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

Transcription

1 WHO/FWC/IVB/QSS/VQR 2011

2 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. 1

3 GUIDE TO MASTER FORMULAE Table of Contents: 1) Introduction 4 2) Terms for Master Formula (MF) 4 3) Definitions of Batch / Lot 5 4) Master Formulae needed 5 5) GMP guidelines on master documentation 5 6) Required Contents of a MF 6 7) MF and corresponding Batch Records 11 8) Formats for MF 11 9) Issuing of MF copy as a blank batch record 12 10) Electronic MF and Batch Records 13 11) Batch Records versus Master Formula 14 12) Batch record review checklist 14 2 Page 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.

4 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 Written procedures; deviations; and Subpart J--Records and Reports; Sec 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 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 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 3

5 1) Introduction Guide to Master Formulae 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

6 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. 5

7 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 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. 6

8 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. 7

9 Table A: Contents of Master Formulae Guide to Master Formulae WHO TRS 908 Annex 4 section The master formula should include name of the product, with a product reference code relating to its specification; 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; EU GMP Guideline (Jan 06) Section 4.14 and 4.15 The Manufacturing Formula/Processing Instructions should include 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); 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; PICs document PE099 (Jan 06) section 4.14 and 4.15 The Manufacturing Formula/Processing Instructions should include 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); 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; 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); 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; the procedures, or reference to the procedures, to be used for preparing the critical equipment, e.g., cleaning (especially after a change in product), assembling, calibrating, sterilizing, etc. detailed 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; 8

10 where necessary, the requirements for storage of the products, including the container, the labelling, and any special storage conditions; Guide to Master Formulae 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 Formally authorized packaging instructions should exist for each product, pack size and type. These should normally include, or make reference to: EU GMP Guideline (Jan 06) Sections 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 PICs document PE099 (Jan 06) Sections 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: the name of the product; a) name of the product name of the product; a description of its pharmaceutical form, strength and, where applicable, method of application; b) description of its pharmaceutical form, and strength where applicable; description of its pharmaceutical form, and strength where applicable; 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 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; 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; 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 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; 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 f) special precautions to be observed, including a careful examination of the area and equipment in order special precautions to be observed, including a careful examination of the area and equipment in order special precautions to be observed, including a careful examination of the packaging area and 9

11 equipment in order to ascertain the line clearance before and after packaging operations; Guide to Master Formulae 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 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. 10

12 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

13 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

14 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

15 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. 14

16 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. 15

17 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 Documents should be approved, signed and dated by the appropriate responsible persons. No document should be changed without authorization and approval 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 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 Where documents require the entry of data, these entries should be clear, legible and indelible. Sufficient space should be provided for such entries 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 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 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. 16

18 Documents required Labels (sections not extracted) Specifications and testing procedures (sections not extracted) Specifications for starting and packaging materials (sections not extracted) Master formulae A formally authorized master formula should exist for each product and batch size to be manufactured 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 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; 17

19 (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 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.) 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 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; 18

20 (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 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.) 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 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; 19

21 (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. 20

22 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. 21

23 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 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; 22

24 d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable 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

25 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; 24

26 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) 25

27 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 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

28 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 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 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 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

29 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 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

30 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. 29

31 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 (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. 30

32 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 Interpretation 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 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

33 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 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 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 32

34 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; the correct functioning of line monitors; handling precautions applied to a partly packaged product; notes on any special problems, including details of any deviation from the packaging instructions with written approval by qualified personnel; the quantity, lot number, and/or analytical control number of each packaging material and bulk drug issued for use; and 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

35 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 Interpretation 2; 43.2 withdrawn against a packaging order; 43.3 issued and checked by persons who have the qualifications outlined under Regulation C 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

36 accordance with Interpretation 21, until released by the quality control department. 50. Every package of a drug is identified by a lot number. 35

37 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 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 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

38 (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 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 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

39 (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 (13) Results of examinations made in accordance with 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 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

40 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

41 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 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 ( , ). 40

42 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. 41

43 (Cont.) 42

44 (Cont.) 43

45 (Cont.) 44

46 (Cont.) 45

47 (Cont.) 46

48 (Cont.) 47

49 (Cont.) 48

50 Appendix 7: Example one of a Master Formula. COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 49 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## Lot Number Issued by (Q.A.) : Date : Production Manager : Date : Contents of Batch Manufacturing Record (BMR) (Note: page numbers are from original document) No. Description Page No. 1. Revival of lyophilized working cell bank 2 2. Transfer of revived culture to xx tube 3 3. Inoculation of Seed Bottle 4 4. Inoculation of Fermenter 5 5. Harvesting of Antigen X 7 6. Filtration details 9 7. Cleaning of system BMR certification 12 Preparation of seed culture: 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 (Approved by) Signature: Signature: 49

51 COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 2 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## 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. Checked by 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 Purity checked Checked by From To Date results Deviations if any: 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 (Approved by) Signature: Signature: 50

52 COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 3 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## Lot Number Microscopic observations (Gram staining). Material Quantity Lot No. Checked by XXXX agar tubes XXXX broth tubes XXXX medium tube Passage carried out on by. Incubation from to Purity test details. SOP No.: XXXX agar / broth tubes Purity checked incubated From To Date results Checked by Deviations if any: 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 (Approved by) Signature: Signature: 51

53 COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 52 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## Lot Number Purity test carried out as per. SOP No.: Material Quantity Lot No. Checked by XXXX agar tubes XXXX broth tubes XXXX agar / broth tubes Purity checked incubated From To Date results Checked by Deviations if any: 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 (Approved by) Signature: Signature: 52

54 COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 53 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## 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 Quantity Lot No. Checked by XXXX agar tubes XXXX broth tubes XXXX agar / broth tubes Purity checked incubated From To Date results Checked by 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.: Adjust the aeration and agitation as per SOP No.: Effective (Approved by) Signature: Signature: 53

55 COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 54 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## Lot Number AERATION AND AGITATION ADJUSTMENTS DURING INCUBATION Date Vibromixer Voltage Air Flow (LPM) Sign Required For XX Required For XX Adjusted to Required For XX Required For XX Adjusted to L L L L xxx xxx x x xxx xxx x x xxx xxx x x xxx xxx x x Deviation if any: 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 (Approved by) Signature: Signature: 54

