clinical trial site pharmacist, in accordance with specific andstandard operating procedures and under contract if applicable. The operation should bechecked by a second person. Documented evidence of this additional labelling should beavailable in the trial documentation and in the batch and packaging batch and packaging batch records should be kept in sufficient detail for thesequence of operations to be accurately traced back. These records should contain anyrelevant remarks which enhance existing knowledge of the product and allowimprovements of the manufacturing operations and justify the procedures consistency of production may be influenced by quality of the starting materials. Theirphysical and chemical properties should therefore be defined, documented in theirspecifications and controlled. Specifications for active starting materials should be ascomprehensive as possible, given the current state of knowledge. Specifications for bothactive and non-active starting materials (excipients) should be periodically re-assessedduring development and updated as information on the quality of active and non-active starting materials should beavailable in order to recognise and, as necessary, allow for variation of the the development phase, validated procedures may not always be available, whichmakes it difficult to know in advance the critical parameters and the in-process controlsthat would help to control these parameters. In these cases, provisional productionparameters and in-process controls may usually be deduced from experience withanalogues. Careful consideration by key personnel is called for in order to formulate thenecessary instructions and to adapt them continually to the experience gained is an essential part of the control of the manufacturing operations. Actualand theoretical yields should be reconciled and any abnormal discrepancy
applicable virus inactivation/removal and/or other impurities of biological originshould be no less than for products authorised for marketing. Cleaning procedures shouldbe very stringent and designed in the light of the incomplete knowledge of the toxicity ofthe investigational product. Where processes such as mixing have not been validated,additional quality control testing may be applicable to comparator studies whereby an investigational medicinal product is compared with a marketedproduct, attention should be paid to ensure the integrity and quality of the comparatorproduct (final dosage form, packaging materials, storage conditions, etc.). If significantchanges are to be made to the product, data should be available (. stability, comparativedissolution, bioavailability) to prove that these changes do not significantly alter theoriginal quality characteristics of the the expiry date stated on the original package has been determined for themedicinal product in that particular package and may not be applicable to the productwhere it has been repackaged in a different container, it is the responsibility of the sponsor,taking into account the nature of the product, the characteristics of the container and thestorage conditions to which the article may be subjected, to determine a suitable use-bydate to be placed on the label. Such date is not later than the expiry date of the originalpackage. In the absence of stability data or if stability is not followed during the clinicaltrial such date should not exceed 25% of the remaining time between the date ofrepackaging and the expiry date on the original manufacturer’s bulk container or a sixmonth period from the date the drug is repackaged, whichever is should describe the generation, distribution, handling and retention of anyrandomisation code used for packaging investigational system should be implemented to allow for a proper identification of the ‘blinded’products. The system, together with the randomisation code and randomisation list mustallow proper identification of the product, including any necessary traceability to the codesand batch number of the product before the blinding of blinded investigational medicinal products should be processes may not be standardised or fully validated, end product testing takes on moreimportance to ensure that each batch meets its control should especially pay attention to the compliance with specifications whichbear on the efficacy of medicinal products, namely:—accuracy of the therapeutic or unitary dose: homogeneity, content uniformity;—release of active substances: solubility, dissolution time,
—estimation of stability, if necessary in accelerated and stress conditions,determination of the preliminary storage conditions and shelf-life of the necessary, Quality Control should also verify the similarity in appearance, smell andtaste of “blinded” medicinal of each batch of product should be retained under the responsibility of either themanufacturer or of the importer which released the batch for use in the EEA. They shouldbe kept in the primary container used for the study or in a suitable bulk container for atleast one year beyond the final shelf-life or two years after completion of the clinical trialwhichever is the longest. If the sample is not stored in the pack used for the study, stabilitydata should be available to justify the shelf-life in the pack of release is often carried out in two stages, before and after final packaging:—bulk product assessment: it should cover all relevant factors, including productionconditions, results of in-process testing, a