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Top 20 observation series # 3 21 CFR 211.192

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- 2014 inspectional observations
- List of Top observations in 2014
- Sec. 21 CFR 211.192
- 483 observations
- Warning Letters
- Other Guidance
- How to avoid observations
- Batch Record Review - Investigations

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Top 20 observation series # 3 21 CFR 211.192

  1. 1. 21 CFR 211.192 pharmauptoday@gmail.comConsult Yourself.... “Know Regulation - No Observation”
  2. 2. - 2014 inspectional observations - List of Top observations in 2014 - Sec. 21 CFR 211.192 - 483 observations - Warning Letters - Other Guidance - How to avoid observations - Batch Record Review - Investigations pharmauptoday@gmail.com Contents
  3. 3. Total Inspectional Observations Center Name 483s Issued Foods 2476 Devices 972 Drugs 645 Veterinary Medicine 337 Bioresearch Monitoring 297 Biologics 146 Human Tissue for Transplantation 115 Parts 1240 and 1250 70 Radiological Health 16 Sum Product Area 483s from System* 5074 Actual Total in System 483s** 4943 Number of 483s Issued from the System* Inspections ending between 10/1/2013 12:00:00 AM and 9/30/2014 12:00:00 AM
  4. 4. Inspectional Observations - Drugs Summary Count (Number) Total 483’s issued for Drugs center in 2014 645 Total number of observations issued for Drugs center in 2014 2997 Total number of observations related to cGMP (21 CFR part 211) violations 2835 Total number of top 10 CFR part 211 violation 1653 (58%) Total number of top 15 CFR part 211 violation 2110 (74%) Total number of top 20 CFR part 211 violation 2398 (85%) Number of CFR part 211 parts violated 54
  5. 5. S.No. CFR Frequency % S.No. CFR Frequency % S.No. CFR Frequency % 1 21 CFR 211.160 235 8.3 19 21 CFR 211.186 48 1.7 37 21 CFR 211.204 10 0.4 2 21 CFR 211.22 218 7.7 20 21 CFR 211.63 41 1.4 38 21 CFR 211.101 9 0.3 3 21 CFR 211.192 209 7.4 21 21 CFR 211.80 41 1.4 39 21 CFR 211.105 6 0.2 4 21 CFR 211.67 184 6.5 22 21 CFR 211.142 32 1.1 40 21 CFR 211.115 6 0.2 5 21 CFR 211.100 167 5.9 23 21 CFR 211.167 32 1.1 41 21 CFR 211.134 6 0.2 6 21 CFR 211.165 143 5.0 24 21 CFR 211.170 31 1.1 42 21 CFR 211.82 6 0.2 7 21 CFR 211.42 143 5.0 25 21 CFR 211.125 29 1.0 43 21 CFR 211.196 5 0.2 8 21 CFR 211.113 128 4.5 26 21 CFR 211.56 28 1.0 44 21 CFR 211.44 5 0.2 9 21 CFR 211.166 115 4.1 27 21 CFR 211.150 23 0.8 45 21 CFR 211.48 4 0.1 10 21 CFR 211.25 111 3.9 28 21 CFR 211.46 20 0.7 46 21 CFR 211.52 4 0.1 11 21 CFR 211.68 99 3.5 29 21 CFR 211.122 19 0.7 47 21 CFR 211.184 3 0.1 12 21 CFR 211.198 95 3.4 30 21 CFR 211.130 19 0.7 48 21 CFR 211.86 3 0.1 13 21 CFR 211.84 91 3.2 31 21 CFR 211.58 18 0.6 49 21 CFR 211.87 3 0.1 14 21 CFR 211.110 89 3.1 32 21 CFR 211.182 17 0.6 50 21 CFR 211.34 2 0.1 15 21 CFR 211.194 83 2.9 33 21 CFR 211.103 14 0.5 51 21 CFR 211.65 2 0.1 16 21 CFR 211.188 74 2.6 34 21 CFR 211.137 13 0.5 52 21 CFR 211.89 2 0.1 17 21 CFR 211.180 72 2.5 35 21 CFR 211.111 12 0.4 53 21 CFR 211.176 1 0.0 18 21 CFR 211.28 53 1.9 36 21 CFR 211.94 11 0.4 54 21 CFR 211.208 1 0.0 21 CFR 211 Observations - Drugs
  6. 6. 21 CFR 211 Observations - Drugs 0 50 100 150 200 250 21CFR211.22 21CFR211.25 21CFR211.28 21CFR211.34 21CFR211.42 21CFR211.44 21CFR211.46 21CFR211.48 21CFR211.52 21CFR211.56 21CFR211.58 21CFR211.63 21CFR211.65 21CFR211.67 21CFR211.68 21CFR211.80 21CFR211.82 21CFR211.84 21CFR211.86 21CFR211.87 21CFR211.89 21CFR211.94 21CFR211.100 21CFR211.101 21CFR211.103 21CFR211.105 21CFR211.110 21CFR211.111 21CFR211.113 21CFR211.115 21CFR211.122 21CFR211.125 21CFR211.130 21CFR211.134 21CFR211.137 21CFR211.142 21CFR211.150 21CFR211.160 21CFR211.165 21CFR211.166 21CFR211.167 21CFR211.170 21CFR211.176 21CFR211.180 21CFR211.182 21CFR211.184 21CFR211.186 21CFR211.188 21CFR211.192 21CFR211.194 21CFR211.196 21CFR211.198 21CFR211.204 21CFR211.208
  7. 7. List of “Top 20 – CFR parts to know” S.No. CFR Frequency % 1 21 CFR 211.160 235 8.3 2 21 CFR 211.22 218 7.7 3 21 CFR 211.192 209 7.4 4 21 CFR 211.67 184 6.5 5 21 CFR 211.100 167 5.9 6 21 CFR 211.165 143 5.0 7 21 CFR 211.42 143 5.0 8 21 CFR 211.113 128 4.5 9 21 CFR 211.166 115 4.1 10 21 CFR 211.25 111 3.9 11 21 CFR 211.68 99 3.5 12 21 CFR 211.198 95 3.4 13 21 CFR 211.84 91 3.2 14 21 CFR 211.110 89 3.1 15 21 CFR 211.194 83 2.9 16 21 CFR 211.188 74 2.6 17 21 CFR 211.180 72 2.5 18 21 CFR 211.28 53 1.9 19 21 CFR 211.186 48 1.7 20 21 CFR 211.63 41 1.4 Total 2398 85 • The top 10 cGMP violations (21 CFR part 211 observations) comprises a huge percentage (58% i.e. 1653 number of observations). • The top 20 cGMP violations (21 CFR part 211 observations) comprises a huge percentage (85% i.e. 2398 number of observations). • If the top 20 violations are eliminated, 85 % of the observations can be reduced.
  8. 8. Subpart I--Laboratory Controls Sec. 211.160 General requirements. 21 CFR 211.160 (a) 21 CFR 211.160 (b) 21 CFR 211.160 can be accessed from the link: http://www.slideshare.net/skvemula/top-20-observation- series-1-21-cfr-211160 pharmauptoday@gmail.com 21 CFR 211.160
