Guide to Master Formulae Final 2012

Guide to Master Formulae WHO/FWC/IVB/QSS/VQR 2011

Guide to Master Formulae Guidance Document 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 the manufacturers for WHO to provide guidance on expectations from the vaccine prequalification programme. The guidance document GUIDE TO MASTER FORMULAE is targeted primarily at manufacturers who are new to the prequalification of vaccines and who require detailed guidance about the level of detail needed for the development 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 notes for guidance on expected standards to be followed for the prequalification of vaccines. They are based on WHO recommended requirements but providing further explanations with examples on how these can be actually implemented.

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Guide to Master Formulae Guidance Document GUIDE TO MASTER FORMULAE Table of Contents:

Page 1) Introduction

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2) Terms for Master Formula (MF)

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3) Definitions of Batch / Lot

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4) Master Formulae needed

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5) GMP guidelines on master documentation

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6) Required Contents of a MF

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7) MF and corresponding Batch Records

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8) Formats for MF

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9) Issuing of MF copy as a blank batch record

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10) Electronic MF and Batch Records

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11) Batch Records versus Master Formula

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12) Batch record review checklist

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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 - Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice: Chapter 4 Documentation. Appendix 3: Extract from: Pharmaceutical Inspection Convention Co-operation Scheme PE 009-3, 1 January 2006; Guide to Good Manufacturing Practice for Medicinal Products; Documentation. Appendix 4: Extract from Canadian GMP Guidelines, Health Canada, Health Products and Food Branch Inspectorate. Good Manufacturing Practices Guidelines, 2002 Edition, Version 2. 2

Guide to Master Formulae Guidance Document Appendix 5: Extracts from US Code of Federal Regulations (CFR) and US FDA Guidelines. App 5-1) US Regulations for Master Production Records for Finished Pharmaceuticals. Extract from: CFR 21, Chapter I, Subchapter F: Biologics, Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals; Subpart F--Production and Process Controls, Sec. 211.100 Written procedures; deviations; and Subpart J--Records and Reports; Sec. 211.186 Master production and control records. App 5-2) US Regulations for Batch Records for Finished Pharmaceuticals: Extract from: CFR 21, Chapter I, Subchapter F: Biologics; Subchapter C: Drugs General; Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals; Subpart J-Records and Reports; Sec. 211.188 Batch production and control records. App 5-3) US Regulations for Batch Records for Biological Products: Extract from: CFR 21, Chapter I, Subchapter F: Biologics, Part 600 Biological Products: General; subpart B Establishment Standards, Sec 600.12 Records App 5-4) US FDA Guidelines for Batch Records for Sterile Products: Extract from: Guidance for Industry. Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER); Office of Regulatory Affairs (ORA). September 2004 (Pharmaceutical cGMPs). Appendix 6: Sample master formula for a hypothetical 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 1) Introduction In the 1997 WHO guidance document: “WHO/VSQ/97.01: (A WHO guide to good manufacturing practice (GMP) requirements. Part 1: Standard operating procedures and master formulae)” some basic explanations and instructions were given for preparing various documents required by Good Manufacturing Practice guidelines from WHO and from several regulatory authorities. GMP guidelines include the requirements for documents (individual), documentation (the systems and formats for documents), and documenting (recording) of production and control activities. Most GMP guidelines provide the same or very similar information as the principles of Good Manufacturing Practice are now international in scope. In this guidance document, the requirement for master manufacturing instructions and the requirements as given in different GMP documents, different names for these documents and various forms that they can take will be described. 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 documents for manufacturing operations.

2) Terms for Master Formula (MF) WHO identifies manufacturing instructions as “Master Formula. Other terms used in GMP guidelines and regulations are “Manufacturing Formula”, “Master Production and Control Record”, but all mean the same thing – an approved master document that describes the full process of manufacturing for the batch of product with at least crossreference to the support operations for a batch of a specific product. Individual companies may give internal names to these documents (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 several 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: “Formally authorised Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document.” • Health Canada GMP guidelines. MASTER FORMULA (formule-type) - A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a detailed description of the procedures and precautions required to produce a specified quantity 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 thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person. The preparation of 4

Guide to Master Formulae Guidance Document master production and control records shall be described 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 batch size. A “batch” or “lot” as defined in the WHO GMP guideline (TRS 908 Annex 4) is” “batch (or lot) A defined quantity of starting material, packaging material, or product processed in a single process or series of processes so that it is expected to be homogeneous. It may sometimes be necessary 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 correspond to a defined fraction of the production, characterized by its intended homogeneity. The batch size can be defined either as a fixed quantity or as the amount produced in a fixed time interval”. In general, the term “batch” more often refers to intermediates or final formulated bulks which are in one or a few large containers, while “lot” usually refers to the final product in the final container. They are, however, interchangeable 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, viral seed lot, bulk concentrate or viral harvest if stored and tested before release for further 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 formula is prepared. For final container product, as explained in the WHO definition above, a final “lot” will be the product that is filled during the same continuous fill-run, and in the case of freezedried products, the filled vials lyophilized in the same lyophilizer at the same time. These should have unique numbers to identify them as having been processed exactly the same way at the same time. On occasion, when only a part of a large final bulk is filled, the lot numbers for these bulks may have a common identifier with a suffix (“-1” or “a”) to show the separate fills. Similarly, a large fill lot with a unique lot number may be lyophilized in different lyophilizers and the suffix would indicate the different freezedryer. A master formula for a batch/lot of product with the possibility to select one of several approved equipment items (e.g. a freeze dryer) should clearly indicate this choice and provide space for the unique lot number designation.

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Guide to Master Formulae Guidance Document 5) GMP guidelines on master documentation To show the consistency of requirements for Master Formulae, the sections on master documents and batch records have been extracted from various guidelines/regulations. The extracted texts are provided in Appendices 1-5: 1) WHO: World Health Organization Technical Report Series, No. 908, 2003, Annex 4. Good Manufacturing Practices for Pharmaceutical Products: Main Principles 2) EU: EUDRALEX; Volume 4 - Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice: Chapter 4: Documentation. 3) Pharmaceutical Inspection Convention (PIC): Pharmaceutical Inspection Co-operation Scheme PE 009-3, 1 January 2006: Guide to Good Manufacturing Practice for Medicinal Products. (© PIC/S January 2006) 4) Canada: Health Canada, Health Products and Food Branch Inspectorate. Good Manufacturing Practices Guidelines, 2002 Edition (Version 2). 5) USA: US Code of Federal Regulations: Chapter 21, subparts 211 and 600. And US FDA: Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Office of Regulatory Affairs (ORA), September 2004. Pharmaceutical cGMPs. 6) Required Contents of a MF Each of the regulation or guidelines above gives a list of the requirements for the contents of the MF. These are given in Table A for the Master (Production) Formula and Table B for the Master Packaging Formula for WHO, EU, PICs and Health Canada. Table C gives the contents Master Production and Control Records required by the USA.

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Guide to Master Formulae Guidance Document 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 very similar text. The USA regulations cover the same information but in a different format and do not distinguish between production and packaging master formulae.

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Guide to Master Formulae Guidance Document 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

The master formula should include

The Manufacturing Formula/Processing Instructions should include

PICs document PE099 (Jan 06) section 4.14 and 4.15 The Manufacturing Formula/Processing Instructions should include

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; a description of the pharmaceutical form, strength of the product and batch size 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

the name of the product, with a product reference code relating to its specification a description of the pharmaceutical form, strength of the product and batch size 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 statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable a statement of the processing location and the principal equipment to be used; the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising);

a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable. a statement of the processing location and the principal equipment to be used; the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising);

a statement of the expected final yield, along with the acceptable limits, and of relevant intermediate yields, where applicable a statement of the principal equipment to be used;

detailed stepwise processing instructions (e.g. checks on materials, pre-treatments, sequence for adding materials, mixing times, temperatures); the instructions for any inprocess controls with their limits;

detailed stepwise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures); the instructions for any inprocess controls with their limits;

detailed stepwise processing instructions (e.g., checks on materials, pretreatment, sequence for adding materials, mixing times or temperatures, etc.) the instructions for any inprocess controls, along with their limits;

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 statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable; a statement of the processing location and 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; detailed step-wise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures); the instructions for any inprocess controls with their limits;

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Health Canada GMP Guideline Version 2 (2002), section 24. Master Manufacturing Formula: Master formula are written to provide not less than 100% of label claim and include the following 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 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);

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.

Guide to Master Formulae Guidance Document 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

Formally authorized packaging instructions should exist for each product, pack size and type. These should normally include, or make reference to: the name of the product; a description of its pharmaceutical form, strength and, where applicable, method of application;

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 a) name of the product b) description of its pharmaceutical form, and strength where applicable;

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: name of the product; 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;

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;

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; 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;

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; 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;

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

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Health Canada GMP Guideline Version 2 (2002), section 25. In the case of a packaged product, the master formula also includes for each product, package size and type, the following:

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; 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

Guide to Master Formulae Guidance Document 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 Records USA 21 CFR 211:186 Master production and control records shall include: The name and strength of the product and a description of the dosage form; The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product, and a statement of the total weight or measure of any dosage unit; A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic; An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component. Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the master production and control records; A statement concerning any calculated excess of component; A statement of theoretical weight or measure at appropriate phases of processing; A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation according to 211.192 is required; A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling; Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed.