review of manufacturing documentationand compliance with the Product Specification File and the Order;—finished product assessment: it should cover, in addition to the bulk productassessment, all relevant factors, including packaging conditions, results of in-processtesting, a review of packaging documentation and compliance with the ProductSpecification File and the investigational products are released (“technical green light”) by appropriatelyqualified staff, subsequent analysis after shipping to other Member States is not justifiedas long as documented evidence is available that appropriate control analysis and productrelease have taken place in the Manufacture and Contract contract must clearly state, among other provisions, that the medicinal products are tobe used in clinical trials. Co-operation between the contracting parties should be very conclusions of any investigation carried out in relation to a complaint should bediscussed between the manufacturer and the sponsor (if different) or between theresponsible person of the manufacturer and those responsible for the relevant clinical trialin order to assess any potential impact on the trial and on the product
Recalls and for retrieving investigational medicinal products and documenting this retrieval(. for defective products recall, returns after trial completion, expired product return)should be in place. They should be understood by the sponsor, investigator and monitor inaddition to the person(s) responsible for – Returns – , return and destruction of unused products should be carried out according towritten of investigational products is conducted according to orders given by the sponsorin the shipping medicinal products are sent to an investigator only after a two step releaseprocedure: the release of the product after quality control (‘technical green light’) and theauthorisation to use the product, given by the sponsor (‘regulatory green light’). Bothreleases should be recorded and packaging must ensure that the medicinal product remains in good condition duringtransport and storage at intermediate destinations. Any opening or tampering of the outerpackaging during transport should be readily sponsor should ensure that the shipment is to be received in the required conditionsand acknowledged by the right detailed inventory of the shipments made by the manufacturer should be maintained. Itshould particularly mention the addressees’ of investigational medicinal products from one trial site to another should remainthe exception and only be allowed in case of very expensive product, limited quantityavailable for clinical trials or in case of emergency. Such transfers should be covered bystandard operating procedures which differentiate between the storage location of theproduct to be transferred (from warehouse under control of the sponsor, from the pharmacyof a trial site, or from the investigator). Should the transferred product have been stored bythe investigator, not at the pharmacy, sufficient precautions and controls have to beconsidered prior to use at an other trial site. In most cases, the product will need to bereturned to the sponsor for re-labelling and full finished product specification retesting toensure that it is still suitable for its intended use and new medicinal products should be returned on agreed conditions defined by thesponsor, specified in written procedures, and approved by authorized staff investigational medicinal products should be clearly identified and stored in adedicated area. Inventory records of the returned medicinal products should be
Sponsor is responsible for the destruction of unused investigational medicinal medicinal products should therefore not be destroyed by the manufacturerwithout prior written authorisation by the of destruction operations should be carried out in such a manner that alloperations may be accounted for. The records should be kept by the Sponsor. Thisdestruction should be done only after the finalisation of the clinical trial and thecompilation of the final the manufacturer is requested to destroy the products, he should deliver a certificate ofdestruction or a receipt for destruction to the Sponsor. These documents should clearlyidentify the batches and/or patient numbers involved and the actual quantities
ANNEX 14MANUFACTURE OF PRODUCTS DERIVED FROM HUMANBLOOD OR HUMAN PLASMAPrincipleMedicinal products derived from human blood or plasma have certain special featuresarising from the biological nature of the source material. For example, disease-transmittingagents, especially viruses, may contaminate the source material. The prevention of thetransmission of viruses by these products relies therefore on the control of source materialsand their origin as well as on the subsequent manufacturing procedures, including virusremoval and inactivation. Since the quality of the final products is affected by all the stepsin their manufacture, including the collection of blood or plasma, the collection of blood orplasma intended for the manufacture of derivatives should be considered as part of themanufacturing process and it should therefore be done in accordance with an appropriatesystem of Quality Assurance and the current Good Manufacturing general chapters of the guide to GMP apply to products derived from human blood orplasma, unless otherwise stated. Some of the annexes may also apply, . manufacture ofsterile medicinal products, use of ionising radiation in the manufacture of