Guide to Master Formulae

Guide to Master Formulae

WHO/FWC/IVB/QSS/VQR

2011


Guidance Document

This guidance document GUIDE TO MASTER FORMULAE is one of a series developed by WHO/FWC/IVB Quality, Safety & Standards team upon request from the manufacturers’ members of the Developing Countries Vaccine Manufacturers Network

(DCVMN), with funds of USAID.

A set of priority topics have been identified by the manufacturers for WHO to provide guidance on expectations from the vaccine prequalification programme.

The guidance document GUIDE TO MASTER FORMULAE is targeted primarily at manufacturers who are new to the prequalification of vaccines and who require detailed guidance about the level of detail needed for the development of batch production records. It may also be a useful guide to National Regulatory Authorities (NRAs) in vaccine producing countries.

These are not official WHO documents but rather notes for guidance on expected standards to be followed for the prequalification of vaccines. They are based on WHO recommended requirements but providing further explanations with examples on how these can be actually implemented.

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GUIDE TO MASTER FORMULAE

Table of Contents:

1) Introduction

2) Terms for Master Formula (MF)

3) Definitions of Batch / Lot

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4) Master Formulae needed

5) GMP guidelines on master documentation

6) Required Contents of a MF

7) MF and corresponding Batch Records

8) Formats for MF

9) Issuing of MF copy as a blank batch record

10) Electronic MF and Batch Records

11) Batch Records versus Master Formula

12) Batch record review checklist

Appendix 1: Extract from: World Health Organization, Technical Report

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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.

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Appendix 5: Extracts from US Code of Federal Regulations (CFR) and US FDA

Guidelines.

App 5-1) US Regulations for Master Production Records for Finished

Pharmaceuticals. Extract from:

CFR 21, Chapter I, Subchapter F: Biologics, Part 211 Current Good Manufacturing

Practice for Finished Pharmaceuticals; Subpart F--Production and Process Controls,

Sec. 211.100 Written procedures; deviations; and Subpart J--Records and Reports;

Sec. 211.186 Master production and control records.

App 5-2) US Regulations for Batch Records for Finished Pharmaceuticals:

Extract from:

CFR 21, Chapter I, Subchapter F: Biologics; Subchapter C: Drugs General; Part 211

Current Good Manufacturing Practice for Finished Pharmaceuticals; Subpart J--

Records and Reports; Sec. 211.188 Batch production and control records.

App 5-3) US Regulations for Batch Records for Biological Products: Extract from:

CFR 21, Chapter I, Subchapter F: Biologics, Part 600 Biological Products: General; subpart B Establishment Standards, Sec 600.12 Records

App 5-4) US FDA Guidelines for Batch Records for Sterile Products: Extract from:

Guidance for Industry. Sterile Drug Products Produced by Aseptic Processing —

Current Good Manufacturing Practice. U.S. Department of Health and Human

Services, Food and Drug Administration, Center for Drug Evaluation and Research

(CDER); Center for Biologics Evaluation and Research (CBER); Office of

Regulatory Affairs (ORA). September 2004 (Pharmaceutical cGMPs).

Appendix 6: Sample master formula for a hypothetical biological product

Appendix 7: Example one of a Master Formula

Appendix 8: Example two of a Master Formula

Appendix 9: Example three of a Master Formula

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1) Introduction

In the 1997 WHO guidance document: “WHO/VSQ/97.01: (A WHO guide to good manufacturing practice (GMP) requirements. Part 1: Standard operating procedures and master formulae)” some basic explanations and instructions were given for preparing various documents required by Good Manufacturing Practice guidelines from WHO and from several regulatory authorities.

GMP guidelines include the requirements for documents (individual), documentation (the systems and formats for documents), and documenting (recording) of production and control activities. Most GMP guidelines provide the same or very similar information as the principles of Good Manufacturing Practice are now international in scope.

In this guidance document, the requirement for master manufacturing instructions and the requirements as given in different GMP documents, different names for these documents and various forms that they can take will be described. This is to guide vaccine manufacturers who are applying for prequalification or re-qualification of their product(s) in the preparation or improvement of current documents for manufacturing operations.

2) Terms for Master Formula (MF)

WHO identifies manufacturing instructions as “Master Formula. Other terms used in

GMP guidelines and regulations are “Manufacturing Formula”, “Master Production and

Control Record”, but all mean the same thing – an approved master document that describes the full process of manufacturing for the batch of product with at least crossreference to the support operations for a batch of a specific product. Individual companies may give internal names to these documents (manufacturing instructions, monographs, etc). In this guidance document the WHO term Master Formula (or MF) will be used.

The following are the extracted definitions from several guidelines:

• WHO GMP Guidelines: A formally authorized master formula should exist for each product and batch size to be manufactured.

• EU and PIC GMP guidelines: “Formally authorised Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document.”

• Health Canada GMP guidelines. MASTER FORMULA (formule-type) - A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a detailed description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls.

• US CFR. To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person. The preparation of

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Guidance Document master production and control records shall be described in a written procedure and such written procedure shall be followed.

3) Definitions of Batch / Lot:

A Master Formula is required for each batch and batch size. A “batch” or “lot” as defined in the WHO GMP guideline (TRS 908 Annex 4) is”

“ batch (or lot )

A defined quantity of starting material, packaging material, or product processed in a single process or series of processes so that it is expected to be homogeneous. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch. In the case of terminal sterilization, the batch size is determined by the capacity of the autoclave.

In continuous manufacture, the batch must correspond to a defined fraction of the production, characterized by its intended homogeneity.

The batch size can be defined either as a fixed quantity or as the amount produced in a fixed time interval”.

In general, the term “ batch ” more often refers to intermediates or final formulated bulks which are in one or a few large containers, while “ lot ” usually refers to the final product in the final container. They are, however, interchangeable as indicated in WHO’s GMP guideline glossary.

4) Master Formulae needed:

As above, batch or lot will refer to all production intermediates, final formulated bulks and final vialed product. Each master cell bank, viral seed lot, bulk concentrate or viral harvest if stored and tested before release for further processing is a batch and a master formula for its production is written and approved. Also, for different scales of production of any batch or lot, a distinct master formula is prepared.

For final container product, as explained in the WHO definition above, a final “lot” will be the product that is filled during the same continuous fill-run, and in the case of freezedried products, the filled vials lyophilized in the same lyophilizer at the same time. These should have unique numbers to identify them as having been processed exactly the same way at the same time. On occasion, when only a part of a large final bulk is filled, the lot numbers for these bulks may have a common identifier with a suffix (“-1” or “a”) to show the separate fills. Similarly, a large fill lot with a unique lot number may be lyophilized in different lyophilizers and the suffix would indicate the different freezedryer. A master formula for a batch/lot of product with the possibility to select one of several approved equipment items (e.g. a freeze dryer) should clearly indicate this choice and provide space for the unique lot number designation.

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5) GMP guidelines on master documentation

To show the consistency of requirements for Master Formulae, the sections on master documents and batch records have been extracted from various guidelines/regulations.

The extracted texts are provided in Appendices 1-5:

1) WHO:

World Health Organization Technical Report Series, No. 908, 2003, Annex 4.

Good Manufacturing Practices for Pharmaceutical Products: Main Principles

2) EU:

EUDRALEX; Volume 4 - Medicinal Products for Human and Veterinary Use:

Good Manufacturing Practice: Chapter 4: Documentation.

3) Pharmaceutical Inspection Convention (PIC):

Pharmaceutical Inspection Co-operation Scheme PE 009-3, 1 January 2006:

Guide to Good Manufacturing Practice for Medicinal Products. (© PIC/S January

2006)

4) Canada:

Health Canada, Health Products and Food Branch Inspectorate. Good

Manufacturing Practices Guidelines, 2002 Edition (Version 2).

5) USA:

US Code of Federal Regulations: Chapter 21, subparts 211 and 600.

And

US FDA: Guidance for Industry: Sterile Drug Products Produced by Aseptic

Processing — Current Good Manufacturing Practice. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER),

Office of Regulatory Affairs (ORA), September 2004. Pharmaceutical cGMPs.

6) Required Contents of a MF

Each of the regulation or guidelines above gives a list of the requirements for the contents of the MF. These are given in Table A for the Master (Production) Formula and Table B for the Master Packaging Formula for WHO, EU, PICs and Health Canada. Table C gives the contents Master Production and Control Records required by the USA.

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From Table A and B it is clear that the guidelines are harmonized and the requirements are formatted the same way and with the same or very similar text. The USA regulations cover the same information but in a different format and do not distinguish between production and packaging master formulae.

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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;

WHO TRS 908 Annex 4 section 15.23

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



Table A: Contents of Master Formulae

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);

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);

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

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Guide to Master Formulae 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.

Guidance Document where necessary, the requirements for bulk storage of the products; including the container, labelling and special storage conditions where applicable; any special precautions to be observed. where necessary, the requirements for bulk storage of the products; including the container, labelling and special storage conditions where applicable; any special precautions to be observed.

Table B: Contents of Master Packaging Formulae

WHO TRS 908 Annex 4

(2003) Section 15.24

Formally authorized packaging instructions should exist for each product, pack size and type.

These should normally include, or make reference to: the name of the product; a description of its pharmaceutical form, strength and, where applicable, method of application; 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; special precautions to be observed, including a careful examination of the packaging area and

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 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

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: name of the product; description of its pharmaceutical form, and strength where applicable; the pack size expressed in terms of the number, weight or volume of the product in the final container; a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications of each packaging material; where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf-life of the product; special precautions to be observed, including a careful examination of the area and equipment in order 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

Health Canada GMP

Guideline Version 2

(2002), section 25.

In the case of a packaged product, the master formula also includes for each product, package size and type, the following: the package size, expressed in terms of the number, weight, or volume of the product in the final container; a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types with the code or reference number relating to the specifications for each packaging material; an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product are to be positioned; special precautions to be observed, including a careful examination of the packaging area and

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Guide to Master Formulae equipment in order to ascertain the line clearance before and after packaging operations; a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; details of in-process controls with instructions for sampling and acceptance limits.

Guidance Document 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 to ascertain the line clearance before operations begin a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; details of in-process controls with instructions for sampling and acceptance limits equipment in order to ascertain the line clearance before operations begin; 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.

Table C: USA: Master Production and Control Records

USA 21 CFR 211:186

Master production and control records shall include:

The name and strength of the product and a description of the dosage form;

The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product, and a statement of the total weight or measure of any dosage unit;

A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic;

An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component. Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the master production and control records;

A statement concerning any calculated excess of component;

A statement of theoretical weight or measure at appropriate phases of processing;

A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation according to 211.192 is required;

A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling;

Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed.

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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.

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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.

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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

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Guidance Document procedures to be followed for electronic batch records. Specific guidelines on computer data entry and validation have been published by PIC and the US which can be consulted for detailed guidance.

For electronic batch records prepared by transcription from a hand-written record to a computer batch record requires additional verification that the computerized entries have been checked and are correct. This would require confirmation at the time of entry and again verified by QA.

11) Batch Records versus Master Formula

In the regulations and guidelines (see appendices 1-4) there are also requirements for completed batch records (for some reason never called “lot records”). The MF is essentially the blank batch record for the production operations as discussed in 7) above.

