4003 regulatory aspect_of_bulk,pharmaceutical,biotech

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4003 regulatory aspect_of_bulk,pharmaceutical,biotech

  1. 1. Prepared by: PARTH M.Pharm (sem-II) Q.A EN-Roll no.:4003DEPARTMENT OF QUALITYASSURANCE(SSPC) January 25, 2013 1
  2. 2. January 25, 2013 2
  3. 3.  Introduction Quality management Personnel Buildings and facilities Process equipment Documentation and records Materials management Production and in-process controls Packaging and identification labelling of API and intermediates Storage and distribution January 25, 2013 3
  4. 4. CONTI..... Validation Rejection and re-use of materials Complaints and recalls Contract manufacturers January 25, 2013 4
  5. 5. Regulatory Applicability Within the world community, materials may vary as to the legal classification as an API. When a material is classified as an API in the region or country in which it is manufactured or used in a drug product, it should be manufactured according to this Guide. January 25, 2013 5
  6. 6. Objective1. Provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality.2. Help ensure that APIs meet the requirements for quality and purity that they purport or are represented to possess. January 25, 2013 6
  7. 7. Scope This Guide applies to the manufacture of APIs. Sterile APIs only up to the point immediately prior to the APIs being rendered sterile. January 25, 2013 7
  8. 8.  This Guide covers APIs that are manufactured by chemical synthesis, extraction, by recovery from natural sources, or by any combination of these processes. Excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs. January 25, 2013 8
  9. 9. QUALITY MANAGEMENTPrinciple Responsibility of all persons involved in manufacturing. Each manufacturer should establish, document, and implement an effective system for managing quality January 25, 2013 9
  10. 10. CONTI.... Should provide the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity Allquality related activities should be defined and documented. January 25, 2013 10
  11. 11. CONTI... There should be a quality unit(s) that fulfils both quality assurance (QA) and quality control (QC) responsibilities. Regular internal audits should be performed. Allquality related activities should be recorded at the time they are performed. deviation should be documented and explained. January 25, 2013 11
  12. 12. PERSONNEL Adequate number Qualified Responsibilities of all personnel should be specified in writing. Adequate training. Personnel Hygiene should be maintained. January 25, 2013 12
  13. 13. BUILDINGS AND FACILITIESFollowing points should be considered: Design and Construction Utilities Water Lighting Sewage and Refuse Sanitation and Maintenance January 25, 2013 13
  14. 14. PROCESS EQUIPMENTFollowing points should be considered Design and Construction Equipment Maintenance and Cleaning Calibration Computerized Systems January 25, 2013 14
  15. 15. DOCUMENTATION AND RECORDS1. Equipment Cleaning and Use Record2.Records of Raw Materials, Intermediates, API Labelling and Packaging Materials3. Master Production and Control Records4. Batch Production and Control Records5. Laboratory Control Records6. Batch Production Record Review January 25, 2013 15
  16. 16. 1. Equipment Cleaning and Use Record Major equipment use, cleaning, sanitization and/or sterilization and maintenance Date, time (if appropriate), product, and batch number of each batch processed The person who performed the cleaning and maintenance. January 25, 2013 16
  17. 17. 2. Records of Raw Materials, Intermediates, API Labelling and Packaging Materials Name of the manufacturer, identity and quantity of each shipment of each batch Name of the supplier; the suppliers control number(s), if known, or other identification number; The number allocated on receipt; and the date of receipt; January 25, 2013 17
  18. 18.  The results of any test or examination performed and the conclusions derived from this; Records tracing the use of materials; The final decision regarding rejected raw materials, intermediates or API labelling and packaging materials. Master(approved) labels should be maintained for comparison to issued labels. January 25, 2013 18
  19. 19. 3. Master Production and Control Records To ensure uniformity from batch to batch Dated,and signed by one person and independently checked, dated, and signed by a person in the quality unit. January 25, 2013 19
  20. 20. should include: The name of the intermediate or API being manufactured A complete list of raw materials and intermediates designated by names or codes The production location and major production equipment to be used; The instructions for storage Special storage conditions with time limits January 25, 2013 20
  21. 21. 4. Batch Production and Control Records Should include complete information relating to the production and control of each batch. Documentation of each significant step like• Dates and, when appropriate, times;• Identity of major equipment• weights, measures, and batch numbers of raw materials, intermediates, or reprocessed materials• Any sampling performed;• Actual yield January 25, 2013 21
  22. 22. Laboratory Control Recordsshould include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays The quantity and date the sample was received for testing; A statement of or reference to each test method used All data generated i.e. graphs, charts, spectra All calculations performed Signature of the person who performed each test Signature of a second person who reviewed January 25, 2013 22
