BPR review and batch release

BPR review and batch release

1. BPR review and Batch Release Dr. A. Amsavel

2. Introduction

3. Content Introductions Definition Deviation, Critical Process Parameters and Critical Quality Attributes Regulatory requirement Q7 and CFR Specific to Batch Review an Release Quality Unit Requirements Batch Record Defined in the Regulations Regulatory Consequences & FDA Citations Batch Record Review and Release SOP & Checklist Records to be Reviewed Cleaning & Line Clearance ALCOA

4. If it isn’t documented, it is not done or It isn’t happened If it isn’t documented, it doesn’t exist. “If it is not documented, it is a rumour!” This is the FDA approach The product considered as “Adulterated” if the procedure not followed/ not documented properly . Importance of Documentation

5. What is BPR Batch Production Record (BPR) / Batch Record/ Production Control Record, Production Batch Record, etc…. Ref 21 CFR Part 211.188: BPR is step-wise procedure that production operators follow to manufacture of API or a drug product or Intermediate for sale “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.” Each BPR is a controlled document from the time it is issued until it can eventually be destroyed.

6. Objective of BPR Review Purpose To confirm that there is sufficient evidence to demonstrate the batch is of acceptable quality and is produced within a state of control. Significance This confirmation is required to release product for distribution. It Is a permanent record in the event documented evidence of conformance to specifications & cGMPs followed. It is needed until the life of the product.

7. Definition Deviation Departure from an approved instruction / procedure or established standard or specification Quality Impacting Incident: Quality impacting incidents are errors or occurrences during execution of an activity which will affect the Quality, Purity, Strength of the drug product. Quality Non-impacting Incident: Quality Non-impacting incidents are errors or occurrences during execution of an activity which may have no impact on the quality, purity and strength of a drug product In-Process Control (or Process Control) Checks performed during production in order to monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or API conforms to its specifications.

8. Definition Critical Process Parameters (CPPs) A process parameter which has impact on a CQA, hence those parameter should be monitored or controlled to ensure the process produces the desired quality. Critical Quality Attributes (CQA’s) A physical, chemical, or microbiological property or characteristic that should be within an appropriate limit, range to ensure the desired product quality. CQAs are the aspects that affecting product purity, strength, drug release, and stability. Process Parameter (PP) Generally, they involve temperature, time, flow rates, pressures, and numerous other discreet input settings or output readings on the process equipment that are employed in a manufacturing process.

9. GMP requirement ICH Q7 - same as WHO-GMP 2.2 Responsibilities of the Quality Unit(s) The main responsibilities of the independent quality unit(s) should not be delegated Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing company; Establishing a system to release or reject raw materials, intermediates, packaging and labelling materials; Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution;

10. GMP requirement ICH Q7 - same as WHO-GMP 2.3 Responsibility for Production Activities Reviewing all production batch records and ensuring that these are completed and signed; Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded;

11. Requirement (ICH Q7) Batch Record, Batch Production Record, Batch Production Control Record, Production Batch Record, or other term, 6.5 Batch Production Records (Batch Production and Control Records) 6.5.1 Batch production records should be prepared for each intermediate and API and should include complete information relating to the production and control of each batch. Batch production record should be current and reference to the current master production 6.5.2 These records should be numbered with a unique batch or identification number, dated and signed when issued

12. Requirement (ICH Q7) 6.5 Batch Production Records (Batch Production and Control Records) 6.52 Documentation of completion of each significant step in the batch production records (batch production and control records) should include: Dates and, when appropriate, times; Identity of major equipment (e.g., reactors, driers, mills, etc.) used; Specific identification of each batch, including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed materials used during manufacturing; Actual results recorded for critical process parameters; Any sampling performed; Signatures of the persons performing and directly supervising or checking each critical step in the operation;

13. Requirement (ICH Q7) 6.5.2 Batch Production Records ... In-process and laboratory test results; Actual yield at appropriate phases or times; Description of packaging and label for intermediate or API; Representative label of API or intermediate if made commercially available; Any deviation noted, its evaluation, investigation conducted (if appropriate) or reference to that investigation and Results of release testing. 6.53 Investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation.

14. GMP requirement Q7 6.7 Batch Production Record Review Written procedures should be established and followed for the review and approval of batch production and laboratory control records, including packaging and labelling, to determine compliance of the intermediate or API with established specifications before a batch is released or distributed. Batch production and laboratory control records of critical process steps should be reviewed and approved by the quality unit(s) before an API batch is released or distributed. Production and laboratory control records of non-critical process steps can be reviewed by qualified production personnel or other units following procedures approved by the quality unit(s). All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released. The quality unit(s) can delegate to the production unit the responsibility and authority for release of intermediates, except for those shipped outside the control of the manufacturing company.

