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2 the regulations

  1. 1. GMP - The Regulations
  2. 2. Objectives  Have an understanding of the regulations governing GMP  Have an understanding of application of regulations  Discuss interpretation of regulations
  3. 3. Goal  You will have a basic understanding of the regulation governing GMPs and be able to apply this understanding when presented with examples.
  4. 4. GMP – CharacteristicsCharacteristics of GMP regulationsand interpretations GMP regulations are largely general and open for interpretation Benefit:  Manufacturers and researchers are able to interpret and apply the regulations in ways that may work best for their unique situations Risk:  The flexibility may lead to confusion during the interpretation of the regulation and misapplied control mechanisms
  5. 5. The Regulations 21 CFR Parts 210 and 211 (Drug Industry) 21 CFR Part 820 (Medical Device Industry) 21 CFR Part 110 (Food Industry) 21 CFR Part 606 (Blood Industry
  7. 7. Remember “current”  In the US, the phrase "current good manufacturing practice" appears in 501(B) of the 1938 Food, Drug, and Cosmetic Act (21USC351). US courts may theoretically hold that a drug product is adulterated even if there is no specific regulatory requirement that was violated as long as the process was not performed according to industry standards.
  8. 8. Part 211  Subpart A – General Provision  Subpart B – Organization and personnel  Subpart C – Buildings and Facilities  Subpart D – Equipment  Subpart E - Control of Components and Drug Products Containers and Closures  Subpart F – Production and process controls
  9. 9. Part 211 cont.  Subpart G – Packaging and Labeling Control  Subpart H – Holding and distribution  Subpart I – Laboratory Controls  Subpart J – Records and Reports  Subpart K – Returned and Salvaged Drug Products
  10. 10. Packaging and Labeling Production Control and Holding and Process Distribution ControlsControl of Laboratorycomponents andDrug Product GMP controlsContainers andClosures Organization and Personnel Equipment Buildings and Facilities
  11. 11. Subpart A – General Provisions  Scope - The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals.
  12. 12. Subpart B- Organizations andPersonnel
  13. 13. Subpart B  211.22 Responsibility of QC  211.25 Personnel Qualifications  211.28 Personnel Responsibilities  211.34 Consultants.
  14. 14. Quality Control Unit  The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.
  15. 15. 211.22 Responsibility of QualityControl Unit  Authorities and Responsibility  Approve or Reject all: o Components o Drug Product Container o Closures o in-process Materials o Packaging Materials o Labeling o Drug Products  Review Production records to assure no erros have occurred  If errors have occurred the responsibility to assure that they have been fully investigated
  16. 16. Subpart B – Organization andPersonnel  Personnel qualifications. Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions.  Personnel responsibilities- Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform.  Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained
  17. 17. Quality Assurance Manual  Should indicate that have a well- documented Quality Assurance (QA) program in place.  The QA program should provide a systematic approach for evaluation, inspection, testing, calibration or whatever is needed to monitor and assure the quality of your product.
  18. 18. Qualifications of Personnel (training)  All personnel in manufacturing or management must have education training and experience or a combination thereof to perform assigned duties  Training in the GMPs and operations performed by the employees  Training conducted on a continuing basis by qualified individuals  Adequate number of personnel to perform functions.  Clean clothing and protective apparel worn as necessary to protect drug products from contamination  Good sanitation and health habits should be followed.
  19. 19. Consultants  Consultants advising on GMP areas and operations must be qualified by education, training or experience.  Maintain records of their qualification, work and address
  20. 20. Summary  The quality unit must have the authority to make independent quality related decisions.  Personnel must have documented adequate training & experience.  Training for staff and contractors
  21. 21. Subpart C-Buildings and Facilities
  22. 22. Subpart C  211.42 Design and Construction  211.44 Lighting  211.46 Ventilation, HVAC  211.48 Plumbing  211.50 Sewage and Refuse  211.52 Washing and Toilet Facilities  211.56 Sanitation  211.58 Maintenance
  23. 23. Design First principle: Quality by Design GMP requirements for Process Design  211.42 Design of Facility  211.63 Design of Equipment  211.100 Design of Production and Control Procedures  211.160 Design of Laboratory Controls
  24. 24. Buildings and Facilities  The temperature and relative humidity should be controlled, monitored in accordance with an SOP, and the results recorded. The limits should be appropriate according to the materials stored and product processed
  25. 25. Premises
  26. 26. Sanitation
  27. 27. Sanitation  Building maintained in a clean and sanitary condition  Written procedures assigning responsibility for sanitation methods.  Written procedures for use of suitable elimination of pests and environmental contaminants  All agents used must be in accordance with EPA standards
  28. 28. Sanitation  Buildings maintained in a clean and sanitary condition  Written procedures assigning responsibility for sanitation methods, equipment, materials & schedules  Written procedures for the use of suitable:  Insecticides  Rodenticides  Fungicides  Fumigating agents  Cleaning and sanitizing agents  All pest control products must be registered and used in accordance with EPA standards.
