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. 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
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3. 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
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4. PART 1 – BARR and ABLE Litigation
USA regulatory environment around late 1980’s through 1993
Current regulatory environment in US
Able
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5. 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)
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6. 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
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7. 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
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8. 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
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9. 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
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10. 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
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11. 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
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?
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12. 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
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
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13. 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)
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14. 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.
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15. 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
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16. 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:
The QU releasing batches failing in-process, finished 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
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17. Resample, Re-injection, Reprocessing
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18. Time for a Break

19. 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
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20. 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?
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21. 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 “5th” injection was dirty glassware or mis-injected, or, or, or……
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22. 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?
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23. 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
Q7A GMP for APIs it DOES because Q7A was written after 1993
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24. Q7A on OOS
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25. 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!”
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26. 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
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27. 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?
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28. 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
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29. 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
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30. 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.”
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31. 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
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32. 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 Rejection Financial Loss
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33. 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
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34. Types of Tests Quantitative: assays and some limits tests
Qualitative: e.g. sterility test, appearance
Chemical
Physical
Microbiological
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35. 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
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36. Physical Tests e.g.1 Black spots in powder 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?
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37. 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
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38. 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
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39. Table of Contents Introduction Background
Identifying and Assessing OOS Results – Phase I: Laboratory Investigation
Responsibility of Analyst
Responsibilities of Laboratory Supervisor
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40. 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
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41. 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
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42. 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!!!
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43. 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: – usual results: 98.5 – OOT result: 96.4
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44. 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)
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45. 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?
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46. 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
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47. Time for Lunch

48. 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]
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49. 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
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50. 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
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51. OOS Flow Chart PCI Pharmaceutical Consulting Israel Ltd
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
One result
OOS
Retest
??? further aliquots
from original sample
Inconclusive
No evidence of production error
QA Investigation
Laboratory Investigation
Report to QA (copy in batch file?)
OOS result
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52. 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
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53. 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
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54. Responsibility of Supervisor
Objective assessment without preconceived assumptions as to cause of OOS
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
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55. 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
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56. 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
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57. 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
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58. 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
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59. Out of Specification Results
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
If the laboratory investigation is NOT conclusive inform QA (or customer for contract lab)
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60. 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
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61. 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
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62. 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
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63. 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
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64. 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
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65. 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
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66. 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
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67. Time for a Break

68. 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
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69. 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
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70. 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
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71. 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
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72. 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
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73. OOS Case Study #3 DO YOU INFORM THE REGULATORS?
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?
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74. 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
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75. 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
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76. 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
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77. 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
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78. 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
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79. 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
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80. 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
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81. 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
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82. Thank you for your attention Any questions?
Find me at
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