21CFR Ventilation, air filtration, air heating and cooling. 21CFR211 Details, Details. 21CFR Equipment Cleaning and Maintenance

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1 21CFR211 Details, Details Kirsten L. Vadheim, Ph.D., RAC th Avenue N.E. Redmond WA Tel: Fax: CFR Ventilation, air filtration, air heating and cooling Aka Heating, ventilation and air conditioning (HVAC) What is adequate? Specs for air pressure cascades, microbes, humidity and temp. Penicillin production - separate HVAC 2 21CFR Equipment Cleaning and Maintenance SOPs include: responsibility schedules detailed description of process Must be able to demonstrate removal of previous product/batch Requires dirty clean flow of materials Check for visual cleanliness Documentation 3 21CFR Testing and approval or rejection of components, drug product containers, and closures. QC release of each lot of components, containers, closures No composite samples Adequate identification of sampled containers and samples (documentation) Identity testing Conformance with specifications for purity, strength, quality 4

2 21CFR Testing and approval or rejection of components, drug product containers, and closures. 6(d)(2) - COA from manufacturer OK *IF* an identity test is performed reliability of supplier s s analyses is established at appropriate intervals routine audits 21CFR Testing and approval or rejection of components, drug product containers, and closures. Potential for filth, insect filtration, adulteration or microbial contamination Know your raw materials! Each lot released for use CFR Calculation of yield Calculated at each appropriate phase determined by process validation performed by one person independently verified by a second standard procedure for calculations 21CFR Control of microbiological contamination Appropriate written procedures, designed to prevent shall be established and followed (b) Shall include validation of any sterilization process 7 8

3 21CFR Reprocessing Introducing an intermediate, drug substance or API back into the process and repeating appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process (Q7A, 14.2) Reworking Subjecting an intermediate or drug substance that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain material that meets acceptance criteria Reprocessing Generally acceptable under specified conditions for drugs and devices Generally unacceptable for vaccines Reprocessing Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing. Q7A, 14.2 BUT process validation defines length of processing steps 11 12

4 Subpart I - Laboratory Controls , General Requirements Product Reprocessing Reworking Remanufacturing Drugs X X Biologics -Plasma products -Allergenics -Vaccines X Devices X X X X All specs, standards, sampling plans, test procedures, etc. shall be reviewed and approved by QA Documented at the time of performance Any deviations recorded and justified establishment of scientifically sound and appropriate specs, sampling plans and test procedures that conform to appropriate standards of identity, strength, quality and purity Subpart I - Laboratory Controls , General Requirements Lab controls shall include: Written specs for each lot of raw materials Specs include the sampling and test methods Determination of conformance to specs for all in- process materials as well as drug product Calibration program including all instruments, apparatus, gauges, and recording devices , Testing and release for distribution Determine whether the drug product meets final specs Testing for objectionable microbes, as necessary Scientific, statistically sound acceptance criteria Validated test methods Reject drug product that doesn t t meet these criteria 15 16

5 , Stability testing Written program that includes: sample sizes and test intervals based on statistics defined storage conditions reliable, meaningful, specific test methods same container-closure closure systems test at time of reconstitution as well as stability of reconstituted product ( (c)) , Stability testing Determination of expiration date: based on testing adequate number of batches requires full shelf life studies accelerated studies define tentative expiration dates tentative expiration dates must be verified by full- scale stability studies Stability testing continues as long as product is commercially distributed , Reserve samples Aka retention samples Appropriately identified Applies to drug product as well as API Representative of each lot in each shipment of each active ingredient Stored under label conditions Same container-closure closure system or essentially the same characteristics , Reserve samples How much? 2x amount required for all tests How long? 1 year after expiration date of last lot containing the active ingredient Annual visual exam 19 20

6 , Penicillin contamination Knowledge of process for shared manufacturing critical Audit contract fillers Re: (d) 21CFR211 Subpart J - Records and Reports , General Requirements Record retention - 1 year beyond expiration Records readily available for inspection Original records or true copies , General Requirements Quality reviews Required at least annually Based on written procedures Include review of a representative number of batches Include review of complaints, recalls, returned/salvaged drug product, and investigations , General Requirements Requires notification of firm s s responsible officials of: recalls 483 observations GMP-related regulatory actions investigations relating to: complaints returned drug product salvaged drugs 23 24

7 , Equipment cleaning and use log Records must be sufficient to accurately link equipment cleaning to production of a specific batch Includes cleaning, maintenance and use Such documents for dedicated equipment become part of the batch production record , Component, drug product container, closure, and labeling records Trace-back information on components, drug product containers, closures and labeling Testing results and conclusions derived Individual inventory records and reconciliation Correlation of each component, etc., with production of specific lot or batch Documented review of labeling materials Disposition of rejected materials , Master Production Records Signed and dated by one person, independently verified by a second Includes: description of containers, closures, packaging materials, labels Complete manufacturing and control instructions, sampling, testing procedures, specs, special notations, precautions , Batch production and control records Individually prepared for each batch manufactured Include complete information for the production and control of each batch An accurate copy of the Master, checked for accuracy, signed and dated 27 28

8 , Batch production and control records , Production record review Documentation that each significant step was performed, including: Complete labeling records, with examples of each Any sampling performed Any investigations performed QA review and release of each batch before distribution Any discrepancy thoroughly investigated Written records kept of investigations, conclusions and follow-up , Laboratory Records Complete record of all data derived during completion of test (not just the final result) Complete sample description Statement of all test methods used References for validation data supporting test methods (USP, etc.) Verify suitability of all test methods under actual conditions of use , Laboratory Records Complete record of all calculations Initials or signature of person performing each test, and the date test was performed Initials/signature of second person reviewing data for accuracy, completion and compliance with standards Complete change control records for any method modifications Calibration records for all equipment used 31 32

9 Complaint files Written procedures for handling complaints Review by QA Determine the need for an investigation Timely review of complaints is critical report as ADE? SAE? 15 days (21CFR and ) BPDR? 45 days (21CFR600.14) Complaint files Maintain written records of each complaint Readily available for inspection Maintain 1y after product expiration, or 1y after complaint received, whichever is longer If investigated, include findings and followup If not investigated, include justification and person who made this determination If reported as ADE, keep10 years 33 34