  29. 29. Buildings and Facilities  Separate receiving and dispatch bays  Materials and products protected from weather  Area to clean incoming materials provided
  30. 30. Summary  Data must exist to show suitability or fitness for use of major instruments., equipment, and systems.  Control, cleaning and maintenance prevents contamination
  31. 31. Subpart D Equipment
  32. 32. Subpart D – Equipment § 211.63 Equipment design, size, and location. § 211.65 - Equipment construction. § 211.67 - Equipment cleaning and maintenance. § 211.68 - Automatic, mechanical, and electronic equipment. § 211.72 - Filters.
  33. 33. Equipment  Adequate space to facilitate cleaning and maintenance of equipment  To prevent contamination there should be separate or defined areas or other control systems for the receipt identification, storage and withholding of all materials.  Orderly placement of equipment.
  34. 34. Equipment Design of areas for weighing of materials  Proper air supply  Dust control measures (including extraction of dust and air)  Easily cleanable surfaces  No areas for dust accumulation  Protection of material, product and operator
  35. 35. Equipment All aspects including  Design, installation, operation, performance, specifications, logs, maintenance, use, cleaning, qualification, calibration etc…
  36. 36. Maintenance Procedures (MP)  Periodic procedures  To minimize the risk of losing raw data and analytical results  Inspection/replacement of normal wear and maintenance items  File back-up and recovery  Data archival and retrieval  Security  Lan administration
  37. 37. Equipment design size and location  Must be suitable for intended use  Easily cleaned and maintained  Must be non reactive  Lubricants coolants etc. required for operation should not contact any component.
  38. 38. Equipment Design, Size, andLocation  Must be suitable for  Equipment intend use: Construction  Appropriate design  Cannot be  Adequate size  Additive  Suitably located  Absorptive  Reactive  Facilitate its  Lubricants, coolants use, cleaning and maintenance etc. required for operations should not contact any component
  39. 39. Equipment Cleaning andMaintenance  Equipment and utensils  Must be cleaned  Maintained at suitable intervals  Written Procedures  Assign responsibility for cleaning  Include schedules for maintenance
  40. 40. Materials
  41. 41. Equipment Cleaning andMaintenance  Equipment and utensils must be cleaned and maintained at suitable intervals  Written procedures assign responsibility for cleaning and schedules for maintenance.  State methods, materials and equipment for cleaning  State disassembly reassembly procedures  Obliteration of previous batch information  Inspection of equipment before use.
  42. 42. Written Procedures  State methods, materials and equipment for cleaning  State disassembly/reassembly methods  Obliteration of pervious batch information  Protection of equipment prior to use  Inspection of equipment immediately before use
  43. 43. Subpart E- Control ofcomponents and drug Productcontainers and Closures
  44. 44. Subpart E- Control of Components  General requirements. § 211.82 - Receipt and storage of untested components, drug product containers, and closures. § 211.84 - Testing and approval or rejection of components, drug product containers, and closures. § 211.86 - Use of approved components, drug product containers, and closures. § 211.87 - Retesting of approved components, drug product containers, and closures. § 211.89 - Rejected components, drug product containers, and closures. § 211.94 - Drug product containers and closures.
  45. 45. General Requirements  Written Procedures  Handled and stored in a describing: manner to prevent  Receipt contamination  Identification  Bagged or boxed component  Storage of containers or closure stored off floor and suitably  Handling spaced to permit cleaning  Sampling and inspection  Testing  Identified with a distinctive  Approval or Rejection code for each lot in each shipment received  Each lot identified as to its status: quarantined, approved, rejected.
  46. 46. Component Tests  At least one test must be conducted to verify the identity of each component of a drug product  Specific identity tests, if they exist, should be used  Each component must be tested for conformity with all appropriate written specification for purity, strength, and quality. A certificate of analysis may be accepted from the supplier provided that:  At least one specific identity test is conducted  The manufacturer has established the reliability of the supplier’s analyses through appropriate validation of the suppliers test results at appropriate intervals
  47. 47. Containers and Closures  Should not be reactive, additive, or adsorptive  Provide adequate protection against foreseeable external factors in storage and use  Clean, and if appropriate, sterilized and processed to remove pyrogenic properties  Written procedures for: standards or specifications, methods of testing, and where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties
  48. 48. Summary  Material must always be released by QC before they are used.  No provisional releases  Vender CoA must be verified.
