An overview of recent updates to requirements for ... · Technical Report Series: GMP related 8...
Transcript of An overview of recent updates to requirements for ... · Technical Report Series: GMP related 8...
1Copenhagen, Denmark 2 – 5 December 2019
An overview of recent updates to requirements
for inspection of Vaccine manufacturing sites
and observations of common deficiencies
Mustapha Chafai
Technical Officer, Lead inspector
WHO/PQT
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Inspection in PQ
Prequalification Team
Vaccines Medicines Diagnostics Inspection Vector control
Coordinator’s office
Copenhagen, Denmark 2 – 5 December 2019
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IVDs Medicines:
FPP and API
Biological products:
Vaccines
snake anti-venoms
Anti-toxins Diagnostics Vector Control
Laboratories Clinical trial sites
Copenhagen, Denmark 2 – 5 December 2019
Inspection in PQ
Prequalification of vaccines❖ vaccine on the priority list for prequalification
❖ functionality of NRA
❖ 3 aspects of vaccine evaluation:
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Inspection in PQ
dossier review
(quality-clinical)
on-site inspection
final product testing
Copenhagen, Denmark 2 – 5 December 2019
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Types of inspections
Copenhagen, Denmark 2 – 5 December 2019
Pre-approval
Re-assessment
For causePost-
approval
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Objective of GMP inspection
What ?
• GMP is that part of quality assurancewhich ensures that products areconsistently produced and controlled tothe quality standards appropriate totheir intended use and as required bythe marketing authorization, clinical trialor product specification.
How ?
• Effective QMS.
• Adequate facility and equipment.
• Qualified personnel.
• Appropriate quality raw materials.
• Adequate validated operatingprocedures.
• Identity, quality and purity of productsby requiring adequate control ofmanufacturing operations.
• Prevention of contamination, cross-contamination and mix-ups.
Copenhagen, Denmark 2 – 5 December 2019
Quality is built into the product and not only tested into the product.
▪ compliance of production with WHO GMP guidelines
▪ existence of adequate pharmaceutical quality system
▪ existence of adequate labelling and packaging
▪ existence of stability program
▪ compliance with WHO guidelines for production and
quality control (product specific TRS)
▪ conformity with UN specifications for tender (which
reflect the needs of the immunization programmes at
country level)
▪ implementation of Vaccine Vial Monitor (when required)
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Inspection strategy
Copenhagen, Denmark 2 – 5 December 2019
Assessment at company level:
Assessment at product level:
❖ Technical Report Series: GMP related
– ………
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Inspection references
Copenhagen, Denmark 2 – 5 December 2019
GMP Main Principles: TRS 986 annex 2 (2014)
Sterile products: TRS 986 annex 6 under review
Biological products: TRS 999 annex 2 (2016)
QRM: TRS 981 annex 2
Guidelines on validation: TRS 981 annex 2 WHO (2019)
Guidance on good data and record management
practices: WHO TRS No. 996 (2016)
❖ Technical Report Series: product
specific (production and QC)
– ….9
Inspection references
Copenhagen, Denmark 2 – 5 December 2019
Poliomyelitis vaccines: TRS 1016 annex 4 (2019)
Antivenom: WHO TRS 1004 annex 5 (2017)
Ebola vaccines: WHO TRS 1011 annex 2 (2018)
Recombinant human papillomavirus virus-like particle
vaccines: WHO TRS 999 annex 4 (2016)
Recombinant Hepatitis E vaccines: WHO TRS 1016
annex 2 (2019)
Scope
❖ essential GMP elements
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Inspection coverage1. pharmaceutical quality system
2. good manufacturing practices
3. sanitation and hygiene
4. qualification and validation
5. complaints
6. product recalls
7. contract product, analysis and other
activities
8. self-inspection, quality/supplier audit and
approval
9. personnel, training and personal hygiene
10. premises
11. training
12. personnel hygiene
13. equipment
14. material
15. documentation
16. good practices in production
17. good practices in quality control
GMP Main Principles:
TRS 986 annex 2 (2014)
Scope
❖ specific GMP elements
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Inspection coverage1. Introduction
2. Scope
3. Terminology
4. Principles and general considerations
5. Pharmaceutical quality system and
quality risk management
6. Personnel
7. Starting materials
8. Seed lot and cell bank
9. Premises and equipment
10. Containment
11. Clean rooms
12. Production
13. Campaign production
14. Labelling
15. Validation
16. Quality control
17. Documentation
18. Use of Animals
Biological products: TRS
999 annex 2 (2016)
WHO GMP- Evolution (Manufacture of Sterile Medicinal Products) WHO
TRS 986 annex 6 vs. Annex 1 review
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Key changes in summary:
Introduction and emphasis of QRM,
Need to have a documented contamination control strategy,
Based on QRM, design is paramount to risk reduction,
Need to use current technologies (e.g. RABS, Isolators and even
robotics),
Old 70s technologies such as open “grade A” or curtains will not
be acceptable going forward,