medicinalproducts and the annex on biological medicinal virtue of Directive 89/381/EEC, the measures necessary to prevent the transmission ofinfectious diseases shall comprise those currently recommended by the Council of Europe(see “Guide to the preparation, use and quality assurance of blood components”, Council ofEurope Press, ISBN 92-871-1808-4) and by the World Health Organisation (see thirty-ninthreport of the WHO Expert Committee on Biological Standardisation, WHO TechnicalReport Series 786, 1989).This annex should also be read in conjunction with the guidelines adopted by the CPMP, inparticular “Medicinal products derived from human blood and plasma” and “Validation ofvirus removal and inactivation procedures” (Vol III addendum 2 of the series “The rulesgoverning medicinal products in the European Union”).As several provisions of this annex apply equally to plasma, to products derived fromplasma, to cellular components and to whole blood, an additional paragraph relating tocellular components and whole blood only has been added for the convenience of thosecompetent authorities wishing to control these components. It should however be noted thatthese components are presently not included in the scope of EC pharmaceutical manufacture of medicinal products derived from placental blood, which aremanufactured and used in some Member States, is not the subject of this annex. There aretherefore no special provisions in this annex for the manufacture of these medicinalproducts; nevertheless, all the relevant provisions of the guide to GMP apply to theirmanufacture129
Quality Assurance should cover all aspects of manufacture, starting with the donor, bloodbags, anticoagulant solutions and including collection, storage, transportation, processing,1quality control and delivery of the finished product (). blood or plasma collected in centres subject to inspection and approved by a competentauthority should be testing of qualitative and quantitative requirements mentioned in the specificationsfor starting materials is not normally performed on intermediate fractions of bloodproducts. Control reports issued by the producer of the intermediate material, includingplasma, will suffice, provided that the producer is a manufacturer authorised in accordancewith Community legislation, is regularly inspected and there is a history of reliability of the controls carried out on the accepted donors should be part of the qualitydocumentation of the collecting centre and should be available to the manufacturerPremises and collection may be done on a campaign basis, . in a room used at the timeexclusively for that purpose, or in dedicated facilities. Dedicated facilities should be used forblood and plasma processing, but are not required for packaging order to prevent cross-contamination, premises and equipment used for manufacturingoperations using products which have undergone a process of virus removal or inactivationshould be dedicated and distinct from those used for non-treated method used to disinfect the skin of the donor should be clearly defined and shown tobe effective. Adherence to that method should then be identity of each donor should be recorded during selection and confirmed beforevenepuncture. A third identification, preferably by a signature check, will be necessaryduring manual apheresis, where components are being returned after attention should be given to the correct labelling and identification (code number) ofdonor should be a system in place which enables the path taken by each donation to betraced, both forward from the donor [and the blood bag] and back from the finished product,including the identification of the customer (hospital or health care professional). It isnormally the responsibility of this customer to identify the recipient. 1()It should be noted that, although desirable, the normal organisational chart of a manufacturing plant, with a full-time Head of Production Department, a Head of the Quality Control Department and the Qualified Person, asdescribed in the Chapter 2 of the Guide, is not necessarily applicable for blood collection and plasmapheresis
-collection measures: A standard operating procedure describing the mutualinformation system between the blood collection centre and the manufacturing orfractionation centre should be set up so that they can inform each other if—it is found subsequent to donation that the donor did not meet the current donorhealth criteria;—it is discovered that testing for viral markers has not been carried out according toagreed procedures;—the donor seroconverts or develops an infectious disease as a result of a transmissibleagent (HBV, HCV and other non-A, non-B, non-C hepatitis viruses, HIV 1 and 2 andother viruses, in the light of current knowledge);—the recipient develops post transfusion infection which implicates or can be tracedback to the these cases, a re-assessment of the batch documentation and re-control of finishedproducts should always be carried out. The need for withdrawal of the given batch shouldbe carefully considered, taking into consideration criteria such as the disease, the type ofseroconversions, the size of the pool, the time period between donation and seroconversion,and the nature of the product and its manufacturing and quality specified storage temperatures of blood, plasma and intermediate products duringtransportation from collection centres to manufacturers or between differentmanufacturing sites should be checked and