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Guide to Master Formulae Guidance Document 7) MF and corresponding Batch Records Master Formula give the complete production instructions for a specific batch and batch size of cell banks, virus seed lots, intermediates, final bulks, final formulated bulks or final container product that are made in one production run with definite start to finish steps. Blank spaces are provided for the entry of data as the production run progresses. Identification or cross-reference to required supporting data is included in the step-bystep instructions. The batch production record (BPR) is the approved copy of the master document with filled in data entries, signatures, dates, production locations, operators, and lot number, records of all supporting data (autoclave records, cleaning records, equipment identification and calibration dates, in-process test results, and QC results) appended. For cell banks, intermediates and final bulks that are stored for significant periods, the BPR is for that product. Once a final product has been produced, the batch record (BR) is comprised of a single document of the sequential batch records for the starting cell banks or virus seed lots, the intermediates, the final bulks, final formulated bulks and the final container with all the supporting documents. If the product is a pool of several intermediates or final bulks then the full batch record includes the individual batch records of all the components. For combined vaccines, the complete batch record of the final product is the composite of the batch records of the complete batch record of the final bulks of each component, the final formulated bulk and the final product, again including all the supporting data. 8) Formats for MF The generally recommended MF format is to prepare a single continuous document that provides step-by-step production instructions, raw materials, equipment used, locations of production, dates, operators, etc for the product, with blank spaces to record the data and sign and date all entries, and at least cross-references to all supporting SOPs and operations. (See Tables A, B and C above). An example of a Master Formula for a hypothetical biological product was provided in the WHO Guidance document: WHO/VSQ/97.01: A WHO guide to good manufacturing practice (GMP) requirements. Part 1: Standard operating procedures and master formulae, Appendix 6: Sample master formula for a hypothetical biological product. A copy of this is reproduced in Appendix 6 in this document. Many other formats are possible for a MF and will depend on the production process and supporting activities, as well as on the documentation system in place at the manufacturing company. Appendix 7, 8 and 9 provide examples of actual master formulae from several manufacturers with details revised to protect confidential information. For individual batches/lots of intermediates and bulks the MF is a complete document. However, for the final container product, the full MF is the total of MF of each step. 11

Guide to Master Formulae Guidance Document Therefore, for any final vaccine, a Master Formula Summary List is recommended. This would be a listing of each MF document number and title for each batch size of final product and would also include the options for any intermediates that are produced in different batch sizes and for the individual bulk components of a combined antigen vaccine. Such a Master Formula Summary List would include as applicable: MFs for: • Master Cell Bank • Working Cell Bank • Fermentation or Culture harvests • Harvest pool, or bulk concentrate • Purified intermediate • Final bulk (The above would be duplicated for each antigen in a combined vaccine) • Final formulated bulk (if stored) • Filling or filling/lyophilization • Labelling/Packaging In some companies, manufacturing instructions have been prepared as a series of SOPs which describe each step and each providing a record sheet for the data to be entered. In this format, there is no continuous production instruction and recording document. If this is the case, then the Master Formula will be a Master SOP List of the production SOPs in order of their use i required to describe the overall master production process, with all the SOPs and record sheets appended. A separate list would be required for each batch size. Although many of the SOPs might be the same, some SOPs for various batch sizes may be different. In this case, rather than the cross-referencing supporting SOPs in a continuous MF, the SOPs for facility and equipment preparation, supporting sterilization runs, in-process tests, etc would be included in the Master SOP List.

9) Issuing of MF copy as a blank batch record While Master Formulae are almost invariably stored on the computer, the official signed form is a paper copy. When a production order is made, QA is responsible to generate a copy, usually adds the lot number and stamps each page of the reproduced MF which is now the blank batch record for the production data for the assigned batch or lot. The MF should make reference to in process tests, QC tests, production parameters that are computer recorded (e.g. fermentation or lyophilization printouts), environmental monitoring or water testing, autoclave run charts or depyrogenation oven charts, etc but generally these supporting operations and records are not within a MF. The batch record, however, includes the record sheets of all the production records and support records. 12

Guide to Master Formulae Guidance Document Master formulae, once approved and signed, should remain under the control of QA. Copies are not stored in the production areas for uncontrolled use. When revisions are made (following the change control process, and document control process) a new version is assigned a revision (or edition) number, the approval signatures and effective dates are added, and the previous version is archived. Unlike routine testing SOPs which have a fairly general distribution and are available in each laboratory or production area using them, a copy of the currently approved MF is issued batch by batch on production orders. When a series of SOPs are used for production operations, then the corresponding SOPs record sheets should also be controlled by QA and issued on production orders. Master copies of the MF (each numbered and recorded on a QA distribution list) can be distributed to relevant departments if needed, but the MF issued for a production run should be stamped by QA to ensure that the currently valid version is used. There will obviously be company-by-company differences in the details of the procedures for QA approval and issuing of MF. 10) Electronic MF and Batch Records As mentioned above, the MF is invariably (in this electronic age) on the computer, and should be under password control of QA. Because the MF master copy is a signed document, the approved and signed original hard-copy of the MF becomes the official copy and should remain with QA. Photocopies – stamped, numbered, and on a distribution list - may be issued (see above) as reference copies to the relevant department head. The electronic version may have the signature and date fields typed in, e.g. “official copy signed by XXX”; “official copy dated ddmmyy”. If the electronic copy is printed out as the blank batch record for each production run, the QA department must stamp each page of the printout and sign that it is the approved current MF. The lot number can be added electronically or by hand on each page by the responsible person in QA. Alternately, the hard-copy can be photocopied for the production run, but will also be stamped and the lot number added. Whatever method is decided by a company, the MF must be issued by QA for each production run and controlled to ensure that only an approved copy of the current MF (or series of SOP record sheets) is issued on a production order. Computerized batch records – e.g.: filling in the blank MF– are more complicated. The computer program for permitting the entering of production data at the time of performance of the production step will require computer access inside the cleanroom. In this case, the MF would be issued electronically with safeguards to ensure that no unofficial copies can be made, or pages replaced. Passwords for entering data, verifying data or correcting data will need to be implemented. Specific procedures for recording any changes made to data records or the recording of deviations to production procedures must be validated and fully traceable retaining the original data and the corrected data. The review of batch records should include the full review of all changes and corrections made on the electronic forms. All of this process must be defined in SOPs for the 13

Guide to Master Formulae Guidance Document procedures to be followed for electronic batch records. Specific guidelines on computer data entry and validation have been published by PIC and the US which can be consulted for detailed guidance. For electronic batch records prepared by transcription from a hand-written record to a computer batch record requires additional verification that the computerized entries have been checked and are correct. This would require confirmation at the time of entry and again verified by QA.

11) Batch Records versus Master Formula In the regulations and guidelines (see appendices 1-4) there are also requirements for completed batch records (for some reason never called “lot records”). The MF is essentially the blank batch record for the production operations as discussed in 7) above. The batch record (BR often called Batch Processing Record BPR) is the MF with all data entered plus all the results of the supporting operations (in-process test results, environmental monitoring, autoclave records, etc). Details of the contents of the Batch Record are found in Appendix 1 (WHO); Appendix 2 (EU); Appendix 3 (PIC); and Appendix 4 (Health Canada) and Appendix 5 (US).

12) Batch record review checklist For a continuous production instruction MF, all the supporting operations are included as data fields or as cross-references within the document. For such a document, a list of the records sheets that are expected to be present in the batch record are itemized in a checklist which can also be a table of contents of the batch record. For a production document using various SOPs to define the production process, the Master SOP List may be essentially the same as the batch record checklist.

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Guide to Master Formulae Guidance Document Appendix 1: Extract from World Health Organization WHO Technical Report Series, No. 908, 2003 Annex 4: Good Manufacturing Practices for pharmaceutical products: main principles. From the Glossary batch records All documents associated with the manufacture of a batch of bulk product or finished product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the final product. master formula A document or set of documents specifying the starting materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls. master record A document or set of documents that serve as a basis for the batch documentation (blank batch record). standard operating procedure (SOP) An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material (e.g.: equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation.

15. Documentation 15.1 Principle. Good documentation is an essential part of the quality assurance system and, as such, should exist for all aspects of GMP. Its aims are to define the specifications and procedures for all materials and methods of manufacture and control; to ensure that all personnel concerned with manufacture know what to do and when to do it; to ensure that authorized persons have all the information necessary to decide whether or not to release a batch of a drug for sale, to ensure the existence of documented evidence, traceability, and to provide records and an audit trail that will permit investigation. It ensures the availability of the data needed for validation, review and statistical analysis. The design and use of documents depend upon the manufacturer. In some cases some or all of the documents described below may be brought together, but they will usually be separate.

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Guide to Master Formulae Guidance Document General 15.2 Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorizations. 15.3 Documents should be approved, signed and dated by the appropriate responsible persons. No document should be changed without authorization and approval. 15.4 Documents should have unambiguous contents: the title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process. 15.5 Documents should be regularly reviewed and kept up to date. When a document has been revised, a system should exist to prevent inadvertent use of the superseded version. Superseded documents should be retained for a specific period of time. 15.6 Where documents require the entry of data, these entries should be clear, legible and indelible. Sufficient space should be provided for such entries. 15.7 Any alteration made to a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded. 15.8 Records should be made or completed when any action is taken and in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records should be retained for at least one year after the expiry date of the finished product. 15.9 Data (and records for storage) may be recorded by electronic data-processing systems or by photographic or other reliable means. Master formulae and detailed standard operating procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data-processing methods, only authorized persons should be able to enter or modify data in the computer, and there should be a record of changes and deletions; access should be restricted by passwords or other means and the entry of critical data should be independently checked. Batch records stored electronically should be protected by backup transfer on magnetic tape, microfilm, paper print-outs or other means. It is particularly important that, during the period of retention, the data are readily available.

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Guide to Master Formulae Guidance Document

Documents required Labels (sections 15.10-15.12 not extracted) Specifications and testing procedures (sections 15.13-15.17 not extracted) Specifications for starting and packaging materials (sections 15.18-15.21 not extracted) Master formulae 15.22 A formally authorized master formula should exist for each product and batch size to be manufactured. 15.23 The master formula should include: (a) the name of the product, with a product reference code relating to its specification; (b) a description of the dosage form, strength of the product and batch size; (c) 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); (d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable; (e) a statement of the processing location and the principal equipment to be used; (f) 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; (g) detailed step-wise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures); (h) the instructions for any in-process controls with their limits; (i) where necessary, the requirements for storage of the products, including the container, the labelling, and any special storage conditions; (j) any special precautions to be observed.

Packaging instructions 15.24 Formally authorized packaging instructions should exist for each product, pack size and type. These should normally include, or make reference to: (a) the name of the product; (b) a description of its pharmaceutical form, strength and, where applicable, method of application; (c) the pack size expressed in terms of the number, weight or volume of the product in the final container;

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Guide to Master Formulae Guidance Document (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 for each packaging material; (e) 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; (f) special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before and after packaging operations; (g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; (h) details of in-process controls with instructions for sampling and acceptance limits.

Batch processing records 15.25 A batch processing record should be kept for each batch processed. It should be based on the relevant parts of the currently approved specifications on the record. The method of preparation of such records should be designed to avoid errors. (Copying or validated computer programmes are recommended. Transcribing from approved documents should be avoided.) 15.26 Before any processing begins, a check should be made that the equipment and work station are clear of previous products, documents, or materials not required for the planned process, and that the equipment is clean and suitable for use. This check should be recorded. 15.27 During processing, the following information should be recorded at the time each action is taken, and after completion the record should be dated and signed by the person responsible for the processing operations: (a) the name of the product; (b) the number of the batch being manufactured; (c) dates and times of commencement, of significant intermediate stages, and of completion of production; (d) the name of the person responsible for each stage of production; (e) the initials of the operator(s) of different significant steps of production and, where appropriate, of the person(s) who checked each of these operations (e.g. weighing); (f) the batch number and/or analytical control number and the quantity of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added); (g) any relevant processing operation or event and the major equipment used;

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Guide to Master Formulae Guidance Document (h) the in-process controls performed, the initials of the person(s) carrying them out, and the results obtained; (i) the amount of product obtained at different and pertinent stages of manufacture (yield), together with comments or explanations for significant deviations from the expected yield; (j) notes on special problems including details, with signed authorization for any deviation from the master formula.

