Out of Specification Results OOS A One Day

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

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

Workshop Structure 09: 00 – 10: 30 l 10: 30 – 11: 00 l Workshop Structure 09: 00 – 10: 30 l 10: 30 – 11: 00 l 11: 00 – 12: 30 l 12: 30 – 13: 30 l 13: 30 – 15: 00 l 15: 00 – 15: 15 l 15: 15 – 16: 30 l 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 PCI Pharmaceutical Consulting Israel Ltd 3

PART 1 – BARR and ABLE Litigation l USA regulatory environment around late 1980’s PART 1 – BARR and ABLE Litigation l USA regulatory environment around late 1980’s through 1993 l Current regulatory environment in US l Able - 2005 l PCI Pharmaceutical Consulting Israel Ltd 4

Some Definitions l What is an OOS Result? l What is a test result Some Definitions l What is an OOS Result? l What is a test result l 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. ” l Torbeck (February 1999, Pharmaceutical Technology) l PCI Pharmaceutical Consulting Israel Ltd 5

Before Barr – Current Practice Prior to 1993 and the court decision – it 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 l Companies had not really thought about the practice l But then…nor had the regulators l PCI Pharmaceutical Consulting Israel Ltd 6

The Barr Court Case and Judge Wolin From the New York Times February 6, 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 PCI Pharmaceutical Consulting Israel Ltd 7

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FDA to court l The judge went into great details as to the meaning and implications of OOS results l The outcome: FDA draft guidance: 1998 l FDA final guidance: 2006 l PCI Pharmaceutical Consulting Israel Ltd 8

Barr: What happened in court The judge heard experts on behalf of FDA and Barr: What happened in court The judge heard experts on behalf of FDA and Barr regarding the practice of retesting l FDA wanted retesting to be banned under all circumstances l 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 l PCI Pharmaceutical Consulting Israel Ltd 9

The Barr Court Case 1993 l Reported problems include – misplaced records – test The Barr Court Case 1993 l 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 PCI Pharmaceutical Consulting Israel Ltd 10

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

Reading the Judgment Reading the Barr Court Judgment is like reading FDA’s draft guidance Reading the Judgment Reading the Barr Court Judgment is like reading FDA’s draft guidance and pretty similar to the final guidance l 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 l 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 l Limited situations where laboratory error could be used l PCI Pharmaceutical Consulting Israel Ltd 12

Guide to Inspection: QC Labs Issued July 1993 (must have been working on it Guide to Inspection: QC Labs Issued July 1993 (must have been working on it while the court case was ongoing) l Addresses OOS results and instructs inspectors to be alert l “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 “ l (Most of the information is now in FDA’s guide) l PCI Pharmaceutical Consulting Israel Ltd 13

Guide to Inspection: QC Labs l l l OOS results fall into three categories: Guide to Inspection: QC Labs l l l 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 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. PCI Pharmaceutical Consulting Israel Ltd 14

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

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

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

Time for a Break 18 Time for a Break 18

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

That isn’t relevant…it’s fraud l Think about the following scenario before saying it couldn’t That isn’t relevant…it’s fraud l 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 l What do you do? PCI Pharmaceutical Consulting Israel Ltd 20

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

It couldn’t happen in my company But you don’t want to show 4 good It couldn’t happen in my company But you don’t want to show 4 good injections, one lousy and another good one l So you cut out the bad one and document only the good ones in the notebook l Sounds “horrendous? ” l 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? l PCI Pharmaceutical Consulting Israel Ltd 22

GMP and OOS Results Do you know where the term OOS appears in – GMP and OOS Results Do you know where the term OOS appears in – EU GMP regulations it didn’t as of June 2006 it does – US GMPs it doesn’t – Q 7 A GMP for APIs it DOES because Q 7 A was written after 1993 PCI Pharmaceutical Consulting Israel Ltd 23

Q 7 A on OOS PCI Pharmaceutical Consulting Israel Ltd 24 Q 7 A on OOS PCI Pharmaceutical Consulting Israel Ltd 24

Ever heard this…. “The Lab don’t know how to test” “Give it to Pete… 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!” PCI Pharmaceutical Consulting Israel Ltd 25

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

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

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

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

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

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

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

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

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

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

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

FDA OOS Guidance, October 2006 l l l Draft from September 1998 for comments FDA OOS Guidance, October 2006 l l l 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 PCI Pharmaceutical Consulting Israel Ltd 37

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

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

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

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

How to Identify OOS Results Compare result with specification l Be sure that specification How to Identify OOS Results Compare result with specification l Be sure that specification is to required degree of accuracy and round the result to this value l E. g. spec 95 - 105 94. 9 passes spec 95. 0 - 105. 0 94. 9 fails l Message for your R&D Department: think carefully before setting specifications!!! PCI Pharmaceutical Consulting Israel Ltd 42

How to Identify OOT Results l Out of Trend or unusual results are generally How to Identify OOT Results l 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 – 110. 0 usual results: 98. 5 – 101. 0 OOT result: 96. 4 PCI Pharmaceutical Consulting Israel Ltd 43

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

Out of Specification Results l Failure of a control is NOT an OOS eg: Out of Specification Results l 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 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? PCI Pharmaceutical Consulting Israel Ltd 45

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

Time for Lunch 47 Time for Lunch 47

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

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

FDA: Laboratory Investigation l Assess accuracy of lab data: – Before test preparations are FDA: Laboratory Investigation l 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 PCI Pharmaceutical Consulting Israel Ltd 50

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

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

Supervisory Role l Supervisors / team leaders / laboratory head: – Should be experienced Supervisory Role l 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 PCI Pharmaceutical Consulting Israel Ltd 53