The batch record (BR often called Batch Processing Record BPR) is the MF with all data entered plus all the results of the supporting operations (in-process test results, environmental monitoring, autoclave records, etc).

Details of the contents of the Batch Record are found in Appendix 1 (WHO); Appendix 2

(EU); Appendix 3 (PIC); and Appendix 4 (Health Canada) and Appendix 5 (US).

12) Batch record review checklist

For a continuous production instruction MF, all the supporting operations are included as data fields or as cross-references within the document. For such a document, a list of the records sheets that are expected to be present in the batch record are itemized in a checklist which can also be a table of contents of the batch record.

For a production document using various SOPs to define the production process, the

Master SOP List may be essentially the same as the batch record checklist.

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Appendix 1: Extract from World Health Organization

WHO Technical Report Series, No. 908, 2003

Annex 4: Good Manufacturing Practices for pharmaceutical products: main principles.

From the Glossary batch records

All documents associated with the manufacture of a batch of bulk product or finished product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the final product. master formula

A document or set of documents specifying the starting materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls. master record

A document or set of documents that serve as a basis for the batch documentation (blank batch record). standard operating procedure (SOP)

An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material (e.g.: equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation.

15. Documentation

15.1 Principle . Good documentation is an essential part of the quality assurance system and, as such, should exist for all aspects of GMP. Its aims are to define the specifications and procedures for all materials and methods of manufacture and control; to ensure that all personnel concerned with manufacture know what to do and when to do it; to ensure that authorized persons have all the information necessary to decide whether or not to release a batch of a drug for sale, to ensure the existence of documented evidence, traceability, and to provide records and an audit trail that will permit investigation. It ensures the availability of the data needed for validation, review and statistical analysis.

The design and use of documents depend upon the manufacturer. In some cases some or all of the documents described below may be brought together, but they will usually be separate.

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General

15.2 Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorizations.

15.3 Documents should be approved, signed and dated by the appropriate responsible persons. No document should be changed without authorization and approval.

15.4 Documents should have unambiguous contents: the title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check.

Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.

15.5 Documents should be regularly reviewed and kept up to date. When a document has been revised, a system should exist to prevent inadvertent use of the superseded version.

Superseded documents should be retained for a specific period of time.

15.6 Where documents require the entry of data, these entries should be clear, legible and indelible. Sufficient space should be provided for such entries.

15.7 Any alteration made to a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.

15.8 Records should be made or completed when any action is taken and in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records should be retained for at least one year after the expiry date of the finished product.

15.9 Data (and records for storage) may be recorded by electronic data-processing systems or by photographic or other reliable means. Master formulae and detailed standard operating procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data-processing methods, only authorized persons should be able to enter or modify data in the computer, and there should be a record of changes and deletions; access should be restricted by passwords or other means and the entry of critical data should be independently checked. Batch records stored electronically should be protected by backup transfer on magnetic tape, microfilm, paper print-outs or other means. It is particularly important that, during the period of retention, the data are readily available.

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Documents required

Labels (sections 15.10-15.12 not extracted)

Specifications and testing procedures (sections 15.13-15.17 not extracted)

Specifications for starting and packaging materials (sections 15.18-15.21 not extracted)

Master formulae

15.22 A formally authorized master formula should exist for each product and batch size to be manufactured.

15.23 The master formula should include:

(a) the name of the product, with a product reference code relating to its specification;

(b) a description of the dosage form, strength of the product and batch size;

(c) a list of all starting materials to be used (if applicable, with the INNs), with the amount of each, described using the designated name and a reference that is unique to that material (mention should be made of any substance that may disappear in the course of processing);

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

(e) a statement of the processing location and the principal equipment to be used;

(f) the methods, or reference to the methods, to be used for preparing and operating the critical equipment, e.g. cleaning (especially after a change in product), assembling, calibrating, sterilizing, use;

(g) detailed step-wise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures);

(h) the instructions for any in-process controls with their limits;

(i) where necessary, the requirements for storage of the products, including the container, the labelling, and any special storage conditions;

(j) any special precautions to be observed.

Packaging instructions

15.24 Formally authorized packaging instructions should exist for each product, pack size and type. These should normally include, or make reference to:

(a) the name of the product;

(b) a description of its pharmaceutical form, strength and, where applicable, method of application;

(c) the pack size expressed in terms of the number, weight or volume of the product in the final container;

17



(d) a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications for each packaging material;

(e) where appropriate, an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product have been marked;

(f) special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before and after packaging operations;

(g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used;

(h) details of in-process controls with instructions for sampling and acceptance limits.

Batch processing records

15.25 A batch processing record should be kept for each batch processed. It should be based on the relevant parts of the currently approved specifications on the record. The method of preparation of such records should be designed to avoid errors. (Copying or validated computer programmes are recommended. Transcribing from approved documents should be avoided.)

15.26 Before any processing begins, a check should be made that the equipment and work station are clear of previous products, documents, or materials not required for the planned process, and that the equipment is clean and suitable for use. This check should be recorded.

15.27 During processing, the following information should be recorded at the time each action is taken, and after completion the record should be dated and signed by the person responsible for the processing operations:

(a) the name of the product;

(b) the number of the batch being manufactured;

(c) dates and times of commencement, of significant intermediate stages, and of completion of production;

(d) the name of the person responsible for each stage of production;

(e) the initials of the operator(s) of different significant steps of production and, where appropriate, of the person(s) who checked each of these operations (e.g. weighing);

(f) the batch number and/or analytical control number and the quantity of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added);

(g) any relevant processing operation or event and the major equipment used;

18



(h) the in-process controls performed, the initials of the person(s) carrying them out, and the results obtained;

(i) the amount of product obtained at different and pertinent stages of manufacture

(yield), together with comments or explanations for significant deviations from the expected yield;

(j) notes on special problems including details, with signed authorization for any deviation from the master formula.

Batch packaging records

15.28 A batch packaging record should be kept for each batch or part batch processed. It should be based on the relevant parts of the approved packaging instructions, and the method of preparing such records should be designed to avoid errors. (Copying or validated computer programmes are recommended. Transcribing from approved documents should be avoided.)

15.29 Before any packaging operation begins, checks should be made that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use.

These checks should be recorded.

15.30 The following information should be recorded at the time each action is taken, and the date and the person responsible should be clearly identified by signature or electronic password:

(a) the name of the product, the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained, the quantity actually obtained and the reconciliation;

(b) the date(s) and time(s) of the packaging operations;

(c) the name of the responsible person carrying out the packaging operation;

(d) the initials of the operators of the different significant steps;

(e) the checks made for identity and conformity with the packaging instructions, including the results of in-process controls;

(f) details of the packaging operations carried out, including references to equipment and the packaging lines used, and, when necessary, the instructions for keeping the product unpacked or a record of returning product that has not been packaged to the storage area;

(g) whenever possible, samples of the printed packaging materials used, including specimens bearing the approval for the printing of and regular check (where appropriate) of the batch number, expiry date, and any additional overprinting;

(h) notes on any special problems, including details of any deviation from the packaging instructions, with written authorization by an appropriate person;

19



(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



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



4.6 Documents should not be handwritten; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries.

4.7 Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.

4.8 The records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable. They should be retained for at least one year after the expiry date of the finished product.

4.9 Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data processing methods, only authorised persons should be able to enter or modify data in the computer and there should be a record of changes and deletions; access should be restricted by passwords or other means and the result of entry of critical data should be independently checked. Batch records electronically stored should be protected by back-up transfer on magnetic tape, microfilm, paper or other means. It is particularly important that the data are readily available throughout the period of retention.

Documents required

Specifications (sections 4.10 to 4.13 not extracted)

Manufacturing Formula and Processing Instructions

Formally authorised Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document.

4.14 The Manufacturing Formula should include: a) the name of the product, with a product reference code relating to its specification; b) a description of the pharmaceutical form, strength of the product and batch size; c) a list of all starting materials to be used, with the amount of each, described using the designated name and a reference which is unique to that material; mention should be made of any substance that may disappear in the course of processing;

22


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

4.15 The Processing Instructions should include: a) a statement of the processing location and the principal equipment to be used; b) the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising); c) detailed stepwise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures); d) the instructions for any in-process controls with their limits; e) where necessary, the requirements for bulk storage of the products; including the container, labelling and special storage conditions where applicable; f) any special precautions to be observed.

Packaging Instructions

4.16 There should be formally authorised Packaging Instructions for each product, pack size and type. These should normally include, or have a reference to, the following: a) name of the product; b) description of its pharmaceutical form, and strength where applicable; c) the pack size expressed in terms of the number, weight or volume of the product in the final container; d) a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications of each packaging material; e) where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf life of the product; f) special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin; g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; h) details of in-process controls with instructions for sampling and acceptance limits.

Batch Processing Records

4.17 A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and

Processing Instructions. The method of preparation of such records should be designed

23


Guidance Document to avoid transcription errors. The record should carry the number of the batch being manufactured. Before any processing begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use.

During processing, the following information should be recorded at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person responsible for the processing operations: a) the name of the product; b) dates and times of commencement, of significant intermediate stages and of completion of production; c) name of the person responsible for each stage of production; d) initials of the operator of different significant steps of production and, where appropriate, of the person who checked each of these operations (e.g. weighing); e) the batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added); f) any relevant processing operation or event and major equipment used; g) a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained; h) the product yield obtained at different and pertinent stages of manufacture; i) notes on special problems including details, with signed authorisation for any deviation from the Manufacturing Formula and Processing Instructions.

Batch Packaging Records

4.18 A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained.

Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use.

The following information should be entered at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person(s) responsible for the packaging operations: a) the name of the product; b) the date(s) and times of the packaging operations; c) the name of the responsible person carrying out the packaging operation; d) the initials of the operators of the different significant steps;

24


Guidance Document e) records of checks for identity and conformity with the packaging instructions including the results of in-process controls; f) details of the packaging operations carried out, including references to equipment and the packaging lines used; g) whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting; h) notes on any special problems or unusual events including details, with signed authorisation for any deviation from the Manufacturing Formula and Processing

Instructions; i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation.

Procedures and records (sections 4.19 to 4.29 not extracted)

25



Appendix 3: Extracted from PHARMACEUTICAL INSPECTION CONVENTION

PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME PE 009-3, 1

January 2006

GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS.

© PIC/S January 2006 (Reproduction prohibited for commercial purposes. Reproduction for internal use is authorised, provided that the source is acknowledged).

DOCUMENTATION

PRINCIPLE

Good documentation constitutes an essential part of the quality assurance system. Clearly written documentation prevents errors from spoken communication and permits tracing of batch history. Specifications, Manufacturing Formulae and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance.

GENERAL

4.1.

Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation.

Manufacturing Formulae, Processing and Packaging Instructions state all the starting materials used and lay down all processing and packaging operations.

Procedures give directions for performing certain operations e.g. cleaning, clothing, environmental control, sampling, testing, equipment operations.

Records provide a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent for the quality of the final product.

DOCUMENTS REQUIRED

MANUFACTURING FORMULA AND PROCESSING NSTRUCTIONS

Formally authorised Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document.