Batch packaging records 15.28 A batch packaging record should be kept for each batch or part batch processed. It should be based on the relevant parts of the approved packaging instructions, and the method of preparing such records should be designed to avoid errors. (Copying or validated computer programmes are recommended. Transcribing from approved documents should be avoided.) 15.29 Before any packaging operation begins, checks should be made that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. These checks should be recorded. 15.30 The following information should be recorded at the time each action is taken, and the date and the person responsible should be clearly identified by signature or electronic password: (a) the name of the product, the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained, the quantity actually obtained and the reconciliation; (b) the date(s) and time(s) 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) the checks made for identity and conformity with the packaging instructions, including the results of in-process controls; (f) details of the packaging operations carried out, including references to equipment and the packaging lines used, and, when necessary, the instructions for keeping the product unpacked or a record of returning product that has not been packaged to the storage area; (g) whenever possible, samples of the printed packaging materials used, including specimens bearing the approval for the printing of and regular check (where appropriate) of the batch number, expiry date, and any additional overprinting; (h) notes on any special problems, including details of any deviation from the packaging instructions, with written authorization by an appropriate person;

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Guide to Master Formulae Guidance Document (i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of product obtained to permit an adequate reconciliation.

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Guide to Master Formulae Guidance Document Appendix 2: Extract from: EUDRALEX; Volume 4 - Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice.

CHAPTER 4 DOCUMENTATION Principle Good documentation constitutes an essential part of the quality assurance system. Clearly written documentation prevents errors from spoken communication and permits tracing of batch history. Specifications, Manufacturing Formulae and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance. General 4.1 Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. Manufacturing Formulae, Processing and Packaging Instructions state all the starting materials used and lay down all processing and packaging operations. Procedures give directions for performing certain operations e.g. cleaning, clothing, environmental control, sampling, testing, equipment operation. Records provide a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent to the quality of the final product. 4.2 Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorisation dossiers. 4.3 Documents should be approved, signed and dated by appropriate and authorised persons. 4.4 Documents should have unambiguous contents; title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process. 4.5 Documents should be regularly reviewed and kept up-to-date. When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents.

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Guide to Master Formulae Guidance Document 4.6 Documents should not be handwritten; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries. 4.7 Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded. 4.8 The records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable. They should be retained for at least one year after the expiry date of the finished product. 4.9 Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data processing methods, only authorised persons should be able to enter or modify data in the computer and there should be a record of changes and deletions; access should be restricted by passwords or other means and the result of entry of critical data should be independently checked. Batch records electronically stored should be protected by back-up transfer on magnetic tape, microfilm, paper or other means. It is particularly important that the data are readily available throughout the period of retention. Documents required Specifications (sections 4.10 to 4.13 not extracted) Manufacturing Formula and Processing Instructions Formally authorised Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document. 4.14 The 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 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;

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Guide to Master Formulae Guidance Document d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable. 4.15 The 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 critical equipment (e.g. cleaning, assembling, calibrating, sterilising); c) detailed stepwise processing instructions (e.g. checks on materials, pretreatments, 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 the container, labelling and special storage conditions where applicable; f) any special precautions to be observed.

Packaging Instructions 4.16 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: 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 in the final container; 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; 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; f) special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin; g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; h) details of in-process controls with instructions for sampling and acceptance limits.

Batch Processing Records 4.17 A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions. The method of preparation of such records should be designed 23

Guide to Master Formulae Guidance Document to avoid transcription errors. The record should carry the number of the batch being manufactured. Before any processing begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use. During processing, the following information should be recorded at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person responsible for the processing operations: a) the name of the product; b) dates and times of commencement, of significant intermediate stages and of completion 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, where appropriate, of the person who checked each of these operations (e.g. weighing); e) the batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered 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 any deviation from the Manufacturing Formula and Processing Instructions. Batch Packaging Records 4.18 A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained. Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. The following information should be entered at the time each action is taken and, after completion, 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;

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Guide to Master Formulae Guidance Document e) records of checks for identity and conformity with the packaging instructions including the results of in-process controls; f) details of the packaging operations carried out, including references to equipment and the packaging lines used; g) whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting; h) notes on any special problems or unusual events including details, with signed authorisation for any deviation from the Manufacturing Formula and Processing Instructions; i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation. Procedures and records (sections 4.19 to 4.29 not extracted)

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Guide to Master Formulae Guidance Document Appendix 3: Extracted from PHARMACEUTICAL INSPECTION CONVENTION PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME PE 009-3, 1 January 2006 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS. © PIC/S January 2006 (Reproduction prohibited for commercial purposes. Reproduction for internal use is authorised, provided that the source is acknowledged). DOCUMENTATION PRINCIPLE Good documentation constitutes an essential part of the quality assurance system. Clearly written documentation prevents errors from spoken communication and permits tracing of batch history. Specifications, Manufacturing Formulae and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance. GENERAL 4.1. Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. Manufacturing Formulae, Processing and Packaging Instructions state all the starting materials used and lay down all processing and packaging operations. Procedures give directions for performing certain operations e.g. cleaning, clothing, environmental control, sampling, testing, equipment operations. Records provide a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent for the quality of the final product. DOCUMENTS REQUIRED

MANUFACTURING FORMULA AND PROCESSING NSTRUCTIONS Formally authorised Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document. 4.14. The 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 using the designated name and a reference which is unique to that material; 26

Guide to Master Formulae Guidance Document mention should 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 relevant intermediate yields, where applicable. 4.15. The 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 critical equipment (e.g. cleaning, assembling, calibrating, sterilising); c) detailed stepwise processing instructions (e.g. checks on materials, pretreatments, 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 the container, labelling and special storage conditions where applicable; f) any special precautions to be observed. PACKAGING INSTRUCTIONS 4.16. 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: 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 in the final container; 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; 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; f) special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin; g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; h) details of in-process controls with instructions for sampling and acceptance limits. BATCH PROCESSING RECORDS 4.17. A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions. The method of preparation of such records should be 27

Guide to Master Formulae Guidance Document designed to avoid transcription errors. The record should carry the number of the batch being manufactured. Before any processing begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use. During processing, the following information should be recorded at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person responsible for the processing operations: a) the name of the product; b) dates and times of commencement, of significant intermediate stages and of completion 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, where appropriate, of the person who checked each of these operations (e.g. weighing); e) the batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered 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 amount of product yield obtained at different and pertinent stages of manufacture; i) notes on special problems including details, with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions. BATCH PACKAGING RECORDS 4.18. A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained. Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. The following information should be entered at the time each action is taken and, after completion, 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; 28

Guide to Master Formulae Guidance Document e) records of checks for identity and conformity with the Packaging Instructions including the results of in-process controls; f) details of the packaging operations carried out, including references to equipment and the packaging lines used; g) whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting; h) notes on any special problems or unusual events including details with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions; i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation.

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Guide to Master Formulae Guidance Document Appendix 4: Extract from Canadian GMP Guidelines.

Health Canada, Health Products and Food Branch Inspectorate GOOD MANUFACTURING PRACTICES GUIDELINES, 2002 EDITION, Version 2 From the GLOSSARY: MANUFACTURING BATCH DOCUMENT (fiche de lot de fabrication) - Instructions that outline in detail the materials and procedures required to fabricate, prepare, and preserve a single lot or batch of a drug in dosage form. MASTER FORMULA (formule-type) - A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a detailed description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls. MASTER PRODUCTION DOCUMENT (document-type de production) - a document that includes specifications for raw material, for packaging material and for packaged dosage form, master formula, sampling procedures, and critical processing related SOPs, whether or not these SOPs are specifically referenced in the master formula. MANUFACTURING CONTROL REGULATION C.02.011 (1) Every fabricator, packager/labeller, distributor referred to in paragraph C.01A.003(b) and importer of a drug shall have written procedures, prepared by qualified personnel, in respect of the drug to ensure that the drug meets the specifications for use of that drug. (2) Every person required to have written procedures referred to in subsection (1) shall ensure that each lot or batch of the drug is fabricated, packaged/labelled and tested in compliance with those procedures. RATIONALE This Regulation requires that a number of measures be taken to maintain the integrity of a drug product from the moment the various raw materials enter the plant to the time the finished dosage form is released for sale. These measures seek to ensure that all manufacturing processes are clearly defined, systematically reviewed in light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their established specifications.

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Guide to Master Formulae Guidance Document MANUFACTURING MASTER FORMULA 23. Processing operations are covered by master formulae, that are prepared by, and are subject to independent checks by, persons who have the qualifications described under Regulation C.02.006 Interpretation 1. 24. Master formulae are written to provide not less than 100% of label claim and include the following: 24.1 the name of the product, with a reference code relating to its specifications; 24.2 a description of the dosage form, strength of the product, and batch size; 24.3 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); 24.4 a statement of the expected final yield, along with the acceptable limits, and of relevant intermediate yields, where applicable; 24.5 a statement of the principal equipment to be used; 24.6 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.; 24.7 detailed stepwise processing instructions (e.g., checks on materials, pretreatment, sequence for adding materials, mixing times or temperatures, etc.); 24.8 the instructions for any in-process controls, along with their limits; 24.9 where necessary, the requirements for storage of the products, including the container, the labelling and any special storage conditions; and 24.10 any special precautions to be observed. PACKAGING MASTER FORMULA 25. In the case of a packaged product, the master formula also includes for each product, package size and type, the following: 25.1 the package size, expressed in terms of the number, weight, or volume of the product in the final container; 25.2 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; 25.3 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; 25.4 special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before operations begin; 31

Guide to Master Formulae Guidance Document 25.5 a description of the packaging operations, including any significant subsidiary operations and the equipment to be used; and 25.6 details of in-process controls, with instructions for sampling and acceptance limits. MANUFACTURING BATCH DOCUMENT 26. Each batch processed is effectively governed by an individually numbered manufacturing order prepared by qualified personnel from the master formula by such means as to prevent errors in copying or calculation and verified by qualified personnel. 27. As it becomes available during the process, the following information is included on or with the manufacturing order: 27.1 the name of the product; 27.2 the number of the batch being manufactured; 27.3 dates and times of commencement and completion of significant intermediate stages, such as blending, heating, etc., and of production; 27.4 the batch number and/or analytical control number, as well as the quantity of each raw material actually weighed and dispensed (for active raw material, the quantity is to be adjusted if the assay value is less than 98% calculated on “as is” basis and on which the master formula was based); 27.5 confirmation by qualified personnel of each ingredient added to a batch; 27.6 the identification of personnel performing each step of the process; and of the person who checked each of these steps; 27.7 the actual results of the in-process quality checks performed at appropriate stages of the process and the identification of the person carrying them out; 27.8 the actual yield of the batch at appropriate stages of processing and the actual final yields, together with explanations for any deviations from the expected yield; 27.9 detailed notes on special problems with written approval for any deviation from the master formula; and 27.10 after completion, the signature of the person responsible for the processing operations. 28. Batches are combined only with the approval of the quality control department and according to pre-established written procedures. 28.1 The introduction of part of a previous batch, conforming to the required quality, into the next batch of the same product at a defined stage of fabrication is approved beforehand. This recovery is carried out in accordance with a validated procedure and is recorded. PACKAGING BATCH DOCUMENT 29. Packaging operations are performed according to comprehensive and detailed written