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

Responsibility of Supervisor To INVESTIGATE: – Review notebook / worksheet with analyst : • 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 PCI Pharmaceutical Consulting Israel Ltd 55

Hypothesis Testing If you re-create an OOS conclusions are stronger l Might retest recent Hypothesis Testing If you re-create an OOS conclusions are stronger l Might retest recent sample to confirm / refute equipment malfunction: retro consequences? l Examine retained samples e. g. l – 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 56 PCI Pharmaceutical Consulting Israel Ltd

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

Hypothesis Testing, Case Study #2 – Perform retest in parallel with production investigation because 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 PCI Pharmaceutical Consulting Israel Ltd 58

Out of Specification Results l If the laboratory investigation is conclusive – – Document Out of Specification Results l 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 l If the laboratory investigation is NOT conclusive inform QA (or customer for contract lab) PCI Pharmaceutical Consulting Israel Ltd 59

Out of Trend Results If the laboratory investigation is conclusive or inconclusive, consult with Out of Trend Results If the laboratory investigation is conclusive or inconclusive, consult with QA l In most cases, DO NOT perform any additional testing or sampling l Make product disposition judgment based on: l – 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 PCI Pharmaceutical Consulting Israel Ltd 60

And now some work for you. . . Specification is 90. 0 – 110. 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 PCI Pharmaceutical Consulting Israel Ltd 61

FDA: Full-Scale OOS Investigation l l l l Use a pre-defined procedure Production/ process FDA: Full-Scale OOS Investigation l l l l 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 PCI Pharmaceutical Consulting Israel Ltd 62

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

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

Interpretation and Results Reporting Report all results, passing and suspect and consider for batch Interpretation and Results Reporting Report all results, passing and suspect and consider for batch release decision l Averaging l – 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 PCI Pharmaceutical Consulting Israel Ltd 65

Interpretation and Results Reporting l Averaging – Inappropriate uses: • May conceal variations in Interpretation and Results Reporting l 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 PCI Pharmaceutical Consulting Israel Ltd 66

Time for a Break 67 Time for a Break 67

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

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

FDA: Concluding the Investigation Example given shows seven retest results which gives the only FDA: Concluding the Investigation Example given shows seven retest results which gives the only indication in the guide regarding numbers of retests l The example given is also extreme: 89. 5% OOS 99. 0, 98. 9, 99. 0, 99. 1, 98. 8, 99. 1, 99. 0% l Consider method precision and validation data in making release / reject decision l PCI Pharmaceutical Consulting Israel Ltd 70

FDA: Cautions Where a series of assay results (to produce a single reportable result) 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. l In this case the company must err on the side of caution and reject the batch l A result that is low but in specification should also be a cause of concern l PCI Pharmaceutical Consulting Israel Ltd 71

FDA on Field Alert Reports (FARs) For products with approved (a)/NDAs, regulations require a 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 l Unless the OOS result is found to be invalid within 3 days, an initial FAR should be submitted l A follow-up FAR should be submitted when the investigation is completed l PCI Pharmaceutical Consulting Israel Ltd 72

OOS Case Study #3 BN 200602 gave an assay result for 3 month stability OOS Case Study #3 BN 200602 gave an assay result for 3 month stability study: 89. 2% (long term / RT) l Limits: 90. 0 – 110. 0% l Test performed at a contract laboratory using an internal instrument control l BN 200701 tested at the same time gave a result of 95. 4% (i. e. in spec. – release test) l DO YOU INFORM THE REGULATORS? PCI Pharmaceutical Consulting Israel Ltd 73

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

OOS Case Study #3 – cont/ Batch number 200701; in-process result: 98. 2% l OOS Case Study #3 – cont/ Batch number 200701; in-process result: 98. 2% l Batch number 200602; time zero result: 92. 8% i. e. an apparent difference of 3. 5% between results in both cases l Hypothesis formulated: problem is with the control sample / equipment and this can be tested using both batches i. e. in-spec and OOS l PCI Pharmaceutical Consulting Israel Ltd 75

OOS Case Study #3 – cont/ l Retesting Protocol (before start of retesting): – OOS Case Study #3 – cont/ l Retesting Protocol (before start of retesting): – BN 200602: OOS on inverted stability sample at 3 months Perform retest at three dilutions in duplicate on: • Same sample • Upright sample = 6 results vs 2 original = 6 additional results – BN 200701: In spec. but 3. 5% lower than IPC Perform retest at three dilutions in duplicate • Same sample = 6 results vs 2 original PCI Pharmaceutical Consulting Israel Ltd 76

OOS Case Study #3 – cont/ l Outcome: – BN 200602: All retest results OOS Case Study #3 – cont/ l Outcome: – BN 200602: All retest results in specification average result: 92. 2% – BN 200701: All retest results in specification average result: 97. 9% – Control sample: difference of 1% beginning and end of run PCI Pharmaceutical Consulting Israel Ltd 77

OOS Case Study #3 – Conclusion Original OOS result for BN 200602 is invalid OOS Case Study #3 – Conclusion Original OOS result for BN 200602 is invalid l Original OOT result for BN 200701 is invalid ? l CAPA required regarding external laboratory as follows: l – 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 200602 at additional stability stations 78 PCI Pharmaceutical Consulting Israel Ltd

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

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

In conclusion l l l l All test results are subject to some element In conclusion l l l l 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 PCI Pharmaceutical Consulting Israel Ltd 81

Thank you for your attention Any questions? Find me at kstaylor@netvision. net. il PCI Thank you for your attention Any questions? Find me at [email protected] net. il PCI Pharmaceutical Consulting Israel Ltd 82




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