Handling an OOS in a QC Lab

Handling

an OOS

in a

QC Lab

04 Sept 2012

Sasha Nezlin

2 04 Sept 2012

Omrix at a glance

Handling an OOS in a QC Lab

3

Barr Laboratories vs. FDA

04 Sept 2012

Barr were audited by FDA in 1989, 1991 and 1992

Refused to accept a consent decree

FDA was forced to go to court

United States of America, Plaintiff V. Barr

Laboratories Inc., Defendants, Civil Suite 92-1744,

August 17 till October 12, 1992

Judge Wolin decided on February 4, 1993 in favor

of the FDA


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Judge Wolin’s decision

04 Sept 2012 Handling an OOS in a QC Lab

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13 years later …


6

and another 5 years …


7

DEFINITION OF RESULTS

04 Sept 2012

OOS Results - Test results laying

outside of the specifications

Questionable

results (e.g. close

to spec / limit)

Out of trend

Out of limits (OOL - alert / alarm)

Unexpected Results

results that are aberrant, abnormal, anomalous, atypical, irregular or deviant

Batch failure,

used by FDA,

disliked by Judge

Wolin (Barr case)

Additional

unexpected peaks in

chromatogram


8

FDA DEFINITION OF REPORTABLE VALUE

04 Sept 2012

A reportable value is the end result of the complete measurement method as documented.

A reportable value is the value compared to the specifications.

A reportable value is the value used for reporting.

A reportable value is the value used for statistical analysis.

REPORTABLE VALUE:

“This determination is considered one test and one result.”

Record in writing the operational definition of the reportable

value for each test method in the method documentation, any

protocols and any reports.

Add “Only this reportable value can be compared to the

specification criteria.”


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Investigations of OOS results should be performed for:

- Batch release testing and testing of starting materials.

- In-Process Control testing: if data is used for batch calculations /

decisions and if it is in a dossier and on Certificates of Analysis.

NOTE: OOS procedure is NOT applicable for in-process testing

used for process adjustment (eg - pH, viscosity, etc.), and for

validation studies (process - variable parameters, analytics -

robustness).

- Stability studies on marketed batches of finished products and or

active pharmaceutical ingredients, ongoing / follow up stability

(NOT applicable for stress / forced degradation tests).

- If the previous released GMP batch used as reference sample in

an OOS investigation produced OOS or questionable results the

investigation should be extended to include it.

- Batches for clinical trials – under cGMP, same rules for

investigation apply as for commercial batches.


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Flow of investigation

04 Sept 2012

In search of a root cause of OOS result

FDA officials say,

“If you didn’t document it, it didn’t happen.

In God we trust, for everyone else we require documentation.”


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Test

Out of Spec?

Report out

resultsNo

Yes

Known Physical

Reason?

USP allows

resamples?

No

Yes2 nd Stage

(i.e. Content

Uniformity)Passes?

Yes

Begin Lab Initial

Investigation

No

No

Resample as

needed

Invalidate data,

Document,

Start Over

Document

Original sample

representative?

No

Yes

Lab or

Analyst

error?

Yes

Retest Passes?Yes

No

Other

reason?

Yes

Finish

Investigation

Yes

Document

and report

Full

Investigation

No

USP <111> Outlier IDHistorical Data

Review is

inconclusive

Retest

justified?

NoRetest n times

Document

justification

All pass?

No

Finish

investigation

Yes

Yes

OOS Logic

by Lynn Torbeck

No

March 1999

Copyright 1999 by

L. Torbeck


12 Handling an OOS in a QC Lab 04 Sept 2012 Sasha Nezlin

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When to open a deviation

04 Sept 2012

If the investigation shows no assignable cause

for the laboratory based failure - i.e. OOS is

confirmed - then full scale manufacturing

investigation should be conducted

this is a regulatory requirement!

When to initiate a manufacturing investigation:

– after initial (phase 1) investigation reveals no

laboratory errors has occurred?

– or after full laboratory investigation (phase 2)

was completed without evidence of lab error?


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RETEST SAMPLE SIZE


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RETEST SAMPLE SIZE (cont.)

04 Sept 2012

One analyst Two analysts, of at least the same level of experience ?

Original test Investigation / Retesting

One analyst, of higher level of experience ?

1 replicate Two tests in duplicates ?

2 replicates Two tests in triplicates ?

3 replicates Two tests in 4 replicates?

Same analyst? Same analyst after training?

Three tests in duplicates?


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04 Sept 2012

Original Instrument Second Instrument

Original

Analyst

2nd

Analyst

Prep

#1

Prep

#2

Inj 1

Prep

#1

Prep

#2

Inj 2 Inj 1 Inj 2 Inj 1 Inj 2 Inj 1 Inj 2


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04 Sept 2012

This is an unresolved issue and the statisticians are

still at it.

Barr case: Judge Wolin indicated 7 retests were

enough to discard an invalid result.

Could be too much or not enough.

Currently n= 3 to n=9.

PDA OOS committee promised to recommend...

Industry has been doing 2 x 2 x 2 (which is 4

sample preparations with 8 measurements), but

your strategy should reflect your assay and its

criticality and use.


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Tracking and Trending Investigations

04 Sept 2012

All laboratory corrective/preventive actions,

investigations and deviations must be tracked

and trended:

To track method / instrumentation problems

To specifically evaluate analyst performance, and

to identify training needs

To track product / process problems

To trend significant shifts in laboratory data

To identify systematic issues and ensure

appropriate actions taken


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Expectations of the regulator / auditor

04 Sept 2012

OOS results will be generated by the lab

Comprehensive, honest approach to

investigation of OOS results is demonstrated

Evaluation of OOS results is performed using

scientifically valid principles 3G

Lab demonstrably learns from the experience

Permanent solution to the problem / root cause

Prevention, not just correction

3G™ Good science, Good judgment, Good documentation


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References and useful links

04 Sept 2012

1. FDA: Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for

Pharmaceutical Production, Guidance for Industry, October 2006

(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070287.pdf)

2. MHRA “Out Of Specification Investigations”

(http://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con100182.pdf)

3. MHRA Out of specification (OOS) FAQs

(http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodManufacturingPractice/FAQ/OOSFA

Qs/index.htm)

4. Jenny Hantzinikolas, GMP Inspector, Office of Manufacturing Quality Laboratory, TGA

“Investigations - A Regulatory Perspective” 2008

5. United States of America, Plaintiff V. Barr Laboratories Inc., Defendants, Civil Suite 92-1744

(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM216425.pdf)

(http://www.navigategmp.com/pdf/BarrLabs.pdf)

6. Lynn Torbeck “Preventing the practice of testing into compliance. A practical solutions guide”,

Pharmaceutical Technology, October 2002

7. Jeffrey D. Hofer “Considerations When Determining a Routine Sample Size for a Retest

Procedure”, Pharmaceutical Technology, November 2003


21 04 Sept 2012

Questions?


Handling an OOS in a QC Lab

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