  9. 9. Subpart B--Organization and Personnel Sec. 211.22 Responsibilities of quality control unit. 21 CFR 211.22 (a) 21 CFR 211.22 (b) 21 CFR 211.22 (c) 21 CFR 211.22 (d) http://www.slideshare.net/skvemula/top-20-observation- series-2-21-cfr-21122 pharmauptoday@gmail.com 21 CFR 211.22
  10. 10. Subpart J--Records and Reports Sec. 211.192 Production record review. 21 CFR 211.192 pharmauptoday@gmail.com 21 CFR 211.192
  11. 11. 483 citations related to 21 CFR 211.192 Year Number 2006 176 2007 163 2008 131 2009 165 2010 182 2011 229 2012 179 2013 239 2014 209 0 50 100 150 200 250 300 2006 2007 2008 2009 2010 2011 2012 2013 2014 483 Observations
  12. 12. pharmauptoday@gmail.com Regulation
  13. 13. CFR part 211 Regulation - 21 CFR 211.192 Sec. 211.192 Production record review. 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 a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) 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 of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow-up.
  14. 14. pharmauptoday@gmail.com Previous observations
  15. 15. 483 citations related to 21 CFR 211.192 Cite Id Reference Number Short Description Long Description Frequency 2014 2013 2027 21 CFR 211.192 Investigations of discrepancies, failures There is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed. Specifically, *** 94 131 4402 21 CFR 211.192 Written record of investigation incomplete Written records of investigations into [unexplained discrepancies] [the failure of a batch or any of its components to meet specifications] do not [always] include the conclusions and follow-up. Specifically, *** 38 32 2028 21 CFR 211.192 Extent of discrepancy, failure investigations Investigations of [an unexplained discrepancy] [a failure of a batch or any of its components to meet any of its specifications] did not extend to [other batches of the same drug product] [other drug products that may have been associated with the specific failure or discrepancy]. Specifically, *** 32 26 4576 21 CFR 211.192 No written record of investigation Written records are not [always] made of investigations into [unexplained discrepancies] [the failure of a batch or any of its components to meet specifications]. Specifically, *** 24 22 2026 21 CFR 211.192 Quality control unit review of records Drug product production and control records, are not [reviewed] [approved] by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Specifically, *** 21 28
  16. 16. 483 citations related to 21 CFR 211.192 Ref: 483 of Teva Parenteral Medicines Inc (07/2009)
  17. 17. 483 citations related to 21 CFR 211.192 Ref: 483 of Ameridose LLC (10/2012)
  18. 18. Warning letter observations -2015 - 21 CFR 211.192 Your quality control unit failed to review and approve all drug product production and control records to determine compliance with all established, approved written procedures before a batch is released or distributed (21 CFR 211.192). b. Your firm’s implementation of the audit program described in the Global Policy "Audit Program" document #GPOL-015 dated September 7, 2013 is inadequate in that it failed to prevent the recurrence of testing unofficial samples of drug product prior to testing the official sample and generating only those results to be reported. c. In addition the inspection revealed that failing or otherwise atypical results were not investigated, nor included in the official laboratory control records as required by 21 CFR 211.192. We reiterate that an investigation is necessary for any out-of-specification (OOS) event. Refer to the FDA's guidance on OOS investigations. Ref: WL: Apotex Research Private Limited 1/30/15 (WL: 320-15-06)
  19. 19. Warning letter observations -2014 - 21 CFR 211.192 Your firm did not properly document or investigate out-of-specifications (OOS) and other discrepancies(21 CFR 211.192). For example, the inspection documented that OOS Investigation #1203, related to the presence of metal particles in (b)(4), failed to determine the root cause of the contamination or explain why the (b)(4) step was unable to prevent the contamination Ref: WL: Novacyl Wuxi Pharmaceutical Co., Ltd. 12/19/14 (WL: 320-15-04)
  20. 20. Warning letter observations -2014 - 21 CFR 211.192 Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). For example, Your firm failed to conduct thorough investigations of your environmental monitoring (EM) excursions (i.e., exceeds action levels) found in your Class 100 areas. During the inspection, the review of the available data for the period of January 2012 to December 2013 revealed that your firm identified 23 EM samples that exceeded action levels in the Class 100 aseptic area on Line (b)(4) in your building identified as Hikma (b)(4). Our review of the investigations collected during the inspection noted that all investigation reports identified “possible root causes” of the EM excursions as mishandling and/or poor aseptic technique during sampling. In all of these investigations you were unable to determine an actual root cause; yet, you disregarded the EM excursions without justification. In addition, your firm failed to evaluate the potential impact of these EM excursions on the quality of the product manufactured. Ref: WL: Hikma Farmaceutica, (Portugal) S.A. 10/21/14 (WL: 320-15-003)
