GMP培训(英文版)(共55张).pptx

Martin L. Jeiven, MS, RPhMartin L. Jeiven, MS, RPhPresidentPresidentJeiven Pharmaceutical Consulting, Inc.Jeiven Pharmaceutical Consulting, Inc.A Comparison of EU and US GMPsA Comparison of EU and US GMPs(Weve much to learn from those “across the pond”)(Weve much to learn from those “across the pond”)Reliable Guidance1The Essential Worldwide Principle of GMPsProduct Quality depends on:nQuality, Safety, and Effectiveness must be designed and built into the product;nQuality cannot be tested into the product; andnEach step in a manufacturing process must be controlled to maximize the probability that the finished product will meet all its quality and design specifications.2Brief GMP History1957: First GMPs issued as a government regulation (by the Canadian Specifications Board for drug supplied to the Canadian military)1963/1978: US FDA GMPs1967: WHO GMPs1968/1973: UK GMPs1984: GMPs in more than 25 countries3US vs. EU GMPs: OverviewIn most aspects, both are similar in content and focus on QualityThere are a number of important differencesThere is considerably more detail in the EU GMPsFDA has been criticized for lack of detail in validation, internal audits, the different roles of QA and QC, etc.4US vs. EU GMPs: Overview (contd)FDAs response to the criticism: the GMPs are minimum requirements, and industrys responsibility is to remain current by incorporating into their procedures information from guidances, inspectional guidelines, Warning Letters, FDA presentations, etc.Most countries within the EU update their GMPs every 1-5 years; the US GMPs are substantially the same as the 1978 Final Rule5The EU GMPs stress:The expectations of Quality Management and the role of the QPThe expectation for, and extensiveness of, validation The need for self-inspection (=internal audits)Training and assessment of competenceThe role of contract manufacture and analysis6EU Countries (2005)AustriaCzech RepPortugalDenmarkHungaryNetherlandsSwedenSloveniaGermany UKCyprusFinlandBelgiumEstoniaFranceItalyLatviaGreeceIrelandMaltaLuxembourgSpainPolandSlovakiaIceland Non EU countryLithuaniaNorway Non EU country7International GMP Lexicon ADRAdverse ReactionCACompetent AuthorityCROContract Research OrganizationCTClinical TrialCTAClinical Trial ApplicationCTDClinical Trial DirectiveCTMClinical Trial MaterialECEuropean CommunityECEthics CommitteeEEAEuropean Economic Area8International GMP Lexicon (contd)EECEuropean Economic CommunityEMEAEuropean Medicines Evaluation AgencyEUEuropean UnionEUDRACT European Clinical Trials DatabaseGCPGood Clinical PracticeGMPGood Manufacturing PracticeHPFBI Health Product and Food Inspection Branch (Canada)ICHInternational Conference of HarmonizationIMPInvestigational Materials Product9International GMP Lexicon (contd)IMPDInvestigational Materials Product DossierMCAMedicines Control AgencyMRAMutual Recognition AgreementMSMember StatePIPharmaceutical InspectoratePICPharmaceutical Inspection ConventionPIC/S Pharmaceutical Inspection Cooperation SchemePSFProduct Specification FileQPQualified PersonWHOWorld Health Organization10International GMPs:GMPs are in effect in 104 countries They may be regulations (as in the US, Japan or Korea), directives (as in the EU), guides (as in the UK), codes (as in Australia), or WHO code (as in many Southeast Asia countries) The intent is the same: strict adherence to consistently assure product quality 11FDA and EU Inspections“FDA inspectors inspect for compliance; EU inspectors inspect for adequate science”. An FDA inspector may spend 80-90% of the time reviewing documentation related to manufacturing and testing, looking for evidence of compliance and the absence of fraud; the EU inspector will spend 80-90% of the time interviewing staff and management, walking the facility to observe manufacturing and testing, and assessing the soundness of the operation.12GMP Inspections in the EU The key document controllingGMP inspections in the EU is theCommission Directive 2003/94/EC (8 October 2003).It represents a proposal by the EU Commission designed to ensure freedom of movement of goods, personnel, finances, and services within the EU. Once approved by the European Parliament, implementation requires that each member state incorporate the directive into its own national legislation within three years of original passage. 13EU GMPs Chapter 1 Quality ManagementPrincipleThe holder of a Manufacturing Authorization must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this Quality objective is the responsibility of Senior Management, and requires the participation and commitment by staff in many different departments and at all levels within the company, by the companys suppliers and by the distributors. 