  23. 23. MATERIALS MANAGEMENTGeneral Controls written procedures for receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials. System evaluation of supplier of critical materials.Receipt and Quarantine Upon receipt and before acceptance container examined visually for correct labelling Materials should be held under quarantine until they have been sampled, examined or tested as appropriate, and then released for use. January 25, 2013 23
  24. 24. Sampling and Testing of Incoming ProductionMaterialsAt least one test to verify the identity of each batchA suppliers Certificate of Analysis used in place forperforming other testsFull analyses should be conducted on at least threebatches before reducing in-house testing January 25, 2013 24
  25. 25. Storage Such to prevent degradation, contamination, and cross- contamination. Materials stored in fiber drums, bags, boxes should be stored off the floor, suitably spaced to permit cleaning and inspection. Usage should be such that oldest stock is used first.Re-evaluation To determine their suitability for use e.g., after prolonged storage or exposure to heat or humidity. January 25, 2013 25
  26. 26. PRODUCTION AND IN-PROCESSCONTROLSProduction OperationsRaw materials should be weighed under appropriateconditions that do not affect their suitability for use.All measuring devices should be calibratedCritical activities should be witnessed or subjected to anequivalent control. January 25, 2013 26
  27. 27.  Actual yields should be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, or manufacturing data. Deviations should be investigated documented and explained. Any critical deviation should be investigated. Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use. January 25, 2013 27
  28. 28. In-process Sampling and Controls Written procedures should be established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of intermediates and APIs. In-process controls and their acceptance criteria should be defined based on the information gained during the development stage or historical data. January 25, 2013 28
  29. 29.  Critical in-process controls, the control points and methods, should be stated in writing and approved by the quality unit. Sampling should be in a manner to prevent contamination of the sampled material. Integrity of samples maintained after collection. January 25, 2013 29
  30. 30. Blending Batches of Intermediates or APIs Process of combining materials within the same specification to produce a homogeneous intermediate or API. Batches should be Adequately controlled documented and tested for conformance If the blending could adversely affect stability, stability testing of the final blended batches should be performed. January 25, 2013 30
  31. 31. PACKAGING AND IDENTIFICATIONLABELLING OF APIs AND INTERMEDIATESPackaging MaterialsProvide adequate protection during transportation and storage.Clean, sanitizedThey should not be reactive, additive or absorptiveFor re-use, clean in accordance with documented proceduresAll previous labels should be removed or defaced. January 25, 2013 31
  32. 32. Label Issuance and Control Access to the label storage areas should be limited to authorised personnel. Proceduresshould be used to evaluate discrepancies found between the number of containers labelled and the number of labels issued. Allexcess labels bearing batch numbers or other batch- related printing should be destroyed. January 25, 2013 32
  33. 33.  Returned labels should be stored in a manner that prevents mix-ups and provides proper identification. Obsolete and out-dated labels should be destroyed.A printed label representative of those used should be included in the batch production record. January 25, 2013 33
  34. 34. Packaging and Labelling Operations Documented procedures should be followed Prevent mix-ups. For transport outside the management system, the name and address of the manufacturer, quantity of contents, and special transport conditions and any special legal requirements should also be included on the label. The expiry date/retest date should be indicated on the label and Certificate of Analysis. January 25, 2013 34
  35. 35.  inspected immediately before use for line clearance examination to ensure correct labelling For containers transported outside of the manufacturers control should be sealed in a manner such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the contents may have been altered. January 25, 2013 35
  36. 36. STORAGE AND DISTRIBUTION Warehousing Procedures Appropriate conditions (e.g. controlled temperature and humidity when necessary). Records should be maintained of these conditions separate storage areas for rejected, returned, or recalled materialsDistribution Procedures Only after they have been released by the quality unit. transferred under quarantine to another unit under the company’s control when authorized by the quality unit and if appropriate controls and documentation are in place. January 25, 2013 36
  37. 37.  Should be transported in a manner that does not adversely affect their quality. Special transport or storage conditions should be stated on the label. Ensure that the contract acceptor (contractor) knows and follows the appropriate transport and storage conditions.A system should be in place to permit its recall. January 25, 2013 37