  21. 21. Warning letter observations -2014 - 21 CFR 211.192 Your firm failed to thoroughly investigate unexplained discrepancies or failures of a batch or its components to meet its specifications, whether or not the batch has already been distributed (21 CFR 211.192). For example, a. Several out-of-specification (OOS) results for the impurity (b)(4) ((b)(4)) from the stability studies of multiples batches of (b)(4) Injection were inadequately investigated. In April 2013, testing at the (b)(4) stability interval for batch (b)(4) resulted in OOS values for (b)(4). The results obtained for one of the three vials tested in duplicate were OOS, with values of (b)(4)% and (b)(4)% (specification: avg. of 3 vials NMT (b)(4)%). Your firm’s investigation PRID 128835, initiated on April 29, 2013, concluded that the(b)(4) in the (b)(4) of the vials was the cause for the OOS, but no action was taken with respect to the affected batch. This investigation also referenced an earlier OOS result of (b)(4)% for the same impurity for batch (b)(4) at the 12-month stability interval. You concluded that the OOS for batch (b)(4) was an isolated event and no action was taken with respect to the affected batch. Ref: WL: Hospira Australia Pty Ltd. 9/26/14 (WL: 320-14-15)
  22. 22. Warning letter observations -2013 - 21 CFR 211.192 • Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). • For example, on multiple occasions, you failed to perform failure investigations for rejected batches or implement any preventive actions. The inspection found that your firm failed to perform an investigation for the failure of (b)(4) Injection (b)(4) mg/ml lot (b)(4) to meet in-process pH requirements. This failing pH result was confirmed by your QC laboratory. Additionally, you rejected filled (b)(4) Injection lot (b)(4) when sub-lots failed to meet the particle in-process acceptance criteria, but did not conduct an adequate investigation into that failure. In your response, you stated that the “…process is known to generate occasional out of limit in-process (b)(4) aggregate particle density results…” However, you did not provide your determination of actual root cause for this failure to meet in-process limits. Additionally, you noted that the sponsor of this product is planning (b)(4) activities for this process and will target consistent particle results as part of the validation of the new process. Please note that your firm is expected to conduct thorough investigations for each failure to meet specifications, regardless of future plans for validation. Ref: WL: Jubilant Hollister Stier General Partnership 2/20/13 (WL: 320-13-08)
  23. 23. Warning letter observations -2013 - 21 CFR 211.192 Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). Two examples of this violation include: • Lot #JU83 of Infant Gripe Mix failed the pH specification. The range was (b)(4) to (b)(4), whereas the result recorded in the batch record was (b)(4). • Lot # KM40 of Diphenhydramine Expectorant failed specific gravity and (b)(4). The results for specific gravity and (b)(4) were (b)(4) and (b)(4), whereas the acceptable ranges were (b)(4)- (b)(4) and (b)(4)-(b)(4), respectively. Ref: WL: P.A. Benjamin Manufacturing Co., Ltd. 1/29/13 (WL: 320-13-07)
  24. 24. Warning letter observations -2013 - 21 CFR 211.192 Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). Our investigator found that your firm released partial batches to the U.S. market without specific criteria for the partial release decision and without appropriate investigations. You have been cited for the same practice in previous warning letters. Indeed, your firm released at least 76 sublots from January 2011 to August 2012 without adequate investigations. • For example, on April 13, 2011, while (b)(4) the (b)(4) during the (b)(4) step for (b)(4) tablets, batch (b)(4), your operator noticed five tablets with breached (b)(4) in (b)(4), a critical defect. The documentation available indicates that the (b)(4) used for (b)(4) of the tablets was (b)(4) prior to the start of (b)(4), and your firm re-sampled (b)(4) and found that (b)(4) had one critical defect. Your firm permits zero critical defects at the (b)(4) step. Your firm rejected (b)(4). On May 4, 2011, your firm released the tablets from (b)(4) to market as batch #(b)(4). Your investigation and your response indicate that the breached (b)(4) was attributed to the use of a (b)(4) with rough edges and variation of the (b)(4) technique. • In addition, on May 25, 2011, during the compression of (b)(4) tablets batch #(b)(4), your Quality Control Unit rejected a portion of the batch due to black specks observed on the tablets. However, your firm failed to identify the contaminant(s) found in this lot, and according to your investigation report, you were not able to determine a definitive root cause. In your September 14, 2012 response you indicated that the specks may have been linked to punches and punch seals, and that you released for distribution the remaining sublot, as #(b)(4). Ref: WL: Apotex Inc. 2/21/13 (WL: 320-13-09)