4.14. The Manufacturing Formula should include: a) the name of the product, with a product reference code relating to its specification; b) a description of the pharmaceutical form, strength of the product and batch size; c) a list of all starting materials to be used, with the amount of each, described using the designated name and a reference which is unique to that material;

26


Guidance Document mention should be made of any substance that may disappear in the course of processing; d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable.

4.15. The Processing Instructions should include: a) a statement of the processing location and the principal equipment to be used; b) the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising); c) detailed stepwise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures); d) the instructions for any in-process controls with their limits; e) where necessary, the requirements for bulk storage of the products; including the container, labelling and special storage conditions where applicable; f) any special precautions to be observed.

PACKAGING INSTRUCTIONS

4.16. There should be formally authorised Packaging Instructions for each product for pack size and type. These should normally include, or have a reference to, the following: a) name of the product; b) description of its pharmaceutical form, and strength where applicable; c) the pack size expressed in terms of the number, weight or volume of the product in the final container; d) a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications of each packaging material; e) where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf-life of the product; f) special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin; g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; h) details of in-process controls with instructions for sampling and acceptance limits.

BATCH PROCESSING RECORDS

4.17. A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and

Processing Instructions. The method of preparation of such records should be

27


Guidance Document designed to avoid transcription errors. The record should carry the number of the batch being manufactured.

Before any processing begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use. During processing, the following information should be recorded at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person responsible for the processing operations: a) the name of the product; b) dates and times of commencement, of significant intermediate stages and of completion of production; c) name of the person responsible for each stage of production; d) initials of the operator of different significant steps of production and, where appropriate, of the person who checked each of these operations (e.g. weighing); e) the batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added); f) any relevant processing operation or event and major equipment used; g) a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained; h) the amount of product yield obtained at different and pertinent stages of manufacture; i) notes on special problems including details, with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions.

BATCH PACKAGING RECORDS

4.18. A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained.

Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use.

The following information should be entered at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person(s) responsible for the packaging operations: a) the name of the product; b) the date(s) and times of the packaging operations; c) the name of the responsible person carrying out the packaging operation; d) the initials of the operators of the different significant steps;

28


Guidance Document e) records of checks for identity and conformity with the Packaging Instructions including the results of in-process controls; f) details of the packaging operations carried out, including references to equipment and the packaging lines used; g) whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting; h) notes on any special problems or unusual events including details with signed authorization for any deviation from the Manufacturing Formula and

Processing Instructions; i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation.

29



Appendix 4: Extract from Canadian GMP Guidelines.

Health Canada, Health Products and Food Branch Inspectorate

GOOD MANUFACTURING PRACTICES GUIDELINES, 2002 EDITION, Version 2

From the GLOSSARY:

MANUFACTURING BATCH DOCUMENT (fiche de lot de fabrication) - Instructions that outline in detail the materials and procedures required to fabricate, prepare, and preserve a single lot or batch of a drug in dosage form.

MASTER FORMULA (formule-type) - A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a detailed description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls.

MASTER PRODUCTION DOCUMENT (document-type de production) - a document that includes specifications for raw material, for packaging material and for packaged dosage form, master formula, sampling procedures, and critical processing related SOPs, whether or not these SOPs are specifically referenced in the master formula.

MANUFACTURING CONTROL

REGULATION

C.02.011

(1) Every fabricator, packager/labeller, distributor referred to in paragraph C.01A.003(b) and importer of a drug shall have written procedures, prepared by qualified personnel, in respect of the drug to ensure that the drug meets the specifications for use of that drug.

(2) Every person required to have written procedures referred to in subsection (1) shall ensure that each lot or batch of the drug is fabricated, packaged/labelled and tested in compliance with those procedures.

RATIONALE

This Regulation requires that a number of measures be taken to maintain the integrity of a drug product from the moment the various raw materials enter the plant to the time the finished dosage form is released for sale. These measures seek to ensure that all manufacturing processes are clearly defined, systematically reviewed in light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their established specifications.

30



MANUFACTURING MASTER FORMULA

23. Processing operations are covered by master formulae, that are prepared by, and are subject to independent checks by, persons who have the qualifications described under

Regulation C.02.006 Interpretation 1.

24. Master formulae are written to provide not less than 100% of label claim and include the following:

24.1 the name of the product, with a reference code relating to its specifications;

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

24.3 a list of all raw materials to be used, along with the amount of each, described using the designated name and a reference that is unique to that material (mention is made of any processing aids that may not be present in the final product);

24.4 a statement of the expected final yield, along with the acceptable limits, and of relevant intermediate yields, where applicable;

24.5 a statement of the principal equipment to be used;

24.6 the procedures, or reference to the procedures, to be used for preparing the critical equipment, e.g., cleaning (especially after a change in product), assembling, calibrating, sterilizing, etc.;

24.7 detailed stepwise processing instructions (e.g., checks on materials, pretreatment, sequence for adding materials, mixing times or temperatures, etc.);

24.8 the instructions for any in-process controls, along with their limits;

24.9 where necessary, the requirements for storage of the products, including the container, the labelling and any special storage conditions; and

24.10 any special precautions to be observed.

PACKAGING MASTER FORMULA

25. In the case of a packaged product, the master formula also includes for each product, package size and type, the following:

25.1 the package size, expressed in terms of the number, weight, or volume of the product in the final container;

25.2 a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types with the code or reference number relating to the specifications for each packaging material;

25.3 an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product are to be positioned;

25.4 special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before operations begin;

31



25.5 a description of the packaging operations, including any significant subsidiary operations and the equipment to be used; and

25.6 details of in-process controls, with instructions for sampling and acceptance limits.

MANUFACTURING BATCH DOCUMENT

26. Each batch processed is effectively governed by an individually numbered manufacturing order prepared by qualified personnel from the master formula by such means as to prevent errors in copying or calculation and verified by qualified personnel.

27. As it becomes available during the process, the following information is included on or with the manufacturing order:

27.1 the name of the product;

27.2 the number of the batch being manufactured;

27.3 dates and times of commencement and completion of significant intermediate stages, such as blending, heating, etc., and of production;

27.4 the batch number and/or analytical control number, as well as the quantity of each raw material actually weighed and dispensed (for active raw material, the quantity is to be adjusted if the assay value is less than 98% calculated on

“as is” basis and on which the master formula was based);

27.5 confirmation by qualified personnel of each ingredient added to a batch;

27.6 the identification of personnel performing each step of the process; and of the person who checked each of these steps;

27.7 the actual results of the in-process quality checks performed at appropriate stages of the process and the identification of the person carrying them out;

27.8 the actual yield of the batch at appropriate stages of processing and the actual final yields, together with explanations for any deviations from the expected yield;

27.9 detailed notes on special problems with written approval for any deviation from the master formula; and

27.10 after completion, the signature of the person responsible for the processing operations.

28. Batches are combined only with the approval of the quality control department and according to pre-established written procedures.

28.1 The introduction of part of a previous batch, conforming to the required quality, into the next batch of the same product at a defined stage of fabrication is approved beforehand. This recovery is carried out in accordance with a validated procedure and is recorded.

PACKAGING BATCH DOCUMENT

29. Packaging operations are performed according to comprehensive and detailed written

32


Guidance Document operating procedures or specifications, which include the identification of equipment and packaging lines used to package the drug, the adequate separation and if necessary, the dedication of packaging lines that are packaging different drugs and disposal procedures for unused printed packaging materials. Packaging orders are individually numbered.

30. The method of preparing packaging orders is designed to avoid transcription errors.

31. Before any packaging operation begins, checks are made that the equipment and work station are clear of previous products, documents, and materials that are not required for the planned packaging operations and that equipment is clean and suitable for use. These checks are recorded.

32. All products and packaging materials to be used are checked on receipt by the packaging department for quantity, identity and conformity with the packaging instructions.

33. Precautions are taken to ensure that containers to be filled are free from contamination with extraneous material.

34. The name and batch number of the product being handled is displayed at each packaging station or line.

35. Packaging orders include the following information (recorded at the time each action is taken):

35.1 the date(s) and time(s) of the packaging operations;

35.2 the name of the product, the batch number, and the quantity of bulk product to be packaged, as well as the batch number and the planned quantity of finished product that will be obtained, the quantity actually obtained and the reconciliation;

35.3 the identification of the personnel who are supervising packaging operations and the withdrawal of bulks;

35.4 the identification of the operators of the different significant steps;

35.5 the checks made for identity and conformity with the packaging instructions, including the results of in-process controls;

35.6 the general appearance of the packages;

35.7 whether the packages are complete;

35.8 whether the correct products and packaging materials are used;

35.9 whether any on-line printing is correct;

35.10 the correct functioning of line monitors;

35.11 handling precautions applied to a partly packaged product;

35.12 notes on any special problems, including details of any deviation from the packaging instructions with written approval by qualified personnel;

35.13 the quantity, lot number, and/or analytical control number of each packaging material and bulk drug issued for use; and

35.14 a reconciliation of the quantity of printed packaging material and bulk drug used, destroyed or returned to stock.

36. To prevent mix-ups, samples taken away from the packaging line are not returned.

33



37. Whenever possible, samples of the printed packaging materials used, including specimens bearing the batch number, expiry date, and any additional overprinting, are attached to packaging orders.

38. Filling and sealing are followed as quickly as possible by labelling. If labelling is delayed, procedures are applied to ensure that no mix-ups or mislabelling can occur.

39. Upon completion of the packaging operation, any unused batch-coded packaging materials are destroyed, and their destruction is recorded. A procedure is followed if non-coded printed materials are returned to stock.

40. Outdated or obsolete packaging materials are destroyed and their disposal is recorded.

41. Products that have been involved in non-standard occurrences during packaging are subject to inspection and investigation by qualified personnel. A detailed record is kept of this operation.

42. Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units packaged is investigated and satisfactorily accounted for before release. Validated electronic verification of all printed packaging materials on the packaging line may obviate the need for their full reconciliation.

43. Printed packaging materials are

43.1 stored in an area to which access is restricted to designated personnel who are supervised by persons who have the qualifications outlined under Regulation

C.02.006 Interpretation 2;

43.2 withdrawn against a packaging order;

43.3 issued and checked by persons who have the qualifications outlined under

Regulation C.02.006 Interpretation 2; and

43.4 identified in such a way as to be distinguishable during the packaging operations.

44. To prevent mix-ups, roll-fed labels are preferred to cut labels. Gang printing is avoided.

45. Cut labels, cartons, and other loose printed materials are stored and transported in separate closed containers.

46. Special care is taken when cut labels are used, when overprinting is carried out offline and in hand-packaging operations. On line verification of all labels by automated electronic means can be helpful in preventing mix-ups. Checks are made to ensure that any electronic code readers, label counters or similar devices are operating correctly.

47. The correct performance of any printing (e.g., of code numbers or expiry dates) done separately or in the course of the packaging is checked and recorded.

48. Raw materials, packaging materials, intermediates, bulk drugs and finished products are (a) stored in locations that are separate and removed from immediate manufacturing areas, and (b) transported under conditions designated by the quality control department to preserve their quality and safety.

49. All intermediate and finished products are held in quarantine and are so identified in

34


Guidance Document accordance with Interpretation 21, until released by the quality control department.

