Events Presentations Raci 121126

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Deviation and Out-of-Specification (OOS)

Investigations

26 November 2012

Lynda Linhart

GMP Inspector, Medicines Inspection Group, Office of

Manufacturing Quality, TGA

RACI Pharmaceutical Science Group (NSW) Seminar


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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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DefinitionsDeviations

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 ).

Can be planned or unplanned.

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Definitions

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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

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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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DefinitionsOut-of-specification (OOS) resul ts

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 RequirementsPIC/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 andinstructions were in fact taken and that the quantity and quality of the product was asexpected.Any significant deviations are fu lly recorded and investigated [Clause1.2vi].

Records are made, manually and/or by recording instruments, which demonstratethat all the required sampling, inspecting and testing procedures were actuallycarried out.Any deviations are fu lly 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 productiondocumentation and an assessment of deviations from specified procedures[Clause 1.3vi].

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Part I: Medicines

PQR includes a review of all signi ficant deviations or non-conformances,their related investigations, and the effectiveness of resultant corrective andpreventative actions taken [Clause 1.4iv].

Notes on any special problems or unusual events including details with signedauthorisation for any deviation from the Manufacturing Formula and ProcessingInstructions [Clauses 4.17(i) and 4.18(h)].

Any deviation from instructions or procedures should be avoided as far aspossible. If a deviation occurs, it should be approved in writing by a competentperson, with the involvement of the Quality Control Department whenappropriate [Clause 5.15].

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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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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 protocolshould be prepared, summarising the results obtained, commenting on anydeviations observed, and drawing the necessary conclusions, includingrecommending changes necessary to correct deficiencies [Annex 15,Clause 7].

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Part II: APIs

Any deviation from established procedures should be documented and

explained. Critical deviations should be investigated, and the investigation andits conclusions should be documented [Clauses 2.16 and 8.15].

PQR includes a review of all critical deviations or non-conformances andrelated investigations [Clause 2.50].

Deviations from approved standards of calibration on critical instruments shouldbe investigated to determine if these could have had an impact on the quality ofthe intermediate(s) or API(s) manufactured using this equipment since the lastsuccessful calibration [Clause 5.35].

... any deviation noted, its evaluation, investigation conducted (if appropriate) orreference to that investigation if stored separately [Clause 6.52]

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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 beenassociated 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 thebatch record review before the batch is released [Clause 6.72].

... Deviations in yield associated with critical process steps should beinvestigated to determine their impact or potential impact on the resultingquality of affected batches [Clause 8.14].

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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. Deviationsshould be documented and evaluated [Clause 8.20].

Any out-of-specification result obtained should be investigated and documentedaccording to a procedure. This procedure should require analysis of the data,assessment of whether a significant problem exists, allocation of the tasks forcorrective actions, and conclusions. Any resampling and/or retesting after OOS

results should be performed according to a documented procedure [Clause11.15].

A validation report that cross-references the validation protocol should beprepared, summarising the results obtained, commenting on any deviationsobserved, and drawing the appropriate conclusions, including recommendingchanges to correct deficiencies [Clause 12.22].

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GMP ExpectationsIn 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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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 ofPQR.

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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! Dont waste theopportunity to learn from the error and formally correct it.

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GMP ExpectationsOOS 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.

16*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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If the OOS result is confirmed as valid, review the sample and the sampling

technique. Was the sample representative of the lot, collected using cleanimplements, 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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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 betweenthe 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 Investigationshttp://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con100182.pdf

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http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070287.pdfhttp://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con100182.pdfhttp://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con100182.pdfhttp://www.fda.gov/downloads/Drugs/.../Guidances/ucm070287.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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