14EU GMPs Chapter 1 Quality Management (contd)Principle (contd)To achieve the Quality objectives reliably, there must be a comprehensively designed and correctly implemented system of QA incorporating GMP and it should be fully documented and its effectiveness monitored. All parts of the QA system should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. 15Quality Management and the Qualified Person (QP) In the US, FDA holds Senior Management directly and personally responsible for compliance to GMPs In Europe, the QP is directly and legally responsible for ensuring that a pharmaceutical product complies with the GMP commitments made by the company in its application to market products (or test clinically). 16Quality Management and the Qualified Person (QP) (contd)QP qualifications include: university degree from a member state, minimum of 4 years theoretical/practical studies in pharmacy, veterinary medicine, chemistry or biology; minimum of 2 years working in the industry, and (in some countries), passage of an examination. 17EU GMPs Chapter 1 Quality Management (contd)Principle (contd)The basic concepts of QA, GMPs and QC are inter-related and fundamental to the production and control of medicinal products.18EU GMPsChapter 2 PersonnelPrincipleThe establishment and maintenance of a satisfactory system of and the correct manufacture of medicinal products relies upon people. There must be sufficient qualified personnel to carry out all the tasks. Individual responsibilities should be clearly understood and recorded. All personnel should be aware of the principles of GMP that affect them, and receive initial and continuing training relevant to their needs.19EU GMPsChapter 3 Premises and Equipment PrinciplePremises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and designmust aim to minimize the risk of errors and permiteffective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products.20EU GMPsChapter 4 - DocumentationPrincipleGood documentation constitutes an essential part of the QA system. Clearly written Documentation prevents errors from spoken communication and permits tracing or batch history. Specifications, manufacturing formulas and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance. 21EU GMPsChapter 5 Production ValidationnValidation studies should reinforce GMPs, and be conducted in accordance with defined procedures. Results and conclusions should be recorded.nWhen any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required Quality. 22EU GMPsChapter 5 Production (contd)Validation (contd)nSignificant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process should be validated.nProcesses and procedures should undergo periodic critical re-validation to ensure that they remain capable of achieving the intended results.23EU GMPs Chapter 6 Quality ControlPrincipleQC is concerned with sampling, specificationsand testing as well as the organization, documentation and release procedures whichensure that the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their Quality has been judged satisfactory. QC is not confined to laboratory operations, but must be involved in all decisions which may concern the quality of the product. The independence of QC from Production is considered fundamental.24EU GMPsChapter 7 Contract Manufacture and AnalysisPrincipleContract manufacture and analysis must be correctly defined, agreed and controlled in order to avoid misunderstandings which could result in a product or work of unsatisfactory quality. There must be a written contract between the Contract Giver and the Contract Acceptor which clearly establishes the duties of each party. The contract must clearly state the way in which the QP releasing each batch of product for sale (or clinical use) exercises his full responsibility.25EU GMPsPrincipleAll complaints and other information concerning potentially defective products must be reviewed carefully according to written procedures. In order to provide for all contingencies, a system should be designed to recall, if necessary, promptly and effectively products known or suspected to be defective from the market (for the clinic).Chapter 8 Complaints and Product Recall26EU GMPsChapter 9 Self Inspection PrincipleSelf inspections should be conducted in order to monitor the implementation and compliance with GMP principles and to propose necessary corrective measures.Personnel matters, premises, equipment, documentation, production, QC, distribution of the medicinal products, arrangements for dealing with complaints and recalls, and self inspections, should be examined at intervals following a pre-arranged programme in