56 COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 55 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## 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 Quantity Lot No. Checked by XXXX agar tubes XXXX broth tubes XXXX agar / broth tubes Purity checked incubated From To Date results Checked by Deviations, if any: 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 (Approved by) Signature: Signature: 55

57 COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 8 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## 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 Rate Collected (LPH) (L) Recirculation Details Observed/ Done by Bulk Antigen is transferred to the Non- culture wing. Bulk Antigen Lot No.: Filtration by XXXX System. Done by Effective (Approved by) Signature: Signature: 56

58 COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 9 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## 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 (Approved by) Signature: Signature: 57

59 COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 10 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## 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 (Approved by) Signature: Signature: 58

60 COMPANY A MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X Department XXXXXXXXXXXXX Page: 11 of 11 Process Step Revival of Working Cell Bank, Inoculation and Harvesting Product Name Bulk Antigen X Production Order: ###### Product Code ######## 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: 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 (Approved by) Signature: Signature: 59

61 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 PRODUCT X FILL SIZE x ml Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 60

62 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 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: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 61

63 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 1. BATCH RECORD REVIEW AND APPROVAL REPORT No Term Details 1 Name of the Product PRODUCT X 2 Batch No. 3 Date of Filling 4 Quantity Filled 5 Quantity Released 6 Mfg. Date 7 Exp. Date Reviewed by QA (Analyst/Officer): Approved by Head QA: 2. CHECKLIST OF BATCH RECORD: No Description Date Document availability checked by Production QA 1 Product X Vaccine Blending 2 Primary packing materials procurement 3 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: Signature of QA: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 62

64 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 3. QUALITY CONTROL REPORTS AND MISCELLANEOUS DOCUMENTS CHECK LIST: No Name of the Report Q.C Ref.No. Availability checked by 1 Formulation buffer 2 Final Blend report (1) 3 Final Blend report (2) 4 Filled vials report (1) 5 Filled vials report (2) 6 Thermo graphs of Autoclave NA 7 Vials Depyrogenation report NA 8 Membrane Integrity report NA 9 Environmental monitoring report NA 10 Particle count report NA 11 NCL report NA 12 WFI report of blending port NA 13 WFI report of washing port NA Production QA Signature of Supervisor: Signature of Quality Assurance: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 63

65 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 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 Bulk antigen requirement for blend: Antigen requirement: Calculate the antigen requirement for the blend as per SOP # Blend volume in ml (A) Total antigen required in mg (A x XX) / 1000 Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 64

66 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 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 Solution #1 (FS#1) requirement for the blend: 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) Details of Formulation Solution #1 (FS#1) No. Batch No. Q.C. Ref. No. and Date FS#1 content (mg/ml) (A) Volume in ml (B) Total FS#1 in (mg) (A x B) as mentioned above Signature of Supervisor: Total volume Total round off to Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 65

67 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 4.5 Requirement of Formulation Solution #2(FS#2) for the blend: Formulation Solution # (FS#2) requirement: Refer SOPs# Blend volume In (ml) A Total Bulk Volume (ml) B Total FS#1 Volume (ml) C Required quantity of FS#2 (ml) D = A- (B+C) 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 Details of blending: Ingredient Temp of Spec. Volume Added Checked Date vessel o C o C/ % added by by FS#1 as per xx to xx o C FS#2 as per xx to xx o C Bulk antigen as per xx to xx o C Stirring (%) xx xx % Stirring start time:. End time: (stirring time specifications: X to X hrs) Signature of Supervisor: Signature of Quality Assurance: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 66

68 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 4.6 Final blend sampling details: For sample collection, labeling, storage details refer SOP# Sampled Quantity Sampled by Date / Time Tests to be done SOP. No. / Spec No. QC Ref. No. / Date Description ph XXX content xx ml XXX content Bacterial Endotoxins (LAL) Sterility XXX Potency Signature of Supervisor: Signature of QA: Report Date 5. PRIMARY PACKING MATERIALS PROCUREMENT: No Name of material Spec. No. AR. No. Quantity required Quantity issued by store Quantity received Checked by Production supervisor 1 X ml vials 2 xx mm grey butyl stoppers 3 xx mm aluminium seals Remarks (if any): Signature of Supervisor: Signature of QA: Q.A. in charge Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 67

69 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 6. WASHING AND STERILIZATION OF STOPPERS AND FILLING ITEMS: 6.1 Stoppers details: Size: xx mm Colour: grey butyl 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: Treatment of stoppers: Treatment procedure of stoppers as per SOP # 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) Details of TS#1 treatment: (Final TS#1 concentration should be xx mg/ml) No Ingredient STP.No./ Spec.No. A.R. No. Qty Required 1 TS#1 xxx mg 2 WFI NA xxxx ml Qty weighed Weighed by Checked by Volume of TS#1 solution prepared Volume of TS#1 solution used Volume of TS#1 solution discarded Excess TS#1 solution discarded by: Checked by: TS#1 treatment of stoppers done by: Date Checked by: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 68

70 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 mm Grey butyl rubber Stopper washing particulars: Stopper washing, WFI inspection procedure refer SOP # Drain water of Stopper washing machine checked by Lot No I Washing details: No Date Operator involved in washing 1 st rinse 2 nd rinse 3 rd rinse Washing Start End Time Time Qty Washed. Final rinse drain water inspected by Details of Stopper Collection into S.S cans for Stopper Lot No I: Can No Date S.S can cleaned by No. of stoppers collected Collected by Thiomersal solution Volume added Added by Checked by Repeat as necessary for as many lots of Stoppers that are required Sterilization of stoppers: Sterilization procedure of stoppers and sterilization by autoclave refer SOP # Equipment particulars: Name of the Machine and AUTOCLAVE XXXXXXX Make I.D. No. ####### Validation Done on: Due on: Cleaned by: Checked by: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 69

