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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

management – In General – OOS Results- specific considerations in the laboratory • Summary 26/11/2012 1

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.

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.

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.

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The possibilities are endless!

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.

• Does apply to stability testing with an added requirement to investigate significant atypical trends. 26/11/2012

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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] . an assessment of deviations from specified procedures [Clause 1.3vi].

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].

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].

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].

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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]

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 investigations [Clause 6.61].

Out-of-specification (OOS)

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].

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].

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 TGA’s 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.

reference to deviations and OOS, however these requirements were always implied in the 2002 Code of

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.

actions implemented. – Trend analysis: not a new requirement, but now a specific component of PQR.

GMP Expectations

In General

Interface between other areas of QMS (rework/reprocessing, release for supply, change control, validation, training, etc). Audit trails via cross- referencing.

Disposition of affected goods. Risk assessment? Stability? Authorisation from QC/QA?

Active use of the system(s). Deviations DO happen! Don’t waste the opportunity to learn from the error and formally correct it.

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.

or the original sample is exhausted. – Re-sampling method/plan must be specified in a procedure. 26/11/2012

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

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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

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 everyone’s best interests.

the deviation & OOS systems to your advantage. Continuous improvement is in everyone’s best interests. 26/11/2012

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Questions? 26/11/2012 21

Questions?