50. Every package of a drug is identified by a lot number.

35



Appendix 5: Extracts from US Code of Federal Regulations (CFR) and US FDA

Guidelines.

App 5-1) US Regulations for Master Production Records for Finished

Pharmaceuticals. Extract from:

CFR 21, Chapter I, Subchapter F: Biologics, Part 211 Current Good Manufacturing

Practice for Finished Pharmaceuticals;

Subpart F--Production and Process Controls:

Sec. 211.100 Written procedures; deviations.

(a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.

(b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.

Subpart J--Records and Reports

Sec. 211.186 Master production and control records

(a) To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person. The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed.

(b) Master production and control records shall include:

(1) The name and strength of the product and a description of the dosage form;

(2) The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product and a statement of the total weight or measure of any dosage unit;

(3) A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic;

36



(4) An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component.

Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the master production and control records;

(5) A statement concerning any calculated excess of component;

(6) A statement of theoretical weight or measure at appropriate phases of processing;

(7) A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation according to 211.192 is required;

(8) A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling;

(9) Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed.

Database Updated April 1, 2005

App 5-2) US Regulations for Batch Records for Finished Pharmaceuticals:

CFR 21, Chapter I, Subchapter F: Biologics; Subchapter C: Drugs General; Part 211

Current Good Manufacturing Practice for Finished Pharmaceuticals;

Subpart J--Records and Reports.

Sec. 211.188 Batch production and control records

Batch production and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch. These records shall include:

(a) An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed;

(b) Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including:

37



(1) Dates;

(2) Identity of individual major equipment and lines used;

(3) Specific identification of each batch of component or in-process material used;

(4) Weights and measures of components used in the course of processing;

(5) In-process and laboratory control results;

(6) Inspection of the packaging and labeling area before and after use;

(7) A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing;

(8) Complete labeling control records, including specimens or copies of all labeling used;

(9) Description of drug product containers and closures;

(10) Any sampling performed;

(11) Identification of the persons performing and directly supervising or checking each significant step in the operation;

(12) Any investigation made according to 211.192.

(13) Results of examinations made in accordance with 211.134.


App 5-3) US Additional Regulations for Batch Records for Biological Products:

CFR 21, Chapter I, Subchapter F: Biologics, Part 600 Biological Products: General;

Subpart B Establishment Standards,

Sec 600.12 Records

(a) Maintenance of records.

Records shall be made, concurrently with the performance, of each step in the manufacture and distribution of products, in such a manner that at any time successive steps in the manufacture and distribution of any

38


Guidance Document lot may be traced by an inspector. Such records shall be legible and indelible, shall identify the person immediately responsible, shall include dates of the various steps, and be as detailed as necessary for clear understanding of each step by one experienced in the manufacture of products.

(b) Records retention --(Not extracted)

(2) Records of recall.

(Not extracted)

(3) Suspension of requirement for retention.

(Not extracted)

(c) Records of sterilization of equipment and supplies.

Records relating to the mode of sterilization, date, duration, temperature and other conditions relating to each sterilization of equipment and supplies used in the processing of products shall be made by means of automatic recording devices or by means of a system of recording which gives equivalent assurance of the accuracy and reliability of the record. Such records shall be maintained in a manner that permits an identification of the product with the particular manufacturing process to which the sterilization relates.

(d) Animal necropsy records.

(Not extracted)

(e) Records in case of divided manufacturing responsibility.

If two or more establishments participate in the manufacture of a product, the records of each such establishment must show plainly the degree of its responsibility. In addition, each participating manufacturer shall furnish to the manufacturer who prepares the product in final form for sale, barter or exchange, a copy of all records relating to the manufacturing operations performed by such participating manufacturer insofar as they concern the safety, purity and potency of the lots of the product involved, and the manufacturer who prepares the product in final form shall retain a complete record of all the manufacturing operations relating to the product.

[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR

11013, Mar. 26, 1990; 70 FR 14982, Mar. 24, 2005]


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



Center for Biologics Evaluation and Research (CBER); Office of Regulatory Affairs

(ORA). September 2004) Pharmaceutical cGMPs).

Manufacturers should build process and environmental control activities into their aseptic processing operation. It is critical that these activities be maintained and strictly implemented on a daily basis. The requirement for review of all batch records and data for conformance with written procedures, operating parameters, and product specifications prior to arriving at the final release decision for an aseptically processed product calls for an overall review of process and system performance for that given cycle of manufacture. All in-process and laboratory control results must be included with the batch record documentation in accordance with section 211.188. Review of environmental and personnel monitoring data, as well as other data relating to acceptability of output from support systems (e.g.,

HEPA / HVAC, WFI, steam generator) and proper functioning of equipment (e.g., batch alarms report; integrity of various filters) are considered essential elements of the batch release decision.

While interventions and/or stoppages are normally recorded in the batch record, the manner of documenting these occurrences varies. In particular, line stoppages and any unplanned interventions should be sufficiently documented in batch records with the associated time and duration of the event. In addition to lengthened dwell time of sterile product elements in the critical area, an extensive intervention can increase contamination risk. Sterility failures have often been attributed to atypical or extensive interventions that have occurred as a response to an undesirable event during the aseptic process. Written procedures describing the need for line clearances in the event of certain interventions, such as machine adjustments and any repairs, should be established. Such interventions should be documented with more detail than minor events. Interventions that result in substantial activity near exposed product or container closures or that last beyond a reasonable exposure time should, where appropriate, result in a local or full line clearance.

Any disruption in power supply, however momentary, that could affect product quality is a manufacturing deviation and must be included in batch records

(211.100, 211.192).

40



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

(Cont.)



42

(Cont.)



43

(Cont.)



44

(Cont.)



45

(Cont.)



46

(Cont.)



47

(Cont.)



48



Appendix 7: Example one of a Master Formula.

COMPANY A

MASTER BATCH MANUFACTURING RECORD

Department

Process Step number: MBMR XXXX, version X

XXXXXXXXXXXXX Page: 49 of 11

Revival of Working Cell Bank, Inoculation and Harvesting

Product Name Bulk Antigen X

Product Code ########

Issued by (Q.A.)

Production

Manager

:

:

Production Order: ######

Lot Number

Date :

Date :

Contents of Batch Manufacturing Record (BMR)

(Note: page numbers are from original document)

No. Description

4.

5.

6.

1.

2.

3.

7.

8.

Revival of lyophilized working cell bank

Transfer of revived culture to xx tube

Inoculation of Seed Bottle

Inoculation of Fermenter

Harvesting of Antigen X

Filtration details

Cleaning of system

BMR certification

5

7

9

10

12

Page No.

2

3

4

Preparation of seed culture: Date: _____________

Culture seed preparation activities are to be performed as per the SOP ______________ “ XX

Seed Preparation”.

Master cell bank and working cell bank lot information

Strain used XXXXXXXXXXXX

Working cell bank lot no.

Effective Date:

(Approved by) Signature: Date:

Signature: Date:

49



COMPANY A

MASTER BATCH MANUFACTURING RECORD number: MBMR XXXX, version X

Department

Process Step

XXXXXXXXXXXXX


Page: 2 of 11



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

From To Date results

Checked by

Deviations if any:

Date: _____________

2) Transfer of revived culture to XX tube.

Confirm the purity. Transfer x-x ml from the vial in step one to a tube containing XX medium.

Check purity by addition of a drop from vial on X agar and in X broth. Incubate the tube at xx ± x ° C for xx hrs. Incubate the purity tubes at xx ± x ° C for xx hrs. Check purity also under microscope.

Effective Date:



50



COMPANY A


Department

Process Step



Product Name Bulk Antigen X Production Order: ######


Microscopic observations (Gram staining)._________________________________________

___________________________________________________________________________

Material

XXXX agar tubes

Quantity Lot No. Checked by

XXXX broth tubes

XXXX medium tube

Passage carried out on___________ by __________. Incubation from________ to_______

Purity test details. SOP No.: ___________

XXXX agar / broth tubes incubated

Purity checked Checked by

From To Date results

Deviations if any:

Date: _____________

3) Inoculation of Seed Bottle.

Confirm the purity on microscope. Transfer x-x ml culture from step 2 into Seed bottle containing XXX medium. Use X L and X L medium for XX and XX L Fermenter batch respectively. Check purity by addition of a drop from tube on xxx agar and in xxx broth.

Incubate the Seed bottle at xx ± x ° C for xx hrs. Incubate the purity tubes at xx ± x ° C for xx hrs.

Seed bottle inoculated on __________ by __________.

Incubation of Seed bottle from __________ to ___________.

Effective Date:



51



COMPANY A


Department

Process Step



Product Name Bulk Antigen X Production Order: ######


Purity test carried out as per. SOP No.: _________

Material

XXXX agar tubes

Quantity Lot No.

XXXX broth tubes


From To

Purity checked

Date results

Checked by

Checked by

Deviations if any:

Date: _____________

4) Inoculation of Fermentor.

Transfer the contents of Seed bottle to Fermentor containing XX medium. Check purity by addition of a drop from Seed bottle on XXX agar and in XXX broth. Incubate the Fermentor at xx ± x ° C for xx days. Incubate the purity tubes at xx ± x ° C for xx hrs. Check purity also under microscope. Adjust aeration and agitation as per SOP No. ________.

Fermentor No. ____ (Working vol. _____L. Sterilized on _____. containing XX Medium Lot

No.___________

SOP No.:____________ for media preparation SOP No.: ___________ for fermentor sterilization

Effective Date:



52



COMPANY A


Department

Process Step






Lot Number

Air pressure in the fermentor checked _________ Pressure released _________

Microscopic observations of seed (gram staining):__________________________________

___________________________________________________________________________

Fermentor No.: ____ inoculated on ___________ by _________

Purity test details. SOP No.: _____________

Material

XXXX agar tubes

XXXX broth tubes

Quantity Lot No. Checked by


From To

Purity checked Checked by

Date results

Incubation of Fermentor from _________ to __________.

Decontaminate the remnant culture, purity tubes and articles used for Culture transfer by

Autoclaving at xxx ° C for xx min.

Decontamination charge No.: _____________

Adjust the aeration and agitation as per SOP No.: ______________

Date: _____________

Effective Date:



53



COMPANY A


Department

Process Step

XXXXXXXXXXXXX


Page: 54 of 11




AERATION AND AGITATION ADJUSTMENTS DURING INCUBATION

Date Vibromixer Voltage

Required

For XX

L xxx

Required

For XX

L xxx

Adjusted to

Air Flow (LPM)

Required

For XX

L x

Required

For XX

L x

Adjusted to

Sign xxx xxx xxx xxx xxx xxx x x x x x x

Deviation if any:

Date: _____________

5) Harvesting of Bulk Antigen X

Harvesting of Bulk antigen X is carried out using XXX system (SOP No.: _____) or by using

Filter press assemblies (SOP No.: _______). Draw sample for purity test. Check purity by addition of a drop from Sample on XXX agar and in XXX broth. Incubate the purity tubes at xx

± x ° C for xx hrs. Check purity also under microscope. For harvesting of a batch carry out following steps:

Effective Date:



54



COMPANY A


Department

Process Step





Production Order:

Lot Number

######

Switch off temp. controller and recorder, Switch off Agitator controls, Stop Air flow

Temp. controller and recorder switched off

Agitator controls switched off

Air flow stopped

Sample drawn by

Purity test details. SOP No.: _______________

Material

XXXX agar tubes

XXXX broth tubes

Quantity Lot No.