15. Production Record Review (21 CFR 211.192) “ All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including theoretical yield or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated whether or not the batch has already been distributed. The investigation shall extend to other batches and other products that may have been associated with the specific failure or discrepancy and recorded

16. Responsibilities of Quality Control Unit 21 CFR 211.22: The Quality Control Unit has the authority for the following: QC shall have Responsibility and authority to approve or reject all components, drug products, containers, in-process material, packaging material and Labels. Authority to Review Production Records to assure that no errors have occurred. If errors have occurred, that they have been fully investigated. Responsibility for approving or rejecting all procedures or specifications impacting the identity, strength, quality and purity of the drug product. Responsibilities and Procedure shall be made available

17. Regulatory Consequences 21 CFR Part 210 cGMP in Manufacturing, Processing, Packaging, or Holding of Drugs; General The failure to comply with any regulation set forth in this part and in parts 211 through 216 of this chapter in the manufacture, processing, packing, or holding of a drug shall render such drug to be adulterated under section 501(a)(2)(B) of the Act and such drug, as well as the person who is responsible for the failure to comply, shall be subject to regulatory action .

18. Regulatory Overview Federal Food, Drug, and Cosmetic Act (the Act)[21 U.S.C § 331(a)(2)(B)] Methods, Facilities, and Controls must comply with cGMP or the drug product is deemed adulterated! Need to provide the evidence that review of the Batch Record including all critical step. The above confirms that the product meets cGMPs with the Batch Record documentation.

19. Regulatory Overview What is stand for Adulterated? “A drug or device shall be deemed adulterated… if it (the product) is a drug and the methods used in, or the facilities or controls used for, it’s manufacture, processing, packing or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identify and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.”

20. Regulatory Observations (483) Batch production and laboratory control records of critical process steps are not reviewed and approved by the Quality Unit before an intermediate or API batch is released or distributed. Specifically, your firm failed to review complete batch records to include all stages of manufacturing prior to batch release for all marketed products. Failure to ensure Batch Production Records are prepared for each of your APIs and include complete information relating to the production and control of each Batch . . Failure to extend the investigation to other batches and other products that may have been associated with the specific failure

21. Regulatory Observations (483) Batch Production and Control Records fail to document the completion of each significant manufacturing step, the signature of the persons performing manufacturing steps, equipment used, and sampling information. There is a failure to throughuly investigate unexplained discrepancy and failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated whether or not the batch has already been distributed Quality contro l Unit did not notice the contradictory yields obtained between your Batch Production Record and Raw Data Record sheet for the same Batch of the drug product. Your Production Records for bulk Batch document the size of this Batch as….

22. Batch Record Review & Release How To Conduct Effective BPR Review: The following documents are needed for an effective, consistent, and systematic review: SOP for Batch Record Review shall cover Production, Packaging, Labeling, Laboratory Testing etc… BPR Review Checklist - to ensure completeness and evidence of BPR review. Also can use Corrections Sheet

23. SOP for Batch Record Review SOP for the Batch Record Review ; Describes the purpose / scope of BPR Review It is not just to identify exceptions (e.g., mistakes, oversights, illegible entries, etc.) and action to be taken Responsibility / authority to release : QA head, or Authorised person or any other person suitably Authorised Describes the significance of an accurate & complete review of BPR. It is to confirm that the records are clear, accurate, and include evidence to support that the batch was manufactured and controlled as per internal procedures and cGMPs . Refer the SOP of review of BPR by production Defines a time for completion of the review

24. SOP for Batch Record Review SOP for the Batch Record Review shall have the following; Details of Production and QA Reviewer feedback and correction. Reviewer identifies the mistakes, missing entries, or failures to follow GDP observed during review Describe the elements of a “ Corrections Sheet”, that can be used by the QA reviewer to record corrections , that are identified during a review. Verification of source data where possible, to verify the contents of the Record. Example, weighing print of materials, temperature record, dispensing record, etc. If critical information is missing, SOP shall describe how and when a QA reviewer should inform to initiate and investigate deviations

25. SOP for Batch Record Review Review elements that should be included in the respective Checklist. Common check list or product specific if required. Eg . API / Intermediate Verify the presence of a signature page that includes the name, initials, and signature for each person, who performed the process . Verify that all pages of the BPR and supporting documentation are attached and cross referenced; examples include, but are not limited to, Reaction monitoring data, in-process data, packing list, Environmental Data (sterile) etc.. Verify that significant steps were verified by a second person (i.e., weighing of materials and charge of components). Verification that the sequence of events is clear and complete. Verify all calculations in the Record as accurate.

26. SOP for Batch Record Review Review / verify the following to ensure that product meets the quality and consistent. This is ensured by controlling the critical steps and other variable in affects the quality Process Parameter (PP) … temperature, time, flow rates, pressures, and other discreet input settings or output readings on the process equipment Critical Process Parameters (CPPs) A process parameter which has impact on a quality attributes; Critical Quality Attributes (CQA’s) In process control / quality parameters- A physical, chemical, or microbiological results are within the limit

27. SOP for Batch Record Review Investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation. All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released.

