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3-2. Assessing Production Documents: executed and master records

This article explains the importance of good production documentation in ensuring consistency, traceability, and accountability throughout the product lifecycle. It discusses the requirements for manufacturing formula, processing instructions, packaging instructions, and batch processing records.

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3-2. Assessing Production Documents: executed and master records

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  1. 3-2. Assessing Production Documents: executed and master records Satish Mallya January , 2011

  2. Documentation • Good production documentation: • Ensures uniformity, consistency and a common understanding of expectations; • Outlines the procedures for handling raw materials, manufacturing and control; • Facilitates decision making on release/quarantine/rejection of a batch; • Ensures accountability, traceability, and documentation trail that will permit investigation in the event of product recall; • Permits retrospective validation and periodic quality review throughout product lifecycle. January 19-22, 2011

  3. Manufacturing Formula • Formally authorised Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. • The Manufacturing Formula 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 intermediateyields, where applicable. Source: PIC/S Guide to GMP for Medicinal Products – September 2009 January 19-22, 2011 January 19-22, 2011

  4. Processing Instructions • The Processing Instructions should include: • a statement of the processing location and the principal equipment to be used; • the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising); • detailed stepwise processing instructions (e.g. checks on materials, pre- treatments, sequence for adding materials, mixing times, temperatures); • the instructions for any in-process controls with their limits; • 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. • Source: PIC/S Guide to GMP for Medicinal Products – September 2009 January 19-22, 2011

  5. Packaging Instructions • 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: • 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; January 19-22, 2011

  6. Packaging Instructions • 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 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 forsampling and acceptance limits. • Source: PIC/S Guide to GMP for Medicinal Products – September 2009 January 19-22, 2011

  7. Batch Processing Records • 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: • the name of the product; • dates and times of commencement, of significant intermediate stages and of completion of production; • name of the person responsible for each stage of production; • initials of the operator of different significant steps of production and, where appropriate, of the person who checked each of these operations January 19-22, 2011

  8. Batch Processing Records • 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); • any relevant processing operation or event and majorequipment used; • a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained; • the amount of product yield obtained at different and pertinent stages of manufacture; • notes on special problems including details, with signed authorisation for any deviation from the Manufacturing Formula and Processing Instructions Source: PIC/S Guide to GMP for Medicinal Products – September 2009 January 19-22, 2011

  9. Batch Packaging Records • A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. • The record should carry: • the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained. • Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. • Source: PIC/S Guide to GMP for Medicinal Products – September 2009 January 19-22, 2011

  10. Batch Packaging Records • 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 bythe person(s) responsible for the packaging operations: • the name of the product; • the date(s) and times of the packaging operations; • the name of the responsible person carrying out the packaging operation; • the initials of the operators of the different significant steps; • records of checks for identity and conformity with the Packaging Instructions including the results of in-process controls; • details of the packaging operations carried out, including references to equipment and the packaging lines used; • whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting; • notes on any special problems or unusual events including details with signed authorisation for any deviation from the Manufacturing Formula and Processing Instructions; • 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 • Source: PIC/S Guide to GMP for Medicinal Products – September 2009 January 19-22, 2011

  11. General Rules • Master records should be in English, if not a translated version should be available. It may not be necessary to obtain a translated version of the executed record if applicant provides an undertaking that the master is identical to the executed except in the matter of populated fields and provides a translation of any observations, comments, reports of deviations or hand written remarks; • Verify that: • all pages of master and executed records have been submitted - each page will generally state the total number of pages (e.g. 1 of 40); • manufacturing sequence is in harmony with the flow chart and the narrative description; • in-process controls are not less stringent than FPP release specs; • equipment are identified by type and capacity and a unique ID number is assigned to each equipment; January 19-22, 2011

  12. General Rules • The master record should be compared with the executed record for biolot in order to ensure that the proposed manufacturing process is representative of that used to manufacture the biolot; • It is desirable that each operation be governed by an individual SOP; • It is desirable that a list of referenced SOPs be included at the end of the batch records. • It is possible that SOPs might make reference to other relevant SOPs; January 19-22, 2011

  13. SOPs • Serve to reduce the bulk of the batch record; • Should be written in a language appropriate to the content and to facilitate understanding by the end user (e.g. operator); • My not necessarily be specific to a product; • Are generally intended to describe in detail, a single event, equipment, operation, process or procedure. January 19-22, 2011

  14. SOPs • Environmental monitoring • Assembly, calibration, operation, cleaning, sterilization of instruments and equipment • Receipt, sampling, labelling, quarantine and dispensing of raw materials and packaging materials • System for assigning batch (lot) numbers for intermediate, bulk or FPP • Manufacturing processes and in-process checks and controls • Transportation of in-process, intermediate PP or FPP • Validation procedures • Criteria and procedures for release/rejection/quarantine of materials and FPP • Criteria for reprocessing batches January 19-22, 2011

  15. Environmental Monitoring Record • SOP No.: • Temperature: 15-25ºC; humidity: 30-50% RH, pressure differential: 1-2 mmH2O January 19-22, 2011