  25. 25. Warning letter observations -2013 - 21 CFR 211.192 Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). • Your firm failed to conduct an adequate investigation that should have resulted in your implementation of corrective actions to prevent recurrence of the problem and evaluate other potentially affected lots. Specifically, on April 17, 2012, your (b)(4) site reported that out-of-specification (OOS) endotoxin results were at or above the (b)(4) EU/ml limit in Torisel Diluent batch AGMV/1. We note that a portion of batch AGMV/1 was shipped to a contractor, (b)(4), for distribution to the U.S. market, on January 5, 2012. • Your investigation into the (b)(4) Torisel Diluent batch AGMV/1 failures began on April 17, 2012, and you continued to test and re-test samples from this lot through August 14, 2012. In an attempt to find the root cause of the OOS results, your firm used different endotoxin testing platforms, tested at three different laboratories, wiped external vials with (b)(4), and used (b)(4) to try to mitigate endotoxin failed results. Subsequently, your firm tested nine Catania AGMV/1 retain samples and six (b)(4) AGMV/1 samples on multiple dates with several failures. In addition, your firm sent one Catania AGMV/1 retention sample and one (b)(4) AGMV/1 sample to an external testing laboratory. The extensive repeat testing of (b)(4) Torisel Diluent batch AGMV/1 samples resulted in inconsistent passing and failing results. At no point did you conduct quantitative endotoxin testing to determine the extent of the endotoxin specification failure. Ref: WL: Wyeth Lederle S.p.A 3/27/13 (WL: 320-13-10)
  26. 26. Warning letter observations -2013 - 21 CFR 211.192 • Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). • For example, your firm failed to determine the cause of the OOS for Spiriva HandiHaler lot 908679 that failed the uniformity of delivered dose test specification with a reported value of (b)(4)% during the 9-month stability interval. This same lot also failed the uniformity of delivered dose attribute during the 12-month stability interval. It was only after the 12-month OOS result that your firm decided to initiate a product recall for this Spiriva lot. We are concerned about the management decision to allow adulterated product to remain in the market between the 9 and 12 month stability stations. Ref: WL: Boehringer Ingelheim Pharma GMBH & Co 5/6/13 (WL: 320-13-15)
  27. 27. Warning letter observations -2013 - 21 CFR 211.192 Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). Specifically, your firm did not initiate an investigation to determine the root cause of a humidity excursion during the packaging of (b)(4) lots # (b)(4) (Master No. (b)(4)), # (b)(4) (Master No. (b)(4)), and # (b)(4) (Master No. (b)(4)). The humidity conditions in blister rooms (b)(4) fell below the lower RH limit ((b)(4)-(b)(4)% RH) specified in your master packaging record. Ref: WL: Contract Pharmaceutical Services of Australia Pty Ltd 5/17/13 (WL: 320-13-16)
  28. 28. Warning letter observations -2013 - 21 CFR 211.192 Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). For example, your firm did not identify, report, or investigate the following out-of-specification (OOS) results. a. On May 06, 2012, the 12-month stability interval assay test for (b)(4) mg tablet batch (b)(4) failed to meet the established specifications with a result of (b)(4) (specifications: (b)(4)-(b)(4)). b. On July 16, 2011, the assay for (b)(4) API batch (b)(4) failed to meet the established specification with a result of (b)(4) (specifications: (b)(4)- (b)(4)). This API batch was used in the manufacture of (b)(4) finished drug product batches. c. On January 26, 2011, the related substance assays for three (b)(4) API raw material batches (b)(4), (b)(4), and (b)(4) exceeded the (b)(4) and (b)(4) impurity specifications ((b)(4)%). These API batches were used in the manufacture of (b)(4) finished drug product batches. d. On October 10, 2012, the two-month stability assays for the (b)(4) USP batch (b)(4)-tablet presentation showed a significant unknown peak at approximately (b)(4) on the chromatograms. Ref: WL: RPG Life Sciences Limited 5/28/13 (WL: 320-13-17)
