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Out of Specification Results (OOS) A One Day Workshop Presented by: Karen S. Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF March 2007.

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Presentation on theme: "Out of Specification Results (OOS) A One Day Workshop Presented by: Karen S. Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF March 2007."— Presentation transcript:

1 Out of Specification Results (OOS) A One Day Workshop Presented by: Karen S. Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF March 2007

2 PCI Pharmaceutical Consulting Israel Ltd 2/82 Purpose of Workshop Understand Current Industry Practice as it relates to all aspects of handling: –Out of Specification –Unusual –Out of Trend Results When is retesting legitimate When does testing have to stop When do the authorities need to be notified

3 PCI Pharmaceutical Consulting Israel Ltd 3/82 Workshop Structure 09:00 – 10:30 10:30 – 11:00 11:00 – 12:30 12:30 – 13:30 13:30 – 15:00 15:00 – 15:15 15:15 – 16:30 Background and Overview: Barr and Able Coffee Break The Making of the FDA Guide Case study: what NOT to do Laboratory investigation and checklist Lunch Break FDA Guide Continued: Extended investigation, retesting protocol Qualitative and quantitative tests Case study Tea Break Case Study and workshop wrap-up Reporting results; reporting to regulators

4 PCI Pharmaceutical Consulting Israel Ltd 4/82 PART 1 – BARR and ABLE Litigation USA regulatory environment around late 1980’s through 1993 Current regulatory environment in US Able

5 PCI Pharmaceutical Consulting Israel Ltd 5/82 Some Definitions What is an OOS Result? What is a test result Definition of reportable value “A reportable value is the end result of the complete measurement method as documented. It is the value compared with the specification, the values collected when the term replicates is used, the values used for official reports, and the values used for any statistical calculation or analysis.” Torbeck (February 1999, Pharmaceutical Technology)

6 PCI Pharmaceutical Consulting Israel Ltd 6/82 Before Barr – Current Practice Prior to 1993 and the court decision – it was COMMON practice to retest once or in exceptionally good companies twice and to release the batch if the retest result was within the specification Companies had not really thought about the practice But then…nor had the regulators

7 PCI Pharmaceutical Consulting Israel Ltd 7/82 The Barr Court Case and Judge Wolin From the New York Times February 6, 1993, Saturday (AP); Financial Desk COMPANY NEWS; Judge Rules On Barr Labs A generic drug manufacturer must recall batches of some of its medicines and stop distributing others until the company completes studies of its manufacturing process, a Federal judge ruled on Thursday. But United States District Judge Alfred M. Wolin refused a request by Federal pharmaceutical regulators to order a complete shutdown

8 PCI Pharmaceutical Consulting Israel Ltd 8/82 Barr and OOS Faced with potential closure, the company took FDA to court The judge went into great details as to the meaning and implications of OOS results The outcome: FDA draft guidance: 1998 FDA final guidance: 2006

9 PCI Pharmaceutical Consulting Israel Ltd 9/82 Barr: What happened in court The judge heard experts on behalf of FDA and Barr regarding the practice of retesting FDA wanted retesting to be banned under all circumstances After a long hearing at which five industry experts, an FDA investigator, and several company employees testified, Judge Alfred M. Wolin, U.S. District Judge for the District of New Jersey, issued a 79-page opinion

10 PCI Pharmaceutical Consulting Israel Ltd 10/82 The Barr Court Case 1993 Reported problems include –misplaced records –test data recorded on scrap paper –failure to control manufacturing steps such as those governing products' physical properties –release of products not meeting their specifications –inadequate investigation of failed products

11 PCI Pharmaceutical Consulting Israel Ltd 11/82 Barr: “Testing into Compliance” Barr had numerous failures Performed retests with –no investigations –no regard for process and product history Tested until results met specifications reporting only the passing results Then irrespective of previous OOS results for the batch, released product reporting only the passing results Q: How do you report passing OOS’s on COA?

