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1、 EUROPEAN COMMISSION ENTERPRISE AND INDUSTRY DIRECTORATE-GENERAL Consumer goods Pharmaceuticals Brussels, 25 October 2005 EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Part I
2、 Chapter 1 Quality Management Document History Revision to include new Chapter on Product Quality Review October 2005 Date of revised version coming into operation, indicating that a first Product Quality Review will be expected in 2006 for a minimum review period of at least 6 months. Subsequent re
3、ports should cover a full 12 months period. 01 January 2006 Commission europenne, B-1049 Bruxelles / Europese Commissie, B-1049 Brussel - Belgium. Telephone: (32-2) 299 11 11 Table of Contents Principle Quality Assurance Good Manufacturing Practice for medicinal products (GMP) Quality Control Produc
4、t Quality Review _ Principle The holder of a Manufacturing Authorisation must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorisation and do not place patients at risk due to inadequate safety, quality or ef
5、ficacy. 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. To achieve the quality objective i
6、n a reliable manner there must be a comprehensively designed and correctly implemented system of Quality Assurance incorporating Good Manufacturing Practice and thus Quality Control. It should be fully documented and its effectiveness monitored. All parts of the Quality Assurance system should be ad
7、equately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the Manufacturing Authorisation and for the Qualified Person(s). 1.1 The basic concepts of Quality Assurance, Good Manufacturing
8、Practice and Quality Control are inter-related. They are described here in order to emphasise their relationships and their fundamental importance to the production and control of medicinal products. Quality Assurance 1.2 Quality Assurance is a wide ranging concept which covers all matters which ind
9、ividually or collectively influence the quality of a product. It is the total sum of the organised arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other
10、 factors outside the scope of this Guide. The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that: (i) medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice and Good Laboratory Pra
11、ctice; (ii) production and control operations are clearly specified and Good Manufacturing Practice adopted; (iii) managerial responsibilities are clearly specified; (iv) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials; (v) all necessary cont
12、rols on intermediate products, and any other in-process controls and validations are carried out; (vi) the finished product is correctly processed and checked, according to the defined procedures; (vii) medicinal products are not sold or supplied before a Qualified Person has certified that each pro
13、duction batch has been produced and controlled in accordance with the requirements of the Marketing Authorisation and any other regulations relevant to the production, control and release of medicinal products; (viii) satisfactory arrangements exist to ensure, as far as possible, that the medicinal
14、products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life; (ix) there is a procedure for Self-Inspection and/or quality audit which regularly appraises the effectiveness and applicability of the Quality Assurance system. Good Manufacturing Pr
15、actice for Medicinal Products (GMP) 1.3 Good Manufacturing Practice is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorisation or product specificatio
16、n. Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that: (i) all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal produc
17、ts of the required quality and complying with their specifications; (ii) critical steps of manufacturing processes and significant changes to the process are validated; (iii) all necessary facilities for GMP are provided including: (iv) appropriately qualified and trained personnel; (v) adequate pre
18、mises and space; (vi) suitable equipment and services; (vii) correct materials, containers and labels; (viii) approved procedures and instructions; (ix) suitable storage and transport; (x) instructions and procedures are written in an instructional form in clear and unambiguous language, specificall
19、y applicable to the facilities provided; (xi) operators are trained to carry out procedures correctly; (xii) records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and
20、that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated; (xiii) records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form; (xiv) th
21、e distribution (wholesaling) of the products minimises any risk to their quality; (xv) a system is available to recall any batch of product, from sale or supply; (xvi) complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respec
22、t of the defective products and to prevent reoccurrence. Quality Control 1.4 Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organisation, documentation and release procedures which ensure that the necessary and r
23、elevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. The basic requirements of Quality Control are that: (i) adequate facilities, trained personnel and approved procedures
24、 are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; (ii) samples of starting materials, packaging materials, intermediate products, bulk
25、 products and finished products are taken by personnel and by methods approved by Quality Control; (iii) test methods are validated; (iv) records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting and testing procedures were actually carr
26、ied out. Any deviations are fully recorded and investigated; (v) the finished products contain active ingredients complying with the qualitative and quantitative composition of the Marketing Authorisation, are of the purity required, and are enclosed within their proper containers and correctly labe
27、lled; (vi) records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from