  29. 29. Warning letter observations -2013 - 21 CFR 211.192 Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). Your firm did not determine a root cause for the clogging of the (b)(4) experienced during the transfer of product from the (b)(4) tank to the (b)(4) tank for batches (b)(4), and (b)(4) of (b)(4) ((b)(4)) (b)(4) between (b)(4) and March 2012. The (b)(4) clogging was not observed prior to these batches and your corrective action was to permit an in-process change of the (b)(4) if it becomes clogged. We note that you continued to manufacture and release these (b)(4) products without determining the most probable root cause of the (b)(4) clogging. The investigations for two media fill (process simulation) failures between September and December 2011 were not adequate Specifically, the investigation report for the “Process Simulation Failure of the (b)(4) Process” concluded that the probable root causes were inadequate cleaning of the pressure gauge and inadequate sampling technique. However, your firm did not provide sufficient basis or perform any studies to confirm these conclusions. Similarly, the investigation for the “Process Simulation failure of (b)(4) Process” concluded that the probable root cause was the handling and use of returned sterile primary packaging material, but the investigation had insufficient basis or studies to support the conclusion. Ref: WL: Promed Exports Private Limited 8/9/13 (WL: 320-13-24)
  30. 30. Warning letter observations -2013 - 21 CFR 211.192 Your firm’s quality control unit failed to review and approve all drug product production and control records to determine compliance with all established, approved written procedures before a batch is released or distributed (21 CFR 211.192). For example, your firm’s quality unit failed to adequately review and approve your firm’s production and control records. There is no assurance that the quality unit fully reviewed and approved all batch-related documentation prior to release of finished product to the U.S. market. Specifically, your firm distributed the following lots to the U.S. market without adequate review: (b)(4) lot (b)(4), (b)(4) lot (b)(4), (b)(4) lot (b)(4) and (b)(4) and Le’dermis Skin Solutions Anti-Acne Medicated Cream lot 130058. Ref: WL: Jabones Pardo S.A. 8/22/13 (WL: 320-13-25)
  31. 31. Warning letter observations -2013 - 21 CFR 211.192 You failed to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications whether or not the batch has already been distributed. In addition, you failed to extend the investigation to other batches of the same product and other products that might have been associated with the discrepancy [21 C.F.R. § 211.192]. Our inspection in 2012, and the current inspection, found that you have received multiple consumer complaints related to mislabeled bags, inadequate bag size, defective product components, and product mix-ups in your blood collection and component preparation units. You have confirmed most of these quality issues. Your investigations have failed to identify the deficiencies in need of correction to avoid the distribution of blood products which are not in full compliance with regulatory specifications. In addition, the scope of your investigations was not expanded to other lots and products potentially affected by these deviations. Ref: WL: Fenwal, a Fresenius-Kaby Company 8/16/13 (WL: 13-SJN-WL-05)
  32. 32. Warning letter observations -2013 - 21 CFR 211.192 Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already has already been distributed (21 CFR 211.192). You failed to initiate investigations following the identification of discrepancies potentially affecting the safety of sterile finished drug products. You have failed to conduct an investigation of the non-integral gloves found during FDA inspection and continued to manufacture (b)(4) batches of drug product using the same lot of defective gloves. Ref: WL: Agila Specialties Private Limited 9/9/13 (WL: 320-13-26)
  33. 33. pharmauptoday@gmail.com Other Guidance …
  34. 34. Questions & Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance - Records and Reports Some products, such as transdermal patches, are made using manufacturing processes with higher in-process material reject rates than for other products and processes. Is this okay? • Maybe. It depends on the cause and consistency of the reject rate. Many transdermal patch manufacturing processes produce more waste (i.e., lower yield from theoretical) than other pharmaceutical processes. This should not of itself be a concern. The waste is usually due to the cumulative effect of roll splicing, line start-ups and stoppages, roll-stock changes, and perhaps higher rates of in-process sampling. This is most pronounced for processes involving lamination of rolls of various component layers. Roll-stock defects detected during adhesive coating of the roll, for example, can often only be rejected from the roll after final fabrication/lamination of the entire patch, which contributes to the final process waste stream. • We expect that validated and well-controlled processes will achieve fairly consistent waste amounts batch-to-batch. Waste in excess of the normal operating rates may need (see 211.192) to be evaluated to determine cause (e.g., due to increase in sampling or higher than normal component defects... or both) and the consequences on product quality assessed. We've seen a small number of cases where unusually high intra-batch rejects/losses were due to excessive component quality variability and poorly developed processes.