From To

Purity checked

Date results

Deviations, if any:

Date: _____________

Harvesting of Bulk antigen X Lot No.: ___________ on _____________.

Details of batch harvesting using XXXX system

Checked by

Checked by

Clean the XXXX system by flushing XXX L W.F.I. (Bulk)

Pre operation cleaning of system XXX L. W.F.I (bulk) flushed from _______to_______

Done by _____

Effective Date:



55



COMPANY A


Department

Process Step






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: Date: _____________

Time Filtration

Rate

(LPH)

Filtrate

Collected

(L)

Recirculation Details Observed/

Done by

Bulk Antigen is transferred to the Non- culture wing.

____________________

Done by

Bulk Antigen Lot No.: __________ Filtration by XXXX System. Date: _____________

Effective Date:



56



COMPANY A


Department

Process Step

XXXXXXXXXXXXX


Page: 9 of 11




Cleaning of the System:

Wash the system with xxx L Potable water. Collect the washing in the fermentor vessel itself by connecting the retentate and permeate pipes to the Fermentor. Thereafter disconnect the pipes from the fermenter and keep these pipes in washing drum. xxx L Potable Water wash: From : ________To ________ Checked by _____

I) Add xxx ml of x % XXX to xx L WFI (Bulk) and recirculate through XXX system for xx minutes

xxx L WFI (Bulk) temp. ____ ° C + _______ml xxx % XXX (QC No. ) Checked by

:

Recirculation from : ________ to : __________ Checked by :

II) Add xx ml of xx % XXX to xx L WFI (Bulk) & recirculate through XXXX system for xx minutes

xxx L WFI (Bulk) temp. ____ ° C + _______ml xxx % XXX (QC No. ) Checked by:

Recirculation from : ________ to : __________ Checked by :

III) Flush the system with W.F.I. (Bulk) xxx L

System flushed with ________W.F.I.(Bulk) From :________To : ______ Checked by ___

IV) XXX XXX wash :

Recirculate XXX XXX solution (Add xxx ml XXX XXX to xxx L W.F.I. (Bulk) temp. xxxx ° C)

xxx L W.F.I. (Bulk) Temp. _____ ° C + ________ml XXX XXX (QC No. )

Checked by _______

Recirculation from : ________ to : __________ Checked by _______ Date :_____

V) Flush the system with W.F.I. (Bulk) xxx L

System flushed with _______W.F.I.(Bulk) From :_______To : ______ Checked by _______

Effective Date:



57



COMPANY A


Department

Process Step






Lot Number

######

Cleaning of the System: (continued)

VI) Check the Flow rate of W.F.I. (Bulk) at xxx bar inlet pressure. If the flow rate is less than xxx LPH repeat washing procedure.

W.F.I.(Bulk) Flow-rate at xxx bar pressure : ______LPH (at ____ ° C) Checked by _______

All the washing from the above steps I to V connected to the drain.

VII) Storage of the system in xxx % XXX after recirculation for xxx minutes :

_______L WFI (Bulk) + ____ml XXX (Q. C. No. ________). Done by : _______

Recirculation from: ________ to: __________ Done by _________.

System disconnected from power supply at:

Operations supervised by:

Effective Date:



58



COMPANY A


Department

Process Step

XXXXXXXXXXXXX


Page: 11 of 11




BMR CERTIFICATION

01. MANUFACTURING DEPARTMENT:

The contents of this Document have been checked and verified by me.

The information contained herein is complete and true to the best of my

Knowledge. Deviations if any are reported.

Hence submitted to Quality Assurance Department.

Signature of Production Officer: ……………………………………..

Date of Completion: …………………………

Date of Submission: ………………………...

02. QUALITY ASSURANCE DEPARTMENT:

I hereby certify that, this batch record is reviewed by me, to ensure that the above mentioned batch process has been carried out according to the Authorized Master

Formula and processing instructions.

All operational steps have been scrutinized & approved according to the

checklist (attached ) and have been found to be complete.

Signature of Quality Assurance Review Officer: …………………………

Date of Receipt: …………………………

Date of Approval: ……………………….

Effective Date:



59



Appendix 8: Example two of a Master Formula.

COMPANY B

Doc. No.# BMR/XX/XX/XX MFR Ref. No.# MFR/XX/XX

Title: BATCH MANUFACTURING RECORD FOR PRODUCT X , x mL

BLENDING AND FILLING

Batch No.:

Date of Manufacture: Expiry Date:

PRODUCT X

FILL SIZE

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:

60

x mL

Effective Date: _______

Revision number: ______



COMPANY B




Batch No.:


CERTIFICATION

CERTIFICATE OF QUALITY ASSURANCE

THIS IS TO CERTIFY THAT THE BATCH No. _______OF PRODUCT X (TRADE

NAME _______), SATISFIES THE REGULATORY AND PHARMACOPOEIAL

REQUIREMENTS FOR PRODUCT X VACCINE.

Signature of Quality Assurance:

Date:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:



61



COMPANY B




Batch No.:


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): Date:

2. CHECKLIST OF BATCH RECORD:

Approved by Head QA: Date:

No Description

1 Product X Vaccine Blending

2 Primary packing materials procurement

3 Washing and sterilization of vials, stoppers and vessels.

4

5

6

Sterilization of filling items

Filling

Filling particulars

7 Recording of deviations

8 Primary packing materials reconciliation record

9 Visual Inspection

11 Packing details for shipment to NCL

12 Finished goods transfer note to NCL

Signature of Supervisor: Date: Signature of QA:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:

Date Document availability checked by

Production QA

Date:



62



COMPANY B




Batch No.:


3. QUALITY CONTROL REPORTS AND MISCELLANEOUS DOCUMENTS CHECK

LIST:

No Name of the Report Q.C Ref.No. Availability checked by

Production QA

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

7 Vials Depyrogenation report

8 Membrane Integrity report

9 Environmental monitoring report

10 Particle count report

11 NCL report

12 WFI report of blending port

13 WFI report of washing port

Signature of Supervisor:

Date:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Signature of Quality Assurance:

Date:

Date:

Date:

Date:

NA

NA

NA

NA

NA

NA

NA

NA



63



COMPANY B




Batch No.:


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 # ____)


4.3

Bulk antigen requirement for blend:

4.3.1 Antigen requirement:

Calculate the antigen requirement for the blend as per SOP # _______

Blend volume in mL (A)

Date:

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

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:



64



COMPANY B




Batch No.:

Expiry Date: Date of Manufacture:

4.3.2 Details of antigen:

Lot No. of Bulk

Q.C. Ref

No. and

Date

Antigen concentration in mg/mL (A)

Volume in mL (B)

Total antigen in mg A x B

As mentioned above

Total volume

Total rounded off to


4.4

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

Date:

4.4.1 Solution #1 (FS#1) requirement:

Calculate Formulation Solution #1 requirement for the blend as per SOP # ______

Blend volume in mL Total XXXX required in mg (Blend volume x XX mg/mL)

4.4.2 Details of Formulation Solution #1 (FS#1)

No. Batch Q.C. Ref. FS#1

No. No. content and Date (mg/mL)

(A)

Volume in mL

(B)

Total FS#1 in (mg)

(A x B) as mentioned above

Total volume

Total round off to

Date: Signature of Supervisor:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:



65



COMPANY B




Batch No.:


4.5

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

4.5.1 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)

4.5.2 Blending vessel Particulars:

1 Type of vessel

2

3

4

5

Make

ID. No.:

Cleaned by

SIP cycle No / Load No

XXX liter blending vessel

XXX

#######

6. LAFU Validation Done on: Due on:

Line clearance given by QA

4.5.3 Details of blending:

Ingredient Temp of vessel o

C

FS#1 as per 4.4.1

FS#2 as per 4.5.1

Bulk antigen as per

4.3.1

Stirring (%)

Spec. o

C/ % xx to xx o

C xx to xx o

C xx to xx o

C

Volume added

Added by

Checked by

Date xx – xx %

Stirring start time: ___________. End time: __________ (stirring time specifications: X to X hrs)


Date:


Date:

Signatures:

Written by: Date:



Reviewed by:

Approved by Q.A.:

Date:

Date:

66



COMPANY B




Batch No.:


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.

Description

QC Ref.

No. /

Date

Report

Date xx mL pH

XXX content

XXX content

Bacterial Endotoxins

(LAL)

Sterility

XXX

Potency

Signature of Supervisor: Date: Signature of QA:

5. PRIMARY PACKING MATERIALS PROCUREMENT:

No Name of material

Spec.

No.

AR.

No.

Quantity required

Quantity issued by store

Quantity received

Date:

Checked by

Production supervisor

Q.A. in charge

1 X mL vials

2 xx mm grey butyl stoppers

3 xx mm aluminium seals

Remarks (if any):


Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date: Signature of QA:

Date:

Date:

Date:

Date:



67



COMPANY B




Batch No.:


6. WASHING AND STERILIZATION OF STOPPERS AND FILLING ITEMS:

6.1 Stoppers details:

6.1.1 Machine particulars:

Size : xx mm Colour : grey butyl

Name of the machine: STOPPER WASHING MACHINE

I.D. No.

Validation xxxxxx

Done on: Due on:

Cleaned by

Checked by

LAFU I.D. No: Validation Due on:

6.1.2 Treatment of stoppers:

Treatment procedure of stoppers as per SOP # ________

6.1.2.1 Quantity of treatment solution (TS#1) required for stoppers:

Total volume of WFI (mL)

(A)

Total TS#1 required in mg at XX mg/mL

(A x XX)

6.1.2.2 Details of TS#1 treatment:

(Final TS#1 concentration should be xx mg/mL)

No Ingredient STP.No./

Spec.No.

1 TS#1

A.R. No. Qty

Required xxx mg

Qty weighed

2 WFI NA xxxx mL

Weighed by

Checked by

Volume of TS#1 solution prepared

Volume of TS#1 solution used

Excess TS#1 solution discarded by:

Volume of TS#1 solution discarded

Checked by:

TS#1 treatment of stoppers done by: Date Checked by: Date:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:



68



COMPANY B




Batch No.:


6.1.3 20 mm Grey butyl rubber Stopper washing particulars:

Stopper washing, WFI inspection procedure refer SOP # ______

6.1.3.1 Drain water of Stopper washing machine checked by ___________

6.1.3.2 Lot No—I

Washing details:

No Date Operator involved in washing

Washing

Start

Time

End Time

Qty

Washed.

Final rinse drain water inspected by

1 st

rinse

2 nd

rinse

3 rd

rinse

Details of Stopper Collection into S.S cans for Stopper Lot No I:

Can

No

Date S.S can cleaned

No. of stoppers

Collected by

Thiomersal solution by collected Volume added

Added by

Checked by

Repeat as necessary for as many lots of Stoppers that are required

6.1.4 Sterilization of stoppers:

Sterilization procedure of stoppers and sterilization by autoclave refer SOP # ________.