  38. 38. VALIDATIONValidation Policy The companys overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in- process control test procedures, computerized systems, and persons responsible for design, review, approval and documentation of each validation phase, should be documented. critical parameters, ranges should be defined. January 25, 2013 38
  39. 39. Validation Documentationhow validation of a particular process is conducted. type of validation conducted (e.g. retrospective, prospective, concurrent)Equipment validation Before starting process validation activities qualification of critical equipment and ancillary systems should be completed i.e. DQ, IQ, PQ, OQ January 25, 2013 39
  40. 40. Cleaning Validation Directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. Sampling should include swabbing, rinsing, or alternative methods as appropriate, to detect both insoluble and soluble residues.Validation of Analytical Methods Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognised standard reference. January 25, 2013 40
  41. 41. REJECTION AND RE-USE OF MATERIALS Rejection failing to meet established specifications Quarantined reprocessed or reworked Reprocessing By repeating a crystallization step or other appropriate chemical or physical manipulation steps e.g. distillation, filtration, chromatography, milling January 25, 2013 41
  42. 42.  Recovery of Materials and Solvents Recovery e.g. from mother liquor or filtrates of reactants, intermediates, or the API and solvents is considered acceptable, provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use. use of recovered solvents should be adequately documented. January 25, 2013 42
  43. 43.  Returns Identified and quarantined. Reprocessed, reworked, or destroyed, as appropriate. Records should be maintained.COMPLAINTS AND RECALLSCONTRACT MANUFACTURERS (INCLUDING LABORATORIES) should comply with the GMP defined in this Guide. January 25, 2013 43
  44. 44. BIOTECHNOLOGY DERIVED PRODUCT January 25, 2013 44
  45. 45. General It is intended to address specific controls for APIs or intermediates manufactured by cell culture or fermentation using natural or recombinant organisms. January 25, 2013 45
  46. 46. Products manufactured by this method include: Allergens extract Antigens Vaccines Human whole blood and plasma derivatives etc..Personnel High standards of personnel hygiene and cleanliness are essential. Personnel should be trained in appropriate fields like chemistry, virology, bacteriology, medicine immunology. All personnel should be vaccinated January 25, 2013 46
  47. 47. PREMISES AND EQUIPMENTS Live organisms shall be handled in equipment to ensure that cultures are maintained in a pure state and are not contaminated during processing. Seed lots and cell banks should be stored separately from other material. Sterilized containers or that are documented as low bioburden should be used. Specific decontamination systems should be considered for effluent when infectious materials are used for production January 25, 2013 47
  48. 48. ANIMAL QUARTER AND CARE Accommodation shall be in separate building with self contained ventilation system Clean and sanitary condition shall be maintained Separate inoculation and postmortem room should be provided Cages should be disinfected possible by steam Incinerator provided for disposing of animal waste Health status should be monitored January 25, 2013 48
  49. 49. PRODUCTION Media and cultures should be carefully added under controlled condition to avoid contamination. If possible media should be sterilized insitu. In line sterilizing filters for routine addition of gases, media, acids etc to fermenters should be used. A wide variety of equipment if used for chromatography such equipment should be dedicated to purification of one product. January 25, 2013 49
  50. 50.  The lifespan of the columns and the sterilization method shall be defined. Particular care should be given to monitoring microbial loads and endotoxins. January 25, 2013 50
  51. 51. Label should include: The name of the drug product A list of active ingredients, amount Batch number Expiry date Storage condition Direction for use Name and address of manufacturer. January 25, 2013 51
  52. 52. LOT PROCESSING RECORDS ANDDISTRIBUTION RECORDSA complete account of the manufacturing historyof each lot of a biological preparation, showingthat it has been manufactured, tested, dispensedinto containers and distributed in accordance withthe licensed procedures. January 25, 2013 52
  53. 53. Processing record shall include; Name and dosage form Date of manufacture and identification number Formulation Yield obtained Record of all in-process control test Specimen of label Identification of packaging material January 25, 2013 53
  54. 54. Quality assurance and quality controlPrincipal duties To prepare detail instruction for each analysis To ensure adequate identification and segregation of test sample to avoid mix up To ensure environmental monitoring To release and reject raw material, intermediates and finished products To establish expiry dates January 25, 2013 54
  55. 55. Performance of all qualitative and quantitativetest for starting material may be replaced bycertificates issued by the producer of startingmaterial provided that :There is history of reliable productThe producer is regularly auditedSample of intermediate and final products shall be retained in the sufficient amount in appropriate storage condition. January 25, 2013 55
  56. 56.  http://www.ich.org/LOB/media/MEDIA433.pdf http://whqlibdoc.who.int/publications/2004/part2. pdf January 25, 2013 56
  57. 57. January 25, 2013 57

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