71 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 Details of stopper sterilization as per load pattern No.: 1 Date Load No. Can No Qty Loaded by Sterilization temp Sterilization time Signature of Supervisor: Specs. Unloaded by 6.2 Details of filling accessories sterilization as per load pattern No 2 Washing and sterilization of filling accessories refer SOP# Date Load No. Items Qty Washed & Loaded Sterilization temp Sterilization time Specs. Filling # sets / glass syringes Stopper # Bowl Chute # Picker # wheel Section # wheel Glass # syringes Forceps # Silicon # tubes 20 L # vessel SS tray # by xx min at XX o C Unloaded by Checke d by Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 70

72 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 Signature of Supervisor: 6.3 Details of garments, gloves and wipes sterilization as per load pattern No 3 Dat e Loa d No. Items Garmen ts Gloves Wipes Mask Qt y Loade d by Sterilizati on temp Sterilizati on time Specifi c-ation xx min at XX o C Unloade d by Checke d by Signature of Supervisor: 6.4 Fumigation of blending and filling area: Fumigating procedure refer SOP# Area Date Formaldehyde Quantity WFI Quantity Fumigation done by From Time To Checked by Signature of Supervisor: Signature of QA: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 71

73 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 7. WASHING AND DEPYROGENATION OF VIALS. 7.1 Washing of vials: Vial washing, inspection and depyrogenation procedure as SOP # 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/cm 2 ) Water pressure: (Spec x to x Kg/cm 2 ) Final rinsing WFI Temperature: (Spec xx to xx o C) Flow of water in all needles Flow of air in all needles Checked by Date & Time Signature of Supervisor: Vial washing particulars: LAFU I.D. No: ############# Date WFI sample Time of washing inspected by Start Time End Time Vials loaded by Validation Due on: Washing machine operated by Total No. of vials Washed No. of vials broken Total Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 72

74 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 Washed vials inspection (For particles): (Frequency every x hours) Date Time Checked by Remarks Signature of Supervisor: 7.2 Depyrogenation of vials: Machine particulars: Equipment Name and Make XXXXXXX I.D. No. ######## Validation Done on: Due on: Cleaned by: Checked by: Date Depyrogenation Details: Tunnel start time Set Temp O C Heater 1 Heater 2 Heater 3 Heater 4 Depyrog'n Tem p O C (> X) Tim e Min. ( x) Tunne l stop time Tunnel Drive mm/min < xxx Temp monitore d by Depyrog'n data enclosed Yes/no Checked by Quantity depyrog'd Signature of Supervisor: Date : Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 73

75 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 8.1 Filling line clearance : line clearance as per SOP# LAFU I.D. No: ######### Validation Due on: Machine particulars and line clearance details: Equipment Name Filling Machine Stoppering Machine Sealing Machine Make XXXXX XXXXX XXXXX I.D. No. ######## ######## ######## Room No. Validation done on Validation due on Cleaned by Checked by Sterilization indicators on stoppers, filling items, garments etc Checked by Verified by QA Filling area cleanliness Fumigation details Line clearance for filling given by QA: 8.2 Filling operation particulars: Filling Operation: Filling operation refer SOP # Filling Operation Details: Filling Date Time Machine operator Stoppering Machine operator Sealing Machine operator Filled vials collected by Signature of Prod. Shift in charge Signature of QA. Shift in charge Signature of Supervisor: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 74

76 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 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 Signature of Supervisor: 8.4 Volume variation check during filling: xx - xx Filling operation: Filling operations, start up activities refer to SOP # and to annex for fill volume standards. Volume variations action limits refer SOP# Volume check up Details: (Frequency every x to x hours) Filling 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 No Date Time Nozzle Nozzle Nozzle Nozzle No-1 No-2 No-3 No-4 Start up volume checks in (ml) Nozzle No-5 Nozzle No-6 Checked by Remarks In process Volume checks during filling in (ml) Signature of Supervisor: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 75

77 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 8.5 Filling area monitoring: (Frequency every x hours) Filling Starting time: Pack size: X ml Closing time: Date Time Temp ( o C) Spec ( o C) Humidity (%) Spec (%) Checked by Signature of Supervisor: xx to xx o C xx to xx% 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 Interference/Deviation Recorded By Checked 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: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 76

78 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 8.7 Filled vials sampling details for QC: Collection of samples Refer SOP# and for number of samples Refer SOP Date Sampled Quantity xx Vials Sampled by QA Report checked by Prod. Report verified by QA Signature of Supervisor: Tests to be done SOP/ Spec. QC Ref. / Date Description Identity ph XX content XX content Abnormal toxicity on guinea pigs Abnormal toxicity on mice Report Date Sterility Bacterial endotoxins (LAL test) Potency Closure integrity test Signature of Quality Assurance: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 77

79 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 8.8 Calculation of practical yield: Theoretical Total Process Loss (B) Yield (A) = Batch Vol. Filling Vol Description Volume in ml Equivalent vials 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 Filled Quantity (C) No. of samples for Q.C. Testing (D) xx Quantity transferred to Visual inspection E = C- D 9. PRIMARY PACKING MATERIALS RECONCILIATION: Name of Material XX ml Vials Stoppers xx mm grey butyl Seals xx mm Quantity issued Total Quantity used Quantity Returned to stores Process loss Quantity % Spec (%) x x x Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 78

80 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 REMARKS (if any): Signature of Supervisor: Signature of Quality Assurance: 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: Signature of Quality Assurance: 11. VISUAL INSPECTION OF VIALS: 11.1 Line clearance for visual inspection: Refer Line clearance SOP# Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 79

81 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 Cleaning of visual inspection area: Cleaning procedure refer SOP # Area cleaned by: Line Clearance Details: No Previous product Present product Batch Pack Batch No. size No. Pack size Previous product material cleared off from the area Yes /No Checked. By Checked by: Line clearance given by QA Date Time Signature of Supervisor: Signature of Quality Assurance: 11.2 Reconciliation of vials after Visual inspection: refer SOP# Quantity Received for Visual inspection: Reconciliation Details: No Date Time From To Total Passed Quantity Tested by Checked by Passed Quantity random checked by Passed Quantity Rejected vials as per possible defects Less volume (A) Glass pieces (B) Other particles (C) Total rejected Quantity % rejection Specification of optical rejection: x % Cap Closures defects (D) Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: Total (A+B+C+D) 80