6.1.4.1 Equipment particulars:

Name of the Machine and

Make

AUTOCLAVE XXXXXXX

I.D. No. #######

Validation Done on: Due on:

Cleaned by: Checked by:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:



69



COMPANY B




Batch No.:


6.1.4.2 Details of stopper sterilization as per load pattern No.: 1

Date Load

No.

Can

No

Qty Loaded by

Sterilization temp

Sterilization time

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:

Date Load

No.

Items

Filling sets / glass syringes

Qty Washed

#

&

Loaded by

Sterilization temp

Sterilization time

Specs. Unloaded by

Stopper

Bowl

Chute

Picker wheel

Section wheel

Glass syringes

#

#

#

#

#

Forceps # xx min at

XX o

C

Silicon tubes

20 L vessel

#

#

SS tray #

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:

Checke d by



70



COMPANY B




Batch No.:


Signature of Supervisor: Date:

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

Dat e

Loa d

No.

Items Qt

Garmen ts

Gloves

Wipes

Mask

Signature of Supervisor: y

Loade d by

Sterilizati on temp

Sterilizati on time

6.4 Fumigation of blending and filling area:

Fumigating procedure refer SOP# ___________

Area Date Formaldehyde

Quantity

WFI

Quantity

Fumigation done by

Specifi c-ation xx min at

XX o

C

Date:

Time

Unloade d by

Checke d by

Checked by

From To


Signature of QA:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:

Date:

Date:



71



COMPANY B




Batch No.:


7. WASHING AND DEPYROGENATION OF VIALS.

7.1 Washing of vials: Vial washing, inspection and depyrogenation procedure as SOP #______.


Equipment Name: XXXXXXXX

Make XXXXXXX

ID.No.

Validation

Cleaned by

Parameter

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

###########

Done on: Due on:

Checked by:

Results

Date & Time


7.1.2 Vial washing particulars:

LAFU I.D. No: ############# Validation Due on:

Date WFI sample inspected by

Washing machine operated by

Total No. of vials

Washed

Time of washing Vials

Start End loaded

Time Time by

Total

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:

No. of vials broken



72



COMPANY B




Batch No.:


7.1.3 Washed vials inspection (For particles): (Frequency every x hours)

Date Time Checked by Remarks


7.2 Depyrogenation of vials:


Date:

Equipment Name and Make XXXXXXX

I.D. No. ########

Validation Done on: Due on:

Cleaned by: Checked by:

7.2.2 Depyrogenation Details:

Date Tunnel start time

Set

Temp

O C

Depyrog'n Tunne

Tem p

O

C

Tim e l stop time

(> Min

X) .

( ≥ x)

Heater

1

Heater

2

Heater

3

Heater

4


Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Tunnel

Drive mm/min

< xxx

Date:

Date:

Date:

Temp monitore d by

Depyrog'n data enclosed

Yes/no

Checked by

Date :

Quantity depyrog'd



73



COMPANY B




Batch No.:


8.1 Filling line clearance : line clearance as per SOP# ____________

LAFU I.D. No: ######### Validation Due on:

8.1.1 Machine particulars and line clearance details:

Equipment Name Filling Machine 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

Filling area cleanliness

Fumigation details

Line clearance for filling given by QA:

8.2 Filling operation particulars:

8.2.1 Filling Operation: Filling operation refer SOP #____________

8.2.2 Filling Operation Details:

Date Time

Filling

Machine operator

Stoppering

Machine operator

Sealing

Machine operator

Filled vials collected by

Signature of Prod.

Shift in charge

########

Verified by QA

Signature of QA.

Shift in charge


Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:

Date:



74



COMPANY B




Batch No.:


8.3 Final blend stirring: (Frequency of checking - Every x hour)

Stirring and temperature of vessel as per SOP# _______________

Date Time Stirring (%) Specification

(%)

Checked by

Production QA xx - xx


8.4 Volume variation check during filling:

Date:

8.4.1

Filling operation: Filling operations, start up activities refer to SOP # ____ and to annex for fill volume standards. Volume variations action limits refer SOP# ______

8.4.2 Volume check up Details: (Frequency every x to x hours)

Filling Date:

Pack Size X mL

Starting time:

Fill Volume Spec xx.x – xx.x mL Calibration due on:

Closing time:

Syringe used for vol. Measurement: X mL

Volume drawn

No Date Time

Nozzle

No-1

Nozzle

No-2

Nozzle

No-3

Nozzle

No-4

Start up volume checks in (mL)

1

Nozzle

No-5

2

3

In process Volume checks during filling in (mL)

1

2

3


Date:

Nozzle

No-6

Checked by

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:

Remarks



75



COMPANY B




Batch No.:


8.5 Filling area monitoring: (Frequency every x hours)

Filling Date: Starting time:

Pack size: X mL Closing time:

Date Time Temp

( o

C)

Spec

( o

C) xx to xx

o

C

Humidity

(%)

Spec

(%) xx to xx%

Checked by


8.6

Recording of Interferences/deviations during filling:

Date:

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).


Signatures:

Written by: Date:



Reviewed by:

Approved by Q.A.:

Date:

Date:

76



COMPANY B




Batch No.:


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

Report checked by Prod.

Report verified by QA


Date:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Sampled by QA

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

Sterility

Bacterial endotoxins (LAL test)

Potency

Report Date

Closure integrity test

Date:

Date:


Date:

Date:

Date:

Date:



77



COMPANY B




Batch No.:


8.8 Calculation of practical yield:

Theoretical

Yield (A)

= Batch

Vol.

÷

Filling Vol

Total Process Loss (B)

Description 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.

Volume in ml

Equivalent vials

Filled

Quantity

(C)

No. of samples for Q.C.

Testing

(D) xx

Quantity transferred to Visual inspection

E = C- D

Date:

Verified by QA Date:

9. PRIMARY PACKING MATERIALS RECONCILIATION:

Name of

Material

Quantity issued

Total Quantity used

Quantity

Returned to stores

Quantity

Process loss

%

XX mL Vials

Spec

(%)

≤ x

≤ x Stoppers xx mm grey butyl

Seals xx mm ≤ x

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:



78



COMPANY B




Batch No.:


REMARKS (if any):


Date:

10. MATERIAL RETURN NOTE:

10.1 Material Return Note Number:


Date:

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:


Date:

11. VISUAL INSPECTION OF VIALS:

11.1

Line clearance for visual inspection:

Refer Line clearance SOP# ________________


Date:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:



79



COMPANY B




Batch No.:


11.1.1

Cleaning of visual inspection area:

Cleaning procedure refer SOP # ______________

Area cleaned by:

Date:

11.1.2 Line Clearance Details:

No Previous product

Batch

No.

Pack size

Present product

Batch

No.

Pack size

Previous product material cleared off from the area

Yes /No

Checked.

By

Checked by:

Date:

Line clearance given by

QA

Date Time


Date:


Date:

11.2 Reconciliation of vials after Visual inspection: refer SOP# _____________

11.2.1 Quantity Received for Visual inspection: _____________________

11.2.2 Reconciliation Details:

No Date

Time

From To

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)

Cap

Closures defects

(D)

Total

(A+B+C+D)

1

2

3

Total Passed Quantity Total rejected Quantity

% rejection

≤ x % Specification of optical rejection:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:



80



COMPANY B




Batch No.:


11.2.3 Good Quantity transferred to labeling after Visual inspection: ______________


Date:

12. DISCARD NOTE:


Date:

Date Item Quantity Reasons for destruction

Destruction approved by

Destroyed by

Destruction

Supervised by

Production QA

Formulation

Solutions

Glass Vials xx mm stoppers xx mm flip top seals

Visual inspection rejections


Date:

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


Date:

4 No. of vials given for visual inspection

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:



81



COMPANY B




Batch No.:


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

2

3

4

5

9 Quantity remaining to be labeled and packed.

13.2 Batch packing details:

Date Breakages P.R.No.

1

Quantity

Packed

Total

No. of

Samples

Quantity

Transferred

Quantity remaining


Date:


Date:

Signatures:

Written by:

Reviewed by:

Approved by Q.A.:

Date:

Date:

Date:



82



Appendix 9: Example three of a Master Formula.

Company Logo COMPANY C

Address: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

BATCH MANUFACTURING RECORD

Department Name Filling Building # __ Page No

CONTROLLED

DOCUMENT

Page 83 of 119

Title

Product Name

Short Text

Blending, Filling,

Lyophilization and Sealing

Product X

X dose Lyophilised

Document No MBR-xxxxxx

Version No X

- -

######## Process

Order

Batch No xxxxxx Product Code xxxxxxx

Issued By (Q.A ): Date:

Production Manager: Date:

Officer In charge:

(Checked by)

Date:

83






Department Name

Title

Product Name

Short Text

Product Code

Filling Building # __

Blending, Filling, Lyophilization and

Sealing

Product X

X dose Lyophilised xxxxxxx

CONTROLLED

DOCUMENT

Page No Page ___ of ____


Version No

-

X

-

Process Order ########

Batch No xxxxxx

INDEX

No Description Page No

Summary of Process

Summary of Activities

Batch Formulation

Thawing of Bulk Antigen

Lyophilizer Trays Processing

Rubber Stopper Processing

Processing Product contact Material for Pooling & Filling

Vial Processing

Room Pressure Recording

Preparation of Lyophilizer

Verification of Bulk Antigen Container Weights.

Pooling & Clarification of Thawed Bulk and Preparation of Final Bulk

Integrity Testing of Product Filter

Filling

Integrity Test of Vent Filters

Loading of Lyophilizer

Lyophilization

Aluminum cap processing

Sealing of vials

Material Reconciliation record

Bulk reconciliation record

BMR Certification


(Checked by)

Date:

84






Department Name Filling Building # __

Title Blending, Filling, Lyophilization and

Sealing

Product Name

Short Text

Product Code

Product X


The entire activity has the following major steps:

CONTROLLED

DOCUMENT



Version No

-

X

-


Batch No xxxxxx

Activity

1.

Thawing of Bulk Antigen

Day No 1 2 3 4 5

2.

Cleaning and Sterilization of Lyophilizer Trays

3.

Sterilization and Drying of Rubber Stoppers

4.

Cleaning, Preparation and Sterilization of

Material Required for Filling and Pooling

5.

6.

Cleaning and Sterilization / Disinfection of

Lyophilizer

Washing and Sterilization of Vials

7.

Pooling and Clarification to Prepare ‘Final

Bulk’

8.

9.

Filling of Vaccine into Vials

Loading of Filled Vials in the Lyophilizer and

Lyophilization

10.

11.

Sterilization and Drying of Aluminium Caps

Sealing

Day 1

Day before filling

Day 2

Day of filling

Day 3 Day 4

Day after filling 2 nd

day after filling

Day 5

3 rd

day after filling

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


(Checked by)

Date:

85





BATCH MANUFACTURING RECORD CONTROLLED

DOCUMENT

Department Name Filling Building # __ Page No Page ___ of ____

Title

Product Name

Short Text

Blending, Filling, Lyophilization and

Sealing

Product X

X dose Lyophilised


Version No

-

X

-

Process Order ######## xxxxxx Product Code xxxxxxx Batch No

Pages 5 and 6 to be issued to Bulk section who will fill the details and send it back.