validated. The same applies to delivery of any blood and plasma donations, or any product derived therefrom, are released forissue and/or fractionation, they should be tested and found non reactive for the followingmarkers of specific disease-transmitting agents:—HBsAg, using a validated and sensitive ELISA or RIA test;—antibodies to HIV 1 and HIV 2;—antibodies to HCV;1—syphilis antibodies ().Testing requirements for other viruses should be considered in the light of knowledgeemerging as to infectious agents and the availability of appropriate test manufacturing operations may place the product at risk and consideration should begiven to the following factors:—bacteria may be introduced by inappropriate handling or from a contaminatedenvironment and may lead to the accumulation of pyrogens;—viruses may be introduced by reagents during manufacture (enzymes from tissuesextracts, such as pepsin or thrombin, or monoclonal antibodies used for affinitychromatography); 1()This test is not required in Denmark131
—the methods of manufacture may introduce chemical contaminants such as enzymes,pepsin, solvents, detergents and antibodies or other ligands from efficacy of cleaning procedures and sterile docking should be regularly controlled labels on single units of plasma stored before pooling and fractionation should bear atleast the identification number of the donation, the name and address of the plasmacollection centre, the batch number of the container, the storage temperature, the totalvolume or weight of the plasma, the quantity and type of the anticoagulant used and thedate of collection and/or order to minimise the microbiological contamination of plasma or the introduction offoreign material, the pooling and thawing of plasma should be performed at least in a gradeD clean area and face masks and gloves should be worn. Methods used for opening bags,pooling and thawing should be regularly which have undergone a process of virus removal or inactivation should be clearlydifferentiated from those which have of methods used for virus removal or virus inactivation should not be conductedin the production facilities in order not to put the routine manufacture at any risk ofcontamination with the viruses used for proceduresa)Precipitation methods: cryoprecipitation is often used as the initial step for the production ofFactor VIII and fibrinogen. It has no impact on the viral safety of such purification techniques, such as precipitation by agents other than ethanol orchromatographic separation as well as procedures for viral inactivation are used to obtainthe finished products. Cryoprecipitate-depleted plasma can be used for the separation ofother coagulation factors or plasma protein methods: among these methods, the ethanol fractionation proceduresderived from the Cohn method are the most widely used, at least for albumin andimmunoglobulins. They commonly incorporate several steps, in each of which compliancewith specific requirements is decisive for product quality; under proper conditions, some ofthese steps may also contribute to the effective reduction of potential viral , there should be clear instructions for ethanol and protein concentration, withdata on acceptable tolerances as well as the means of controlling instructions should also exist for methods relying on other chemical agentssuch as ethylacridinlactate, methanol, ammonium sulphate, polyethylene glycol, cationicdetergents, which are sometimes used in the preparation of certain plasma derivatives, as arule in combination with other purification procedures. Some of these substances may havean impact on viral
b)Solid phase separation and filtration basic types of procedures play an increasing role in the processing of plasmaderivatives, as a rule in combination with precipitation procedures and often with eachother:—gel filtration, mainly used for desalination or separation of components ofsignificantly different sizes;—ion exchange and hydrophobic interaction chromatography;—affinity chromatography based on specific interactions with immunological or otherreceptors immobilised on the selectivity of these procedures and the yields depend critically on the quality of thematerial as well as on factors such as the capacity of the column, the nature andconcentration of proteins in the product, the ionic strength and pH of buffers, as well as theflow rate and temperature. Therefore, all appropriate data, including acceptable tolerancesshould be described in specifications and the control data should be recorded in the other compounds such as charcoal, bentonite, and colloidal silica are sometimesused for removing various impurities such as pigments, lipoproteins, etc. Details of thecharacteristics of these compounds and their decontamination should be described in theirspecifications and the operating conditions should be detailed in for the storing of columns, the preservation and elution of preservatives and themethods of regeneration should also be given in procedures. Procedures used forclarification and sterile, dia- or ultra- filtration should also be of of each pool of plasma should be stored under suitable conditions for at least oneyear after the expiry date of the finished product with the longest products and whole monitoring should be carried out in such a way that major deviations of qualityspecifications are visual inspection for the absence of haemolysis and aggregation should be carried outbefore red cells products or whole blood are issued. Platelet concentrates should be checkedfor the swirling , platelets and whole blood which have been returned unused should normally not bere-issued (see point f the guide).133