Needs to be designed to keep operators outside of the Grade A,
…
Key changes in summary:
Introduction and emphasis of QRM,
Need to have a documented contamination control strategy,
Based on QRM, design is paramount to risk reduction,
Need to use current technologies (e.g. RABS, Isolators and even
robotics),
Old 70s technologies such as open “grade A” or curtains will not
be acceptable going forward,
Needs to be designed to keep operators outside of the Grade A,
…
Annex 1 updated
Draft published 20th December 2017
Published by EMA/WHO and PIC/S
Consultation period closes 20th March 2018
Review and redraft being discussed at present
Annex 1 updated
Draft published 20th December 2017
Published by EMA/WHO and PIC/S
Consultation period closes 20th March 2018
Review and redraft being discussed at present
Copenhagen, Denmark 18-21 September 2018
Scope
specific GAPIII elements
Inspection coverage
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1. Introduction
2. Purpose and scope
3. Background
4. Terminology
5. General consideration
6. Biosafety implementation
within production facility
for IPV
1. Personnel
2. Premises and equipment
3. Documentation and
validation
1. Production
2. Quality control
3. Emergency procedure
4. Risk assessment of new safer
strains of poliovirus
References
Poliomyelitis vaccines:
TRS 1016 annex 4 (2019)
❖ deficiencies
– non compliance with GMP requirements
– origin➢ defective system
➢ failure to comply with system
– classification➢ critical: potential risk/harm to user
➢ major: major deviation from GMP
➢ other: departure from GMP
– risk-based approach for definition and classification
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Inspection outcome
Serious non-compliances can lead to:
✓ notice of concern;✓ notice of suspension;✓ de-listing
GMP compliance lead to Prequalification and access to vaccines
Facility and equipment:
– Inadequate design of:
• Facilityo Segregationo Cross flows
• Filling lineso Extensive manual operations within grade Ao Open doors
• Equipmento Manuafcturing vessel (Not SIP/CIP)o Lyophilisers
✓ Fully manual✓ Not SIP/filter integrity tested batch wise
– Use of disposable without appropriate
qualification and validation
• Leachable, extractibles, integrity, …
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Observations of common deficienciesObservations of common deficiencies
Copenhagen, Denmark 24 – 27 September 2018
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Manufacturing processes and procedures:
Sterile filtration Not in place for filterable product
Not validated
No bioburden
Lyophilisation process
Viral inactivation
Holding storage periods of intermediates, media and buffers
Observations of common deficienciesObservations of common deficiencies
Copenhagen, Denmark 24 – 27 September 2018
Environmental monitoring program:
– Performed during set up of the filling machine
– Risk assessment based
– EM devices of adequate design
– Media containing appropriate neutralizers
– Personnel garments and gloves monitored after
manufacturing operations in grade A/B areas
– Control for detection of the presence of specific micro-
organisms used for production
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Observations of common deficienciesObservations of common deficiencies
Copenhagen, Denmark 24 – 27 September 2018
The good data and record management practices:
Data integrity issues on:
✓ Computerized Systems –
Quality control
✓ Computerized Systems –
Manufacturing and utilities
✓ Microbiology including
Environmental monitoring
… The data on which …
decisions are based should
… be complete as well as
being
attributable, legible,
contemporaneous, original
and accurate, commonly
referred to as
“ALCOA”.
WHO TRS No. 996, 2016.
Observations of common deficienciesObservations of common deficiencies
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Designed for failure
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Technical limitations can not be addressed with
procedures
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Designed for failure
Design, restricted access barrier system, gowning and
procedures are of paramount importance in aseptic
processes.
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Design for failure
Extensive manual human intrusions within grade A
close by the open vials.
What might be expected
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Nil excursion or count in cfu in classified areas (aseptic
room) with poor aseptic practices is a red flag.
What is unexpected
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False reporting of critical environmental monitoring
test results
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Root cause investigation
Data integrity issues are corrosive to
science and trust, once lost, trust cannot
be overnight restored as there are no
CAPAs to fix the trust.
Key home messages
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GMP compliance is not a one-off exercice,
Sustainable over life cycle of the product
Manufacturer knowledge management is
critical
WHO TRS should help clarify expectations and drive
consistency between industry and regulators through
the globe.
The balance of quality is priceless versus quality has a
price must be in favor of the patients and recipients.