  49. 49. Subpart F- Production&Process Controls
  50. 50. Subpart F- Production and ProcessControls  Written procedures; deviations. § 211.101 - Charge-in of components. § 211.103 - Calculation of yield. § 211.105 - Equipment identification. § 211.110 - Sampling and testing of in- process materials and drug products. § 211.111 - Time limitations on production. § 211.113 - Control of microbiological contamination. § 211.115 - Reprocessing.
  51. 51. Validation Requirement Process Validation is an Enforceable Requirement  Finished Dosage Form Products  21 CFR 211.100  21 CFR 211.110  21 CFR 211.113  21 CFR 211.42  21 CFR 211.63  21 CFR 211.165  21 CFR 211.180
  52. 52. Validation Requirement Process Validation is an Enforceable Requirement  Active Pharmaceutical Ingredients  Statutory CGMP provisions of 501(a)(2)(b) of the Food Drug and Cosmetic Act  No regulations  GMP guidance available - ICH Q7A
  53. 53. Goal of Process Validation Drug product meeting the needs of the patient, i.e., safe and effective; and has the identity, strength, purity, and quality characteristics it is represented to possess.  Achieved through proper product development and proper process validation.
  54. 54. Process Validation Lifecycle Design Confirm Assess Monitor
  55. 55. Validation Principle  Documented evidence: Process is capable of reliably and repeatedly rendering a product of the required quality  Planning, organizing and performing process validation  Process validation protocols  Data collected and reviewed against predetermined acceptance criteria – recorded in validation report
  56. 56. Qualification  Installation Qualification (IQ)  Operational Qualification (OQ)  Performance Qualification (PQ)  Maintenance Procedures (MP)
  57. 57. Production and process control
  58. 58. Pertains to processing steps-Dispensing to Bulk dose  Written Procedures: Deviations  Change Control  Charge-in of components  Calculation of yield  Equipment ID  Sampling  Production time limits
  59. 59. In-process testing Rejected Product Action Limits Target value Acceptable Range Action Limits Rejected Product
  60. 60. In-process testing Rejected Product Release Specifications Action Limits Target value Acceptable Range Action Limits Release Specifications Rejected Product
  61. 61. Summary  Use only valid processes and systems.  Keep adequate records to allow deviations to be recorded and investigated.  Make drug products right, first time, every time.
  62. 62. Subpart G Packaging and LabelingControl
  63. 63. Subpart G – Packaging andLabeling Control  Materials examination and usage criteria. § 211.125 - Labeling issuance. § 211.130 - Packaging and labeling operations. § 211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug products. § 211.134 - Drug product inspection. § 211.137 - Expiration dating.
  64. 64. Labeling Issuance  Labeling issued for each batch shall be examined for identity and conformity with labeling in master or batch records  Reconciliation between labeling issued, used and returned and product produced  Discrepancies outside of narrow preset limits, based on historical data, require an investigation
  65. 65. Packaging and Labeling Operations  Written procedures  Procedures should incorporate the following features: • Prevention of mix-ups and cross-contamination • Identification and handling of filled drug containers • Examination of labels for correctness • Line inspection before packaging to assure that lines have been cleared • Documentation of all activities in the batch record
  66. 66. Drug Product Inspection  Examine packaged and labeled products during finishing operations to assure the correct label has been used  Collect a representative sample of units at the completion of finishing and examined for correct labeling  Record results of the examination of the batch record
  67. 67. Subpart H- Holding and Distribution
  68. 68. Subpart H- Holding and Distribution  § 211.142 - Warehousing procedures.  § 211.150 - Distribution procedures.
  69. 69. Warehouse Procedures  Written procedures for  Quarantine prior to QC release  Storage under appropriate conditions of temperature, humidity and light
  70. 70. Subpart I lab controls: InstrumentControls, Training, Standards/Reagents, Testing and Release, OOS
  71. 71. Subpart I- Laboratory Controls  § 211.160 - General requirements. § 211.165 - Testing and release for distribution. § 211.166 - Stability testing. § 211.167 - Special testing requirements. § 211.170 - Reserve samples. § 211.173 - Laboratory animals. § 211.176 - Penicillin contamination.
  72. 72. Out of Specification (OOS)  What does the cGMP Regulation say about Handling OOS Results?