82 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 Good Quantity transferred to labeling after Visual inspection: Signature of Supervisor: 12. DISCARD NOTE: Date Item Quantity Reasons for destruction Formulation Solutions Glass Vials xx mm stoppers xx mm flip top seals Visual inspection rejections Signature of Supervisor: Signature of Quality Assurance: Destruction approved by Destroyed by Destruction Supervised by Production QA Signature of Quality Assurance: 13. BATCH ACCOUNT: 13.1 Details of batch account: 1 Theoretical yield 2 Filled quantity (b) 3 No. of vials given for Q.C + other samples 4 No. of vials given for visual inspection Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 81

83 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 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 Batch packing details: P.R.No. Date Breakages Quantity Packed Total Signature of Supervisor: No. of Samples Quantity Transferred Quantity remaining Signature of Quality Assurance: Signatures: Effective Written by: Revision number: Reviewed by: Approved by Q.A.: 82

84 Company Logo Appendix 9: Example three of a Master Formula. COMPANY C Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department Name Filling Building # Page No Page 83 of 119 Title Blending, Filling, Document No MBR-xxxxxx Lyophilization and Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process ######## Order Product Code xxxxxxx Batch No xxxxxx Issued By (Q.A ): Production Manager: Officer In charge: (Checked by) 83

85 Company Logo COMPANY C Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department Name Filling Building # Page No Page of Title Blending, Filling, Lyophilization and Document No MBR-xxxxxx Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx No Description INDEX 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 Page No Officer In charge: (Checked by) 84

86 Company Logo COMPANY C Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department Name Filling Building # Page No Page of Title Blending, Filling, Lyophilization and Document No MBR-xxxxxx Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx The entire activity has the following major steps: Activity Day No Thawing of Bulk Antigen 2. Cleaning and Sterilization of Lyophilizer Trays 3. Sterilization and Drying of Rubber Stoppers Cleaning, Preparation and Sterilization of Material Required for Filling and Pooling Cleaning and Sterilization / Disinfection of Lyophilizer 6. 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 Day 1 Day 2 Day 3 Day 4 Day 5 Day before Day of filling Day after filling 2 nd day after 3 rd day after filling filling filling Sealed vials with lyophilized vaccine are handed over to Screening Dept. for visual inspection. Officer In charge: (Checked by) 85

87 Company Logo COMPANY C Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department Name Filling Building # Page No Page of Title Blending, Filling, Lyophilization and Document No MBR-xxxxxx Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No 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 XXXX Lyophilizer Batch Capacity Vials Volume per vial ml (23) Batch Volume as Dispensed by Bulk Mfg Dept L (24) Date of Filling dd/mm/yyyy Fill volume per vial (xx x xx) (Overfill mid point at +X ml (25) %) Batch Volume as Rechecked by Filling Dept L Theoretical Batch Size Vials (28) Approx Filling Yield. [Quantity loaded in Vials (22) Lyophilizer] Approx Sealing Yield. [Quantity transferred to Vials (19) screening] 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) 86

88 Company Logo COMPANY C Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department Name Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization and Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Component Bulk Ag No. Antigen Titre Vol. L *Gr Wt kg Tare Wt kg Limit XX L ± X% Actual Vol. L kg kg Set Ag Titre / vial Volume Formulation: Dt: Weighing: Dt: Product X / 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 CR No Bldg 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) 87

89 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx No Handling of Bulk Antigen Containers Done By Date Name Initials 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) 88

90 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx No Description of Activity Done By 1 No of trays cleaned Quantity for batches: 2 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 3 Sterilization temperature xxx C achieved h at (applicable for option A above) 4 Sterilization temperature xxx C h maintained till (applicable for option A above) Remarks:- Checked By Date 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) 89

91 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization & Sealing Document No MBR-xxxxxx Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No 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: B. No 2) Processed b/f: B. No 3) Fresh quantity issued 4) Fresh used from issue 5) Option for Process A =1+2+4 B =1+4 Actually Loaded for Sterilization Unprocessed Done by Checked by Date 9) No of stoppers Pouches 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) 90

92 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Autoclave No. / Equipment No. Charge No. Load Pattern No. Program No. ######## XX XX X ######### XX XX X Quantity for 1 / 2 batches Done by Checked by Date DHS No / Equip No #################### Charge No.: Drying temperature xxx C for xxx minutes for drying in Done by DHS Achieved at : h Maintained till: h Sample for Moisture Content (11) Nos. X Checked by Date 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) 91

93 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx INTEGRITY TESTING OF xx µm FILTER Make Name Part No Quantity/ Bubble Point Diffusion batch A B Tst pr. Rate XXXX xx 1 xx 2 xx 3 YYYY yy 1 yy 2 No bubbles at A, Bubbles should be seen < B, Units: BP, Diffusion Pr: Bar, rate: ml/min A) Pre-Sterilization Integrity Testing Application Stage Method Equipment Equipment No Test Type Step A Presteriliz n Manual XXXX Bubble Pt Auto XXXX Diffusion Filter Details Mfg/ Brand Part No Pore Size Wetting Liq. Test Parameter XXXX xx um WFI XXXX Filter Lot No Remarks:- Filter S. No Observation Result Done by Bubbles Printout seen at attached bar Check by Date Officer In charge: (Checked by) 92

94 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization & Sealing Document No MBR-xxxxxx Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Activity: PROCESSING PRODUCT CONTACT MATERIAL FOR POOLING AND FILLING Ref SOP No.: 1. Inactivation: Inactivate the Material used for Pooling and Filling in the Autoclave by heating it to xxx C for x minutes. Record in the autoclave Log Book. (Variation xx C to xx C). 2. Preparation: Unload the inactivated material from the Autoclave on the Washing room side; Wash inactivated material by passing Cooled WFI. Draw a sample from the tanks & check conductivity. Draw samples from Tanks, Silicon tube to header, Header, Syringes, needles & screen for particulates. In case the previous product is Media fill, draw additional samples submit to QC with Product Changeover TRF. On clearance wrap in sterilization pouches. 3. In case the vent filters on BV2 are new, carry out WIT and attach the results on opposite page. In case they continue from the previous day, the Post use integrity test of the previous batch will be treated as the pre-use integrity test of this batch. 4. Check the plan for the next day & select the loading pattern. Load the wrapped material on the autoclave trolley as per validated loading pattern. Attach a list of material sterilized, to this BMR. Write Product, B. No., Charge No and date on the sterilizer printout / thermograph (for Autoclave XX only) sign it and attach it to this BMR. Check xx ms/cm ms/cm Conductivity check on product tank rinse sample NMT 1 ms/cm BV1 BV2 Product C/O Done by Checked by NA ms/cm ms/cm TRF attached Date Officer In charge: (Checked by) 93