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Guide to Master Formulae Guidance Document operating procedures or specifications, which include the identification of equipment and packaging lines used to package the drug, the adequate separation and if necessary, the dedication of packaging lines that are packaging different drugs and disposal procedures for unused printed packaging materials. Packaging orders are individually numbered. 30. The method of preparing packaging orders is designed to avoid transcription errors. 31. Before any packaging operation begins, checks are made that the equipment and work station are clear of previous products, documents, and materials that are not required for the planned packaging operations and that equipment is clean and suitable for use. These checks are recorded. 32. All products and packaging materials to be used are checked on receipt by the packaging department for quantity, identity and conformity with the packaging instructions. 33. Precautions are taken to ensure that containers to be filled are free from contamination with extraneous material. 34. The name and batch number of the product being handled is displayed at each packaging station or line. 35. Packaging orders include the following information (recorded at the time each action is taken): 35.1 the date(s) and time(s) of the packaging operations; 35.2 the name of the product, the batch number, and the quantity of bulk product to be packaged, as well as the batch number and the planned quantity of finished product that will be obtained, the quantity actually obtained and the reconciliation; 35.3 the identification of the personnel who are supervising packaging operations and the withdrawal of bulks; 35.4 the identification of the operators of the different significant steps; 35.5 the checks made for identity and conformity with the packaging instructions, including the results of in-process controls; 35.6 the general appearance of the packages; 35.7 whether the packages are complete; 35.8 whether the correct products and packaging materials are used; 35.9 whether any on-line printing is correct; 35.10 the correct functioning of line monitors; 35.11 handling precautions applied to a partly packaged product; 35.12 notes on any special problems, including details of any deviation from the packaging instructions with written approval by qualified personnel; 35.13 the quantity, lot number, and/or analytical control number of each packaging material and bulk drug issued for use; and 35.14 a reconciliation of the quantity of printed packaging material and bulk drug used, destroyed or returned to stock. 36. To prevent mix-ups, samples taken away from the packaging line are not returned. 33

Guide to Master Formulae Guidance Document 37. Whenever possible, samples of the printed packaging materials used, including specimens bearing the batch number, expiry date, and any additional overprinting, are attached to packaging orders. 38. Filling and sealing are followed as quickly as possible by labelling. If labelling is delayed, procedures are applied to ensure that no mix-ups or mislabelling can occur. 39. Upon completion of the packaging operation, any unused batch-coded packaging materials are destroyed, and their destruction is recorded. A procedure is followed if non-coded printed materials are returned to stock. 40. Outdated or obsolete packaging materials are destroyed and their disposal is recorded. 41. Products that have been involved in non-standard occurrences during packaging are subject to inspection and investigation by qualified personnel. A detailed record is kept of this operation. 42. Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units packaged is investigated and satisfactorily accounted for before release. Validated electronic verification of all printed packaging materials on the packaging line may obviate the need for their full reconciliation. 43. Printed packaging materials are 43.1 stored in an area to which access is restricted to designated personnel who are supervised by persons who have the qualifications outlined under Regulation C.02.006 Interpretation 2; 43.2 withdrawn against a packaging order; 43.3 issued and checked by persons who have the qualifications outlined under Regulation C.02.006 Interpretation 2; and 43.4 identified in such a way as to be distinguishable during the packaging operations. 44. To prevent mix-ups, roll-fed labels are preferred to cut labels. Gang printing is avoided. 45. Cut labels, cartons, and other loose printed materials are stored and transported in separate closed containers. 46. Special care is taken when cut labels are used, when overprinting is carried out offline and in hand-packaging operations. On line verification of all labels by automated electronic means can be helpful in preventing mix-ups. Checks are made to ensure that any electronic code readers, label counters or similar devices are operating correctly. 47. The correct performance of any printing (e.g., of code numbers or expiry dates) done separately or in the course of the packaging is checked and recorded. 48. Raw materials, packaging materials, intermediates, bulk drugs and finished products are (a) stored in locations that are separate and removed from immediate manufacturing areas, and (b) transported under conditions designated by the quality control department to preserve their quality and safety. 49. All intermediate and finished products are held in quarantine and are so identified in 34

Guide to Master Formulae Guidance Document accordance with Interpretation 21, until released by the quality control department. 50. Every package of a drug is identified by a lot number.

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Guide to Master Formulae Guidance Document Appendix 5: Extracts from US Code of Federal Regulations (CFR) and US FDA Guidelines. App 5-1) US Regulations for Master Production Records for Finished Pharmaceuticals. Extract from: CFR 21, Chapter I, Subchapter F: Biologics, Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals; Subpart F--Production and Process Controls: Sec. 211.100 Written procedures; deviations. (a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. (b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified. Subpart J--Records and Reports Sec. 211.186 Master production and control records (a) To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person. The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed. (b) Master production and control records shall include: (1) The name and strength of the product and a description of the dosage form; (2) The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product and a statement of the total weight or measure of any dosage unit; (3) A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic; 36

Guide to Master Formulae Guidance Document (4) An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component. Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the master production and control records; (5) A statement concerning any calculated excess of component; (6) A statement of theoretical weight or measure at appropriate phases of processing; (7) A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation according to 211.192 is required; (8) A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling; (9) Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed. Database Updated April 1, 2005

App 5-2) US Regulations for Batch Records for Finished Pharmaceuticals: CFR 21, Chapter I, Subchapter F: Biologics; Subchapter C: Drugs General; Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals; Subpart J--Records and Reports. Sec. 211.188 Batch production and control records Batch production and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch. These records shall include: (a) An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed; (b) Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including: 37

Guide to Master Formulae Guidance Document (1) Dates; (2) Identity of individual major equipment and lines used; (3) Specific identification of each batch of component or in-process material used; (4) Weights and measures of components used in the course of processing; (5) In-process and laboratory control results; (6) Inspection of the packaging and labeling area before and after use; (7) A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing; (8) Complete labeling control records, including specimens or copies of all labeling used; (9) Description of drug product containers and closures; (10) Any sampling performed; (11) Identification of the persons performing and directly supervising or checking each significant step in the operation; (12) Any investigation made according to 211.192. (13) Results of examinations made in accordance with 211.134. Database Updated April 1, 2005

App 5-3) US Additional Regulations for Batch Records for Biological Products: CFR 21, Chapter I, Subchapter F: Biologics, Part 600 Biological Products: General; Subpart B Establishment Standards, Sec 600.12 Records (a) Maintenance of records. Records shall be made, concurrently with the performance, of each step in the manufacture and distribution of products, in such a manner that at any time successive steps in the manufacture and distribution of any 38

Guide to Master Formulae Guidance Document lot may be traced by an inspector. Such records shall be legible and indelible, shall identify the person immediately responsible, shall include dates of the various steps, and be as detailed as necessary for clear understanding of each step by one experienced in the manufacture of products. (b) Records retention--(Not extracted) (2) Records of recall. (Not extracted) (3) Suspension of requirement for retention. (Not extracted) (c) Records of sterilization of equipment and supplies. Records relating to the mode of sterilization, date, duration, temperature and other conditions relating to each sterilization of equipment and supplies used in the processing of products shall be made by means of automatic recording devices or by means of a system of recording which gives equivalent assurance of the accuracy and reliability of the record. Such records shall be maintained in a manner that permits an identification of the product with the particular manufacturing process to which the sterilization relates. (d) Animal necropsy records. (Not extracted) (e) Records in case of divided manufacturing responsibility. If two or more establishments participate in the manufacture of a product, the records of each such establishment must show plainly the degree of its responsibility. In addition, each participating manufacturer shall furnish to the manufacturer who prepares the product in final form for sale, barter or exchange, a copy of all records relating to the manufacturing operations performed by such participating manufacturer insofar as they concern the safety, purity and potency of the lots of the product involved, and the manufacturer who prepares the product in final form shall retain a complete record of all the manufacturing operations relating to the product. [38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 70 FR 14982, Mar. 24, 2005] Database Updated April 1, 2005

App 5-4) Extract from US FDA Guidelines for Batch Records for Sterile Products: Guidance for Industry. Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice: U.S. Department of Health and Human Services, Food and Drug Administration; Center for Drug Evaluation and Research (CDER); 39

Guide to Master Formulae Guidance Document Center for Biologics Evaluation and Research (CBER); Office of Regulatory Affairs (ORA). September 2004) Pharmaceutical cGMPs).

Manufacturers should build process and environmental control activities into their aseptic processing operation. It is critical that these activities be maintained and strictly implemented on a daily basis. The requirement for review of all batch records and data for conformance with written procedures, operating parameters, and product specifications prior to arriving at the final release decision for an aseptically processed product calls for an overall review of process and system performance for that given cycle of manufacture. All in-process and laboratory control results must be included with the batch record documentation in accordance with section 211.188. Review of environmental and personnel monitoring data, as well as other data relating to acceptability of output from support systems (e.g., HEPA / HVAC, WFI, steam generator) and proper functioning of equipment (e.g., batch alarms report; integrity of various filters) are considered essential elements of the batch release decision. While interventions and/or stoppages are normally recorded in the batch record, the manner of documenting these occurrences varies. In particular, line stoppages and any unplanned interventions should be sufficiently documented in batch records with the associated time and duration of the event. In addition to lengthened dwell time of sterile product elements in the critical area, an extensive intervention can increase contamination risk. Sterility failures have often been attributed to atypical or extensive interventions that have occurred as a response to an undesirable event during the aseptic process. Written procedures describing the need for line clearances in the event of certain interventions, such as machine adjustments and any repairs, should be established. Such interventions should be documented with more detail than minor events. Interventions that result in substantial activity near exposed product or container closures or that last beyond a reasonable exposure time should, where appropriate, result in a local or full line clearance. Any disruption in power supply, however momentary, that could affect product quality is a manufacturing deviation and must be included in batch records (211.100, 211.192).

40

Guide to Master Formulae Guidance Document Appendix 6: WHO/VSQ/97.01: A WHO guide to good manufacturing practice (GMP) requirements. Part 1: Standard operating procedures and master formulae, Appendix 6: Sample master formula for a hypothetical biological product.

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Guide to Master Formulae Guidance Document (Cont.)

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Guide to Master Formulae Guidance Document (Cont.)

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Guide to Master Formulae Guidance Document Appendix 7: Example one of a Master Formula.

COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step Product Name Product Code Issued by (Q.A.) Production Manager

Page: 49 of 11 XXXXXXXXXXXXX Revival of Working Cell Bank, Inoculation and Harvesting Production Order: ###### Bulk Antigen X ######## Lot Number :

Date

:

:

Date

:

Contents of Batch Manufacturing Record (BMR)

(Note: page numbers are from original document) No. 1. 2. 3. 4. 5. 6. 7. 8.