  73. 73. Averaging  Assay results should never be averaged because averaging hides individual variability:  e.g. 89, 89, 92 (x=90)  Individual content uniformity tests should not be averaged to obtain passing value  Microbiology averaging is acceptable due to biological variability
  74. 74. Make sure each technicianunderstands the calculations
  75. 75. General Requirements  Scientifically sound specifications, standards, sampling plans, test procedures and other laboratory controls procedures and any changes should be drafted by the appropriate organization and approved by QC  Documented at the time of performance  Deviations recorded and justified
  76. 76. Testing and Release  Appropriate laboratory determination of each lot for conformance to final specifications  Appropriate laboratory testing of each lot of drug required to be free of objectionable microorganisms
  77. 77. Stability Defined  Definition (ICH/FDA)  The capacity of a drug substance or drug product to remain within specifications established to ensure its identity, strength, quality and purity throughout a retest or expirations dating period.
  78. 78. Stability Testing  Written testing program designed to assess stability of drug and determine expiration dates  Sample size & test interval based on statistical criteria for each attribute examined.  Storage conditions  Reliable, meaningful and specific test methods.  Utilization of same container/closure system as marketed drug  Test products for reconstitution at time of dispensing and after reconstitution
  79. 79. Stability Testing  An adequate number of batches need to be tested to determine the expiration date.  Accelerated studies, combined with data from long-term stability studies support tentative expiration dates.  Expiration dates assigned from accelerated study data much be verified by ongoing shelf-life studies
  80. 80. Reserve Samples  2X quantity for tests (except sterility &pyrogen)  Representative samples, selected statistically, examined visually at least annually for deterioration  Any evidence of deterioration shall be investigated and results maintained with other stability data
  81. 81. Subpart J- Records andReports
  82. 82. Subpart J- Records and Reports  § 211.180 - General requirements. § 211.182 - Equipment cleaning and use log. § 211.184 - Component, drug product container, closure, and labeling records. § 211.186 - Master production and control records. § 211.188 - Batch production and control records. § 211.192 - Production record review. § 211.194 - Laboratory records. § 211.196 - Distribution records. § 211.198 - Complaint files.
  83. 83. If it was not documented, it was not done! 83
  84. 84. Great Mounds of Paper? Some may think that GMP stands for Great Mounds of Paper! There’s some truth to that.
  85. 85. Records and Reports
  86. 86. TYPE OF GMP DOCUMENTS QUALITY MANUAL S.O.P. Equipment Status Master production Specification/ Testing Work Protocol Identity/ Material Status document Standard Method (WP) Label Product Status Master Formula Raw & packaging materialMaster Prod. Procedure Bulk Validation Protocol ReportMaster Pack. Procedure Finished product Sampling record Testing result record and report Microbial and particle monitoring record Batch Production Record Stability test record Return Product Handling Record Recall Record Product Destruction Record Note : Product Complaint Record •Blue : WI (standard, specification & procedure) Distribution Record •Red : record
  87. 87. Not untilCan we ship thethis batch? paperwork is released! QC Lot no. XYZ
  88. 88. The GMP Paperwork is aProduct The paperwork produced is of equal importance to the products produced. Product = Paperwork
  89. 89. General Requirements  Retain all records at least 1 year after expiration date of the batch  OTC drugs lacking expiration dates retain all records for at least 3 years after distribution of the batch  Records for components, containers, closures, and labeling follow the same rules.
  90. 90. cGMP Part 211.192  The failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated…  The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure of discrepancy…
  91. 91. cGMP Part 211.194  A written record of the investigation shall include the conclusions and follow-up…  A complete record of all data secured in the course of each test…  Complete records shall be maintained of all stability testing performed…
  92. 92. Packaging and Labeling
  93. 93. Holding and Distribution
  94. 94. General Requirements  Written Procedures  Handled and stored describing in a manner to handle o Receipt contamination o Identification  Stored off the floor o Storage  Identified with a o Handling distinctive code o Stamping  Each lot identified as o Testing to its status o Approval or quarantined, approv rejection ed or rejected
  95. 95. Subpart K- Returned andSalvaged Drugs
  96. 96. Subpart K – Returned and SalvagedDrug Products  § 211.204 - Returned drug products.  § 211.208 - Drug product salvaging.
  97. 97. Returned and Salvaged Drugs  Returned Drug Products  Shall be identified and held  If the condition of the drug, packaging or labeling casts doubt on its safety, identity, strength, quality or purity, it must be destroyed unless examination, testing, or investigation proves the drug meets its specifications.
  98. 98. Returned Products- Maintained in aseparate defined area
  99. 99. Packaging and Labeling Production Control and Holding and Process Distribution ControlsControl of Laboratorycomponents andDrug Product GMP controlsContainers andClosures Organization and Personnel Equipment Buildings and Facilities
  100. 100. This is for your family… Manufacture Raw Materials Dispense
  101. 101. A word about Drug Master File… http://wwwbdp.ncif crf.gov/pdf1/Guidet oRegSubsR1.pdf
  102. 102. Questions