28. SOP for Batch Record Review BPR Review Checklist: Checklist can be prepared to address; Review details/ standard elements, observation and action taken Cover manufacture, packaging, and labeling section Reporting deviations observed during review

29. Records Examples of Records to be Reviewed: Production and Process Control Records Material used are traceable and quantity is as per standard (KSM, RM, reagents, Solvents, Catallyst , seed etc…. Calculation & verification of Yield Reconciliation of intermediate if used from multiple lots /batches Equipment Identification & log book Sampling and Testing of in-process materials Critical Quality Attributes- test results are meeting the specification Time Limits of Production as applicable Critical Process Parameters are as per standard limit Room / Area Cleaning & Clearing – Line Clearance Calibration of instruments

30. Records Packaging and Labeling Control Records Label issuance and reconciliation Laboratory Control Records Specifications & test Method followed Test report / Certificate of Analysis Test Records / Raw Data Deviations and investigations related to the production, packaging, labeling, and testing operations for the batch. OOS and investigations Changes that occurred during the production, packaging, labeling, and testing operations for the batch.

31. Check list Sr. No. Check point Observation Corrective action taken 1 Yield ( %/ Kg) is complying with the standard limits. 2 Calibration & Cleaning is verified as per BPR manufacturing equipment. 3 Procedure followed for each operation is as per BPR/ECR. 4 All entries in BPR/ECR is complete, signed and dated. 5 Over writing if any, have been corrected as per SOP. 6 Equipments used for manufacturing are as per the BPR. 7 Input UIN & quantities recorded in BPR / ECR is complying with raw/packing material issue slip. ` 8 Entries on raw / packing material issue slip are complete.

32. Check list Sr. No. Check point Observation Corrective action taken 9 Entries of In process weights & results are done 10 In process test results are complying with the standard specification. 11 Critical process parameters are meeting the requirement. 12 Supporting data like raw / packing material issue slip, in process test reports and equipment cleaning sample reports are attached. 13 Packing list with seal umber is correct 14 Specimen product label of the batch is attached. 15 Finished product results are complying with the standard specification 16 Any other information

33. Check list Sr. No Deviations / OOS / OOC Observation (Minor/ Major) Corrective action taken 1 Deviations if any reported and status 2 OOS if any reported and status 3 OOC if any reported and status Remark: (Justification if any open issues): Status: The Batch is Released / Not Released Reviewed by (QA): Approved by QA: Date: Date:

34. Correction Sheet Sr. No Page / Section No Observation Action taken Reason / Justification if required 1 2 3 Reviewed by QA: Approved by QA: Date: Date:

35. Batch Release Consider all aspects before important decision is made. “ Do I release, reject or what?” RELEASE OF PRODUCT IS NOT JUST BASED ON THE BPR Endure that the Quality system Supporting Manufacture is ‘in control’. Ensure GDP is followed Ensure there is no DATA INTEGRITY

36. Batch Cleaning Record Review 21 CFR 211.182 Equipment Cleaning and Use Log Verify equipment and usage log & Cleaning log are correct Verify the Cleaning of equipment & area are cleaned appropriately. All cleaning related logbooks are reviewed to indicate Date, Time, Product & Lot Number of previous batch processed Before Batch Release, verify cleaning, room clearance and line clearance via Line Clearance Checklist(s) filed with the Batch Record. Equipment Cleaning Record should be reviewed Verifies the PCO / Line Clearance Checklist. Residual content is within the limit, physical verification –Equipment is clean, Area is cleared of all previous batch materials, utensils, labels, etc.)

37. Let us learn DATA INTEGIRITY

38. ALCOA ACRONYM (Data verification) ALCOA Explanation A Attributable Who performed and when? L Legible Can it be read? Permanent Record C Contemporaneous Recorded at the time the activity was performed O Original` Original record or certified true copy A Accurate Error free

39. ALCOA (Data verification) ALCOA Description/Explanation A Attributable Who performed an action and when ? If a record is amended / changed, who did it and why? Why- reason & explain in detail Traceable to the source data. L Legible Data shall be recorded permanently Record shall be durable & readable . C Contemporaneous The data shall be recorded at the time the work is performed. Signature / initial with date O Original Is the information the original record or a certified true copy ? A Accurate No errors or if editing shall be amended properly

40. ALCOA Plus (Data verification) ALCOA + Description/Explanation 1 Complete All data including repeat or reanalysis performed on the sample. 2 Consistent Consistent application of data time stamps in the expected sequence 3 Enduring Recorded on controlled worksheets, laboratory notebooks, or electronic media. 4 Available Available/accessible for review/audit for the lifetime of the record.

41. Thank You