95 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Visual Inspection of Product Contact material rinse sample Item BV 1 BV 2 Silicon Header Syringe Needle tube Fibres Particles Sampled by: Screened by: STERILIZATION OF MATERIAL FOR POOLING AND FILLING 1 Autoclave No / Equip No ######### / ######## Done by Checked by 2 Load Pattern number XXX XXX 3 Charge No XX XX 4 Program No XXXXX XXXXX Remarks:- Date Activity: VIAL PROCESSING WASHING Ref SOP No.: 1. Verify that QC approved vials of correct type have been taken for de-cartoning. 2. De-carton the Vials, transfer them into clean SS trays and pass them to the washing area. 3. Ensure WFI cooling assembly is sanitized before commencing Washing of x st batch. Ensure pressure of Fresh and Recycled WFI and compressed air, conductivity of Fresh WFI are within limits. Ensure area is free of previous product vials. 4. Perform Test for Adequacy using X washed vials. 5. After operation is completed, drain the WFI assembly and clean the machine. Officer In charge: (Checked by) 94

96 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx A) Vial input: x ml, xx mm X xx mm height, (Amber, tubular, USP type-1) 1) Unprocessed b/f: B.No 2) Processed b/f: B.No 3) Fresh qty issued 4) Fresh used from issue Done By 5) Option for A= ) Taken for washing: - Process B=1+4 B Pre-washing and Washing operation checks: Done By WFI cooling ass ly sanitized Line Clearance Checked WFI Conductivity (NMT X ms/cm) WFI Temp (xx to xx C) Yes / No Yes / No ms/cm C Checked by Checked by Date Date Washing Media Outlet Fresh Recycled Comp. Air Pressure (Range Bar ) WFI WFI Set XXXXXXX xx - xx xx - xx xx-xx ########## Observed (Bar) Washing Started at : h Completed at: h Adequacy Sampled by Results Time Pass / Fail h C Vial Output (7) Sampled (8) Rejected For Sterilization 6 - (7+ 8) = 9 Unprocessed 18 = 3-4 Remarks Officer In charge: (Checked by) 95

97 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Activity: VIAL PROCESSING STERILIZATION Ref SOP No.: 1. At the start of washing activity, ensure there is enough paper in the printer and a fresh circular chart is placed in the recorder. Ensure that the set points of the Heater Banks of the Tunnel Sterilizer are as per the following chart. Charge no: SET TEMPERATURES OF HEATER BANKS Heater Bank No Temperature ºC S1 S2 S3 S4 S5 S6 S7 S8 Done by Checked by Date 2. At the start of washing for the day, after the vials have reached the exit gate of the sterilization zone, the conveyor of the Tunnel shall automatically stop for ten minutes. This event shall be printed by the controller. 3. The conveyor speed at the start of the washing i.e. till the vials reach the infeed of the filling machine should be xx Hz. Thereafter it will automatically switch to xx Hz. This event shall be printed by the controller. No Description of Activity Time Done By Checked Date by 1 Tunnel sterilizer started at h 2 Minimum set temperature (xxx o C) achieved at 3 xx Minute hold 4 Tunnel Set to Night operation (Process End) h to h* h h Officer In charge: (Checked by) 96

98 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx 4. Attach the printout and circular chart to the BMR. Operators Washing and Sterilization:- Remarks: - * x st / x nd batch of the day. Activity: VIAL PROCESSING STERILIZATION, continued Ref SOP No.: 1. Check the pressures of the three zones of the tunnel, at least once, preferably at start of washing. If the pressures are not within the range given below, immediately stop washing activity and inform the Officer in charge. 2. At the end of washing, perform sanitization of the bulk WFI cooling assembly. 3. Write the Product, B. No., Charge no and date on the sterilizer printout / graph, sign it and attach it with this page of BMR. CHART SHOWING THE PRESSURES OF THE VARIOUS ZONES OF THE TUNNEL #XXX Drying Zone Sterilization Zone Cooling Done by Checked Pressure Range (P1) mm wg (P2) mm wg Zone (P3) mm wg by Observed Observed xx --xx xx --xx xx --xx Time Remarks:- Officer In charge: (Checked by) 97

99 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Activity: ROOM PRESSURE RECORDING Ref SOP No.: 1. Record Room differential pressure before entering the clean area for pooling and filling. No Room & range Observed value (Pa) 1. PAL 1 (xx-xx) 2. PAL 2 (xx-xx) 3. PAL 3 (xx-xx) 4. Filling (xx-xx) 5. Tunnel Room (xx-xx) 6. Sealing (xx-xx) 7. Pooling (xx-xx) Done by Checked by Date Time Remarks: Activity: PREPARATION OF LYOPHILIZER Ref SOP No.: 1. After Unloading, Carry out cleaning of Lyophilizer and record in the BMR. 2. Carry out Sterilization / Disinfection as below: A week 1 denotes 6 working days with the day the Lyophilizer gets Steam Sterilized/Steamed being declared the 1 st day of the week and the batch filled after steam sterilization/ steaming the 1 st batch. If the third batch is to be loaded later than the 6 th day of the week, it is treated as the first batch of the next week. The gap between Sterilization/disinfection step and loading should not be more than xx hours. Officer In charge: (Checked by) 98

