Inspection Technical Update (covering Finished Pharmaceutical … · 2018-10-05 · Finished...

1 Copenhagen, Denmark 24 – 27 September 2018

Inspection Technical Update (covering

Finished Pharmaceutical Products,

Active Pharmaceutical Ingredients and

Contract Research Organizations)

Vimal SACHDEVA

Senior Inspector (Technical officer)

PQ Inspection Services Group

WHO, Geneva

1. PQ inspection risk based process 2. Desk assessment 3. Inspection statistics and top 5 observations 4. WHO requirements:

a. Health based exposure limits

b. GMP for sterile pharmaceutical products

c. Guidance on good practices for Desk Assessment

5. Recommendations 6. Summary

Copenhagen, Denmark 24 – 27 September 2018 2

Topics

• The evaluation of a medicine for prequalification includes inspection of FPP and API manufacturing sites, and CROs, i.e. no dossier, no inspection

• The sites must be GMP (Good Manufacturing Practices), GCP (Good Clinical Practices) or GLP (Good Laboratory Practices) compliant (as appropriate) for a product to be prequalified

• The need for inspections of API sites and Contract research Organizations (CROs) are decided on a case by case risk basis.

• Inspections are conducted during the assessment process, on an on-going basis and in special circumstances.

25/09/2018 3

Inspections

4 Copenhagen, Denmark 18-21 September 2017

Inspection team and scope

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

Data integrity verification – data manipulation, falsification, (validation, stability, clinical, bio-analytical)


WHO PQT-RX Inspection Timelines

First inspection: 6 months from dossier acceptance for assessment or from site confirms it is ready. Routine inspection: 1 – 3 years and ± 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.


Use of inspection reports from other NMRAs: SOP 424 DESK REVIEW Inspectorates whose reports are recognized:

√ PICS member inspectorates √ EU (EDQM + EMA) √ USFDA – 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 FPP or API Is comprehensive and supports the final outcome.

PQP reserves the right to inspect the FPP/API manufacturer – as long as product is active in WHO-PQP. on-going GMP compliance will be confirmed by WHO


Risk based approach to inspections Ref: SOP 401: Inspection Frequency and Scheduling

Inspections are scheduled using a risk based approach, taking into account all known factors that could affect quality, safety and efficacy, including the following:

– results of previous WHO inspections

results of inspections by other National Regulators

– type of APIs, products and dosage form manufactured or - activities performed

recalls or complaints since last inspection

results of product testing

– significant changes within the manufacturer, e.g. changes to key personnel, buildings, equipment, products etc.

– any other relevant information (e.g. variations)


Guide to manufacturer risk classification Ref: SOP 401: Inspection Frequency and Scheduling

RELATIVE RISK CATEGORY PRODUCT TYPE / ACTIVITY

LOW MEDIUM HIGH CRITICAL

Finished Products:

Sterile finished products

Non-sterile finished products

APIs:

Sterile APIs

Non-sterile APIs where there is a special risk (e.g.

isomerism, polymorphism, special risk of harmful

impurities, etc)

Other non-sterile APIs

QC Laboratories

CROs


Risk assessment form for Active pharmaceutical ingredients within the WHO PQ Programme (1 of 2)

API

Manufacturer

Number of Products Present in Product

(Ref. Nos.)

Risk Score Risk = 1 Risk = 2 Parameter

N Y Polymorphism 1

High Low Solubility in water 2

Not complex Complex Synthesis 3

Low risk High Risk Solvents 4

Low risk High Risk Impurities 5

N Y Sterile 6

N Y Fermentation 7


Risk assessment form for Active pharmaceutical ingredients within the WHO PQ Programme (2 of 2)

Risk Score Risk = 1 Risk = 2 Parameter

Low High Toxicity 8

Low risk High Risk Activity/potency 9

Low risk High Risk Particle size 10

Other property consideration 11

Positive Negative Site compliance information

(WHO/EDQM/Other) 12

Total Risk Score

General remarks:

Compliant Outcome Last inspection date

Not Compliant

High

Inspection prioritization Medium

Low


Guide to inspection frequency (In months) Ref: SOP 401: Inspection Frequency and Scheduling

GMP Compliance Rating: RISK

CATEGORY: Unacceptable Acceptable:

Basic Satisfactory Good

Determine on a case by case basis

12 18 24 Critical (C)


15 20 30 High (H)


18 24 36 Medium (M)


24 36 48 Low (L)


Inspection duration guide (ON-SITE DAYS) Ref: SOP 401: Inspection Frequency and Scheduling

RISK

Manufacturer Size L M H C L M H C

Re-inspection Initial Inspection

2 3 3 4 3 3 4 5 Large

2 2 3 3 3 3 4 4 Major

2 2 2 3 2 3 3 4 Standard


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


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 be required


Information put in public domain - available for use by NMRAs: 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.