GLOSSARY
GLOSSARYDefinitions given below apply to the words as used in this guide. They may have differentmeanings in other -LOCKAn enclosed space with two or more doors, and which is interposed between two or morerooms, . of differing class of cleanliness, for the purpose of controlling the air-flowbetween those rooms when they need to be entered. An air-lock is designed for and used byeither people or (OR LOT)A defined quantity of starting material, packaging material or product processed in oneprocess or series of processes so that it could be expected to be complete certain stages of manufacture, it may be necessary to divide a batchinto a number of sub batches, which are later brought together to form a finalhomogeneous batch. In the case of continuous manufacture, the batch mustcorrespond to a defined fraction of the production, characterised by its control of the finished product, the following definition has been given in Directive75/318/EEC: ‘For the control of the finished product, a batch of a proprietary medicinalproduct comprises all the units of a pharmaceutical form which are made from the sameinitial mass of material and have undergone a single series of manufacturing operations ora single sterilisation operation or, in the case of a continuous production process, all theunits manufactured in a given period of time’.BATCH NUMBER (OR LOT NUMBER)A distinctive combination of numbers and/or letters which specifically identifies a contained system, such as a fermenter, into which biological agents are introduced alongwith other materials so as to effect their multiplication or their production of othersubstances by reaction with the other materials. Biogenerators are generally fitted withdevices for regulation, control, connection, material addition and material AGENTSMicro-organisms, including genetically engineered micro-organisms, cell cultures andendoparasites, whether pathogenic or
BULK PRODUCTAny product which has completed all processing stages up to, but not including, set of operations which establish, under specified conditions, the relationship betweenvalues indicated by a measuring instrument or measuring system, or values represented bya material measure, and the corresponding known values of a reference BANKCell bank system: A cell bank system is a system whereby successive batches of a productare manufactured by culture in cells derived from the same master cell bank. A number ofcontainers from the master cell bank are used to prepare a working cell bank. The cell banksystem is validated for a passage level or number of population doublings beyond thatachieved during routine cell bank: A culture of [fully characterised] cells distributed into containers in asingle operation, processed together in such a manner as to ensure uniformity and stored insuch a manner as to ensure stability. A master cell bank is usually stored at - 70°C cell bank: A culture of cells derived from the master cell bank and intended for usein the preparation of production cell cultures. The working cell bank is usually stored at - 70°C or CULTUREThe result from the in-vitro growth of cells isolated from multicellular AREAAn area with defined environmental control of particulate and microbial contamination,constructed and used in such a way as to reduce the introduction, generation and retentionof contaminants within the different degrees of environmental control are defined in the SupplementaryGuidelines for the Manufacture of sterile medicinal AREAAn area constructed and operated in such a manner that will achieve the aims of both aclean area and a contained area at the same action of confining a biological agent or other entity within a defined containment: A system of containment which prevents the escape of a biologicalagent into the immediate working environment. It involves the use of closed containers orsafety biological cabinets along with secure operating
Secondary containment: A system of containment which prevents the escape of a biologicalagent into the external environment or into other working areas. It involves the use ofrooms with specially designed air handling, the existence of airlocks and/or sterilisers forthe exit of materials and secure operating procedures. In many cases it may add to theeffectiveness of primary AREAAn area constructed and operated in such a manner (and equipped with appropriate airhandling and filtration) so as to prevent contamination of the external environment bybiological agents from within the AREAAn area constructed and operated in such a manner that some attempt is made to controlthe introduction of potential contamination (an air supply approximating to grade D may beappropriate), and the consequences of accidental release of living organisms. The level ofcontrol exercised should reflect the nature of the organism employed in the process. At aminimum, the area should be maintained at a pressure negative to the immediate externalenvironment and allow for the efficient removal of small quantities of SYSTEMA system including the input of data, electronic processing and the output of information tobe used either for reporting or automatic CONTAMINATIONContamination of a material or of a product with another material or PLANT (VEGETABLE DRUG)Fresh or dried medicinal plant or parts VESSELA container designed to contain liquified gas at extremely low container designed to contain gas at a high ORGANISMA biological agent where either the corresponding disease does not exist in a given countryor geographical area, or where the disease is the subject of prophylactic measures or aneradication programme undertaken in the given country or geographical
