MASTER FORMULA (formule-type) – A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a
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Guide to Master Formulae Guidance Document 1 This guidance document GUIDE TO MASTER FORMULAE is one of a series developed by WHO/FWC/IVB Quality, Safety & Standards team upon request from the manufacturers™ members of the Developing Countries Vaccine Manufacturers Network (DCVMN), with funds of USAID. A set of priority topics have been identified by th e manufacturers for WHO to provide guidance on expectations from the vaccine prequalif ication programme. The guidance document GUIDE TO MASTER FORMULAE is targeted primarily at manufacturers who are new to the prequalification o f vaccines and who require detailed guidance about the level of detail needed for the d evelopment of batch production records. It may also be a useful guide to National Regulatory Authorities (NRAs) in vaccine producing countries. These are not official WHO documents but rather not es for guidance on expected standards to be followed for the prequalification o f vaccines. They are based on WHO recommended requirements but providing further expl anations with examples on how these can be actually implemented.
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Guide to Master Formulae Guidance Document 2 GUIDE TO MASTER FORMULAE Table of Contents: Page 1) Introduction 4 2) Terms for Master Formula (MF) 4 3) Definitions of Batch / Lot 5 4) Master Formulae needed 5 5) GMP guidelines on master documentation 5 6) Required Contents of a MF 6 7) MF and corresponding Batch Records 11 8) Formats for MF 11 9) Issuing of MF copy as a blank batch record 1 2 10) Electronic MF and Batch Records 13 11) Batch Records versus Master Formula 14 12) Batch record review checklist 14 Appendix 1: Extract from: World Health Organization , Technical Report Series, No. 908, 2003; Annex 4: Good Manufacturing Practices for pharmaceutical products: main principles. Appendix 2: Extract from: EUDRALEX; Volume 4 – Medi cinal Products for Human and Veterinary Use: Good Manufacturing Practi ce: Chapter 4 Documentation. Appendix 3: Extract from: Pharmaceutical Inspection Convention Co-operation Scheme PE 009-3, 1 January 2006; Guide to Good Manu facturing Practice for Medicinal Products; Documentation. Appendix 4: Extract from Canadian GMP Guidelines, H ealth Canada, Health Products and Food Branch Inspectorate. Good Manufac turing Practices Guidelines, 2002 Edition, Version 2.
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Guide to Master Formulae Guidance Document 3 Appendix 5: Extracts from US Code of Federal Regul ations (CFR) and US FDA Guidelines. App 5-1) US Regulations for Master Production Records for Fi nished Pharmaceuticals. Extract from: CFR 21, Chapter I, Subchapter F: Biologics, Part 21 1 Current Good Manufacturing Practice for Finished Pharmaceuticals; Subpart F–P roduction and Process Controls, Sec. 211.100 Written procedures; deviations; and Su bpart J–Records and Reports; Sec. 211.186 Master production and control records. App 5-2) US Regulations for Batch Records for Finished Phar maceuticals: Extract from: CFR 21, Chapter I, Subchapter F: Biologics; Subchap ter C: Drugs General; Part 211 Current Good Manufacturing Practice for Finished Ph armaceuticals; Subpart J– Records and Reports; Sec. 211.188 Batch production and control records. App 5-3) US Regulations for Batch Records for Biological Pr oducts: Extract from: CFR 21, Chapter I, Subchapter F: Biologics, Part 60 0 Biological Products: General; subpart B Establishment Standards, Sec 600.12 Recor ds App 5-4) US FDA Guidelines for Batch Records for Sterile Pr oducts: Extract from: Guidance for Industry. Sterile Drug Products Produc ed by Aseptic Processing Š Current Good Manufacturing Practice. U.S. Departmen t of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Researc h (CBER); Office of Regulatory Affairs (ORA). September 2004 (Pharmaceu tical cGMPs). Appendix 6: Sample master formula for a hypothetic al biological product Appendix 7: Example one of a Master Formula Appendix 8: Example two of a Master Formula Appendix 9: Example three of a Master Formula
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Guide to Master Formulae Guidance Document 4 1) Introduction In the 1997 WHO guidance document: fiWHO/VSQ/97.01: (A WHO guide to good manufacturing practice (GMP) requirements. Part 1: Standard operating procedures and master formulae)fl some basic explanations and instr uctions were given for preparing various documents required by Good Manufacturing Pr actice guidelines from WHO and from several regulatory authorities. GMP guidelines include the requirements for documen ts (individual), documentation (the systems and formats for documents), and documenting (recording) of production and control activities. Most GMP guidelines provide th e same or very similar information as the principles of Good Manufacturing Practice are n ow international in scope. In this guidance document, the requirement for mast er manufacturing instructions and the requirements as given in different GMP documents, d ifferent names for these documents and various forms that they can take will be descri bed. This is to guide vaccine manufacturers who are applying for prequalification or re-qualification of their product(s) in the preparation or improvement of current docume nts for manufacturing operations. 