order to verify their conformity with the principles of QA.27EU GMPsChapter 9 Self Inspection (contd)Self inspections should be conducted in an independent and detailed way by designated competent person(s) from the company. Independent audits by external experts may also be useful.All self inspections should be recorded. Reports should contain all the observations made during the inspections and, where applicable, proposals for corrective measures. Statements on the actions subsequently taken should also be recorded.28EU GMPsThe “Orange Guide”This publication from the Medicines Control Agency includes the main pharmaceutical Regulations, Directives, and guidances, including the GMPs, which manufacturers and wholesales are expected to follow when manufacturing and distributing medicinal products in the EU. The latest edition is 2002 and includes key annexes, UKs Code of Practice for QPs, and notes on mutual recognition agreements.29Certification by a Qualified Person and Batch Release Annex 16PrincipleEach batch of finished product must be certified by a QP within the EC/EEA or for export.The purpose of controlling the batch release in this way is:To ensure that the batch has been manufactured and checked in accordance with the requirements of its marketing authorization, the principles and guidelines of EC GMP or the GMP of a third country recognized as equivalent under an MRA and any other relevant legal requirement before it is placed on the market30Certification by a Qualified Person and Batch Release Annex 16 (contd)Routine duties of a Qualified PersonBefore certifying a batch prior to release, the QP doing so should ensure, with reference to the guidance above, that at least the following requirements have been met:The batch and its manufacture comply with the provisions of the marketing authorization (including the authorization required for importation where relevant);31Certification by a Qualified Person and Batch Release Annex 16 (contd) Routine duties of a Qualified Person All the necessary checks and tests have been performed, including any additional sampling, inspection, tests or checks initiated because of deviations or planned changes;All necessary production and QC documentation has been completed and endorsed by the staff authorized to do so;All audits have been carried out as required by the QA system;The QP should in addition take into account any other factors of which he is aware which are relevant to the quality of the batch. 32Certification by a Qualified Person and Batch Release Annex 16 (contd)Routine duties of a Qualified Person A QP who confirms the compliance of anintermediate stage of manufacture, has the same obligations as above in relation to that stage unless specified otherwise in the agreement between the QPsA QP should maintain his knowledge andexperience up to date in the light of technical and scientific progress and changes in quality management relevant to the products which he is required to certify.33Certification by a Qualified Person and Batch Release Annex 16 (contd)Routine duties of a Qualified Person If a QP is called upon to certify a batch of a product type with which he is unfamiliar, he should first ensure that he has gained the relevant knowledge and experience necessary to fulfill this duty. 34Certification by a Qualified Person and Batch Release Annex 16 (contd)Routine duties of a Qualified PersonManufacture has been carried out in accordance with GMP or, in the case of a batch imported from a third country, in accordance with GMP standards at least equivalent to EC GMP;The principal manufacturing and testing processes have been validated; with documented production conditions and manufacturing records;Deviations or planned changes in production or QC have been authorized by the responsible person(s). Any changes requiring variation to the marketing or manufacturing authorization have been authorized by the relevant authority35Harmonization of API GMPs FDA and many of the EU member states have routinely conducted inspections of API manufacturers since 1979. Following the death of 87 children in Haiti from contaminated acetaminophen liquid, and realizing that there was a lack of clear GMP regulations and guidelines for API manufacture, ICH enacted an international set of GMPs governing the manufacture, testing, and distribution of APIs: the ICH-Q7A guideline has been adopted as law in the US, EU, Japan, and other countries. 36Self-InspectionThe role of self-inspection is not discussed, or required, in the US GMPs; however this plays a majorrole in the European and WHO GMPs. The European GMPs describe self-inspections in the following way:Self-inspections should be