12 PCI Pharmaceutical Consulting Israel Ltd 12/82 Reading the Judgment Reading the Barr Court Judgment is like reading FDA’s draft guidance and pretty similar to the final guidance Judge Wolin preferred to use the term "out-of-specification" (OOS) laboratory results rather than the term "product failure" which was more common to (preferred by?) FDA's investigators not a product failure Ruled that an OOS result identified as laboratory error by a failure investigation or an outlier test, or overcome by retesting is not a product failure BUT Limited situations where laboratory error could be used

13 PCI Pharmaceutical Consulting Israel Ltd 13/82 Guide to Inspection: QC Labs Issued July 1993 (must have been working on it while the court case was ongoing) Addresses OOS results and instructs inspectors to be alert “Evaluate the company's system to investigate laboratory test failures. These investigations represent a key issue in deciding whether a product may be released or rejected and form the basis for retesting, and resampling “ (Most of the information is now in FDA’s guide)

14 PCI Pharmaceutical Consulting Israel Ltd 14/82 Guide to Inspection: QC Labs OOS results fall into three categories: –laboratory error –non-process related or operator error –process related or manufacturing process error Evaluate the company's retesting SOP for compliance with scientifically sound and appropriate procedures A very important ruling in one recent court decision sets forth a procedure to govern the retesting program This district court ruling provides an excellent guide to use in evaluating some aspects of a pharmaceutical laboratory, but should not be considered as law, regulation or binding legal precedent The court ruled that a firm should have a predetermined testing procedure and should consider a point where testing ends and product is evaluated. If results are not satisfactory, product is rejected.

15 PCI Pharmaceutical Consulting Israel Ltd 15/82 After Barr – Current Industry Practice 2007 ALL pharmaceutical companies in developed countries and many in less developed countries have SOPs for handling Out of Specification results There are still many investigational findings concerning out of specification results There are still numerous issues, particularly with transparency: What do you report on the COA? Able laboratories suspended activity in 2005 because of Out of Specification results

16 PCI Pharmaceutical Consulting Israel Ltd 16/82 When it all goes wrong….Able 2005 The Quality Unit failed to: Review computer audit trails in the Waters Empower Data Acquisition System Provide adequate training to analytical chemists These practices led to: failing in-process, finish ed product and stability specifications The QU releasing batches failing in-process, finish ed product and stability specifications Submission of erroneous data in Annual Reports and Prior Approval Supplements Ceasing manufacture, distribution and recall of all products as of 13 May 2005 and withdrawal of at least 5 ANDAs

17 PCI Pharmaceutical Consulting Israel Ltd 17/82 Resample, Re-injection, Reprocessing

18 18 Time for a Break

19 PCI Pharmaceutical Consulting Israel Ltd 19/82 From Able Laboratories 483 Notebooks and binders lacked data from all testing conducted in the QC Laboratory. Records did not include all data such as OOS results, chromatograms, sample weights, and processing methods. OOS results were substituted by passing results by Analysts and Supervisors. The substitution of data was performed by cutting and pasting of chromatograms, substituting vials, changing sample weights and changing processing methods

20 PCI Pharmaceutical Consulting Israel Ltd 20/82 That isn’t relevant…it’s fraud Think about the following scenario before saying it couldn’t happen: –You are just starting up your HPLC system in the morning –You inject 5 replicates of standard –The first four give perfect responses –The fifth is way off / makes no sense, obviously incorrect What do you do?

21 PCI Pharmaceutical Consulting Israel Ltd 21/82 It couldn’t happen in my company A split second wrong judgment can appear as fraud to the inspector You inject one more standard injection and it gives a perfect response Clearly you were right and the original “5 th ” injection was dirty glassware or mis-injected, or, or, or……

22 PCI Pharmaceutical Consulting Israel Ltd 22/82 It couldn’t happen in my company But you don’t want to show 4 good injections, one lousy and another good one So you cut out the bad one and document only the good ones in the notebook Sounds “horrendous?” It has been done, probably in some of your laboratories! Can you be sure none of your analysts ever did this? How can you be so sure?

