Deviation and Out-of-Specification (OOS)

Investigations

Lynda Linhart
GMP Inspector, Medicines Inspection Group, Office of
Manufacturing Quality, TGA
RACI Pharmaceutical Science Group (NSW) Seminar
26 November 2012

Overview
Definitions
Deviation
OOS
Code of GMP requirements
GMP expectations for deviation management
In General
OOS Results- specific considerations in the laboratory
Summary

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Definitions
Deviations
A deviation is an unusual or abnormal event.
Formally defined as a departure from an approved instruction or established
standard (PIC/S Guide to GMP PE009-8, Pt II and USP <1078>).
Can be planned or unplanned.

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Definitions
Deviations- Planned
Examples encountered at inspection:
Equipment substitution eg. Change of mixing vessel.
Early/provisional release of starting materials.
Upsizing or downsizing a batch to a non-standard quantity.
Alternative source of starting material.

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Definitions
Deviations- Unplanned
Examples encountered at inspection:
Process error.
Mix ups/ cross-contamination.
Equipment malfunction or calibration failure.
Over or under yield.
Material reconciliation failure.
Human error.
Temperature excursion in storage area or lab incubator.
The possibilities are endless!
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Definitions
Out-of-specification (OOS) results
An OOS result is a specific type of deviation pertaining to QC testing.
Results that fall outside their pre-determined acceptance criteria = OOS.
Does not apply to routine in-process testing where tests are performed for the
purpose of monitoring and/or adjusting the process until the end-point is
achieved.
Does apply to stability testing with an added requirement to investigate
significant atypical trends.
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Code of GMP Requirements

PIC/S Guide to GMP for Medicinal Products 15 Jan 2009
Part I: Medicines
Records are made, manually and/or by recording instruments, during manufacture
which demonstrate that all the steps required by the defined procedures and
instructions were in fact taken and that the quantity and quality of the product was as
expected. Any significant deviations are fully recorded and investigated [Clause
1.2vi].
Records are made, manually and/or by recording instruments, which demonstrate
that all the required sampling, inspecting and testing procedures were actually
carried out. Any deviations are fully recorded and investigated [Clause 1.3iv].
Records are made of the results of inspection and that testing of materials,
intermediate, bulk, and finished products is formally assessed against specification.
Product assessment includes a review and evaluation of relevant production
documentation and an assessment of deviations from specified procedures
[Clause 1.3vi].
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Code of GMP Requirements

PIC/S Guide to GMP for Medicinal Products 15 Jan 2009
Part I: Medicines
PQR includes a review of all significant deviations or non-conformances,
their related investigations, and the effectiveness of resultant corrective and
preventative actions taken [Clause 1.4iv].
Notes on any special problems or unusual events including details with signed
authorisation for any deviation from the Manufacturing Formula and Processing
Instructions [Clauses 4.17(i) and 4.18(h)].
Any deviation from instructions or procedures should be avoided as far as
possible. If a deviation occurs, it should be approved in writing by a competent
person, with the involvement of the Quality Control Department when
appropriate [Clause 5.15].
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Code of GMP Requirements

PIC/S Guide to GMP for Medicinal Products 15 Jan 2009
Part I: Medicines
Any significant deviation from the expected yield should be recorded and
investigated [Clause 5.39].
Products which have been involved in an unusual event should only be
reintroduced into the process after special inspection, investigation and
approval by authorised personnel. Detailed record should be kept of this
operation [Clause 5.55].

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Code of GMP Requirements

PIC/S Guide to GMP for Medicinal Products 15 Jan 2009
Part I: Medicines
... an on-going stability study should be conducted after any significant
change or significant deviation to the process or package [Clause 6.30].
Out of specification or significant atypical trends should be investigated.
Any confirmed out of specification result, or significant negative trend,
should be reported to the relevant competent authorities [Clause 6.32].
A report that cross-references the qualification and/or validation protocol
should be prepared, summarising the results obtained, commenting on any
deviations observed, and drawing the necessary conclusions, including
recommending changes necessary to correct deficiencies [Annex 15,
Clause 7].
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Code of GMP Requirements

PIC/S Guide to GMP for Medicinal Products 15 Jan 2009
Part II: APIs
Any deviation from established procedures should be documented and
explained. Critical deviations should be investigated, and the investigation and
its conclusions should be documented [Clauses 2.16 and 8.15].
PQR includes a review of all critical deviations or non-conformances and
related investigations [Clause 2.50].
Deviations from approved standards of calibration on critical instruments should
be investigated to determine if these could have had an impact on the quality of
the intermediate(s) or API(s) manufactured using this equipment since the last
successful calibration [Clause 5.35].
... any deviation noted, its evaluation, investigation conducted (if appropriate) or
reference to that investigation if stored separately [Clause 6.52]
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Code of GMP Requirements