  35. 35. Do the CGMP regulations permit the destruction of an internal quality assurance audit report once the corrective action has been completed? The CGMP regulations (21 CFR 210 and 211) for finished pharmaceutical manufacturing do not specifically address the requirement to conduct, or to keep records of, internal quality assurance audits. If the report in question were from a routine audit to verify that the firm's quality system is operating as intended, then it would be acceptable if the firm elected to discard the report once all corrections have been verified. • However, any documentation of corrective action as a result of such an audit would have to be retained (see 211.180 and 211.188). For example, if a routine internal audit finds a problem with a mixing step and the outcome is a change in mixing time, all affected procedures, including the master production record, are to reflect the necessary changes, and such records are subject to FDA inspection as usual. Any investigation into the impact this problem had on related batches is to be retained and also made available for inspection by FDA (see 211.192). • In addition, any reports of investigations or evaluations prepared in response to, for example, a product complaint (211.198), vendor qualification (211.84), periodic review of records and data (211.180(e)), and a failure investigation (211.192) are not internal audits as discussed above. Such records are subject to FDA inspection and must be retained for at least the time specified in the CGMP regulations (see 211.180). Questions & Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance - Records and Reports
  36. 36. EC GMP Guide Chapter 1 Pharmaceutical Quality System Product Quality Review: 1.10 Regular periodic or rolling quality reviews of all authorised medicinal products, including export only products, should be conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product, to highlight any trends and to identify product and process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least:
  37. 37. EC GMP Guide (i) A review of starting materials including packaging materials used in the product, especially those from new sources and in particular the review of supply chain traceability of active substances. (ii) A review of critical in-process controls and finished product results. (iii) A review of all batches that failed to meet established specification(s) and their investigation. A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventive actions taken. (iv) A review of all changes carried out to the processes or analytical methods. (v) A review of Marketing Authorisation variations submitted, granted or refused, including those for third country (export only) dossiers. (vi) A review of the results of the stability monitoring programme and any adverse trends. (vii) A review of all quality-related returns, complaints and recalls and the investigations performed at the time. (viii) A review of adequacy of any other previous product process or equipment corrective actions. (ix) For new marketing authorisations and variations to marketing authorisations, a review of post-marketing commitments. (x) The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc. (xi) A review of any contractual arrangements as defined in Chapter 7 to ensure that they are up to date.
  38. 38. EC GMP Guide Chapter 4 Documentation Generation and Control of Documentation: 4.3 Documents containing instructions should be approved, signed and dated by appropriate and authorised persons. Documents should have unambiguous contents and be uniquely identifiable. The effective date should be defined. 4.24 There should be written procedures for the internal labeling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.
  39. 39. EC GMP Guide Chapter 5 Production General: 5.8 Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits. Processing operations: intermediate and bulk products: 5.44 Any significant deviation from the expected yield should be recorded and investigated.
  40. 40. EC GMP Guide Chapter 9 Self Inspection 9.3 All self inspections should be recorded. Reports should contain all the observations made during the inspections and, where applicable, proposals for corrective measures. Statements on the actions subsequently taken should also be recorded.
  41. 41. EU Non-Compliance Reports Firm Name Nature of non-compliance Sri Krishna Pharmaceuticals Ltd., Hyderabad, India; Dec 2014 Written production and process control procedures are not documented at the time of performance. Specifically, Too Numerous to Count (TNTC) torn and discarded controlled manufacturing batch records for a variety of different products issued by the Quality Unit were found during a walk-through inspection of the facility. Five batch records were compared with the archived manufacturing one and it was ascertained that no records had been made for duplicate issuance of these five batches chosen for review, as required per SOP QA/SOP/DOC/001. Notably, after subsequent investigation it was found that the Master Batch Record (version 0) had been back-dated by the most responsible persons within your firm’s Quality and Manufacturing departments, which was confirmed by these persons during our inspection.
  42. 42. EU Non-Compliance Reports Firm Name Nature of non-compliance IND-SWIFT LIMITED, Punjab; Mar 2014 Established processes to verify data accuracy and integrity had failed and there had been no formal investigation raised by the company. Medreich Limited – Unit V; Dec 2014 5 were related to poor level of quality management (inadequate deviations management system with no exhaustive record, no classification and no thorough investigation) Renown Pharmaceuticals Pvt. Ltd., Gujarat, India; Aug 2014 Record integrity and veracity: some records were made up or altered. Defects on deviation recording and investigation.
  43. 43. Health Canada – GMP 7.3 Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution; 7.8 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). 8.1 Written procedures followed for the review and approval of batch production and laboratory control records, including packaging and labelling, to determine compliance of the API with established specifications before a batch is released or distributed. 18. Where critical data are entered into a computerized system manually, there should be an additional check on the accuracy of the entry. This can be done by a second operator or by the system itself. 19. Incidents related to computerized systems that could affect the quality of APIs or the reliability of records or test results should be recorded and investigated. 21. All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released.
  44. 44. ICH
  45. 45. ICH 6.7 Batch Production Record Review 6.70 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. 6.71 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). 6.72 All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released. 6.73 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.
  46. 46. APIC
  47. 47. APIC 6.7 Batch Production Record Review 6.71 During a batch record review check for • missing records and out-prints • incomplete entries • illegible corrections • equipment maintenance, breakdown and replacement • valid calibrations and service intervals of test equipment (as a useful cross check to routine control of test equipment) • reports on OOS-results • completeness of deviation reports • impact of reported deviations on product quality • compliance with specifications, parameter ranges or acceptance criteria including tighter customer specifications • usage decision
  48. 48. pharmauptoday@gmail.comHow to avoid 21 CFR 211.192 observations ?