28、specified procedures; (vii) no batch of product is released for sale or supply prior to certification by a Qualified Person that it is in accordance with the requirements of the Marketing Authorisation; (viii) sufficient reference samples of starting materials and products are retained to permit fut
29、ure examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced. Product Quality Review 1.5. Regular periodic or rolling quality reviews of all licensed medicinal products, including export only products, should be conducte
30、d with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product to highlight any trends and to identify product and process improvements. Such reviews should normally be conducted and documented
31、 annually, taking into account previous reviews, and should include at least: (i) A review of starting materials and packaging materials used for the product, especially those from new sources. (ii) A review of critical in-process controls and finished product results. (iii) A review of all batches
32、that failed to meet established specification(s) and their investigation. (iv) A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventative actions taken. (v) A review of all changes carried out to the proces
33、ses or analytical methods. (vi) A review of Marketing Authorisation variations submitted/granted/refused, including those for third country (export only) dossiers. (vii) A review of the results of the stability monitoring programme and any adverse trends. (viii) A review of all quality-related retur
34、ns, complaints and recalls and the investigations performed at the time. (ix) A review of adequacy of any other previous product process or equipment corrective actions. (x) For new marketing authorisations and variations to marketing authorisations, a review of post-marketing commitments. (xi) The
35、qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc. (xii) A review of Technical Agreements to ensure that they are up to date. The manufacturer and marketing authorisation holder, where different, should evaluate the results of this review and an assess
36、ment should be made whether corrective and preventative action or any revalidation should be undertaken. Reasons for such corrective actions should be documented. Agreed corrective and preventative actions should be completed in a timely and effective manner. There should be management procedures fo
37、r the ongoing management and review of these actions and the effectiveness of these procedures verified during self- inspection. Quality reviews may be grouped by product type, e.g. solid dosage forms, liquid dosage forms, sterile products, etc. where scientifically justified. Where the marketing au
38、thorisation holder is not the manufacturer, there should be a technical agreement in place between the various parties that defines their respective responsibilities in producing the quality review. The Qualified Person responsible for final batch certification together with the marketing authorisat
39、ion holder should ensure that the quality review is performed in a timely manner and is accurate. CHAPTER 2 PERSONNEL Principle The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people. For this reason there
40、must be sufficient qualified personnel to carry out all the tasks which are the responsibility of the manufacturer. Individual responsibilities should be clearly understood by the individuals and recorded. All personnel should be aware of the principles of Good Manufacturing Practice that affect the
41、m and receive initial and continuing training, including hygiene instructions, relevant to their needs. General 2.1 The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be
42、 so extensive as to present any risk to quality. 2.2 The manufacturer must have an organisation chart. People in responsible positions should have specific duties recorded in written job descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designa
43、ted deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice. Key Personnel 2.3 Key Personnel include the head of Production, the head of Quality Control, a
44、nd if at least one of these persons is not responsible for the duties described in Article 51 of Directive 2001/83/EC1, the Qualified Person(s) designated for the purpose. Normally key posts should be occupied by full-time personnel. The heads of Production and Quality Control must be independent fr
45、om each other. In large organisations, it may be necessary to delegate some of the functions listed in 2.5, 2.6 and 2.7. 2.4 The duties of the Qualified Person(s) are fully described in Article 51 of Directive 2001/83/EC, and can be summarised as follows: a) for medicinal products manufactured withi
46、n the European Community, a Qualified Person must ensure that each batch has been produced and tested/checked in accordance with the directives and the marketing authorisation (2); (b) for medicinal products manufactured outside the European Community, a Qualified Person must ensure that each import
47、ed batch has undergone, in the importing country, the testing specified in paragraph 1 (b) of Article 51; 1 Article 55 of Directive 2001/82/EC (2) According to Directive 75/319/EEC (now codified Directive 2001/83/EC) and the Ruling (Case 247/81) of the Court of Justice of the European Commununities,
48、 medicinal products which have been properly controlled in the EU by a Qualified Person do not have to be recontrolled or rechecked in any other Member State of the Community. (c) a Qualified Person must certify in a register or equivalent document, as operations are carried out and before any relea
49、se, that each production batch satisfies the provisions of Article 51. The persons responsible for these duties must meet the qualification requirements laid down in Article 493 of the same Directive, they shall be permanently and continuously at the disposal of the holder of the Manufacturing Authorisation to carry out their responsibilities. Their responsibilities may be delegated, but only to other Qualified Person(s). 2.5 The head of the Production Department generally has
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