Description Revival of lyophilized working cell bank Transfer of revived culture to xx tube Inoculation of Seed Bottle Inoculation of Fermenter Harvesting of Antigen X Filtration details Cleaning of system BMR certification

Page No. 2 3 4 5 7 9 10 12

Preparation of seed culture:

Date: _____________

Culture seed preparation activities are to be performed as per the SOP ______________ “ XX Seed Preparation”. Master cell bank and working cell bank lot information Strain used XXXXXXXXXXXX Working cell bank lot no.

Effective Date: (Approved by)

Signature: Signature:

Date: Date:

49

Guide to Master Formulae Guidance Document COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step Product Name Product Code

XXXXXXXXXXXXX Page: 2 of 11 Revival of Working Cell Bank, Inoculation and Harvesting Bulk Antigen X Production Order: ###### ######## Lot Number

1) Revival of Lyophilized working cell bank: Draw one tube of Lyophilized working cell bank from Cold room No. 1 and disinfect it from outside with absolute alcohol. Cut and open it under LAF. Transfer approximately x ml of xxx medium to opened tube. Draw the suspension and transfer it to a vial containing xxx medium (approx. x-x ml). Check purity by addition of a drop from vial on xxx agar and in xxx broth. Incubate the vial and purity tubes at xx ± x °C for xx hrs. Material Quantity Lot No. Lyophilized culture tube XX medium tube XXXX agar tubes XXXX broth tubes Revival carried out on___________ by ____________. Purity test details. SOP No.: ____________ XXX agar / broth tubes and vial incubated From To

Checked by

Purity checked Date results

Checked by

Deviations if any: Date: _____________ 2) Transfer of revived culture to XX tube. Confirm the purity. Transfer x-x ml from the vial in step one to a tube containing XX medium. Check purity by addition of a drop from vial on X agar and in X broth. Incubate the tube at xx ± x °C for xx hrs. Incubate the purity tubes at xx ± x °C for xx hrs. Check purity also under microscope.

Effective Date: (Approved by)

Signature: Signature:

Date: Date:

50

Guide to Master Formulae Guidance Document

COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step Product Name Product Code

XXXXXXXXXXXXX Page: 3 of 11 Revival of Working Cell Bank, Inoculation and Harvesting Bulk Antigen X Production Order: ###### ######## Lot Number

Microscopic observations (Gram staining)._________________________________________ ___________________________________________________________________________ Material XXXX agar tubes XXXX broth tubes XXXX medium tube

Quantity

Lot No.

Checked by

Passage carried out on___________ by __________. Incubation from________ to_______ Purity test details. SOP No.: ___________ XXXX agar / broth tubes Purity checked incubated From To Date

Checked by results

Deviations if any:

Date: _____________ 3) Inoculation of Seed Bottle. Confirm the purity on microscope. Transfer x-x ml culture from step 2 into Seed bottle containing XXX medium. Use X L and X L medium for XX and XX L Fermenter batch respectively. Check purity by addition of a drop from tube on xxx agar and in xxx broth. Incubate the Seed bottle at xx ± x °C for xx hrs. Incubate the purity tubes at xx ± x °C for xx hrs. Seed bottle inoculated on __________ by __________. Incubation of Seed bottle from __________ to ___________.

Effective Date: (Approved by)

Signature: Signature:

Date: Date:

51

Guide to Master Formulae Guidance Document

COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step Product Name Product Code

XXXXXXXXXXXXX Page: 52 of 11 Revival of Working Cell Bank, Inoculation and Harvesting Bulk Antigen X Production Order: ###### ######## Lot Number

Purity test carried out as per. SOP No.: _________ Material Quantity XXXX agar tubes XXXX broth tubes XXXX agar / broth tubes incubated From To

Lot No.

Checked by

Purity checked Checked by Date

results

Deviations if any: Date: _____________ 4) Inoculation of Fermentor. Transfer the contents of Seed bottle to Fermentor containing XX medium. Check purity by addition of a drop from Seed bottle on XXX agar and in XXX broth. Incubate the Fermentor at xx ± x °C for xx days. Incubate the purity tubes at xx ± x °C for xx hrs. Check purity also under microscope. Adjust aeration and agitation as per SOP No. ________. Fermentor No. ____ (Working vol. _____L. Sterilized on _____. containing XX Medium Lot No.___________ SOP No.:____________ for media preparation SOP No.: ___________ for fermentor sterilization

Effective Date: (Approved by)

Signature: Signature:

Date: Date:

52

Guide to Master Formulae Guidance Document

COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step Product Name Product Code

XXXXXXXXXXXXX Page: 53 of 11 Revival of Working Cell Bank, Inoculation and Harvesting Bulk Antigen X Production Order: ###### ######## Lot Number

Air pressure in the fermentor checked _________ Pressure released _________ Microscopic observations of seed (gram staining):__________________________________ ___________________________________________________________________________ Fermentor No.: ____ inoculated on ___________ by _________ Purity test details. SOP No.: _____________ Material XXXX agar tubes XXXX broth tubes

Quantity

XXXX agar / broth tubes incubated From To

Lot No.

Checked by

Purity checked Date

Checked by results

Incubation of Fermentor from _________ to __________. Decontaminate the remnant culture, purity tubes and articles used for Culture transfer by Autoclaving at xxx °C for xx min. Decontamination charge No.: _____________ Date: _____________ Adjust the aeration and agitation as per SOP No.: ______________

Effective Date: (Approved by)

Signature: Signature:

Date: Date:

53

Guide to Master Formulae Guidance Document COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step Product Name Product Code

XXXXXXXXXXXXX Page: 54 of 11 Revival of Working Cell Bank, Inoculation and Harvesting Bulk Antigen X Production Order: ###### ######## Lot Number

AERATION AND AGITATION ADJUSTMENTS DURING INCUBATION Date

Vibromixer Voltage Required Required Adjusted For XX For XX to L L xxx xxx

Air Flow (LPM) Required Required Adjusted For XX For XX to L L x x

xxx

xxx

x

x

xxx

xxx

x

x

xxx

xxx

x

x

Sign

Deviation if any: Date: _____________ 5) Harvesting of Bulk Antigen X Harvesting of Bulk antigen X is carried out using XXX system (SOP No.: _____) or by using Filter press assemblies (SOP No.: _______). Draw sample for purity test. Check purity by addition of a drop from Sample on XXX agar and in XXX broth. Incubate the purity tubes at xx ± x °C for xx hrs. Check purity also under microscope. For harvesting of a batch carry out following steps:

Effective Date: (Approved by)

Signature: Signature:

Date: Date:

54

Guide to Master Formulae Guidance Document COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step

XXXXXXXXXXXXX Page: 55 of 11 Revival of Working Cell Bank, Inoculation and Harvesting

Product Name Product Code

Bulk Antigen X ########

Production Order: ###### Lot Number

Switch off temp. controller and recorder, Switch off Agitator controls, Stop Air flow Temp. controller and recorder switched off Agitator controls switched off Air flow stopped Sample drawn by Purity test details. SOP No.: _______________ Material XXXX agar tubes XXXX broth tubes

Quantity

XXXX agar / broth tubes incubated From To

Lot No.

Checked by

Purity checked Date

Checked by results

Deviations, if any: Date: _____________ Harvesting of Bulk antigen X Lot No.: ___________ on _____________. Details of batch harvesting using XXXX system Clean the XXXX system by flushing XXX L W.F.I. (Bulk) Pre operation cleaning of system XXX L. W.F.I (bulk) flushed from _______to_______ Done by _____

Effective Date: (Approved by)

Signature: Signature:

Date: Date:

55

Guide to Master Formulae Guidance Document COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step

XXXXXXXXXXXXX Page: 8 of 11 Revival of Working Cell Bank, Inoculation and Harvesting

Product Name Product Code

Bulk Antigen X ########

Production Order: ###### Lot Number

Use of XXXX system for filtration of toxin. Follow SOP No.: _______. Set inlet pressure in order to have initial filtrate rate of xxx to xxx LPH Inlet Pressure set at _____bar. Initial filtrate flow-rate __________ LPH done by ________ FILTRATION DETAILS: Time Filtration Filtrate Collected Rate (LPH) (L)

Date: _____________ Recirculation Details Observed/ Done by

Bulk Antigen is transferred to the Non- culture wing. ____________________ Bulk Antigen Lot No.: __________ Filtration by XXXX System.

Effective Date: (Approved by)

Signature: Signature:

Done by

Date: _____________

Date: Date:

56

Guide to Master Formulae Guidance Document COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step Product Name Product Code

XXXXXXXXXXXXX Page: 9 of 11 Revival of Working Cell Bank, Inoculation and Harvesting Bulk Antigen X Production Order: ###### ######## Lot Number

Cleaning of the System: Wash the system with xxx L Potable water. Collect the washing in the fermentor vessel itself by connecting the retentate and permeate pipes to the Fermentor. Thereafter disconnect the pipes from the fermenter and keep these pipes in washing drum. xxx L Potable Water wash: From : ________To ________ Checked by _____ I) Add xxx ml of x % XXX to xx L WFI (Bulk) and recirculate through XXX system for xx minutes xxx L WFI (Bulk) temp. ____°C + _______ml xxx % XXX (QC No. ) Checked by : Recirculation from : ________ to : __________ Checked by : II) Add xx ml of xx % XXX to xx L WFI (Bulk) & recirculate through XXXX system for xx minutes xxx L WFI (Bulk) temp. ____°C + _______ml xxx % XXX (QC No. ) Checked by: Recirculation from : ________ to : __________ Checked by : III) Flush the system with W.F.I. (Bulk) xxx L System flushed with ________W.F.I.(Bulk) From :________To : ______ Checked by ___ IV) XXX XXX wash : Recirculate XXX XXX solution (Add xxx ml XXX XXX to xxx L W.F.I. (Bulk) temp. xxxx °C) xxx L W.F.I. (Bulk) Temp. _____°C + ________ml XXX XXX (QC No. ) Checked by _______ Recirculation from : ________ to : __________ Checked by _______ Date :_____ V) Flush the system with W.F.I. (Bulk) xxx L System flushed with _______W.F.I.(Bulk) From :_______To : ______ Checked by _______

Effective Date: (Approved by)

Signature: Signature:

Date: Date:

57

Guide to Master Formulae Guidance Document COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step Product Name Product Code

XXXXXXXXXXXXX Page: 10 of 11 Revival of Working Cell Bank, Inoculation and Harvesting Bulk Antigen X Production Order: ###### ######## Lot Number

Cleaning of the System: (continued) VI) Check the Flow rate of W.F.I. (Bulk) at xxx bar inlet pressure. If the flow rate is less than xxx LPH repeat washing procedure. W.F.I.(Bulk) Flow-rate at xxx bar pressure : ______LPH (at ____°C) Checked by _______ All the washing from the above steps I to V connected to the drain. VII) Storage of the system in xxx % XXX after recirculation for xxx minutes : _______L WFI (Bulk) + ____ml XXX (Q. C. No. ________). Done by : _______ Recirculation from: ________ to: __________ Done by _________.

