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GMP issues in Q assessmentGMP issues in Q assessment

Wondiyfraw Worku

Assessor

6th CPH assessment training workshop,

May 2014

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OutlineOutline

Regulatory strategy- reminder

GMP documentations in Q dossier Mfg license GMP certificate CPP

Dossier documentation that must be QA approved and signed

Assessor-inspector communication Possible scenarios

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Regulatory strategy- Risk reduction

Regulatory strategy- Risk reduction

One does not make sense without the others! One assumes that the

others are being met• assumptions are verified

through the life cycle of the product

There may be overlaps in certain aspects e.g. review/inspection of process validation data

Post approval regulatory activities

Dossier review Inspection of

mfg, testing and clinical

sitesProduct

Variations, compliant handling, quality

surveillance,Vigilance, safety update

etc..

- Readiness for commercial mfg- Conformity to dossier info- Dossier data integrity audit

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GMP documentation in dossiers- provide minimum basis for review

GMP documentation in dossiers- provide minimum basis for review

Manufacturing licenseissued by national competent authorityusually certifies that a given site has been

authorized to perform the claimed dutiesmay or may not specify specific products but at

least the authorized dosage form/lineimportant to establish the basic legal and

regulatory status of the manufacturer

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GMP documentation- ContdGMP documentation- Contd

GMP certificateCertifies that a given site has been inspected by the

national inspector (in accordance with local requirements) and deemed to be of acceptable compliance.

• Local requirement may make reference to WHO GMP requirements but does not mean that the site has been inspected by WHO

In some jurisdictions, GMP certification is part of the manufacturing license

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GMP documentation- ContdGMP documentation- Contd

Certificate of Pharmaceutical Product WHO format, comprehensive issued to a specific formulation certifies whether the formulation has been reviewed/licensed by the

country of origin and whether it is on the market includes composition of the approved formulation states all sites involved in manufacturing of the FPP but may not state

API sites may include summaries as approved by the issuing agency

• Product information• Summary of basis of approval (similar to public assessment reports)

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Certificate of Pharmaceutical Product-contdCertificate of Pharmaceutical Product-contd

Primarily intended to promote faster approval and speedy access to medicines by helping recipient countries to depend on sending authorities marketing authorization

Being also used in various other ways• As a key criteria for registration even though the

application is supported by full dossier data• As supporting document for tenders• As a substitute for mfg license and GMP certificates

WHO’s blue book provides recommendations on appropriate use of CPP in various scenarios

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WHO Blue Book recommendationWHO Blue Book recommendation

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Implementation in PQImplementation in PQFull dossier route SRA route

If available, CPP, should be submitted- As a minimum, manufacturing license for the specific sites involved in manufacturing activities should be submitted

CPP as issued by the reference SRA should be submitted

Registration or marketing in the country of origin is not a requirement- As we are fully reviewing and assuring the quality, safety/efficacy as well as compliance of CROs and manufacturing sites

Registration and marketing in the country of origin is a requirement

GMP certificate may be submitted to support the application - In any case, the site’s compliance status needs to be confirmed by our inspectors

GMP certificate may be submitted to support the application - In any case, the site’s compliance status needs to be confirmed by our inspectors

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Documents that must be signed by QA, dated and/or version tracked

Documents that must be signed by QA, dated and/or version tracked

Cover and undertaking letter

Application form- not applicable for PQ except variations and amendments

Letters of authorization

CEP/API PQ confirmation document

Filled and Blank BMRs

Process validation and stability protocols

Specifications

Commitments

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Assessor-inspector communicationAssessor-inspector communication Via common databases

Easy traceability of all sites related to a given application

Via summary dossier information (QIS) A quick but critical summary for inspection preparation

Assessment reports and inspection reports e.g. summarized stability data with assessor’s interpretation Inspection report from a previous inspection may tell compliance status of a

given QC lab within a manufacturing site

Specific recommendations/feedbacks Recommendation for inspection of raw data The need for re-review of bioequivalence data

At the time of PQ PQ decision form to be signed in by assessment and inspection heads

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Examples of possible recommendations from assessors

Examples of possible recommendations from assessors

Instances of unsolicited major changes in QA signed documentations (e.g. Specs, batch records) Questions document approval procedure within the company

Instances of failure to investigate OOS or clear OOT results Indicates a possible breach in quality system

Instances of “never completed” studies e.g. stability studies that are claimed to have been interrupted

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Examples- contdExamples- contd

Unaccounted deviations in batch records Questions reliability of the batch record and the whole quality system

Failure to comply with written commitments Seen during variation applications

Specific critical steps that may not be immediately visible in flow charts/method description but considered critical by assessors e.g. steps that may involve or result in potential change in polymorph

form will help inspectors to factor in that in their inspection risk assessment

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Example-contdExample-contd

Inconsistent responses e.g.- “ we have data” but then fails to provide the data or they may state “ we do not have data” but then after a while “ we

had the data” “We did that” and after a while “ it was a typo”

Data that looks too good compared to prior experiences (“surprising results”) for example, absence/ND levels of a major and common

degradation product

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Example-contdExample-contd

Several versions of specifications and BMRs

Matters that may better be resolved by being at the site e.g. issues related to media fill validation data

• extent of simulation of interventions• extent of environmental control

e.g. release assay results close to limit, with no mass balance and with no other explanation

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Example-contdExample-contd

Very similar batch to batch results, as in the case of dissolution profiles

Too clean trend or too variable data

Unusual large number of rejects

Unusual large number of repeat analysis (BE)

Unaccounted protocol deviations (BE)

Significantly different pK values compared to literature reported values (BE)

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Thank you, Questions?