  49. 49. pharmauptoday@gmail.comBatch Record Review
  50. 50. Purpose of Batch Record Review In general, all components of the batch record are assembled, records are reviewed, questions and issues are resolved, and the batch is released by QA. This review has several purposes: • Assure compliance with all procedures • Assure GMP compliance • Assure product quality
  51. 51. Purpose of Batch Record Review • Assure compliance with all procedures: GMP regulations require that all written procedures for manufacturing and testing pharmaceutical products be followed. The batch record review assures that the required materials procedures are used in manufacturing product, and that all requirements for manufacturing and testing were met. QA should only focus on critical parameters and review each parameter once. Capturing errors and omissions on the same shift reduces risk and improves quality of resolution. Batch Records, therefore, should be reviewed and corrected immediately, and with the people who are executing the production task. Setting a rule that the personnel do not leave until the batch is cleared is a good approach.
  52. 52. Purpose of Batch Record Review • Assure GMP compliance: GMP also require that any deviation from requirements be documented and investigated. Deviations could include problems in manufacturing, OOS results, or any other issue that could potentially impact product quality. One purpose of the batch record review is to determine if overall GMP requirements have been met. There are a range of well-known tools and techniques for optimizing the deviation-management process so that it runs quickly and effectively. Rapid root-cause investigations teams trained to use Define, Measure, Analyze, Improve, Control (DMAIC) approaches, are armed with standard ways of categorizing deviations supported by black-belt facilitators. Appropriate tools and a well-trained team should be brought into play as soon as any critical deviation is identified. Such an approach is now considered best practice across the industry.
  53. 53. Purpose of Batch Record Review • Assure product quality: The batch record review is also important to assure the quality of the product produced. It is essential to provide an independent review of all documentation and results to assure that requirements were achieved, and that the final product meets release specification.
  54. 54. Approach for Batch Record Review • One key element necessary to assure a complete and thorough batch record review is providing the reviewer with a means to know what should be present in the record. There are several approaches to this:  Design batch records  Develop a batch record checklist  Organize and number batch record pages  Right-First-Time Approach
  55. 55. Approach for Batch Record Review Design batch records: • Poor Batch Record design can also lead to overly lengthy review and approval. For some companies, compliance and completeness are the only concerns in the design of the Batch Record. • There is little or no consistency in the way requirements are stated in the document, and the entry format and location are not clear to the operator. • The document and work sequence differ, confusing the operator. The operator must regularly interpret tolerances in the BR and make many transcriptions. These procedures are a recipe for error and delay. • In addition, the Batch Record should mirror the operator work sequence. • No mental calculations and few transcriptions should be needed to complete the Batch Record. • Only the required information should be entered. • Crucial or license-related parameters need to be highlighted so they are clear to the operator. • There should be an obvious distinction for parameter outputs between target and required. • In addition, there needs to be a statement of policy and principle that protects Batch Record simplicity and effectiveness from being eroded over time with additional statements, checks, and signatures from poorly- constructed corrective action and preventive action changes.
  56. 56. Approach for Batch Record Review Develop a batch record checklist: A product specific checklist that includes all required elements of the batch record can be an excellent tool for the record reviewer to assure that all components of the record are present. This checklist must be QA controlled and current. The use of this checklist also provides documentation that each element of the record was present and reviewed.
  57. 57. Approach for Batch Record Review Organize and number batch record pages: • Some firms develop batch records to include all possible elements into the numbered batch record. • Thus, assuring completeness involves only verifying that all pages are present. For example, if the record has 43 pages, each labeled with “page 21 of 43,” etc., the reviewer needs only to assure that all pages are present to conclude that the record is complete. • This is often not completely possible because batch records often include chart recordings, temperature strips, and other miscellaneous documents. • The review must be aware of which of these are required to assure that the review is complete.
  58. 58. Approach for Batch Record Review Right-First-Time Approach: • To achieve a one-day Batch Record review and approval, a right-first-time (RFT) culture must pervade the organization. This means that 95% of batch records should be RFT. • Best practice dictates that the Batch Record be error-proofed, based on a clear methodology to make the person and document interface error-free. • There should be an obvious pattern to the way requirements are stated and laid out that helps the user.
