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

[email protected]

2

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


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


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Types of inspections


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.


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


Assessment at company level:

Assessment at product level:

❖ Technical Report Series: GMP related

– ………

8

Inspection references


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


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

03/12/2019 10

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

03/12/2019 11

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

03/12/2019 13

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

03/12/2019 14

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

16

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



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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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.


Copenhagen, Denmark 24 – 27 September 2018 18

Designed for failure

Copenhagen, Denmark 2 – 5 December 2019 19

Technical limitations can not be addressed with

procedures


Designed for failure

Design, restricted access barrier system, gowning and

procedures are of paramount importance in aseptic

processes.


Design for failure

Extensive manual human intrusions within grade A

close by the open vials.

What might be expected


Nil excursion or count in cfu in classified areas (aseptic

room) with poor aseptic practices is a red flag.

What is unexpected


False reporting of critical environmental monitoring

test results


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


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.

26Copenhagen, Denmark 18-21 September 2018

an overview of recent updates to requirements for ... · technical report series: gmp related 8...

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