100 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx For Lyophilizer No.: A, B, C Batch Before Loading /week 1 1 st batch of week 2 nd batch of week 3 rd batch of week Lyo A Lyo B, C Lyo A, B, C Lyo A, B, C 3 Steam Exposure xxx mins Steam Exposure xxx C, xx mins Disinfection with XXX Disinfection with XXX 2 Steam Exposure xxx mins Steam Exposure xxx C, xx mins Disinfection with XXX 1 Steam Exposure xxx mins Steam Exposure xxx C, xx mins In case there is a change of product, with the virus of the current product not in the present product, the lyophilizer should be sterilized. Display boards: Cleaned, ready for Steam Exposure, and Disinfected with XXX ready for evacuation after Steam Sterilization, Steaming and treatment with XXX respectively. No Description of Activity Done By 1 Lyophilizer No: - Cleaning done after unloading of Product /Batch. No.: 2 Strike out what is not used Steam Exposure Steam Exposure xxx mins xxx C, xx mins Remarks:- XX disinfection Checked by Date Officer In charge: (Checked by) 99

101 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Activity: VERIFICATION OF BULK ANTIGEN CONTAINER WEIGHTS No.: Ref SOP 1. Unwrap the outer packing of the thawed bulk antigen containers. 2. Check the Bulk antigen container numbers and record their gross Weights in the Batch Formulation Sheet. 3. Carry out surface disinfection and transfer them to clean room, through hatch. Net Weight of Formulation (Gross Tare on Page 5) Weight in g /ml (B) (From Page 20) (Same as kg /L) Net Volume of formulation (Net Wt / kg/l) kg kg/l (26) L Remarks:- Done by Checked by Activity: POOLING & CLARIFICATION OF THAWED BULK AND PREPARATION OF FINAL BULK Ref SOP No.: Date 1. The contents of the Bulk antigen containers are pooled in a sterilized, SS blending vessel, with the jacket at a temperature NMT XX C. Start the magnetic stirrer (xxx to xxx rpm) after the level of bulk antigen inside the tank has gone above the impeller. If the temperature of the pool exceeds xx o C, immediately shut off the heating immersion circulator and the magnetic stirrer. 2. The pool of bulk antigens is clarified using a sterilized xx µm filter capsule/s. The outlet of the xx µm filter/s is connected to a 2 nd sterilized SS blending vessel with the jacket at a temperature of XX XX C. Clarification should be started only after the temperature of the pool is in the range of XX XX C for xx minutes. The contents of the second SS blending vessel will be the final bulk for the batch. Officer In charge: (Checked by) 100

102 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx No Particulars Done by Checked by Date 1 Bath temp before Pooling Pooling: xx-xx C Start End Blending vessel C h h A B 2 Temperature of Stirrer Clarification: A, B Pool Final RPM Start time End time xx - xx C Bulk xx - xx C xxx-xxx C C h h 3 Filtration Residue Sampled Bulk (30) (29) ml XX ml x X bottles = XX ml Remarks:- Activity: POOLING & CLARIFICATION OF THAWED BULK AND PREPARATION OF FINAL BULK Ref SOP No.: 1. Check the integrity of xx µm filter capsule by bubble point method. Connect the SS blending vessel with the final bulk to the glass header only after the integrity test is done and the filter capsule has passed the test. 2. Inactivation: Inactivate the Material used for Pooling in the Autoclave by heating it to XXX C for X minutes. (Variation permitted XX C to XX C). 3. Perform the environmental monitoring activities as per SOP No.:. This includes exposing settle plates, contact plates and Air sampling as per location map, Swabs of critical surfaces, Finger dabs of operators involved in pooling & filling operation. Officer In charge: (Checked by) 101

103 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx FILTER INTEGRITY TESTING Application Stage Method Equipment Equipment No Test Type Clarification Post-Clarific n XXXXX XXXXX ######## Bubble Pt Filter Details Mfg/ Brand Part No Pore Size Wetting Liq. Test Parameter Filter Lot No Pooling material Inactivation Filter S. No. Autoclave No: Observation: bar Result Done by Checked by Charge no: Done by Checked by Date Date Remarks:- Activity: FILLING Ref SOP No.: 1. Volume per vial (23) is indicated on page 5 of this BMR. The Volume per vial is the lower limit of the permitted volume range. The upper range is calculated by adding X % of the Volume per vial. The weight range is derived from this volume range by multiplying it with weight/ml of the bulk. Calibrate the balance to be used for verifying the Fill volume. 2. Check for absence of previous product components. Carry out the priming of the header and the pumps, collect the priming liquid and send as sample of final bulk to Q.C. Officer In charge: (Checked by) 102

104 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization & Document No MBR-xxxxxx Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx No Description of Activity Done by Checked by Date 1 Volume / Balance Line vial (23), XX Calibrated Clearance: Pg 5 ml YES / NO 2 Weight per ml Calculation Volume Wt (Bulk WFI) (C) Wt (Final bulk) (D) Wt/mL (D/C) = (B) XX ml g g 3 Volume Range to weight range setting Lower Vol. Limit (23) Upper Vol. Limit (23) x XXX=(E) Lower Wt Limit (23) x (B) Upper Wt. Limit (E) x (B) XX ml XX ml g g 4 Sampling for Visual Inspection (Sample size: XX vials) Fibre Black Part. White Part. Glass Total (%) 5 Filling activity : Filling machine XXXXXXXXX Room Started at Room Completed at Temp C h Temp C h Rh % Rh % Remarks: Officer In charge: (Checked by) 103

105 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Activity: FILLING Ref SOP No.: Rejection Quantity Vials (12A) Sample to QC Stopper (12B) (13) XX Total Loaded in Lyophilizer Done By Filled Appr. Vials Trays Vials (F) F- (G) (12A+13)=22 Checked by Date Stoppers rejection details (12B=R1+R2) Balance processed (17) During filling Balance in hopper Vials Nos (R1) (R2) Stoppers Nos No Description of Activity Done By Checked by Date 6 Rejection Inactivation details Autoclave No: Charge No: Operators: I Shift II Shift III Shift ID numbers of syringes used for filling Remark: STATION NUMBER Officer In charge: (Checked by) 104

106 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Activity: FILLING Ref SOP No.: 1. At the start of filling, reject the vials used for checking the centering of filling needles, volume setting etc. (Reject Not less than first xx vials). Syringe Number Attach Fill Volume Print or record manually, on weight basis, every xx Minutes Time (h) Officer In charge: (Checked by) 105