Pages 25 To 27 to be issued to Lyophilization section who will fill the details and send it back.

SUMMARY OF ACTIVITIES

Target Lyophilizer Number

Lyophilizer Batch Capacity

Volume per vial

Batch Volume as Dispensed by Bulk Mfg Dept

Date of Filling

Fill volume per vial (xx x xx) (Overfill mid point at +X

%)

XXXX

Vials mL (23)

L (24) dd/mm/yyyy mL (25)

Batch Volume as Rechecked by Filling Dept

Theoretical Batch Size

Approx Filling Yield. [Quantity loaded in

Lyophilizer]

Approx Sealing Yield. [Quantity transferred to screening]

L

Vials (28)

Vials (22)

Vials (19)

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


(Checked by)

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.

Date:

86






Department Name Filling Building # __

Title

Product Name

Short Text

Product Code

Blending, Filling,

Lyophilization and Sealing

Product X


Component Bulk Ag No. Antigen Titre Vol. ‘L’

CONTROLLED

DOCUMENT



Version No

-

X

-


Batch No xxxxxx

*Gr Wt

‘kg’

Tare Wt

‘kg’

Limit XX L ± X% Actual Vol.

Set Ag Titre / vial

Product X

Volume

/ vial

X mL

Formulation: Dt: ___

Done by Checked by

L kg kg

Weighing: Dt: _____

Done by Checked by

Date:

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

Incubator set temp

(Range xx to xx °C)

Thawing completed on (date)

Thawing completed at h

ºC h h

ºC h


(Checked by)

87






DOCUMENT

Department: Filling Building # __ Page No Page ___ of ____

Title Blending, Filling,

Lyophilization & Sealing


Version No X

- - Product Name Product X

Short Text X dose Lyophilised

Product Code xxxxxxx

No

Process Order

Batch No

Handling of Bulk Antigen Containers Done By

######## xxxxxx

Date

Name Initials

1

2

3

4

Bulk Antigen Containers Received By:

Remarks if any:

Activity: LYOPHILIZER TRAY PROCESSING Ref SOP No.

: __________

1.

Clean the trays to be used for collecting filled vials using a clean lint free mop wetted with

WFI/xx % Isopropyl alcohol.

2.

The trays can be processed in either of two ways.

A) Load the cleaned trays on the dry heat sterilizer (DHS) trolley, as per validated max loading pattern in DHS No xxxx and sterilize at xxx°C, xxx minutes .

B) Load the trays in Autoclave and sterilize at xxx °C ± x °C for XX minutes.

No of Trays

Pattern No

Pattern No

3.

If option A above is selected, run the cycle to hold the trays at xxx°C for xxx minutes.

Normal variation –x ° to + x °C.

4.

Write Product, B.No., Charge No & date on the sterilizer thermograph/printout (for Option

A only) sign it and attach it to this BMR.


(Checked by)

Date:

88






DOCUMENT

Department: Filling Building # __ Page No

Title Blending, Filling, Lyophilization

& Sealing

Product Name Product X



No Description of Activity

Document No

Version No

-

Process Order

Batch No

Done

By

Page ___ of ____

MBR-xxxxxx

X

-

######## xxxxxx

Checked

By

Date

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 at (applicable for option A above)

4 Sterilization temperature xxx°C maintained till (applicable for option A above) h h

Remarks:-

Activity: RUBBER STOPPERS PROCESSING Ref SOP No: ___________

1.

Verify that QC approved stoppers of correct type have been taken for de-cartoning.

2.

For RFS stoppers, after de cartoning directly move to sterilization.

3.

Load stoppers as per validated loading pattern given below.

RFS

Max No of stoppers / pouches

Pattern No for Autoclave X

Pattern No for Autoclave Y xxxx xxxx xxxx


(Checked by)

Date:

89






DOCUMENT


Title Blending, Filling, Lyophilization & Sealing Document No MBR-xxxxxx

Version No X

Product Name Product X - -



4.

The stoppers can be processed in either of the two ways:

Process Order

Batch No

######## xxxxxx

No ___

A) Sterilization in Autoclave X (xxx to xxx °C) and drying in dry heat sterilizer (DHS)

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

9) No of stoppers Pouches

Unprocessed Done by Checked by Date


(Checked by)

Remarks:

Activity: RUBBER STOPPERS PROCESSING, cont'd Ref SOP No.:

7.

Load pouches on the Autoclave trolley as per validated loading pattern.

___________

Date:

90






Department: Filling Building # __






Page No

Document No

Version No

-

Process Order

Batch No

CONTROLLED

DOCUMENT

Page ___ of ____

MBR-xxxxxx

X

-

######## xxxxxx

Autoclave

No. /

Equipment

No.

########

Charge

XX

No.

Load

Pattern

No.

XX

Program

No.

X

######### XX XX X

DHS No / Equip No ####################

Quantity for 1 / 2 batches

Done by

Checked by

Date

Drying temperature xxx °C for xxx minutes for drying in

DHS

Achieved at : h

Maintained till: h

Sample for Moisture Content (11) Nos.

Charge

No.:

X

Done by 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


(Checked by)

Date:

91






DOCUMENT

Department:

Title


Blending, Filling,





INTEGRITY TESTING OF xx µm FILTER

Page No

Document No

Version No

-

Process Order

Batch No

Page ___ of ____

MBR-xxxxxx

X

-

######## xxxxxx

Make

XXXX

Name xx 1 xx 2

Part No Quantity/ batch

Bubble Point

A

Diffusion

B Tst pr. Rate

YYYY xx 3 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

Step A

Mfg/ Brand

Presteriliz’n Manual

Auto

Part No

XXXX

XXXX

Pore Size

Filter Details

Wetting Liq. Test Parameter xx um WFI XXXX

XXXX

Filter Lot

No

Filter S. No Observation

Bubbles seen at

_____bar

Printout attached

Result Done by

Remarks:-


(Checked by)

Date:

Test Type

Bubble Pt

Diffusion

Check by

Date

92






DOCUMENT


Title Blending, Filling, Lyophilization & Sealing Document No MBR-xxxxxx

Version No X

Product Name Product X - -




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.

Conductivity check on product tank rinse sample NMT 1 mS/cm

Check xx mS/cm

_____ mS/cm


(Checked by)

BV1

____ mS/cm

BV2

____ mS/cm

Product C/O Done by Checked by

NA

TRF attached

Date:

Date

93






DOCUMENT







Document No

Version No

-

Process Order

Batch No

Page ___ of ____

MBR-xxxxxx

X

-

######## xxxxxx

Visual Inspection of Product Contact material rinse sample

Item BV 1 Header Syringe Needle

Fibres

Particles

Sampled by:

BV 2 Silicon tube

Screened by: Date:

STERILIZATION OF MATERIAL FOR POOLING AND FILLING

1 Autoclave No / Equip No

2 Load Pattern number

######### / ######## Done by Checked by

XXX XXX

Date

3 Charge No

4 Program No

XX

XXXXX

XX

XXXXX

Remarks:-

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.


(Checked by)

Date:

94






DOCUMENT



& Sealing




Document No

Version No

-

Process Order

Batch No

A) Vial input : x mL, xx mm X xx mm height, (Amber, tubular, USP type-1)

1) Unprocessed b/f:

2) Processed b/f:

3) Fresh qty issued

4) Fresh used from issue

Done

By

B.No________ B.No________

5) Option for

Process

A=1+2+4

B=1+4

6) Taken for washing: -

B Pre-washing and Washing operation checks:

WFI cooling ass’ly sanitized

Yes / No

Line

Clearance

Checked

Yes / No

WFI

Conductivity

(NMT X mS/cm) mS/cm

WFI Temp

(xx to xx°C)

°C

Done

By

MBR-xxxxxx

X

-

######## xxxxxx

Checked by

Checked by

Date

Date

Washing Media Outlet

Pressure (Range ‘Bar’)

Fresh

WFI

Recycled

WFI

Comp. Air

Set –XXXXXXX

##########

Observed (Bar) xx - xx xx - xx xx-xx

Washing Started at : h Completed at: h

Adequacy Sampled by Results

Pass / Fail

Time h

C Vial Output

(7) Sampled (8) Rejected For

Sterilization

6 - (7+ 8) = 9

Unprocessed

18 = 3 - 4

Remarks


(Checked by)

Date:

95






DOCUMENT




Document No

Version No

-

MBR-xxxxxx

X

- Product Name Product X



Process Order

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

S1 S2 S3 S4 S5 S6 S7 S8 Done by

Checked by

Date

Temperature

ºC

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 by

Date h 1 Tunnel sterilizer started at

2

Minimum set temperature

(xxx o

C) achieved at h

3 xx Minute hold

____ h to ____ h*

4

Tunnel Set to Night operation (Process End)


(Checked by)

h

Date:

96






DOCUMENT

Department:

Title


Blending, Filling, Lyophilization

& Sealing




4. Attach the printout and circular chart to the BMR.



Version No X

- -


Batch No xxxxxx

Operators – Washing and Sterilization:-

Remarks: - * x st

/ x nd

batch of the day.

Activity: VIAL PROCESSING – STERILIZATION, continued

Sterilization Zone

(P2) mm wg xx --xx

Cooling

Zone (P3) mm wg xx --xx

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

Done by Checked by Pressure

Range

Drying Zone

(P1) mm wg xx --xx

Observed

Observed

Remarks:-


(Checked by)

Date:

Time

97






DOCUMENT



& Sealing


Version No X





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

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)

Observed value

(Pa)

Done by

Checked by

Date Time


(Checked by)

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.

Date:

98






DOCUMENT



& Sealing


Version No X




For Lyophilizer No.: A, B, C

Batch

/week

1

1 st

batch of week

3

Lyo A

Steam Exposure xxx mins

Process Order

Batch No

######## xxxxxx

Before Loading

2 nd

batch of week 3 rd

batch of week

Lyo B, C

Steam Exposure xxx°C, xx mins

Lyo A, B, C

XXX

Disinfection with

Lyo A, B, C

Disinfection with

XXX

2

1

Disinfection with

XXX

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.


1





Lyophilizer No: _____ - Cleaning done after unloading of

Done

By

Checked by

Date

Product ______________ /Batch. No.:

____________________

2 Strike out what is not used

□ Steam Exposure xxx mins

Remarks:-


(Checked by)

□ Steam Exposure xxx°C, xx mins

□ XX disinfection

Date:

99






DOCUMENT




Document No

Version No

-

MBR-xxxxxx

X




Process Order

Batch No

######## xxxxxx

Activity: VERIFICATION OF BULK ANTIGEN CONTAINER WEIGHTS Ref SOP

No.: _____

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

Done by

Checked by

Date

Remarks:-

Activity: POOLING & CLARIFICATION OF THAWED BULK AND PREPARATION

OF FINAL BULK Ref SOP No.: ________

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 nd xx µm filter/s is connected to a 2 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.