23 PCI Pharmaceutical Consulting Israel Ltd 23/82 GMP and OOS Results Do you know where the term OOS appears in –EU GMP regulationsit didn’t as of June 2006 it does –US GMPsit doesn’t –Q7A GMP for APIsit DOES because Q7A was written after 1993

24 PCI Pharmaceutical Consulting Israel Ltd 24/82 Q7A on OOS

25 PCI Pharmaceutical Consulting Israel Ltd 25/82 Ever heard this…. “The Lab don’t know how to test” “Give it to Pete… he knows how to do that test… Dave always gets bad results!”

26 PCI Pharmaceutical Consulting Israel Ltd 26/82 OOS Case Study #1 Complex biochemical assay: 6 replicates Inherent variability allows for wider than usual specification of 80 – 120% Results: 45, 50, 46, 52, 65, 69% What would you think if it happened to you? The lab technician has 20 years seniority No other technician is familiar with the test

27 PCI Pharmaceutical Consulting Israel Ltd 27/82 OOS Case Study #1 - continued “Must be my mistake!” WRONG Analyst retested (not in accordance with SOP) Results: 72, 69, 81, 80, 82, 81% NOW what would you think?

28 PCI Pharmaceutical Consulting Israel Ltd 28/82 OOS Case Study #1 - continued “Results: 72, 69, 81, 80, 82, 81% 72 and 69% must be “OUTLIERS” Average 81, 80, 82 and 81 and result passes Batch can be released Report only this set of results

29 PCI Pharmaceutical Consulting Israel Ltd 29/82 OOS Case Study #1 - continued The outcome….. Product complaints from patients and doctors: Product is sub-potent Litigation Product recall Investigation reveals weighing error in production

30 PCI Pharmaceutical Consulting Israel Ltd 30/82 What is the purpose of testing? To find out the value of a specific parameter To assess if that parameter meets the pre-determined specification for each lot So as to make a sound scientific judgment regarding product release or rejection What happens in your company when there is an OOS result? IDEALLY the analyst doesn’t know the specification because of “BIAS.”

31 PCI Pharmaceutical Consulting Israel Ltd 31/82 Is it possible to ensure a correct result? Not at a 100% certainty level Just as it is not possible to prevent an incorrect result (at the 100% certainty level) What is a correct result? A result that is identical to the true result…. BUT When testing, we NEVER know the true result

32 PCI Pharmaceutical Consulting Israel Ltd 32/82 Consequences of an Incorrect Test Result? FALSE NEGATIVE Product declared fit for use when not Side Effects Death FALSE POSITIVE Product declared unfit for use when fit RejectionFinancial Loss

33 PCI Pharmaceutical Consulting Israel Ltd 33/82 Is it possible to ensure a correct result? It is possible to ensure a result as close as possible to the true result Using a quality assurance program in the laboratory Validate methods Qualify analysts Follow methods as written Qualify, calibrate and maintain equipment Report deviations / malfunctions

34 PCI Pharmaceutical Consulting Israel Ltd 34/82 Types of Tests Quantitative: assays and some limits tests Qualitative: e.g. sterility test, appearance Chemical Physical Microbiological

35 PCI Pharmaceutical Consulting Israel Ltd 35/82 Chemical Testing Inherently reliable Precision is usually considerably better than for microbiolgical and biochemical testing Outlier testing is forbidden by the FDA guide for chemical testing (usually have less replicates anyway) Don’t forget case study #1 – How NOT to handle OOS results

36 PCI Pharmaceutical Consulting Israel Ltd 36/82 Physical Tests e.g.1Black spots in powder e.g.2Fill volume are particularly problematic, since results are almost certainly correct. Is there any place for retesting? In e.g. 1Probably not In e.g. 2Maybe Is there any place for resampling?