107 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Water bath temp xx-xx 0 C Done by *Checked by * Fill in case no printout is available, otherwise sign on printout Remarks:- Activity: INTEGRITY TESTING VENTS FILTERS Ref SOP No.: 1. On completion of the Filling activity, carry out integrity testing of the two vent filters (XXXX) of the Blending vessel tank attached to the filling machine by WIT method. 2. Fill the upstream side with WFI at xx-xx o C. A hold at xxxx mbar should not produce an intrusion rate greater than xxx ml/min. Officer In charge: (Checked by) 106

108 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx 3. Attach printouts below:- Remarks:- Officer In charge: (Checked by) 107

109 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Activity: LOADING OF LYOPHILIZER Ref SOP No.: 1. Ensure that the Lyophilizer to be loaded has been cleaned and Sterilized/disinfected, the date of loading should not be later than the date on the board (Page. no 16). 2. The trays containing filled and half stoppered vials are to be transported to the Lyophilizer in a mobile class 100 trolley. 3. Ensure that the temperature of the Lyophilizer shelves is xx ºC before loading of trays containing filled and half-stoppered vials. 4. After all the trays have been loaded in the lyophilizer, inform lyophilizer operator on duty. He will check the loading of the lyophilizer, insert product temperature probes and close the door of the lyophilizer. No Description of Activity Done by Checked by Date 1. Checked, that Lyophilizer is Sterilized / Disinfected 2. Checked that Class 100 trolley is Switched ON 3. Vials Loaded in Lyophilizer No: Remarks:- Vol. Per Vial (23) xx ml Lyo. No:- Loading date Recipe No. Sterilization Details (see page 15) For Filling Dept: Lyophilizer B, C: 1 st Batch Steam Steriliz n. Lyophilizer A: 1 st Batch Steaming. 2 nd Batch / 3 rd Batch All Lyophililzers XX disinfection Officer In charge: (Checked by) 108

110 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx LYOPHILIZER CHAMBER CLEANING, DISINFECTION AND STERILIZATION: 1. For Lyophilizers B and C, If Status board Cleaned, Ready for Steam exposure is displayed on clean room side, evacuate chamber to xxx mbar (Water ring vac pump: WP), followed by steam exposure at xxx - xxx C for xx minutes. 2. For Lyophilizer A, If Status board Cleaned, Ready for Steam exposure is displayed on clean room side, evacuate chamber to xxx mbar (WP), followed by steaming for xx mins. 3. Above steps are followed by drying of chamber with WP for minimum xx mins. 4. For all Lyophilizers, If status board Disinfected with XXX, Start evacuation is displayed on clean room side, carry out evacuation as per SOP (XXX cycle: xx min evacuation by vacuum pump with shelf at xx C). No Description of Activity Done By Date 1. Status board: Lyo B and C:'Cleaned, Ready for Steam Exposure Process xxx - xxx C maintained Process Start Start End End h h h h 2 Status board: Lyo A:Cleaned, Ready for Steam Exposure Vacuum Pull down Started xxx min Exposure Drying Start End Steam Start End End h h h h h h Drain temperature at the end of Steaming: C 3 Status board: Disinfected with XXX, Start evacuation Shelf temp. Evacuation with vac pump +xx C attained at Start End h h h 4. Display Board: Ready for Loading up to: Officer In charge: (Checked by) 109

111 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx 5. SHELF PRE-COOLING: (Set Shelf temperature: -xx C). yy C attained: h. Inform production dept. the achievement of yy C by displaying the status board indicating time of attaining temperature 6. CHECK LOADING OF VIALS ON SHELVES (SOP No.: ) No of shelves Loaded Loading end Time h No. of product temp. Probes Door closing time 7. LYOPHILIZATION CYCLE DETAILS Step Freezing Condenser cooling Chamber Evacuation Primary drying Shelf Temp - xx C NA NA -xx to xx C Start Time Date End Time Date Duration Norm h Sec. Drying xx C X / X x ± x h x h x h xx ± x h x ± x h X x ± x h x h x h 8 BATCH STOPPERING AND UNLOADING Ensure the following parameters before stoppering the vials. Avg. Product Temp Spec: xx ± x C Vacuum Spec: xx ± xx µbar Condenser Temp. Spec: - xx C C µbar C Stop the cycle and stopper the vials as per SOP No.. Time of Stoppering: h. xx h xx min ± x h Done / Checked By x ± x h Date Officer In charge: (Checked by) 110

112 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx 9 Chamber vacuum released by sterile air at h. Instruct production department to unload the vials after breaking the vacuum by air. DEVIATIONS DURING LYOPHILIZATION (if any): Activity: ALUMINUM CAPS PROCESSING Ref SOP No.: 1. Verify that QC approved Aluminum Caps of correct colour have been taken for decartoning. 2. Remove the outer package and transfer the inner plastic bag to the sterilizer loading area. 3. The caps can be processed in either of the two ways: A) Sterilization in Autoclave X and drying in dry heat sterilizer (DHS) XX; B) Sterilization and drying in Autoclave Y. If option A is selected, then transfer the caps into clean SS trays, load into the autoclave as per validated loading pattern and sterilize it at XXX C to XXX C for xx minutes. Pattern No 1 II No of Caps/trays 4. After sterilization, transfer the trays containing the Aluminium caps from the autoclave to the DHS via clean room side for drying at xxx C for xx mins Normal variation x C to + x C. 5. If option B is selected then process the caps at xxx C ± x C for xx minutes in the autoclave. 5. Write /verify Product, B. No., Charge No and date on the sterilizer thermograph / printout (for Option A only) sign it and attach it to this BMR. Officer In charge: (Checked by) 111