System disconnected from power supply at: Operations supervised by:

Effective Date: (Approved by)

Signature: Signature:

Date: Date:

58

Guide to Master Formulae Guidance Document COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department Process Step Product Name Product Code

XXXXXXXXXXXXX Page: 11 of 11 Revival of Working Cell Bank, Inoculation and Harvesting Bulk Antigen X Production Order: ###### ######## Lot Number

BMR CERTIFICATION 01. MANUFACTURING DEPARTMENT: The contents of this Document have been checked and verified by me. The information contained herein is complete and true to the best of my Knowledge. Deviations if any are reported. Hence submitted to Quality Assurance Department. Signature of Production Officer: …………………………………….. Date of Completion: ………………………… Date of Submission: ………………………... 02. QUALITY ASSURANCE DEPARTMENT: I hereby certify that, this batch record is reviewed by me, to ensure that the above mentioned batch process has been carried out according to the Authorized Master Formula and processing instructions. All operational steps have been scrutinized & approved according to the checklist (attached ) and have been found to be complete.

Signature of Quality Assurance Review Officer: ………………………… Date of Receipt: ………………………… Date of Approval: ……………………….

Effective Date: (Approved by)

Signature: Signature:

Date: Date:

59

Guide to Master Formulae Guidance Document Appendix 8: Example two of a Master Formula.

COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date:

PRODUCT X

FILL SIZE

Signatures: Written by: Reviewed by: Approved by Q.A.:

x mL

Date: Date: Date:

60

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: CERTIFICATION

CERTIFICATE OF QUALITY ASSURANCE

THIS IS TO CERTIFY THAT THE BATCH No. _______OF PRODUCT X (TRADE NAME _______), SATISFIES THE REGULATORY AND PHARMACOPOEIAL REQUIREMENTS FOR PRODUCT X VACCINE.

Signature of Quality Assurance: Date:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date: Date: Date:

61

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 1. BATCH RECORD REVIEW AND APPROVAL REPORT No 1 2 3 4 5 6 7

Term Name of the Product Batch No. Date of Filling Quantity Filled Quantity Released Mfg. Date Exp. Date

Details PRODUCT X

Reviewed by QA (Analyst/Officer): 2.

Date:

Approved by Head QA:

Date:

CHECKLIST OF BATCH RECORD:

No

Description

Date

Product X Vaccine Blending Primary packing materials procurement Washing and sterilization of vials, stoppers and vessels. 4 Sterilization of filling items 5 Filling 6 Filling particulars 7 Recording of deviations 8 Primary packing materials reconciliation record 9 Visual Inspection 11 Packing details for shipment to NCL 12 Finished goods transfer note to NCL Signature of Supervisor: Date: Signature of QA:

Document availability checked by Production QA

1 2 3

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date: Date: Date:

62

Date:

Effective Date: _______ Revision number: ______

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COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 3. QUALITY CONTROL REPORTS AND MISCELLANEOUS DOCUMENTS CHECK LIST: No

Name of the Report

Q.C Ref.No.

Availability checked by Production

1 2 3 4 5 6 7 8 9 10 11 12 13

Formulation buffer Final Blend report (1) Final Blend report (2) Filled vials report (1) Filled vials report (2) Thermo graphs of Autoclave Vials Depyrogenation report Membrane Integrity report Environmental monitoring report Particle count report NCL report WFI report of blending port WFI report of washing port

NA NA NA NA NA NA NA NA

Signature of Supervisor: Date:

Signatures: Written by: Reviewed by: Approved by Q.A.:

QA

Signature of Quality Assurance: Date:

Date: Date: Date:

63

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: Product X VACCINE BLENDING: 4.1 Volume of blend:

_____ Liters.

4.2 Details of blending materials: Description of material Lot No / B. No

Q.C. Ref No.

Assay (mg/mL)

A) Bulk antigen (xx mg/mL) (SOP # ___/ Spec # ___) B) Formulation solution #1 (xx mg/mL) (SOP #_____) C) Formulation solution #2 (xx mg/mL) (SOP # ____) Signature of Supervisor: 4.3

Date:

Bulk antigen requirement for blend:

4.3.1 Antigen requirement: Calculate the antigen requirement for the blend as per SOP # _______ Blend volume in mL (A)

Signatures: Written by: Reviewed by: Approved by Q.A.:

Total antigen required in mg (A x XX) / 1000

Date: Date: Date:

64

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 4.3.2 Details of antigen: Lot No. of Bulk

Q.C. Ref No. and Date

Antigen concentration in mg/mL (A)

Volume in mL (B)

Total antigen in mg A x B As mentioned above

Total volume Total rounded off to Signature of Supervisor: 4.4

Date:

Solution #1 (FS#1) requirement for the blend:

4.4.1 Solution #1 (FS#1) requirement: Calculate Formulation Solution #1 requirement for the blend as per SOP # ______ Blend volume in mL Total XXXX required in mg (Blend volume x XX mg/mL)

4.4.2 Details of Formulation Solution #1 (FS#1) No. Batch Q.C. Ref. FS#1 No. No. content and Date (mg/mL) (A)

Volume in mL (B)

Total FS#1 in (mg) (A x B) as mentioned above

Total volume Total round off to Signature of Supervisor:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date:

Date: Date: Date:

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Effective Date: _______ Revision number: ______

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COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 4.5

Requirement of Formulation Solution #2(FS#2) for the blend:

4.5.1 Formulation Solution # (FS#2) requirement: Refer SOPs# _____________ Blend volume Total Bulk Total FS#1 Required quantity of FS#2 (mL) Volume (mL) Volume (mL) D = A- (B+C) In (mL) A B C

4.5.2 Blending vessel Particulars: 1 Type of vessel XXX liter blending vessel 2 Make XXX 3 ID. No.: ####### 4 Cleaned by 5 SIP cycle No / Load No 6. LAFU Validation Done on: Due on: Line clearance given by QA 4.5.3

Details of blending: Spec. Volume Added Checked Date Ingredient Temp of o vessel oC C/ % added by by FS#1 as per 4.4.1 xx to xx oC FS#2 as per 4.5.1 xx to xx oC Bulk antigen as per xx to xx oC 4.3.1 Stirring (%) xx – xx % Stirring start time: ___________. End time: __________ (stirring time specifications: X to X hrs) Signature of Supervisor: Date:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Signature of Quality Assurance: Date:

Date: Date: Date: 66

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 4.6 Final blend sampling details: For sample collection, labeling, storage details refer SOP# _________ Sampled Sampled Quantity by

Date / Time

xx mL

Signature of Supervisor:

Tests to be done

SOP. No. / Spec No.

Description pH XXX content XXX content Bacterial Endotoxins (LAL) Sterility XXX Potency Date: Signature of QA:

QC Ref. Report No. / Date Date

Date:

5. PRIMARY PACKING MATERIALS PROCUREMENT: No

Name of material

Spec. No.

X mL vials xx mm grey butyl stoppers 3 xx mm aluminium seals Remarks (if any): Signature of Supervisor:

AR. No.

Quantity Quantity Quantity Checked by required issued received Production Q.A. by store supervisor in charge

1 2

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date:

Signature of QA:

Date: Date: Date:

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Date:

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 6. WASHING AND STERILIZATION OF STOPPERS AND FILLING ITEMS: 6.1 Stoppers details: Size: xx mm Colour: grey butyl 6.1.1 Machine particulars: Name of the machine: STOPPER WASHING MACHINE I.D. No. xxxxxx Validation Done on: Due on: Cleaned by Checked by LAFU I.D. No: Validation Due on: 6.1.2 Treatment of stoppers: Treatment procedure of stoppers as per SOP # ________ 6.1.2.1 Quantity of treatment solution (TS#1) required for stoppers: Total volume of WFI (mL) (A)

Total TS#1 required in mg at XX mg/mL (A x XX)

6.1.2.2 Details of TS#1 treatment: (Final TS#1 concentration should be xx mg/mL) No Ingredient STP.No./ A.R. No. Qty Spec.No. Required 1 TS#1 xxx mg 2 WFI NA xxxx mL Volume of TS#1 solution prepared

Volume of TS#1 solution used

Excess TS#1 solution discarded by: TS#1 treatment of stoppers done by:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date

Date: Date: Date:

68

Qty weighed

Weighed by

Checked by

Volume of TS#1 solution discarded

Checked by: Checked by:

Date:

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 6.1.3 20 mm Grey butyl rubber Stopper washing particulars: Stopper washing, WFI inspection procedure refer SOP # ______ 6.1.3.1 Drain water of Stopper washing machine checked by___________ 6.1.3.2 Lot No—I Washing details: No Date Operator Washing Qty Final rinse drain involved Start End Time Washed. water inspected by in Time washing 1st rinse 2nd rinse 3rd rinse Details of Stopper Collection into S.S cans for Stopper Lot No I: Can Date S.S can No. of Collected Thiomersal No cleaned stoppers by solution by collected Volume Added added by

Checked by

Repeat as necessary for as many lots of Stoppers that are required 6.1.4 Sterilization of stoppers: Sterilization procedure of stoppers and sterilization by autoclave refer SOP # ________. 6.1.4.1 Equipment particulars: Name of the Machine and AUTOCLAVE XXXXXXX Make I.D. No. ####### Validation Done on: Due on: Cleaned by: Checked by:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date: Date: Date:

69

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 6.1.4.2 Details of stopper sterilization as per load pattern No.: 1 Date Load Can Qty Loaded Sterilization Sterilization No. No by temp time

Specs.

Signature of Supervisor:

Date:

6.2 Details of filling accessories sterilization as per load pattern No 2 Washing and sterilization of filling accessories refer SOP# _______ Date Load Items Qty Washed Sterilizat- Sterilizat- Specs. No. & ion temp ion time Loaded by Filling # sets / glass syringes Stopper # Bowl Chute # xx Picker # min at wheel XX Section # o C wheel Glass # syringes Forceps # Silicon # tubes 20 L # vessel SS tray #

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date: Date: Date:

70

Unloaded by

Unloaded by

Checke d by

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: Signature of Supervisor:

Date:

6.3 Details of garments, gloves and wipes sterilization as per load pattern No 3 Dat e

Loa d No.