37 PCI Pharmaceutical Consulting Israel Ltd 37/82 FDA OOS Guidance, October 2006 Draft from September 1998 for comments Was confusing and open to misinterpretation particularly by persons not familiar with the industry Final guidance is still confusing but a lot better than the draft The draft was referenced, as was the Barr court case during inspections, so the final guidance will definitely be used Should be considered in preparing an OOS SOP

38 PCI Pharmaceutical Consulting Israel Ltd 38/82 FDA Guide on OOS Results Finalized October 2006 Contains “nonbinding recommendations” Requires that an investigation is performed ANYTIME that an OOS is obtained Wants to include ALL suspect results Wants an SOP stating number of retests UPFRONT

39 PCI Pharmaceutical Consulting Israel Ltd 39/82 Table of Contents Introduction Background Identifying and Assessing OOS Results – Phase I: Laboratory Investigation –Responsibility of Analyst –Responsibilities of Laboratory Supervisor

40 PCI Pharmaceutical Consulting Israel Ltd 40/82 Table of Contents (continued) Investigating OOS Results – Phase II: Full Scale OOS Investigation –Review of Production –Additional Laboratory Testing –Reporting Testing Results Concluding the Investigation –Interpretation of Investigation Results –Cautions –Field Alert Reports

41 PCI Pharmaceutical Consulting Israel Ltd 41/82 Out of Specification Results IF you don’t know the specification you should never have an OOS, but we don’t live in an ideal world! HOW can you have an OOS if: –the method is validated –analysts are qualified –equipment is calibrated and well-maintained –notebooks have full record of testing

42 PCI Pharmaceutical Consulting Israel Ltd 42/82 How to Identify OOS Results Compare result with specification Be sure that specification is to required degree of accuracy and round the result to this value E.g. spec passes spec fails Message for your R&D Department: think carefully before setting specifications!!!

43 PCI Pharmaceutical Consulting Israel Ltd 43/82 How to Identify OOT Results Out of Trend or unusual results are generally results that: –MEET the product specification –ARE outside the control limits of the process, where control charts are used or –ARE different to results usually obtained (e.g. spec: 95.0 – usual results:98.5 – OOT result:96.4

44 PCI Pharmaceutical Consulting Israel Ltd 44/82 Initial Assessment of OOS Result Bear in mind prior: –Product history –Process history –Test history –Reliability of equipment –Reliability of the analyst –Precision of the test (validation)

45 PCI Pharmaceutical Consulting Israel Ltd 45/82 Out of Specification Results Failure of a control is NOT an OOS eg: –Standard shows impurity peak and assays at incorrect retention time –Standard shows assay of 80% –System suitability drift –In this case all test results SHOULD BE INVALIDATED and the test REPEATED using an additional aliquot of the same preparation if possible, or an additional aliquot from the same sample (What if product degrades and this is not possible? – need to define duplicate sampling procedure so that always have spare material) –Data collected is retained on file ANYWAY –What happens if results are OOS? Do you need to err on the side of caution e.g. possible homogeneity issue?

46 PCI Pharmaceutical Consulting Israel Ltd 46/82 OOS – Laboratory Investigation IF you don’t question an “in-spec” result, why do you question an OOS? Must have a Retesting Policy: –Laboratory investigation equipment -e.g. glassware, calibration, maintenance question large differences between replicates calculations Product history etc. etc. etc. (to be continued) 4M’s: man, machine, methods, materials

47 47 Time for Lunch

48 PCI Pharmaceutical Consulting Israel Ltd 48/82 FDA Guide: Introduction Applies to chemistry – based testing [KSG: primarily HPLC and GC] Includes in-process testing except (footnote), where the purpose is to prevent process drift [KSG: discuss – could still have OOS!] Principles apply to CONTRACT firms Timely, unbiased investigation [KSG: OOS Policy is major SOP approved by senior management]

49 PCI Pharmaceutical Consulting Israel Ltd 49/82 FDA: Laboratory Investigation The source of OOS should be identified as: –Aberration of measurement process –Aberration of manufacturing process [KSG: sampling process?] Even if the batch is rejected, an investigation is required: –Other batches involved? –Other products involved? Need written investigation, conclusions, follow-up