  59. 59. pharmauptoday@gmail.comInvestigations
  60. 60. Investigation - Definition • A formal, organized, and documented study conducted to identify the cause in order to correct and prevent deviations and unexplained events in the manufacturing or testing of pharmaceutical products. • Formal: an investigation must occur in a prescribed and planned manner, not occur randomly – an SOP describing the investigation approach is required • Organized: an investigation must be organized, preferably following a specific predetermined pattern of data gathering and assessment • Documented: as with all GMP activities, investigations must be documented, including the study rationale, data, decisions, actions, and follow-up • Cause: an extensive effort must occur to determine the single root cause, when possible • Correct and Prevent: the ultimate goal of an investigation is to correct the problem and prevent a recurrence
  61. 61. What must be investigated ? • Deviation From Requirements: A deviation from an established or published requirement requires that an investigation occur. The key to this or any investigation is to learn what happened, and what can prevent a recurrence. Examples: • Required drying temperature not maintained • SOP requirements could not be followed • Time limits for conducting stability tests were not met • Incorrect analytical method used • Room differential pressure below limits
  62. 62. What must be investigated ? • Failure to Achieve Required Results: Failure to obtain expected results should result in an investigation. The inability to achieve an expected result is a sign that some facet of the process is not operating normally. Thus, an investigation should be conducted to determine what is happening, and what can stop or prevent failures. Examples: • Product final assay specification not attained • In-process tablet hardness results not achieved • Stability test failure • Sterility failure • Blend homogeneity fails • Black specks in solution • Environmental monitoring results fail
  63. 63. What must be investigated ? • Any Failure in Product, Process, Equipment, or Personnel: Any real or possible product, process, equipment, or personnel failure should result in an investigation. In many cases, though a product failure has not yet occurred, a solid investigation can prevent a future failure. Examples: • Weighing error • Failure to blend for required time • Failure to use the proper cleaning procedure • Excessive capping for compressed tablets • Documentation for required process steps was incomplete • Equipment failure causing extended line downtime • Equipment visually dirty after cleaning completed • Foreign tablet found on-line during packaging
  64. 64. 7 Elements of Investigation
  65. 65. 7 Elements of Investigation 1. Discovery/Problem Description: • The initial step in any investigation is the problem discovery and description. • Systems and procedures must exist that allow early detection and communication of problems. • It is not sufficient to rely upon final batch record review to detect deviations and unexplained events. • A culture that encourages and allows operators, technicians, and associates to raise concerns and issues as they arise, is imperative to early detection and correction of problems. • Once a problem is discovered, it is important that all known details be described in as much detail as possible. • The investigation system, SOP, or form must include a listing of the types and kinds of details that should be gathered and recorded early in the stages of an investigation.
  66. 66. 7 Elements of Investigation 2. Containment: • Another key early step in the investigation process is to contain or limit the problem. • Unless containment occurs, the problem can extend beyond its original scope, or become more difficult to assess. For example, if an equipment malfunction occurs on-line during filling, early containment can assure that affected product is isolated to limit involvement to minimal pallets of product. • Proper containment usually involves the following actions: • Stop – halt production, testing, or other actions that could extend the problem until it is properly described • Establish limits – define the start and stop points of the problem, and • Establish control – isolate affected product or processes
  67. 67. 7 Elements of Investigation 3. Corrective Action: • Once the problem is described and contained, the next step is to determine the immediate actions needed to correct the specific problem and restart operations. • In other words, you must now answer the question, “What do I need to do to assure that product manufactured (or tested, etc.) after restart will not be affected by this same problem?” • Corrective action can be as simple as correcting the equipment problem, re-sanitizing the equipment, shifting to a new lot of material, or other similar actions. • However, you must assure that the problem is sufficiently described and a likely cause identified, or the problem may still extend to other products or batches.
  68. 68. 7 Elements of Investigation 4. Cause and Analysis: • Possibly the most important phase of an investigation is to thoroughly analyze the problem, and determine the likely “root cause.” • A root cause is that single action or event that created the problem or deviation studied. • It is important to determine the root cause to provide a sense of confidence that once corrective and preventative action has occurred, the problem will not reoccur. • When the potential exists that the problem could reoccur, or if you do not know the root cause of the incident, you cannot have confidence that the problem is solved. So, extensive effort is needed to identify the root cause. • There are several successfully used systems that identify root cause. Several commercially available systems exist, and other “classical” systems are in use.
  69. 69. 7 Elements of Investigation 5. Preventive Actions: • For any verified or unknown cause, the investigation must eventually include an action to eliminate that cause from contributing to future similar concerns. • The investigation should include a listing of these causes, and specific actions with individuals responsible, and target dates for completion. • By conducting a thorough identification of possible causes and eliminating these causes from future involvement, you have a high likelihood that recurring investigational issues will not occur or be significantly reduced. • Preventive actions must be both specific and definitive. In other words, preventive action must result in change in order to be effective. • It is not usually adequate for preventive actions to involve only communication or notification.
  70. 70. 7 Elements of Investigation 6. Conclusions/Product Disposition: • A final step in conducting an effective investigation is to recommend and document the final conclusions and disposition of all products, materials, or systems affected. • It is critical to clearly state what will occur with segregated materials, why that action was taken, and the justification for this final disposition. • Unless these decisions are clearly listed, the possibility for miscommunication or unintended actions exists.
  71. 71. 7 Elements of Investigation 7. Follow-up and Tracking: • Once an investigation is closed, a system is needed to track promised actions to assure that, they were implemented as promised and, they were effective in eliminating the cause. • Investigations with open action items must be visible in a database or other tool to allow routine review. • Failure to assure that investigation action items are complete is a GMP violation often cited on FDA 483s.
  72. 72. pharmauptoday@gmail.com Thank You The module Consult Yourself.... “Know Regulation - No Observation” deals with most common (top 20) basic CFR regulations having frequent violations and previous observations for better understanding. The module will be continued with # 4 21 CFR 211.67 For “Pharma Uptoday” free daily newsletter write a mail to pharmauptoday@gmail.com for other Pharma Uptoday presentations & Monthly Magazines browse: http://www.slideshare.net/skvemula

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