2) Terms for Master Formula (MF) WHO identifies manufacturing instructions as fiMaste r Formula. Other terms used in GMP guidelines and regulations are fiManufacturing F ormulafl, fiMaster Production and Control Recordfl, but all mean the same thing Œ an approved master document that describes the full process of manufacturing for the batch of product with at least cross- reference to the support operations for a batch of a specific product. Individual companies may give internal names to these document s (manufacturing instructions, monographs, etc). In this guidance document the WHO term Master Formula (or MF) will be used. The following are the extracted definitions from se veral guidelines: · WHO GMP Guidelines: A formally authorized master formula should exist for each product and batch size to be manufactured. · EU and PIC GMP guidelines: fiFormally authorised Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one docume nt.fl · Health Canada GMP guidelines. MASTER FORMULA (formule-type) – A document or set of documents specifying the raw mat erials with their quantities and the packaging materials, together with a detail ed description of the procedures and precautions required to produce a specified qua ntity of a finished product as well as the processing instructions, including the in-process controls. · US CFR. To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size t hereof, shall be prepared, dated, and signed (full signature, handwr itten) by one person and independently checked, dated, and signed by a secon d person. The preparation of
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Guide to Master Formulae Guidance Document 5 master production and control records shall be desc ribed in a written procedure and such written procedure shall be followed. 3) Definitions of Batch / Lot: A Master Formula is required for each batch and bat ch size. A fibatchfl or filotfl as defined in the WHO GMP guideline (TRS 908 Annex 4) isfl fibatch (or lot ) A defined quantity of starting material, packaging material, or product processed in a single process or series of processe s so that it is expected to be homogeneous. It may sometimes be nec essary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch. In the case of terminal sterilization, the batch size is determined by the capacity of the autoclave. In continuous manufacture, the batch must correspon d to a defined fraction of the production, characterized by its in tended homogeneity. The batch size can be defined either as a fixed qua ntity or as the amount produced in a fixed time intervalfl. In general, the term fi batch fl more often refers to intermediates or final formu lated bulks which are in one or a few large containers, while fi lot fl usually refers to the final product in the final container. They are, however, intercha ngeable as indicated in WHO™s GMP guideline glossary. 4) Master Formulae needed: As above, batch or lot will refer to all production intermediates, final formulated bulks and final vialed product. Each master cell bank, v iral seed lot, bulk concentrate or viral harvest if stored and tested before release for fur ther processing is a batch and a master formula for its production is written and approved. Also, for different scales of production of any batch or lot, a distinct master f ormula is prepared. For final container product, as explained in the WH O definition above, a final filotfl will be the product that is filled during the same conti nuous fill-run, and in the case of freeze- dried products, the filled vials lyophilized in the same lyophilizer at the same time. These should have unique numbers to identify them as havi ng been processed exactly the same way at the same time. On occasion, when only a par t of a large final bulk is filled, the lot numbers for these bulks may have a common identifie r with a suffix (fi-1fl or fiafl) to show the separate fills. Similarly, a large fill l ot with a unique lot number may be lyophilized in different lyophilizers and the suffi x would indicate the different freeze- dryer. A master formula for a batch/lot of product with the possibility to select one of several approved equipment items (e.g. a freeze dry er) should clearly indicate this choice and provide space for the unique lot number designa tion.
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Guide to Master Formulae Guidance Document 7 From Table A and B it is clear that the guidelines are harmonized and the requirements are formatted the same way and with the same or ver y similar text. The USA regulations cover the same information but in a different forma t and do not distinguish between production and packaging master formulae.