50 PCI Pharmaceutical Consulting Israel Ltd 50/82 FDA: Laboratory Investigation Assess accuracy of lab data: –Before test preparations are discarded (composite / homogeneous source of aliquot tested) –Hypothesis testing using same test preparation for laboratory error or instrument malfunction –IF no meaningful errors were made [found?], conduct a full scale OOS investigation –Contract lab conveys data and findings to you

51 PCI Pharmaceutical Consulting Israel Ltd 51/82 Invalidate result Perform new test on same sample Convincing evidence of Laboratory Error Correct if possible or Reject Batch Production Error Resample Double sample Revise sampling procedures Sampling Error QA decision regarding batch disposition All within specifications Reject Batch One result OOS Retest ??? further aliquots from original sample Inconclusive No evidence of production error QA Investigation Inconclusive Laboratory Investigation Report to QA (copy in batch file?) OOS result OOS Flow Chart

52 PCI Pharmaceutical Consulting Israel Ltd 52/82 Responsibility of Analyst To follow test procedure as written To be alert to errors and STOP test BEFORE obtaining the result if error is suspected, recording what happened e.g. spill Analyst responsible for ensuring that instruments meet performance specifications and are properly calibrated [KSG: maintained?] Once an OOS result is obtained to review all records relative to the test to identify possible laboratory error

53 PCI Pharmaceutical Consulting Israel Ltd 53/82 Supervisory Role Supervisors / team leaders / laboratory head: –Should be experienced analysts –Frequently audit while tests ARE BEING performed in order to be able to objectively investigate OOS results

54 PCI Pharmaceutical Consulting Israel Ltd 54/82 Responsibility of Supervisor Objective assessment without preconceived assumptions as to cause of OO S Immediate assessment may include: –Re-examination of: actual solutions Test units Glassware used in the original measurements and preparations This could provide more credibility for laboratory error hypotheses

55 PCI Pharmaceutical Consulting Israel Ltd 55/82 Responsibility of Supervisor To INVESTIGATE: –Review notebook / worksheet with analyst : Was method was followed: with a copy of the method in your hand, have the analyst describe exactly how they performed each step: confirm that the method was understood & followed Review raw data: Perform calculations again including checking dilution schemes Unauthorised changes to automated calculations Examine reagents, (reference) standards, solutions Examine glassware Performance of instruments

56 PCI Pharmaceutical Consulting Israel Ltd 56/82 Hypothesis Testing If you re-create an OOS conclusions are stronger Might retest recent sample to confirm / refute equipment malfunction: retro consequences? Examine retained samples e.g. –Re-inject solutions where a transient equipment malfunction is suspected [air bubbles] Hard to prove, but re-injection of same preparation can provide strong evidence –Release rate testing of slow release tab / cap: retest of original unit may show it was damaged during testing –Additional extraction to show that problem is method related – then revise method

57 PCI Pharmaceutical Consulting Israel Ltd 57/82 Hypothesis Testing, Case Study #2 LAL test on radioactive product (short half-life) is positive Product history – no previous failure Other products tested in same series passed Initial laboratory investigation: no evidence of lab error Dilution used: 1:70 specification allows up to 1:140 dilution

58 PCI Pharmaceutical Consulting Israel Ltd 58/82 Hypothesis Testing, Case Study #2 –Perform retest in parallel with production investigation because of short half-life –Production investigation included sampling glassware and equipment for LAL residues NO positive results –Repeat test at 1:70 and 1:140 dilutions Results were in spec i.e. no positive LAL –New LAL reagent prepared and same sample tested with old and new reagent: Old: failed New: passed

59 PCI Pharmaceutical Consulting Israel Ltd 59/82 Out of Specification Results conclusive If the laboratory investigation is conclusive –Document findings –INVALIDATE original test –Perform NEW test on same sample –Report original result with investigation as well as new result in batch record for QA review prior to release –COA carries new result only; some companies use an asterisk and indicate that there was an OOS NOT If the laboratory investigation is NOT conclusive inform QA (or customer for contract lab)