(Checked by)

Date:

100






DOCUMENT



& Sealing




No Particulars

Document No

Version No

-

Process Order

Batch No

Page ___ of ____

MBR-xxxxxx

X

-

######## xxxxxx

Done by Checked by Date

1 Bath temp before Pooling

2

Pooling: xx-xx°C

Temperature of

Start

°C ______ h

End

______ h

Blending vessel

A

B

Stirrer Clarification: A, B

Pool Final

Bulk

RPM xx - xx°C xxx-xxx

Start time End time xx - xx°C

°C

3 Filtration Residue

(29)

°C ______ h ______ h

Sampled Bulk (30)

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.


(Checked by)

Date:

101






DOCUMENT







FILTER INTEGRITY TESTING

Document No

Version No

-

Process Order

Batch No

MBR-xxxxxx

X

-

######## xxxxxx

Application Stage Method

Clarification Post-Clarific’n XXXXX

Equipment Equipment No

XXXXX

Filter Details

########

Test Type

Bubble Pt

Mfg/ Brand Part No

Filter Lot

No

Filter S. No.

Pore Size Wetting

Liq.

Observation: bubbles @

Test Parameter

Result Done by Checked by

Date

Pooling material

Inactivation

Autoclave

No:

_______________ bar

Charge no: Done by Checked by

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.


(Checked by)

Date:

102




Department:

Title



DOCUMENT

Filling Building # __ Page No

Blending, Filling, Lyophilization &

Sealing





Document No

Version No

-

Process Order

Batch No

Page ___ of ____

MBR-xxxxxx

X

-

######## xxxxxx

Done by Checked by Date

1 Volume / vial (23),

Pg 5

XX mL

2 Weight per mL Calculation

Balance

Calibrated

YES / NO

Volume Wt (Bulk

WFI) (C)

XX mL g

Wt (Final bulk)

( D)

3 Volume Range to weight range setting g

Wt/mL

(D/C) = (B)

Lower

Vol.

Limit

(23)

XX mL

Upper Vol.

Limit

(23) x

XXX= (E)

XX mL

Lower Wt

Limit (23) x

(B) g

Line

Clearance:

Upper Wt.

Limit (E) x (B) g

4 Sampling for Visual Inspection (Sample size: XX vials)

Glass Total (%) Fibre Black Part. White

Part.

5 Filling activity : Filling machine XXXXXXXXX

Room Started at Room Completed at

Temp

°C

Rh

%

Remarks:


(Checked by) h

Temp

°C

Rh

% h

Date:

103






DOCUMENT



& Sealing

Document No

Version No

-

MBR-xxxxxx

X




Process Order

Batch No

######## xxxxxx

Activity: FILLING Ref SOP No.: _________________

Rejection

Quantity

Vials

(12A)

Stopper

(12B)

Sample to QC

(13)

XX

Total Loaded in Lyophilizer Done

Filled

Vials (F)

Appr. Vials

F-

(12A+13)=22

Trays

(G)

By

Checked by

Date

Stoppers rejection details (12B=R1+R2) Balance processed (17)

During filling

(R1)

Balance in hopper

(R2)

Vials Nos

Stoppers Nos


6 Rejection Inactivation details

Autoclave

No:

Operators:

I Shift II Shift

Charge

No:

Done By Checked by

III Shift

Date

STATION NUMBER

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

ID numbers of syringes used for filling

Remark:


(Checked by)

Date:

104






DOCUMENT



& Sealing

Attach Fill Volume Print or record manually, on weight basis, every xx

Minutes

Time (h)

Document No

Version No

-

MBR-xxxxxx

X




Process Order

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

1

2

3

4

5

6

7

8

9


(Checked by)

Date:

105




Department:



DOCUMENT



& Sealing




Document No

Version No

-

Process Order

Batch No

Page ___ of ____

MBR-xxxxxx

X

-

######## xxxxxx

Water bath temp

0 xx-xx 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.


(Checked by)

Date:

106






DOCUMENT

Department:

Title



& Sealing




3.

Attach printouts below:-



Version No X

- -


Batch No xxxxxx

Remarks:-


(Checked by)

Date:

107






DOCUMENT




Document No

Version No

-

MBR-xxxxxx

X




Process Order

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:-

Sterilization

Details (see page 15)

□ Lyophilizer B, C:

1 st

Batch Steam

Steriliz’n.

For Filling Dept:

Loading date

□ Lyophilizer A: 1

Batch Steaming. st

Recipe

No.

□ 2 nd

Batch / 3 rd

Batch

All Lyophililzers XX disinfection


(Checked by)

Date:

108






DOCUMENT




Document No

Version No

-

MBR-xxxxxx

X




Process Order

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).


1. Status board: Lyo B and C:'Cleaned, Ready for Steam Exposure’

Done By Date

Process

Start h xxx - xxx °C maintained

Start End h h

Process

End

2 Status board: Lyo A:Cleaned, Ready for Steam Exposure’ h

Vacuum Pull down Started

Start h

End h

Steam h xxx min Exposure

Start h

End h

Drying

End

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

4. Display Board: ‘Ready for Loading up to: _________’ h h


(Checked by)

Date:

109






DOCUMENT







Document No

Version No

-

Process Order

Batch No

Page ___ of ____

MBR-xxxxxx

X

-

######## 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

No. of product temp. Probes

Door closing time h h

7. LYOPHILIZATION CYCLE DETAILS

8

Step

Shelf Temp

Start

End

Time

Date

Time

Date

Duration

X / X

X

Freezing

- xx °C x ± x h x ± x h

Condenser cooling

≤

≤

NA

x h

x h

BATCH STOPPERING AND UNLOADING

Ensure the following parameters before stoppering the vials.

Avg. Product Temp

Spec: xx ± x °C

°C

Vacuum

Spec: xx ± xx µbar

µbar

Chamber

Evacuation

NA

Primary drying

-xx to xx

°C

≤ x h xx ± x h

≤ x h

Condenser Temp.

Spec: ≤ - xx °C

°C

Sec.

Drying xx °C x ± x h xx h xx min ± x h

Done /

Checked

By x ± x h

Date

Stop the cycle and stopper the vials as per SOP No. __________.

Time of Stoppering: ____________ h.


(Checked by)

Date:

110






DOCUMENT



& Sealing




Document No

Version No

-

Process Order

Batch No

Page ___ of ____

MBR-xxxxxx

X

-

######## 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

No of Caps/trays

1 II

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.


(Checked by)

Date:

111




Title



DOCUMENT

Department: Filling Building # __


& Sealing




A) Aluminum Cap input : 13 mm, Colour ______



Version No X

- -


Batch No xxxxxx

Date

1) Unprocessed b/f:

B.No_____________

2) Processed b/f:

B.No___________

Nos Nos

3) Fresh quantity issued

Nos

Done by

4) Fresh used from issued

Nos

Checked by

5) Option of Process

A =1+ 2 + 4

B =1+ 4

Unprocessed quantity

from this batch

(18) (3 - 4)

Nos

6) Taken for Sterility =

9

(For 1 / 2 batch/es)

Description of Activity

No

B) Loaded in Autoclave No.

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

Charge No. Load Pattern No Prog No.

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:


(Checked by)

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.

Date:

112






DOCUMENT



& Sealing

Document No

Version No

-

MBR-xxxxxx

X


Short Text

Product Code


Process Order

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.

Description of Activity Date

Unloading & line Clearance:

Done

By

Checked by

Rejection in

Lyo

Sensor

(14)

Vials

Approx. Vial for sealing

(22)-(14) =

(H)

Sealing machine used

(h)

Sealing

Started Completed

(h)

XXXXXX

XXXXXX

Rejection & inactivation details

Empty vial

(15A) nos

Bad seal

(15B) nos

Autoclave No:

______

Breakage

(15C) nos

Charge No:

Vial, Stopper

Rej 15A to

15C =(15D)

Cap rej

(15E) nos nos

Processed

Caps (17) nos

Approx No of Vials Handed Over To Visual Inspection Department

H-15D= _____


(Checked by)

Date:

Trays Vials

113






DOCUMENT



& Sealing


Version No X





Batch No xxxxxx

Vials Received by screening: Name: ______________: ____________ (for Screening Dept)

Activity: MATERIAL RECONCILIATION RECORD

No Description Vial Stoppe r

Caps

2

3

1

4

5

6

Bal. Unprocessed Material b/f

(18)

Quantity

Prod / Batch No

Bal. Processed Material b/f (19) Quantity

Prod / Batch No

Fresh Material Issued Quantity

Res. Doc No.

Quantity used from Fresh material

Option for washing/sterilizing [A: 1+2+4, B: 1+4]

Total Quantity for Washing or Transfer based on (5)

7

8

Sampled for Adequacy of Washing

Rejected during Washing or Transfer

8A Rejection in % [(8/6) x 100] Limit: 2%

9

10

Sterilized [6-(7+8)]

Quantity for Filling/Sealing (If 5: A, 10=9) (If 5: B,

10=9+2)

11 Sampled- Post Sterilization

12 Rejection- Filling stage

13 Sampled- Filling stage


(Checked by)

A / B A / B A / B

XX X

X

X

X x xx xx x x xx

Date:

114






DOCUMENT







Document No

Version No

-

Process Order

Batch No

Page ___ of ____

MBR-xxxxxx

X

-

######## 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

Material

[3-4]

Quantity c/f Prod/Batch No or ICN

19 Quantity of vials for visual inspection

20 Variance

*

In No: [(1+2+3)-(7+8+16+17+18+19)]

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)

Vials 22 Quantity of vials Loaded in Lyophilizer

23 Volume per Vial as declared by Bulk Mfg Dept

24 Batch Vol. dispensed by Bulk Mfg Dept

25 Fill Volume

26 Batch Vol. rechecked by Filling Dept


(Checked by)

Date:

X mL

L

X mL

L

115






DOCUMENT







Document No

Version No

-

Process Order

Batch No

Page ___ of ____

MBR-xxxxxx

X

-

######## xxxxxx

27 Post Clarification Yield [26-(29/1000)] L

28 Theoretical yield [(26) x 1000]/ (25)

29

Blending & Filtration residue (29A=26-27)

29B=29A/25

30 Sample in Liquid Form [Filling stage] mL

XX mL

Vials

Vials

31 Excess Volume Balance in Tank after filling

32

Total Liq Samples /Losses [32A=29+30+31] 32B

=32A/ 25

33 Total Loss/Samples as vials (32B+16) mL mL

34 Expected Yield 28-33B

35 Final yield [(19) / (28B) x 100] (not less than XX%)

36 Percentage Reconciliation [(19) / (34B) x 100]

Stage: Post Clarific’n Filling

Calc x 100 29B / 28

Lyophiliz’n and

Sealing

(22-19) / 22

%

%

Norm (NMT)

Actual: x %

[(28-29B)-22]/(28-

29B)

x % x %

Vials

Vials

Vials

Total

Sum of all x %

Remarks:

DEVIATION: Yes / No. If yes, Report date/s:


(Checked by)

Date:

116




Department:



DOCUMENT



& Sealing




Document No

Version No

-

Process Order

Batch No

Page ___ of ____

MBR-xxxxxx

X

-

######## xxxxxx

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

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 : __________________________


(Checked by)

Date:

117



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.

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Guide to Master Formulae - World Health Organization

WHO Quality Safety & Standards of Vaccines and Biologicals

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