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Guide to Master Formulae Guidance Document 8 Table A: Contents of Master Formulae WHO TRS 908 Annex 4 section 15.23 EU GMP Guideline (Jan 06) Section 4.14 and 4.15 PICs document PE099 (Jan 06) section 4.14 and 4.15 Health Canada GMP Guideline Version 2 (2002), section 24. The master formula should include The Manufacturing Formula/Processing Instructions should include The Manufacturing Formula/Processing Instructions should include Master Manufacturing Formula: Master formula are written to provide not less than 100% of label claim and include the following name of the product, with a product reference code relating to its specification; the name of the product, with a product reference code relating to its specification; the name of the product, with a product reference code relating to its specification the name of the product, with a reference code relating to its specifications a description of the dosage form, strength of the product and batch size a description of the pharmaceutical form, strength of the product and batch size a description of the pharmaceutical form, strength of the product and batch size a description of the dosage form, strength of the product, and batch size a list of all starting materials to be used (if applicable, with the INNs), with the amount of each, described using the designated name and a reference that is unique to that material (mention should be made of any substance that may disappear in the course of processing); a list of all starting materials to be used, with the amount of each, described using the designated name and a reference which is unique to that material; mention should be made of any substance that may disappear in the course of processing a list of all starting materials to be used, with the amount of each, described using the designated name and a reference which is unique to that material; mention should be made of any substance that may disappear in the course of processing; a list of all raw materials to be used, along with the amount of each, described using the designated name and a reference that is unique to that material (mention is made of any processing aids that may not be present in the final product); a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable; a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable. a statement of the expected final yield, along with the acceptable limits, and of relevant intermediate yields, where applicable a statement of the processing location and the principal equipment to be used; a statement of the processing location and the principal equipment to be used; a statement of the processing location and the principal equipment to be used; a statement of the principal equipment to be used; the methods, or reference to the methods, to be used for preparing and operating the critical equipment, e.g. cleaning (especially after a change in product), assembling, calibrating, sterilizing, use; the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising); the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising); the procedures, or reference to the procedures, to be used for preparing the critical equipment, e.g., cleaning (especially after a change in product), assembling, calibrating, sterilizing, etc. detailed step-wise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures); detailed stepwise processing instructions (e.g. checks on materials, pre-treatments, sequence for adding materials, mixing times, temperatures); detailed stepwise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures); detailed stepwise processing instructions (e.g., checks on materials, pretreatment, sequence for adding materials, mixing times or temperatures, etc.) the instructions for any in- process controls with their limits; the instructions for any in- process controls with their limits; the instructions for any in- process controls with their limits; the instructions for any in- process controls, along with their limits;
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Guide to Master Formulae Guidance Document 9 where necessary, the requirements for storage of the products, including the container, the labelling, and any special storage conditions; where necessary, the requirements for bulk storage of the products; including the container, labelling and special storage conditions where applicable; where necessary, the requirements for bulk storage of the products; including the container, labelling and special storage conditions where applicable; where necessary, the requirements for storage of the products, including the container, the labelling and any special storage conditions; any special precautions to be observed. any special precautions to be observed. any special precautions to be observed. any special precautions to be observed Table B: Contents of Master Packaging Formulae WHO TRS 908 Annex 4 (2003) Section 15.24 EU GMP Guideline (Jan 06) Sections 4.16 PICs document PE099 (Jan 06) Sections 4.16 Health Canada GMP Guideline Version 2 (2002), section 25. Formally authorized packaging instructions should exist for each product, pack size and type. These should normally include, or make reference to: There should be formally authorised Packaging Instructions for each product, pack size and type. These should normally include, or have a reference to, the following There should be formally authorised Packaging Instructions for each product for pack size and type. These should normally include, or have a reference to, the following: In the case of a packaged product, the master formula also includes for each product, package size and type, the following: the name of the product; a) name of the product nam e of the product; a description of its pharmaceutical form, strength and, where applicable, method of application; b) description of its pharmaceutical form, and strength where applicable; description of its pharmaceutical form, and strength where applicable; the pack size expressed in terms of the number, weight or volume of the product in the final container; c) the pack size expressed in terms of the number, weight or volume of the product in the final container; the pack size expressed in terms of the number, weight or volume of the product in the final container; the package size, expressed in terms of the number, weight, or volume of the product in the final container; 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 to the specifications for each packaging material; 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 to the specifications of each packaging material; 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 to the specifications of each packaging material; 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 to the specifications for each packaging material; where appropriate, an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product have been marked; e) where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf life of the product; where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf-life of the product; an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product are to be positioned; special precautions to be observed, including a careful examination of the packaging area and f) special precautions to be observed, including a careful examination of the area and equipment in order special precautions to be observed, including a careful examination of the area and equipment in order special precautions to be observed, including a careful examination of the packaging area and
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Guide to Master Formulae Guidance Document 10 equipment in order to ascertain the line clearance before and after packaging operations; to ascertain the line clearance before operations begin; to ascertain the line clearance before operations begin equipment in order to ascertain the line clearance before operations begin; a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; a description of the packaging operations, including any significant subsidiary operations and the equipment to be used details of in-process controls with instructions for sampling and acceptance limits. h) details of in-process controls with instructions for sampling and acceptance limits details of in-process controls with instructions for sampling and acceptance limits details of in-process controls, with instructions for sampling and acceptance limits. Table C: USA: Master Production and Control Record s USA 21 CFR 211:186 Master production and control records shall include : The name and strength of the product and a descript ion of the dosage form; The name and weight or measure of each active ingre dient per dosage unit or per unit of weight or meas ure of the drug product, and a statement of the total weight or mea sure of any dosage unit; A complete list of components designated by names o r codes sufficiently specific to indicate any speci al quality characteristic; An accurate statement of the weight or measure of e ach component, using the same weight system (metric , avoirdupois, or apothecary) for each component. Reasonable variatio ns may be permitted, however, in the amount of comp onents necessary for the preparation in the dosage form, p rovided they are justified in the master production and control records; A statement concerning any calculated excess of com ponent; A statement of theoretical weight or measure at app ropriate phases of processing; A statement of theoretical yield, including the max imum and minimum percentages of theoretical yield b eyond which investigation according to 211.192 is required; A description of the drug product containers, closu res, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by th e person or persons responsible for approval of suc h labeling; Complete manufacturing and control instructions, sa mpling and testing procedures, specifications, spec ial notations, and precautions to be followed.
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