60 PCI Pharmaceutical Consulting Israel Ltd 60/82 Out of Trend Results If the laboratory investigation is conclusive or inconclusive, consult with QA In most cases, DO NOT perform any additional testing or sampling Make product disposition judgment based on: –Original result –Product history (e.g. stability data – statistical analyses of particular use here) –Batch history (e.g. review indicates that there were no processing errors / there were errors) –Other investigational findings

61 PCI Pharmaceutical Consulting Israel Ltd 61/82 And now some work for you..... Specification is 90.0 – 110.0% for an oral suspension Three batches are tested simultaneously, each sample in duplicate Two batches show (average) 98.2% and 99.7% respectively Third batch gives one result of 88.2% and a second result of 89.3% PREPARE A CHECKLIST OF QUESTIONS TO REVIEW AS PART OF THE LABORATORY INVESTIGATION

62 PCI Pharmaceutical Consulting Israel Ltd 62/82 FDA: Full-Scale OOS Investigation Use a pre-defined procedure Production/ process review and / or additional laboratory work Identify root cause and implement CAPA QA / QCU responsibility, includes CMOs if used Documented in the batch record Involves all aspects of manufacture, quality control and sampling Describes corrective actions and endpoint Is performed PRIOR to ANY retesting

63 PCI Pharmaceutical Consulting Israel Ltd 63/82 FDA: Full-Scale OOS Investigation If cause of OOS is identified, batch is rejected In this case need CAPA on process / product May not identify cause and may need additional lab testing: –Retest additional portion of original sample –Resample

64 PCI Pharmaceutical Consulting Israel Ltd 64/82 FDA: Retesting and Resampling Use another analyst? Where possible The maximum number of retests should be specified in advance in an SOP May, on rare occasions, deviate from SOP but with documented rationale and protocol The number may vary depending upon the variability of the test method and NOT depending on the results obtained Resampling raises questions as to sampling procedure validity

65 PCI Pharmaceutical Consulting Israel Ltd 65/82 Interpretation and Results Reporting Report all results, passing and suspect and consider for batch release decision Averaging –Has appropriate and inappropriate uses: Appropriate: optical rotation test: several discrete measurements averaged for result; microbiology; HPLC average of 2 or 3 peak responses from replicate injections of the same preparation = one test and one result as described in the test method Have acceptance criteria for deviation between replicates This is different to analysis of different portions of a single batch

66 PCI Pharmaceutical Consulting Israel Ltd 66/82 Interpretation and Results Reporting Averaging –Inappropriate uses: May conceal variations in different portions of the batch or sample e.g. for powder blend uniformity or dosage form uniformity of content. Averaging the results of the original OOS and additional retest or resample results is inappropriate All individual results must be provided and considered by the QCU / QA for release

67 67 Time for a Break

68 PCI Pharmaceutical Consulting Israel Ltd 68/82 Outlier Tests Possible use of the outlier test should be determined in advance Should be written in an SOP for data interpretation Should include the specific test to be used Should specify the minimum number of results required to obtain a statistically significant assessment from the test For validated chemical tests its use is suspect

69 PCI Pharmaceutical Consulting Israel Ltd 69/82 FDA: Concluding the Investigation Evaluate results and determine batch quality Release decision by QCU / QA An initial OOS does not necessarily mean that the batch fails and must be rejected. Where the suspect result is invalidated, the result should not be used to evaluate the quality of the batch or lot For inconclusive results – give full consideration to the OOS result

70 PCI Pharmaceutical Consulting Israel Ltd 70/82 FDA: Concluding the Investigation Example given shows seven retest results which gives the only indication in the guide regarding numbers of retests The example given is also extreme: 89.5% OOS 99.0, 98.9, 99.0, 99.1, 98.8, 99.1, 99.0% Consider method precision and validation data in making release / reject decision