  16. Line Clearance Record January 19-22, 2011

  17. Cleaning Records for Processing Areas • May run into several pages • SOP Nos.: January 19-22, 2011

  18. Batch Records January 19-22, 2011

  19. Batch Recordsformulation • Material Dispensing SOP No.: Balance ID Nos.: • Each tablet contains: January 19-22, 2011

  20. Batch Recordsformulation • Calculation of quantity of API per batch: • Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30Kg Lot 1: Total available quantity (as is basis) (A) = 23.50Kg Actual assay (B) = 99.4% ; Water content (C) = 0.34% Qty of API equivalent to 100% assay and nil water (D) = A x B/100 x (100-C)/100 = 23.50 x 99.4/100 x (100 – 0.34)/100 = 23.28 Kg Balance quantity of API required (100% assay and nil water)(E) = 30– 23.28Kg = 6.72 Kg January 19-22, 2011

  21. Batch Recordsformulation Lot 2 Quantity of API required (100% assay and nil water) = 6.72 Kg Actual assay (B) = 99.1% Water content (C) = 0.50% Equivalent quantity of API required from container 2 (E) = D x 100/B x 100/(100-C) = 6.72x 100/99.1x 100/100-0.50Kg = 6.815Kg January 19-22, 2011

  22. Batch Records formulation Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30Kg January 19-22, 2011

  23. Batch Recordsformulation • The total quantity of API + filler will be the same for every batch of the FPP; • Quantity of filler required will vary with the assay and water content of the API lot(s); • If several lots of the API are used in the preparation of a single batch of the FPP, the total equivalent quantity of API on as is basis (∑E) determines the quantity of filler to be added in the batch; Calculation of filler = {Theoretical quantity of API required + theoretical quantity of filler} – Total quantity of API (∑E) January 19-22, 2011

  24. Raw Material Dispensing Record January 19-22, 2011

  25. Manufacturing Instructionslist of equipment January 19-22, 2011

  26. Manufacturing Instructionssifting January 19-22, 2011

  27. Mesh sizes January 19-22, 2011

  28. Manufacturing Instructions mixing & granulation • Mixing SOP No.: Granulation SOP No.: January 19-22, 2011

  29. Manufacturing Instructions wet milling and drying • Wet Milling SOP No.: • Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC) January 19-22, 2011

  30. Manufacturing Instructions size reduction & blending • Size reduction SOP No.: Blending SOP No.: January 19-22, 2011

  31. Manufacturing Instructions lubrication • Lubrication SOP No.: January 19-22, 2011

  32. Yield Reconciliationlubricated granules Reconciliation Yield = B+C+D/A x 100 =…. .% Reconciliation Yield Limit: 97-101% Actual yield = actual wt. of granules (B)/ theoretical batch size x 100 = ….%, Yield limit = 95-101% January 19-22, 2011

  33. Manufacturing Instructions compression • Balance no.: Vernier Caliper no.: • Hardness tester no.: Friability tester no.: • Disintegration tester no.: January 19-22, 2011

  34. Manufacturing Instructions compression January 19-22, 2011

  35. In-process Checks January 19-22, 2011

  36. Yield Reconciliation compressed tablets • Yield = ∑NW/ theor. wt. x 100 = …… % January 19-22, 2011

  37. Yield Reconciliation compressed tablets Reconciliation Yield = B+C+D+E / A x 100 = ……..%, Limit : 97-101% Actual yield = actual tablets compressed (B)/ theoretical batch size x 100 = ….%, Yield limit = 92-101% January 19-22, 2011

  38. Manufacturing Instructions coating January 19-22, 2011

  39. Yield Reconciliation coated tablets Reconciliation Yield = B+C+D+E / A x 100 = ……..%, Limit : 97-101% Actual yield = actual tablets coated (B) / theoretical batch size x 100 =.. ….% Yield limit = 90-101% January 19-22, 2011

  40. Sterile Products • Focus • Environmental conditions • In-process tests • SOPs • Type and make of sterilizing filter • Type and make of rubber stopper January 19-22, 2011

  41. Environmental Conditions sterile products • Grade A: Zone for high risk operations, e.g. filling zone. Normally such conditions are provided by a laminar air flow work station. • Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone. • Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products • Positive pressure should be maintained relative to surrounding areas of a lower grade under all operational conditions. Adjacent rooms of different grades should have a pressure differential of 10-15 pascals (recommended values) • 1 Pa (N/m2) = 0.10207 Millimeter of water (15.56º C)1 Pa (N/m2) = 0.10197 Millimeter of water (4º C) January 19-22, 2011

  42. Environmental Conditions sterile products January 19-22, 2011

  43. Environmental Conditions sterile products • Recommended limits for microbial contamination January 19-22, 2011

  44. Manufacturing Instructions list of equipment January 19-22, 2011

  45. Manufacturing Instructionssterile products January 19-22, 2011

  46. In-process Checkssterile products January 19-22, 2011

  47. Critical SOPssterile products January 19-22, 2011

  48. Thanks

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