WHO-PQP GMP Inspections: Updates · Acting Head of Inspections . World Health Organisation . EMP/QSM/PQM . [email protected]. WHO-PQP GMP Inspections: ... • Life-cycle approach

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

Joint 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 • Joint 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 QCLAverage all

observations 15.6 19.2 18.7 10.6 14.1

Average critical 0.4 0.2 0.5 0.7 0.7Average Major 3.9 3.8 4.7 3.0 3.1

0

500

1000

1500

2000

2500

3000

All FPP API CRO QCLTotal Observations 2885 1440 1218 329 198Critical Observations 82 15 34 23 10Major 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 16

http://apps.who.int/prequal/assessment_inspect/info_inspection.htm#2/

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HOW TO CONTACT US

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