FINISHED PRODUCTA medicinal product which has undergone all stages of production, including packaging inits final MEDICINAL PRODUCTMedicinal product containing, as active ingredients, exclusively plant material and/orvegetable drug with extraneous biological agents and therefore capable of -PROCESS CONTROLChecks performed during production in order to monitor and if necessary to adjust theprocess to ensure that the product conforms its specification. The control of theenvironment or equipment may also be regarded as a part of in-process PRODUCTPartly processed material which must undergo further manufacturing steps before itbecomes a bulk GASESThose which, at the normal filling temperature and pressure, remain as a liquid in or apparatus designed to enable one or more gas containers to be filledsimultaneously from the same operations of purchase of materials and products, Production, Quality Control, release,storage, distribution of medicinal products and the related of a Manufacturing Authorisation as described in Article 16 of Directive75/319/ PLANTPlant the whole or part of which is used for medicinal
MEDICINAL PRODUCTAny substance or combination of substances presented for treating or preventing disease inhuman beings or substance or combination of substances which may be administered to human beingsor animals with a view to making a medical diagnosis or to restoring, correcting ormodifying physiological functions in human beings or in animals is likewise considered amedicinal operations, including filling and labelling, which a bulk product has to undergo in orderto become a finished filling would not normally be regarded as part of packaging, the bulkproduct being the filled, but not finally packaged, primary MATERIALAny material employed in the packaging of a medicinal product, excluding any outerpackaging used for transportation or shipment. Packaging materials are referred to asprimary or secondary according to whether or not they are intended to be in direct contactwith the of the operations to be carried out, the precautions to be taken and measures tobe applied directly or indirectly related to the manufacture of a medicinal operations involved in the preparation of a medicinal product, from receipt of materials,through processing and packaging, to its completion as a finished of proving that any equipment works correctly and actually leads to the expectedresults. The word validation is sometimes widened to incorporate the concept CONTROLSee Chapter status of starting or packaging materials, intermediate, bulk or finished productsisolated physically or by other effective means whilst awaiting a decision on their release
RADIOPHARMACEUTICAL“Radiopharmaceutical” shall mean any medicinal product which, when ready for use,contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose(Directive 89/343/EEC extending the scope of Directives 65/65/EEC and 75/319/EEC toradiopharmaceuticals and laying down additional comparison, making due allowance for normal variation, between the amount of productor materials theoretically and actually produced or Chapter introduction of all or part of previous batches of the required quality into another batchat a defined stage of reworking of all or part of a batch of product of an unacceptable quality from a definedstage of production so that its quality may be rendered acceptable by one or more back to the manufacturer or distributor of a medicinal product which may or maynot present a quality LOTSeed lot system: A seed lot system is a system according to which successive batches of aproduct are derived from the same master seed lot at a given passage level. For routineproduction, a working seed lot is prepared from the master seed lot. The final product isderived from the working seed lot and has not undergone more passages from the masterseed lot than the vaccine shown in clinical studies to be satisfactory with respect to safetyand efficacy. The origin and the passage history of the master seed lot and the working seedlot are seed lot: A culture of a micro-organism distributed from a single bulk into containersin a single operation in such a manner as to ensure uniformity, to prevent contaminationand to ensure stability. A master seed lot in liquid form is usually stored at or below - 70° freeze-dried master seed lot is stored at a temperature known to ensure seed lot: A culture of a micro-organism derived from the master seed lot andintended for use in production. Working seed lots are distributed into containers and storedas described above for master seed
SPECIFICATIONSee Chapter MATERIALAny substance used in the production of a medicinal product, but excluding is the absence of living organisms. The conditions of the sterility test are given inthe European used in the sense of a regulated pattern of interacting activities and techniques whichare united to form an organised of proving, in accordance with the principles of Good Manufacturing Practice, thatany procedure, process, equipment, material, activity or system actually leads to theexpected results (see also qualification).143
