WHO Prequalification of Medicines Programme

Deusdedit K. Mubangizi
Technical Officer
Acting Head of Inspections
World Health Organisation
EMP/QSM/PQM
[email protected]
WHO-PQP GMP Inspections: Updates
JOINT UNICEF, UNFPA & WHO MEETING WITH MANUFACTURERS AND
SUPPLIERS OF DIAGNOSTIC PRODUCTS, FINISHED PHARMACEUTICAL
PRODUCTS AND ACTIVE PHARMACEUTICAL INGREDIENTS
23 25 September 2013, Copenhagen, Denmark
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WHO-PQP GMP Inspections: Updates
In this presentation:
Introduce the team
Enhanced focus on international collaboration
Use of SRA-PIC/S inspection reports
New guidelines: QRM, validation, hold time
Inspection timelines and statistics
Current trends and press headlines: worrying
Towards harmonization and consistency among
inspectors and TA experts
How to contact WHO-PQP inspection team
The inspection Team
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Deus Mubangizi
Ag. Head of Inspections
Stephanie Croft
CROs/CRM
Vimal Sachdeva
Training/FPP/RH
Xingyu Chen
APIs
Ian Thrussell
Expert Inspector
Iveta Streipa-Naumane
QMS/Complaints/QCLs

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Prequalification: Inspection Processes
By a team of qualified and experienced inspectors
WHO representative (qualified inspector)
Inspector from well-established inspectorate (Pharmaceutical
Inspection Cooperation Scheme countries PIC/S)
National inspector/s invited to be part and observe the
inspection
Observer from recipient/developing countries (nominated by
DRA of the country)
Scope:
Compliance with guidelines:
GMP for API and FPP sites,
GCP for CROs,
GLP for FPP/API factory QCL, CRO-BAL, NQCL, IQCL
Compliance with the dossier and commitments:
Data verification data manipulation, falsification, (validation, stability, clinical,
bioanalytical)
International Collaboration has
been enhanced
Share the workload and
promote avoiding duplicative
inspections.
Facilitation of harmonization
through joint inspections and
sharing of outcomes.
Capacity building of NMRAs
inspectors.
Facilitating use of WHO-PQ
inspection results in national
regulatory environment for
information and decision
making.

Mainly EU Inspectorates
EAC NMRAs
J oint
Inspections
PICS Inspectorates
Independent Experts
Co-
inspectors
Host country inspectorates
Recipient country NMRAs
Observers
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USFDA, EMA, TGA, WHO
EU NCAs (UK, FR, IT, GER, IR)
EDQM
International
API
inspection
Collaboration
Teleconferences
J oint investigations
Coordinated actions,
press releases
Collaboration
in handling
GMP related
crises
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Prequalification Programme: Use of
Inspection reports from other NMRAs
Inspectorates whose reports are used:
PICS member inspectorates
EU (EDQM + EMA)
USFDA new member of PICS
What GMP evidence to submit:
SMF Up-to-date
Inspection report - conducted NMT 2 years
+CAPAs to deficiencies +final conclusion
Product Quality Review not more than 1 year old
Review of the report:
scope covered the specific API, FPP or BE study
Is comprehensive and supports the final outcome.
PQP reserves the right to inspect the manufacturer as long as
product is active in WHO-PQP.
on-going GMP compliance will be confirmed by WHO-PQ
New Guidelines: approved or under discussion
More focus on Pharmaceutical industry than HACCP
Applies to MRA and Industry
Facilitates science-based decision-making
Resources can be focused on risks to patients
Restrictive and unnecessary practices can be avoided
The level of effort, formality and documentation of the
QRM process should be commensurate with the level
of risk
Quality Risk
Management
WHO-TRS981-Annex2
For materials for further processing (dispensed
materials, intermediate materials and bulk materials)
Guidance on:
max storage periods with no hold time data
design & number of batches for hold time studies
stages & tests for hold time studies
Draft Guidance on
hold-time studies
Apply quality risk management and quality by design
principles
Requires thorough knowledge of product and process
development studies; previous manufacturing
experience; and quality risk management (QRM)
principles.
Life-cycle approach links product and process
development, validation of the commercial
manufacturing process and maintenance of the process
during routine commercial production
Draft on Non-Sterile
Process Validation
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Risk-based approach in:
definition and classification of deficiencies
Deficiencies are descriptions of non-compliance
with GMP requirements.
A distinction is made between deficiencies as a
result of: -
a defective system or,
failure to comply with the system.
Deficiencies may be classified as:
Critical Observation potential risk harm to the user
Major Observation major deviation from GMP/GCP
Minor or Other Observation departure from good
practice
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Risk-based approach in:
Conclusion following an inspection
When there are " other" observations only:
considered to be operating at an acceptable level of compliance with WHO
GMP.
The manufacturer is expected to provide CAPAs.
CAPAs are evaluation and followed up during the next routine inspection.