Items

Qt y

Loade d by

Sterilizati on temp

Sterilizati on time

Specifi c-ation

Garmen ts Gloves Wipes Mask

Unloade d by

Checke d by

xx min at XX oC

Signature of Supervisor:

Date:

6.4 Fumigation of blending and filling area: Fumigating procedure refer SOP# ___________ Area

Date

Formaldehyde WFI Fumigation Quantity Quantity done by

Time From

Signature of Supervisor: Signature of QA:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Checked by

To

Date: Date:

Date: Date: Date:

71

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 7. WASHING AND DEPYROGENATION OF VIALS. 7.1 Washing of vials: Vial washing, inspection and depyrogenation procedure as SOP #______. 7.1.1 Machine particulars: Equipment Name: XXXXXXXX Make XXXXXXX ID.No. ########### Validation Done on: Due on: Cleaned by Checked by: Parameter Results Air pressure: (Spec x to x Kg/cm2 ) Water pressure: (Spec x to x Kg/cm2 ) Final rinsing WFI Temperature: (Spec xx to xx oC) Flow of water in all needles Flow of air in all needles Checked by Date & Time Signature of Supervisor: Date: 7.1.2 Vial washing particulars: LAFU I.D. No: ############# Date WFI sample Time of washing inspected by Start End Time Time

Vials loaded by

Validation Due on: Washing Total No. machine of vials operated by Washed

No. of vials broken

Total

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date: Date: Date:

72

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 7.1.3 Washed vials inspection (For particles): (Frequency every x hours) Date Time Checked by Remarks

Signature of Supervisor:

Date:

7.2 Depyrogenation of vials: 7.2.1 Machine particulars: Equipment Name and Make XXXXXXX I.D. No. ######## Validation Done on: Cleaned by:

Due on: Checked by:

7.2.2 Depyrogenation Details: Date

Tunnel start time

Set Temp O

C

Depyrog'n Tem p OC (> X)

Heater 1 Heater 2 Heater 3 Heater 4

Tim e Min . (≥ x)

Tunne l stop time

Tunnel Drive mm/min

Depyrog'n data enclosed Yes/no

Checked by

Quantity depyrog'd

< xxx

Signature of Supervisor:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Temp monitore d by

Date :

Date: Date: Date:

73

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 8.1 Filling line clearance : line clearance as per SOP# ____________ LAFU I.D. No: ######### Validation Due on: 8.1.1 Machine particulars and line clearance details: Equipment Name Filling Machine Make XXXXX I.D. No. ######## Room No. Validation done on Validation due on Cleaned by Checked by Sterilization indicators on stoppers, filling items, garments etc

Stoppering Machine XXXXX ########

Sealing Machine XXXXX ########

Checked by

Verified by QA

Filling area cleanliness Fumigation details Line clearance for filling given by QA: 8.2 Filling operation particulars: 8.2.1 Filling Operation: Filling operation refer SOP #____________ 8.2.2 Filling Operation Details: Filling Date Time Machine Stoppering Machine operator operator

Sealing Machine operator

Signature of Supervisor:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Filled vials collected by

Signature of Prod. Shift in charge

Signature of QA. Shift in charge

Date:

Date: Date: Date:

74

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 8.3 Final blend stirring: (Frequency of checking - Every x hour) Stirring and temperature of vessel as per SOP# _______________ Date Time Stirring (%) Specification Checked by (%) Production QA

xx - xx Signature of Supervisor:

Date:

8.4 Volume variation check during filling: 8.4.1 Filling operation: Filling operations, start up activities refer to SOP # ____ and to annex for fill volume standards. Volume variations action limits refer SOP# ______ 8.4.2 Volume check up Details: (Frequency every x to x hours) Filling Date: Starting time: Closing time: Pack Size X mL Syringe used for vol. Measurement: X mL Fill Volume Spec xx.x – xx.x mL Calibration due on: Volume drawn Nozzle Nozzle Nozzle Nozzle Nozzle Nozzle Checked No Date Time No-1 No-2 No-3 No-4 No-5 No-6 by Remarks Start up volume checks in (mL) 1 2 3 In process Volume checks during filling in (mL) 1 2 3 Signature of Supervisor: Date:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date: Date: Date:

75

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 8.5 Filling area monitoring: (Frequency every x hours) Filling Date: Starting time: Pack size: X mL Closing time: Date

Time

Temp (oC)

Spec (oC)

Humidity (%)

xx to xx oC Signature of Supervisor:

Spec (%)

Checked by

xx to xx% Date:

8.6 Recording of Interferences/deviations during filling: Deviation action limits and procedures followed refer SOP# ____________ Note: This is the provision to record online interferences during filling if any. Possible deviations: power failure, temperature out of specification, stirring of blend out of specification, Fill volume out of specification, equipment problems etc. Crate No

Date

Time

Description of Recorded Checked Interference/Deviation By by

Deviation report No. if any

Note: This table helps to trace those vials that could have been filled during interferences (if filled during interferences). Signature of Supervisor: Date:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date: Date: Date:

76

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 8.7 Filled vials sampling details for QC: Collection of samples Refer SOP# _______and for number of samples Refer SOP ______ Date

Sampled Quantity

Sampled by QA

xx Vials

Tests to be done Description Identity pH XX content XX content Abnormal toxicity on guinea pigs Abnormal toxicity on mice Sterility Bacterial endotoxins (LAL test) Potency Closure integrity test

Report checked by Prod. Report verified by QA Signature of Supervisor: Date:

Signatures: Written by: Reviewed by: Approved by Q.A.:

SOP/ Spec.

QC Ref. / Date

Report Date

Date: Date: Signature of Quality Assurance: Date:

Date: Date: Date:

77

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 8.8 Calculation of practical yield: Theoretical Yield (A) = Batch Vol.÷ Filling Vol

Total Process Loss (B) Description

Filled Quantity

Volume Equivalent in ml vials

(C)

a) Sampled of final blend b) No. of volume checked vials c) Vol. discarded after breaks d) Dead volume Total (B) Process Loss (%) = B X 100/A Checked by Prod. Verified by QA

No. of samples for Q.C. Testing (D)

Quantity transferred to Visual inspection E = C- D

xx

Date: Date:

9. PRIMARY PACKING MATERIALS RECONCILIATION: Name of Material

Quantity issued

Total Quantity used

XX mL Vials Stoppers xx mm grey butyl Seals xx mm

Signatures: Written by: Reviewed by: Approved by Q.A.:

Quantity Returned to stores

Quantity

Process loss %

Spec (%) ≤x ≤x

≤x

Date: Date: Date:

78

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: REMARKS (if any):

Signature of Supervisor: Date:

Signature of Quality Assurance: Date:

10. MATERIAL RETURN NOTE: 10.1 Material Return Note Number: 10.2 Material Return Details: No Item code Description

AR No.

Indent No.

Units

Quantity

Reason for Returning

REMARKS (if any):

Returned By:

Approved By:

Received By:

Signature of Supervisor: Date:

Signature of Quality Assurance: Date:

11. VISUAL INSPECTION OF VIALS: 11.1 Line clearance for visual inspection: Refer Line clearance SOP# ________________

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date: Date: Date:

79

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 11.1.1 Cleaning of visual inspection area: Cleaning procedure refer SOP # ______________ Area cleaned by: Date: 11.1.2 Line Clearance Details: No Previous Present Previous product product product Batch Pack Batch Pack material cleared No. size No. size off from the area Yes /No

Checked. By

Signature of Supervisor: Date:

Signature of Quality Assurance: Date:

Checked by: Date: Line clearance given by QA

Date

Time

11.2 Reconciliation of vials after Visual inspection: refer SOP# _____________ 11.2.1 Quantity Received for Visual inspection: _____________________ 11.2.2 Reconciliation Details: No

Date

Tested by

Time From

To

Checked by

Passed Quantity random checked by

1 2 3 Total Passed Quantity

Rejected vials as per possible defects Less volume (A)

Glass pieces (B)

Other particles (C)

Cap Closures defects (D)

Total rejected Quantity % rejection ≤x%

Specification of optical rejection:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Passed Quantity

Date: Date: Date:

80

Effective Date: _______ Revision number: ______

Total (A+B+C+D)

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 11.2.3

Good Quantity transferred to labeling after Visual inspection: ______________

Signature of Supervisor: Date: 12. DISCARD NOTE: Item Quantity Date

Signature of Quality Assurance: Date:

Reasons Destruction Destruction for approved Destroyed Supervised by destruction by by Production QA

Formulation Solutions Glass Vials xx mm stoppers xx mm flip top seals Visual inspection rejections Signature of Supervisor: Date:

Signature of Quality Assurance: Date:

13. BATCH ACCOUNT: 13.1 Details of batch account: 1 2 3 4

Theoretical yield Filled quantity (b) No. of vials given for Q.C + other samples No. of vials given for visual inspection

Signatures: Written by: Reviewed by: Approved by Q.A.:

Date: Date: Date:

81

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document COMPANY B Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL BLENDING AND FILLING Batch No.: Date of Manufacture: Expiry Date: 13.1 Details of batch account (cont.): 5 Total Optical rejections + breakages during optical testing (e) 6 Passed quantity after Visual inspection. 7 No. of vials packed and sent to NCL 8 Net percentage Yield = (b - e X100)/b 9 Quantity remaining to be labeled and packed. 13.2 Batch packing details: P.R.No. Date Breakages

Quantity Packed

No. of Samples

Quantity Transferred

Quantity remaining

1 2 3 4 5 Total Signature of Supervisor: Date:

Signatures: Written by: Reviewed by: Approved by Q.A.:

Signature of Quality Assurance: Date:

Date: Date: Date:

82

Effective Date: _______ Revision number: ______

Guide to Master Formulae Guidance Document Appendix 9: Example three of a Master Formula. Company Logo

COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx CONTROLLED BATCH MANUFACTURING RECORD DOCUMENT Filling Building # __ Department Name Page No Page 83 of 119 Product Name Short Text

Blending, Filling, Lyophilization and Sealing Product X X dose Lyophilised

Product Code

xxxxxxx

Title

Issued By (Q.A ): Production Manager:

Document No Version No Process Order Batch No

Date: Date:

Officer In charge: (Checked by)

Date:

83

MBR-xxxxxx X ######## xxxxxx

Guide to Master Formulae Guidance Document Company Logo

COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx CONTROLLED BATCH MANUFACTURING RECORD DOCUMENT Filling Building # __ Department Name Page No Page ___ of ____ Title Product Name Short Text Product Code

Blending, Filling, Lyophilization and Sealing Product X X dose Lyophilised xxxxxxx

Document No Version No Process Order Batch No

MBR-xxxxxx X ######## xxxxxx

INDEX No Description

Page No

Summary of Process Summary of Activities Batch Formulation Thawing of Bulk Antigen Lyophilizer Trays Processing Rubber Stopper Processing Processing Product contact Material for Pooling & Filling Vial Processing Room Pressure Recording Preparation of Lyophilizer Verification of Bulk Antigen Container Weights. Pooling & Clarification of Thawed Bulk and Preparation of Final Bulk Integrity Testing of Product Filter Filling Integrity Test of Vent Filters Loading of Lyophilizer Lyophilization Aluminum cap processing Sealing of vials Material Reconciliation record Bulk reconciliation record BMR Certification

Officer In charge: (Checked by)

Date:

84

Guide to Master Formulae Guidance Document Company Logo

COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx CONTROLLED BATCH MANUFACTURING RECORD DOCUMENT Filling Building # __ Department Name Page No Page ___ of ____ Title Product Name Short Text Product Code

Blending, Filling, Lyophilization and Sealing Product X X dose Lyophilised xxxxxxx

Document No Version No Process Order Batch No

MBR-xxxxxx X ######## xxxxxx

The entire activity has the following major steps: Day No

1


2.