71 PCI Pharmaceutical Consulting Israel Ltd 71/82 FDA: Cautions Where a series of assay results (to produce a single reportable result) have some individual results OOS and some in spec and all within the known method variability, passing results no more likely to represent the true value than the OOS result. In this case the company must err on the side of caution and reject the batch A result that is low but in specification should also be a cause of concern

72 PCI Pharmaceutical Consulting Israel Ltd 72/82 FDA on Field Alert Reports (FARs) For products with approved (a)/NDAs, regulations require a FAR within 3 working days concerning any failure of a distributed batch to meet any of the specifications established in an application Unless the OOS result is found to be invalid within 3 days, an initial FAR should be submitted A follow-up FAR should be submitted when the investigation is completed

73 PCI Pharmaceutical Consulting Israel Ltd 73/82 OOS Case Study #3 BN gave an assay result for 3 month stability study: 89.2% (long term / RT) Limits: 90.0 – 110.0% Test performed at a contract laboratory using an internal instrument control BN tested at the same time gave a result of 95.4% (i.e. in spec. – release test) DO YOU INFORM THE REGULATORS?

74 PCI Pharmaceutical Consulting Israel Ltd 74/82 OOS Case Study #3 – cont/ The samples have to be diluted during preparation and as far as records showed there was no evidence of laboratory error Calculations were satisfactory No evidence that reagents were outdated or faulty technique Control sample showed a 3.5% difference at beginning and end of run: usually around 1%; NMT 5% allowed by method

75 PCI Pharmaceutical Consulting Israel Ltd 75/82 OOS Case Study #3 – cont/ Batch number ; in-process result: 98.2% Batch number ; time zero result: 92.8% i.e. an apparent difference of 3.5% between results in both cases Hypothesis formulated: problem is with the control sample / equipment and this can be tested using both batches i.e. in-spec and OOS

76 PCI Pharmaceutical Consulting Israel Ltd 76/82 OOS Case Study #3 – cont/ Retesting Protocol (before start of retesting): –BN : OOS on inverted stability sample at 3 months Perform retest at three dilutions in duplicate on: Same sample= 6 results vs 2 original Upright sample= 6 additional results –BN : In spec. but 3.5% lower than IPC Perform retest at three dilutions in duplicate Same sample= 6 results vs 2 original

77 PCI Pharmaceutical Consulting Israel Ltd 77/82 OOS Case Study #3 – cont/ Outcome: –BN :All retest results in specification average result: 92.2% –BN : All retest results in specification average result: 97.9% –Control sample: difference of 1% beginning and end of run

78 PCI Pharmaceutical Consulting Israel Ltd 78/82 OOS Case Study #3 – Conclusion Original OOS result for BN is invalid Original OOT result for BN is invalid ? CAPA required regarding external laboratory as follows: –Tighten allowed limits for control sample (NMT 5% is too high) –Revalidate method? Investigation showed validation last done 15 years ago and a new instrument had been introduced since then! –Closely follow BN at additional stability stations

79 PCI Pharmaceutical Consulting Israel Ltd 79/82 OOS Logs and Trending Data Should keep a record of OOS results Analyse periodically according to: –Analyst –Instrument –Product –Test method Take appropriate actions where repeat problems appear

80 PCI Pharmaceutical Consulting Israel Ltd 80/82 And in Conclusion.... Always report OOS or OOT result to Supervisor Have a pre-approved SOP that provides a flow-chart for handling OOS Conduct detailed and genuine investigation Document investigational findings clearly and concisely Transparency regarding reporting on COA At some point...notification of regulators

81 PCI Pharmaceutical Consulting Israel Ltd 81/82 In conclusion All test results are subject to some element of doubt Use controls and validated, approved test methods Use replicates where inherent variation exists Use qualified, calibrated and well maintained equipment Perform trend analyses and report deviations NEVER continue a suspect test At some point, testing ends and a product disposition decision must be made

82 PCI Pharmaceutical Consulting Israel Ltd 82/82 Thank you for your attention Any questions? Find me at


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