113 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx A) Aluminum Cap input: 13 mm, Colour Done by 1) Unprocessed b/f: 2) Processed b/f: 3) Fresh 4) Fresh B.No B.No quantity used issued from issued Nos Nos Nos Nos 5) Option of Process A = B =1+ 4 No Description of Activity Unprocessed quantity from this batch (18) (3-4) Nos 6) Taken for Sterility = 9 (For 1 / 2 batch/es) B) Loaded in Autoclave No. ################ Charge No. Load Pattern No Prog No. Checked by Date C) Aluminum Cap Drying at xxx C in DHS No: ########### Charge No. xxx C Achieved at xxx C Held till h h Remarks: -. Activity: SEALING OF VIALS Ref SOP No.: Lyophilizer Unloading: 1. After the lyophilization operator on duty has informed you about completion of lyophilization cycle, open the door of the Lyophilizer &unload the trays containing the lyophilized vaccine. Officer In charge: (Checked by) 112

114 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx 2. Clean and Sterilize/disinfect the lyophilizer. Record the same in the BMR of the batch to be loaded. Sealing Operation: 1. Carry out sealing operation on the vials unloaded from the Lyophilizer. 2. The trays containing the good sealed vials should be transferred to visual inspection department through the material transfer hatch. 3. The sealing rejection should be loaded in autoclave and heated at xxx ºC (xx to xxx o C) for x minutes and then unloaded from the autoclave from the washing room side. Unloading & line Clearance: Rejection in Lyo Sensor (14) Vials Rejection & inactivation details Empty vial (15A) Bad seal (15B) Approx. Vial for sealing (22)-(14) = (H) Description of Activity Sealing machine used XXXXXX XXXXXX Autoclave No: Breakage (15C) Vial, Stopper Rej 15A to 15C =(15D) Started (h) Charge No: Cap rej (15E) Sealing Completed (h) Processed Caps (17) Done By Checked by Date nos nos nos nos nos nos Approx No of Vials Handed Over To Visual Inspection Department H-15D= Trays Vials Officer In charge: (Checked by) 113

115 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx Vials Received by screening: Name: : (for Screening Dept) Activity: MATERIAL RECONCILIATION RECORD No Description Vial Stoppe r 1 Bal. Unprocessed Material b/f Quantity (18) Prod / Batch No 2 Bal. Processed Material b/f (19) Quantity Prod / Batch No 3 Fresh Material Issued Quantity 4 Quantity used from Fresh material Res. Doc No. Caps 5 Option for washing/sterilizing [A: 1+2+4, B: 1+4] A / B A / B A / B 6 Total Quantity for Washing or Transfer based on (5) 7 Sampled for Adequacy of Washing XX X X 8 Rejected during Washing or Transfer X X 8A Rejection in % [(8/6) x 100] Limit: 2% 9 Sterilized [6-(7+8)] 10 Quantity for Filling/Sealing (If 5: A, 10=9) (If 5: B, 10=9+2) 11 Sampled- Post Sterilization x x 12 Rejection- Filling stage x 13 Sampled- Filling stage xx xx xx Officer In charge: (Checked by) 114

116 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx 14 Rejection: Lyophilization stage x 15 Rejection: Sealing stage 16 Post Sterilization Sample and Rejection (Sum 11 to 15) 17 Bal. Processed Material Quantity c/f Prod/Batch No or ICN 18 Bal. Unprocessed Quantity Material [3-4] c/f Prod/Batch No or ICN 19 Quantity of vials for visual inspection 20 Variance * In No: [(1+2+3)-( )] In percent: [(In no)/(10-17)] x 100, 21 Consumption (1+2+3)-(17+18) *Permissible variance ± X % Vial and Cap, ± X % Stoppers Activity: BULK RECONCILIATION RECORD After the sealing activity is over, reconciliation on the basis of final bulk should be done to determine the percentage yield for the batch. No Description (A) (B) 22 Quantity of vials Loaded in Lyophilizer Vials 23 Volume per Vial as declared by Bulk Mfg Dept X ml 24 Batch Vol. dispensed by Bulk Mfg Dept L 25 Fill Volume X ml 26 Batch Vol. rechecked by Filling Dept L Officer In charge: (Checked by) 115

117 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Document No MBR-xxxxxx Lyophilization & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx 27 Post Clarification Yield [26-(29/1000)] L 28 Theoretical yield [(26) x 1000]/ (25) Vials 29 Blending & Filtration residue (29A=26-27) 29B=29A/25 ml Vials 30 Sample in Liquid Form [Filling stage] XX ml 31 Excess Volume Balance in Tank after filling ml 32 Total Liq Samples /Losses [32A= ] 32B =32A/ 25 ml Vials 33 Total Loss/Samples as vials (32B+16) Vials 34 Expected Yield 28-33B Vials 35 Final yield [(19) / (28B) x 100] (not less than XX%) % 36 Percentage Reconciliation [(19) / (34B) x 100] % Stage: Post Clarific n Filling Lyophiliz n and Sealing Total Calc x B / 28 [(28-29B)-22]/(28- (22-19) / 22 Sum of all 29B) Norm (NMT) x % x % x % x % Actual: Remarks: DEVIATION: Yes / No. If yes, Report date/s: Officer In charge: (Checked by) 116

118 COMPANY C Company Logo Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BATCH MANUFACTURING RECORD CONTROLLED DOCUMENT Department: Filling Building # Page No Page of Title Blending, Filling, Lyophilization Document No MBR-xxxxxx & Sealing Version No X Product Name Product X - - Short Text X dose Lyophilised Process Order ######## Product Code xxxxxxx Batch No xxxxxx 01. MANUFACTURING DEPARTMENT: BMR CERTIFICATION 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 acknowledge. 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 and 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 : : Officer In charge: (Checked by) 117

119 WHO Quality Safety & Standards of Vaccines and Biologicals WHO has played a key role in developing WHO guidelines and recommendations on the production and control of biological products and technologies. These recommendations are aimed to assist WHO Member States in ensuring the quality and safety of biological medicines worldwide, and are based on scientific consensus achieved through international consultations as well as involving close collaboration with the international scientific and professional communities, regional and national regulatory authorities, manufacturers and expert laboratories worldwide. Written guidelines and recommendations describe procedures for the manufacture and quality control testing of biological medicinal products to ensure safe and effective products. Guidance documents, like this one, provide more general information on a range of topics of interest to National Regulatory Authorities (NRAs) and manufacturers. It also advises NRAs and manufacturers on the control of biological products, with the aim of establishing a harmonized regulatory framework for products moving in international markets. 118