PIC/S Guide to GMP for Medicinal Products 15 Jan 2009
Part II: APIs
Written procedures should be established and followed for investigating critical
deviations or the failure of a batch of intermediate or API to meet specifications.
The investigation should extend to other batches that may have been
associated with the specific failure or deviation [Clause 6.53].
Complete records should also be maintained for... Out-of-specification (OOS)
investigations [Clause 6.61].
All deviation, investigation, and OOS reports should be reviewed as part of the
batch record review before the batch is released [Clause 6.72].
... Deviations in yield associated with critical process steps should be
investigated to determine their impact or potential impact on the resulting
quality of affected batches [Clause 8.14].
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Code of GMP Requirements

PIC/S Guide to GMP for Medicinal Products 15 Jan 2009
Part II: APIs
If time limits are specified in the master production instruction, these time limits
should be met to ensure the quality of intermediates and APIs. Deviations
should be documented and evaluated [Clause 8.20].
Any out-of-specification result obtained should be investigated and documented
according to a procedure. This procedure should require analysis of the data,
assessment of whether a significant problem exists, allocation of the tasks for
corrective actions, and conclusions. Any resampling and/or retesting after OOS
results should be performed according to a documented procedure [Clause
11.15].
A validation report that cross-references the validation protocol should be
prepared, summarising the results obtained, commenting on any deviations
observed, and drawing the appropriate conclusions, including recommending
changes to correct deficiencies [Clause 12.22].
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GMP Expectations
In General...
What deviations must be recorded?
Generally those resulting in non-conforming material and/or processes, with
potential to impact on product quality, safety, efficacy, or data integrity.
Have the TGAs expectations changed with the adoption of PE009-8?
No. Some new clauses do make specific reference to deviations and OOS,
however these requirements were always implied in the 2002 Code of GMP.

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GMP Expectations
In General...
System(s) to document and control deviations- SOPs, registers or databases,
and individual full records of incident investigation:
Who, what, when, where, why, how?
Complete account from identification through to resolution. Level of detail
appropriate to the classification of the deviation (critical/major/minor).
Root causes identified and corrective/preventative actions implemented.
Trend analysis: not a new requirement, but now a specific component of
PQR.

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GMP Expectations
In General...
Interface between other areas of QMS (rework/reprocessing, release for
supply, change control, validation, training, etc). Audit trails via crossreferencing.
Disposition of affected goods. Risk assessment? Stability? Authorisation from
QC/QA?
Active use of the system(s). Deviations DO happen! Dont waste the
opportunity to learn from the error and formally correct it.

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GMP Expectations
OOS Results- specific considerations in the laboratory
Record and investigate first. No re-testing* or re-sampling** until evidence
proves it is required.
Initial assessment of the OOS result to establish whether the result is valid or
invalid.
Encompasses many factors eg. analyst training, reagent preparation and
expiry, equipment calibration, verification of calculations, correct dilution
technique, test method validated and followed correctly, etc.
Useful to have a pro-forma checklist for this step.
If assignable cause is found, re-calculation with original data or re-test can
be performed to replace the invalid OOS result.
*Re-test: re-analysis of the original sample.
**Re-sample: collection of a new sample from the lot/batch in question.

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GMP Expectations
OOS Results- specific considerations in the laboratory
If the OOS result is confirmed as valid, review the sample and the sampling
technique. Was the sample representative of the lot, collected using clean
implements, correctly labelled and submitted to the laboratory without delays?
Re-sampling can be justified when there are doubts about the sample
integrity, or the original sample is exhausted.
Re-sampling method/plan must be specified in a procedure.

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GMP Expectations
OOS Results- specific considerations in the laboratory
If the confirmed OOS result cannot be traced to a sampling issue:
For starting materials, disposition can be decided at this point ie/ reject or
release under deviation.
For bulk or finished product, the next phase moves outside the laboratory
and into manufacturing to investigate process failure. Traceability between
the OOS report and subsequent deviation investigations is required.

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Guidance Documents for OOS

US FDA Guidance for Industry- Investigating Out-of-Specification (OOS) Test
Results for Pharmaceutical Production, October 2006
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070287.pdf
UK MHRA Out of Specification Investigations
http://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con100182.pdf

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Summary
The expectations of OMQ Inspectors have not changed, but there are now
more clauses with specific reference to deviation & OOS management.
Deviations and OOS results must be:
fully recorded and investigated,
assessed before batch release, and
reviewed in PQRs.
Fully implies documenting the whole story from incident identification through
to resolution. If the full story spans multiple systems within the overall QMS,
maintain traceability between the individual documents/reports.
Zero deviations reported does not equal zero problems! Use the deviation &
OOS systems to your advantage. Continuous improvement is in everyones
best interests.
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Questions?

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