When the are " other" and a few " major" observations:
compliance with WHO GMP is made after the CAPAs have been assessed.
CAPAs for majors to include documented evidence of completion.
CAPAs paper evaluated an on-site follow up inspection.

When there are " critical" or several " major" observations:
considered to be operating at an unacceptable level of compliance with
WHO GMP guidelines.
Another inspection will most likely be required
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Information put in public domain - for use by
NMRAs and Procurers: WHOPIRs and NOCs
These are published in response to the WHA Resolution WHA57.14
of 22 May 2004, which requested WHO, among other actions:
"3. (4) to ensure that the prequalification review process and the results
of inspection and assessment reports of the listed products, aside from
proprietary and confidential information, are made publicly available;"
A WHO Public Inspection Report (WHOPIR) reflects a positive
outcome after an inspection
A Notice of Concern (NOC) is a letter reflecting areas of concern
where the non-compliances require urgent attention and corrective
action by the manufacturer or research organization.
Update on timelines and statistics
First inspection: 6 months from dossier acceptance for
assessment or from site confirms it is ready.
Routine inspection: 3 months from due date.
Notification: 1 2 months before inspection.
Onsite days: 3 5 days.
Report: 30 days from last date of inspection.
CAPAs: 30 days from receipt of report (max 2 rounds,
comprehensive, on CDs and not hard copies)
Closing of inspection: 6 months from inspection.
Follow-up inspection: 6 months from inspection


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Inspections performed 2011 - 2012 (N=185)
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75
65
31
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FPP
API
CRO
QCL
Analysis of inspection of observations
Total number of Observations
Average number of observations
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0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
All FPP API CRO QCL
Average all
observations
15.6 19.2 18.7 10.6 14.1
Average critical 0.4 0.2 0.5 0.7 0.7
Average Major 3.9 3.8 4.7 3.0 3.1
0
500
1000
1500
2000
2500
3000
All FPP API CRO QCL
Total Observations 2885 1440 1218 329 198
Critical Observations 82 15 34 23 10
Major Observations 727 246 304 93 43
Worrying Trends
Press is awash with NOCs, warning letters, import
alerts, statements of non-compliance, complaints,
recalls, etc.
Data integrity and falsification.
Show-case and shadow industries.
Knee-jerk responses to inspection observations.
Many Awaits CAPAs on routine inspection:
poor maintenance of quality systems
work hard to pass first inspection and then go on holiday
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Meeting to harmonise interpretation
of GMP requirements: May 2013
Attended by:
Inspectors and co-inspectors
Experts for Technical assistance
Topics Discussed:
Product quality review (PQR)
Deviations, out of specifications and investigation practices
Risk management and Root cause analysis
Heating, ventilation and air conditioning (HVAC) system and
GMP for hazardous substances
Outcome:
Questions and Answers still under finalisation.
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Selected GMP topics for
manufacturers and GMP inspectors
Nairobi, May 9-12, 2011
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http://apps.who.int/prequal/assessment_inspect/info_inspection.htm#2/
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HOW TO CONTACT US