assessment Self

1. 1
GMP issues in Q assessment
Wondiyfraw Worku
Assessor
6th CPH assessment training workshop,
May 2014

2. 2
Outline
 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

3. 3
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 sites
Product
Variations, compliant
handling, quality
surveillance,
Vigilance, safety update
etc..
- Readiness for
commercial mfg
- Conformity to
dossier info
- Dossier data
integrity audit

4. 4
GMP documentation in dossiers- provide
minimum basis for review
 Manufacturing license
issued by national competent authority
usually certifies that a given site has been
authorized to perform the claimed duties
may or may not specify specific products but at
least the authorized dosage form/line
important to establish the basic legal and
regulatory status of the manufacturer

5. 5
GMP documentation- Contd
 GMP certificate
Certifies 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

6. 6
GMP 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)

7. 7
Certificate 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

8. 8
WHO Blue Book recommendation

9. 9
Implementation in PQ
Full 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

10. 10
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

11. 11
Assessor-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

12. 12
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

13. 13
Examples- 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

14. 14
Example-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

15. 15
Example-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

16. 16
Example-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)

17. 17
 Thank you, Questions?