WHO-PQT Medicines inspections

32

26

3 10

71

All inspections 2017

FPP

API

QCL

CRO

Total



15

11

5

1

32

FPP inspections 2017

FPP routine

FPP Initial

FPP follow up

FPP pre-inspection

Total

13

8

3

2

1 2

1 1

1

FPP inspections per country 2017

India

China

Indonesia

Bangladesh

Kenya

Pakistan

Thailand

Ethiopia

Egypt



15

6

2

3

26

API inspections 2017

APP routine

API Initial

API follow up

API desk review

Total

14 10

1

1

API inspection per country 2017

India

China

Reublic of Korea

Saudi Arabia



0 1 2 3 4 5 6

Investigation of deviations

CAPA

Cleaning validation

Computerised systems – data integrity

Investigation of OOS

Product quality review (PQR)

Contamination &c cross-contamination

Production and packaging operations - FPP

Design, maintenance and cleaning of QCL premises

Quality risk management (QRM)

Management review (MR)

Quality control - chemical

Quality control - microbiological

Materials Management

OSD Routine Major Deficiencies 2017



0 2 4 6 8 10 12 14 16 18

Data integrity


Contamination &c cross-contamination

Documentation control

Change control

Quality risk management (QRM)

Investigation of OOS

Duties of key personnel

Process validation

Investigation of deviations

Utilities - HVAC

Stability studies

Cleaning validation

Design, maintenance and cleaning of equipment

Training

CAPA

Comparison Major deficiencies FPP non sterile routine inspections 2015 (10 sites)-2016 (19 sites) - 2017 (13 sites)

Year 2017

Year 2016

Year 2015



0 1 2 3 4 5 6


Change control(CC)

CAPA

Starting material and packaging component testing

Supplier and contractor selection/monitoring/audit

Computerised systems – documentation and control

Computerised systems – data manipulation

Hygiene and clothing

Process validation

Routine API Major Deficiencies 2017


WHO-PQT Medicines GCP/GLP inspections


Health based exposure limit for shared or multiple product facilities

• The Health Based Exposure Limit (HBEL) is a direct indication of the potential harm to patient using the scientific knowledge to meet one of the primary principles laid out in ICH Q9.

• The HBEL provides a value that meets the intent of ICH Q9’s requirement that the evaluation of risk is based on scientific knowledge that ultimately links to the protection of the patient

• HBEL’s are used to set cleaning limits as well as for assessment of airborne and mechanical transfer


Revision of WHO GMP for sterile pharmaceutical products – A joint EU, PIC/S and WHO project

Key changes from the earlier text (WHO TRS 961, Annex-6) are:

• introduction of new sections: scope, utilities, environmental and process monitoring sections and glossary;

• introduction of the principles of quality risk management to allow for the inclusion of new technologies and innovative processes;

• restructuring to give more logical flow;

• addition of detail to provide further clarity


Guidance on desk assessment

• The performance of on-site inspection of manufacturing, testing and clinical trials resource intensive

25/09/2018 26

Recommendations

Understand requirements and expectations,

Have good quality metrics and monitoring processes,

Keep systems up to date, and perform robust investigations,

Financial incentives don’t reduce errors. Employees must be passionate about eliminating mistakes,

Have pride in whatever work assigned - small or big,

Celebrate success of not doing things twice


Conclusion

1. Collaborative and risk management principles are applied to ensure efficient use of available resources

2. WHO-PQ evaluation results show that there are still a lot of poor manufacturing practices out there. Collaborative effort and skills are needed to ensure access to medicines of assured quality.

3. Most of the sites (FPPs) are located in China and India. Most of the sites (FPPs) do not comply with WHO requirements when inspected first time.

4. Encouraging to see a number of countries from developing world are coming forward.

5. Results show that WHO-PQP has made tremendous contribution in this respect.


Thank you for your attention!

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