Cleaning and Sterilization of Lyophilizer Trays




3.

Sterilization and Drying of Rubber Stoppers




4.

Cleaning, Preparation and Sterilization of Material Required for Filling and Pooling













1.

Activity Thawing of Bulk Antigen

2

6.

Cleaning and Sterilization / Disinfection of Lyophilizer Washing and Sterilization of Vials

7.

Pooling and Clarification to Prepare ‘Final Bulk’




8.

Filling of Vaccine into Vials




9.

Loading of Filled Vials in the Lyophilizer and Lyophilization




10.

Sterilization and Drying of Aluminium Caps

11.

Sealing

5.

Day 1 Day before filling

Day 2 Day of filling

Day 3 Day after filling

3

4

5




Day 4 2nd day after filling

Day 5 3rd day after filling

Sealed vials with lyophilized vaccine are handed over to Screening Dept. for visual inspection.

Officer In charge: (Checked by)

Date:

85

Guide to Master Formulae Guidance Document Company Logo

COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx CONTROLLED BATCH MANUFACTURING RECORD DOCUMENT Filling Building # __ Department Name Page No Page ___ of ____ Title Product Name Short Text Product Code

Blending, Filling, Lyophilization and Sealing Product X X dose Lyophilised xxxxxxx

Document No Version No Process Order Batch No

MBR-xxxxxx X ######## xxxxxx

Pages 5 and 6 to be issued to Bulk section who will fill the details and send it back. Pages 25 To 27 to be issued to Lyophilization section who will fill the details and send it back. SUMMARY OF ACTIVITIES Target Lyophilizer Number Lyophilizer Batch Capacity Volume per vial Batch Volume as Dispensed by Bulk Mfg Dept Date of Filling Fill volume per vial (xx x xx) (Overfill mid point at +X %) Batch Volume as Rechecked by Filling Dept Theoretical Batch Size Approx Filling Yield. [Quantity loaded in Lyophilizer] Approx Sealing Yield. [Quantity transferred to screening]

XXXX Vials mL (23) L (24) dd/mm/yyyy mL (25) L Vials (28) Vials (22) Vials (19)

Note: Acceptable variation between 24 and 26 which is caused by removal of outer packaging / double bagging should not be more than ± X %

Activity: BATCH FORMULATION

Ref SOP No.: ______

Select the bulks for the batch on the basis of bulk Ag titre, volume, filling volume per vial, and batch size. Filling personnel* to cross check in terms of Weights on receipt.

Officer In charge: (Checked by)

Date:

86

Guide to Master Formulae Guidance Document Company Logo

COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx CONTROLLED BATCH MANUFACTURING RECORD DOCUMENT Filling Building # __ Department Name Page No Page ___ of ____ Blending, Filling, Lyophilization and Sealing Product X X dose Lyophilised xxxxxxx

Title Product Name Short Text Product Code Component

Bulk Ag No.

Limit XX L ± X% Set Ag Titre / vial Product X

Antigen Titre

Document No Version No Process Order Batch No Vol. ‘L’

MBR-xxxxxx X ######## xxxxxx *Gr Wt ‘kg’

Tare Wt ‘kg’

Actual Vol. L kg kg Volume Formulation: Dt: ___ Weighing: Dt: _____ / vial Done by Checked Done by Checked by by X mL

Remarks:Activity: THAWING OF BULKS

Ref SOP No.: ________________

The Bulks should be removed for thawing not more than xx Hours prior to estimated time of start of filling. THAWING DETAILS Particulars Product #12 Diluent Removed for thawing on (date) Location of cold room Bldg No Bldg No CR No CR No Removed for thawing at h h Incubator set temp ºC ºC (Range xx to xx °C) Thawing completed on (date) Thawing completed at h h Officer In charge: (Checked by)

Date:

87

Guide to Master Formulae Guidance Document Company Logo

COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Filling Building # __ Department: Page No Page ___ of ____ Blending, Filling, Lyophilization & Sealing Product X X dose Lyophilised xxxxxxx

Title Product Name Short Text Product Code No

Document No Version No Process Order Batch No

Handling of Bulk Antigen Containers Done By Name Initials

MBR-xxxxxx X ######## xxxxxx Date

1 2 3 4 Bulk Antigen Containers Received By: Remarks if any:

Activity:

LYOPHILIZER TRAY PROCESSING

Ref SOP No.: __________

1. Clean the trays to be used for collecting filled vials using a clean lint free mop wetted with WFI/xx % Isopropyl alcohol. 2. The trays can be processed in either of two ways. A) Load the cleaned trays on the dry heat sterilizer (DHS) trolley, as per validated max loading pattern in DHS No xxxx and sterilize at xxx°C, xxx minutes. B) Load the trays in Autoclave and sterilize at xxx °C ± x °C for XX minutes. No of Trays Pattern No Pattern No 3. If option A above is selected, run the cycle to hold the trays at xxx°C for xxx minutes. Normal variation –x ° to + x °C. 4. Write Product, B.No., Charge No & date on the sterilizer thermograph/printout (for Option A only) sign it and attach it to this BMR.

Officer In charge: (Checked by)

Date:

88

Guide to Master Formulae Guidance Document Company Logo

COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Filling Building # __ Department: Page No Page ___ of ____ Title Product Name Short Text Product Code

2

3 4

Document No Version No Process Order Batch No

Description of Activity

No 1

Blending, Filling, Lyophilization & Sealing Product X X dose Lyophilised xxxxxxx

Done By

MBR-xxxxxx X ######## xxxxxx Checked By

No of trays cleaned Quantity for batches: ____ _______ Loaded ______ cleaned trays onto the trolley. Loaded in Sterilizer Load pattern no Charge No # xxxxxx xxxx xx # xxxxxx xxxx xx Checked Cycle parameters A) xxx °C, xxx minutes B) xxx °C ± x°C for xx minutes Sterilization temperature xxx °C achieved h at (applicable for option A above) Sterilization temperature xxx°C h maintained till (applicable for option A above)

Remarks:Activity: RUBBER STOPPERS PROCESSING

Ref SOP No: ___________

1. Verify that QC approved stoppers of correct type have been taken for de-cartoning. 2. For RFS stoppers, after de cartoning directly move to sterilization. 3. Load stoppers as per validated loading pattern given below. RFS Max No of stoppers / pouches xxxx Pattern No for Autoclave X xxxx Pattern No for Autoclave Y xxxx

Officer In charge: (Checked by)

Date:

89

Date

Guide to Master Formulae Guidance Document Company Logo

Department: Title

COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Filling Building # __ Page No Page ___ of ____

Product Name Short Text Product Code

Blending, Filling, Lyophilization & Sealing Product X X dose Lyophilised xxxxxxx

Document No Version No Process Order Batch No

MBR-xxxxxx X ######## xxxxxx

4. The stoppers can be processed in either of the two ways: A) Sterilization in Autoclave X (xxx to xxx °C) and drying in dry heat sterilizer (DHS) No ___ B) Sterilization and drying in Autoclave Y. In both the cases, carry out sterilization at 121°C for xxx minutes, Write Product, B. No., Charge No and date on the sterilizer printout / thermograph sign it and attach it to this BMR 5. If option A above is selected, then transfer the sterilized rubber stoppers from the autoclave to the DHS from clean room side for drying. Start drying cycle: xxx°C for xxx mins. Normal variation - x °C to + x °C/ ± x min. If option B above is selected then Sterilize stoppers at xxx °C ± x °C for xxx minutes followed by a drying cycle for xxx mins in the autoclave. In case of greater variation in temperature or time, the deciding factor will be the moisture content. Write Product, B. No., Charge No and date on the sterilizer thermograph /printout (for Option A only) sign it and attach it to this BMR. 6. Draw one sample for Moisture content analysis (Limit NMT xxx mg/stopper). In case stoppers of 2 batches are sterilized in 1 load, draw only 1 sample, record both batch nos on TRF, attach copies to both BMRs. A) Stopper input: xx mm, Lyo Grey Butyl Rubber 1) Unprocessed b/f: 2) Processed b/f: B. 3) Fresh quantity B. No________ No__________ issued

Actually Loaded for Sterilization 9) No of stoppers Pouches

Unprocessed

4) Fresh used from issue

Done by

5) Option for Process  A =1+2+4  B =1+4 Checked by Date

Remarks: Activity: RUBBER STOPPERS PROCESSING, cont'd

Ref SOP No.: ___________

7. Load pouches on the Autoclave trolley as per validated loading pattern. Officer In charge: (Checked by)

Date:

90

Guide to Master Formulae Guidance Document

Company Logo

COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Filling Building # __ Department: Page No Page ___ of ____ Blending, Filling, Lyophilization & Sealing Product X X dose Lyophilised xxxxxxx

Title Product Name Short Text Product Code Autoclave No. / Equipment No. ######## #########

Charge No.

XX XX

DHS No / Equip No

Load Pattern No.

Program No.

XX XX

Quantity for 1 / 2 batches

Done by

Checked by

Date

X X

####################

Drying temperature xxx °C for xxx minutes for drying in DHS

Achieved at :

MBR-xxxxxx X ######## xxxxxx

Document No Version No Process Order Batch No

Charge No.: Done by

X Checked by

Date

h

Maintained till: h Sample for Moisture Content (11)

Nos.

NOTE: Filling activity should not be started before the result of moisture content estimation is received from Q.C. Remarks: Activity: PROCESSING PRODUCT CONTACT MATERIAL FOR POOLING AND FILLING Ref SOP No.: _______________________ 1. Use filters based on the following table for B. Size for Filtration> xx L 2. Carry out pre-filtration integrity test using the following data

Officer In charge: (Checked by)

Date:

91

Guide to Master Formulae Guidance Document Company Logo

COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Filling Building # __ Department: Page No Page ___ of ____ Blending, Filling, Lyophilization & Sealing Product X X dose Lyophilised xxxxxxx

Title Product Name Short Text Product Code

Document No Version No Process Order Batch No

MBR-xxxxxx X ######## xxxxxx

INTEGRITY TESTING OF xx µm FILTER Make

Name

Part No

Quantity/ batch

Bubble Point A B

Diffusion Tst pr. Rate

XXXX

xx 1 xx 2 xx 3 YYYY yy 1 yy 2 No bubbles at ‘A’, Bubbles should be seen