Introduction to Medicines Inspections Service Group: GMP inspections of Active Pharmaceutical Ingrédients

and Finished Pharmaceutical Products

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Vimal Sachdeva, Senior inspector, WHO Prequalification Team (PQT),

WHO/HIS/EMP/RHT 20 Avenue Appia, CH - 1211, Geneva 27, Switzerland

e-mail: sachdevav@who.int

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TALKING POINTS

WHO Prequalification Team (PQT) International Norms, Standards & Guidelines PQT Medicines (PQTm) Inspection Process Use of Risk-Based Approach Analysis of Inspection Findings Recommendations Concluding Remarks

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STRUCTURE OF DEPARTMENT OF ESSENTIAL MEDICINES & HEALTH PRODUCT

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STRUCTURE OF THE PREQUALIFICATION TEAM

Prequalification Team

Administrative team

Vaccines Assessment

Medicines Assessment

Diagnostics Assessment Inspections Vector Controls

Coordinator’s office

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https://extranet.who.int/prequal/

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Prequalification Programme: International norms, standards and guidelines used in inspection activities to ensure wide

applicability

USP BP

Ph. Eur. Ph. Int.

Other guidelines e.g. ICH, ISO

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PREQUALIFICATION PROCESS Expression of Interest

Acceptable

Additional information and data

Corrective actions

Compliance

Assessment – Q & E Inspections

Prequalification/Listing Maintenance and monitoring -handling complaints, variations,

requalification

Product dossier +site master file

Screening

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PQTm INSPECTION PROCESS

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INSPECTIONS (GMP) • The evaluation of a medicine for prequalification includes

inspection of FPP and API manufacturing sites, and CROs, i.e. no dossier, no inspection

• Inspections conducted by WHO listed Authorities are taken into account when planning inspections

• WHO reserves the right to inspect all manufacturers and clinical sites listed in a product dossier - to assess compliance with WHO GMP, GCP and GLP

• The need for inspections of API sites (for Prequalification of APIs versus APIMF) and CROs (study specific) are decided on a case by case risk basis.

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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) / WHO listed authorities 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)

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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.

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USE OF INSPECTION REPORTS FROM OTHER NMRAs: SOP 424 DESK REVIEW

Inspectorates whose reports are recognized / WHO listed authorities: √ 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

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USE OF RISK-BASED APPROACH TO INSPECTIONS

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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)

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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

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RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION 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

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RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION 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

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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)

Determine on a case by case basis 15 20 30 High (H)

Determine on a case by case basis 18 24 36 Medium (M)

Determine on a case by case basis 24 36 48 Low (L)

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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

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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 be required

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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.

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ANALYSIS OF INSPECTION FINDINGS-

FINISHED PHARMACEUTICAL PRODUCTS

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WHO-PQT MEDICINES INSPECTIONS

GMP INSPECTIONS: 2016

42%

32%

19%

8%

All inspections 2016

FPP

API

QCL

CRO

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17 7

91

All inspections 2016

FPP

API

QCL

CRO

Total

INITIAL COMPLIANCE STATUS

68%

18%

13%

Initial GMP status FPP 2016

Awaits CAPA

Non Compliant

Compliant 79%

7% 14%

Initial GMP status API 2016

Awaits CAPA

Non Compliant

Compliant

57% 29%

14%

Initial GMP status CROs 2016

Awaits CAPA

Non compliant

Compliant53% 35%

12%

Initial Compliance status QCLs

Awaits CAPA

Non-compliant

Compliant

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INSPECTIONS DEFICIENCIES

0 1 2 3 4 5 6

Cleaning validation

Computerised systems – data integrity

Quality risk management (QRM)

Computerised systems – validation

Design, maintenance and cleaning of equipment

Documentation – batch processing records

Process validation

Production and packaging operations - API

Computerised systems – documentation and control

Equipment qualification/calibration - production

Stability studies

Product quality review (PQR)

Top major deficiencies routine inspections year 2016 API sites

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INSPECTIONS DEFICIENCIES

0 1 2 3 4 5 6 7 8

Data integrityInvestigation of deviationsQuality control - chemical

Product quality reviewContamination &c cross-contamination

Pharmaceutical Quality SystemDesign, maintenance and cleaning of equipment

Documentation controlStability studies

CAPAInvestigation of OOS

Documentation – batch processing records

Equipment qualification/calibration - productionTraining

Process validationQuality risk management (QRM)

Supplier and contractor selection/monitoring/auditSelf-inspection

Materials Management

Major deficiencies (routine, non sterile sites) 2016 FPP sites

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RECOMMENDATIONS FOR RECURRING DEFICIENCIES

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The SOP should include clear objectives of PQR or regular reviews. The objective is not to look into whether batches manufactured during a year were within specification or not, but to verify consistency of the process and identify where there is a need for improvement;

Wisely use data collected for review. It is not for the inspectors, but for you and your company to improve the processes;

It is important to identify trends, interpret data and draw conclusions from the data.

What makes a Good PQR-1

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Control Charts (Shewhart control charts enables manufacturers to determine upper and lower control limits, and identify trend & shift in mean etc) and,

Process Capability Study (to determine whether a process is stable and capable, Cp is used to evaluate variation of the process whereas CpK is used to evaluate centering of process) are recommended to verify process variability, where applicable;

Conclusion should be based on the critical review of data, and should propose recommendations for further improvements.

What makes a Good PQR-2

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Inadequate number of software licences for the number of workstations;

Sharing of common password – not attributable Trial system suitability was not included in the sample set,

not mentioning in analytical report and chromatogram not filed;

Procedure not in place giving details of how manual integration be performed and control over such events;

Audit trail on HPLC systems were disabled without justification;

Audit trials were not reviewed as part of CDS data.

Computerised Systems – Data Integrity-1

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During testing of related substances test, there was shift in the retention time which necessitated re-designation of integration events. Whilst in this case the correction was scientifically justified and could be tracked in the software audit trial, the changes were not discussed and reported in the relevant test record;

Allocation of access rights presented potential conflict of interest. Laboratory supervisor had system administrator rights to the CDS software;

No procedure and practice in place for scientifically sound, timely back-up and archive of the e-data generated by Empower software;

Computerised Systems – Data Integrity-2

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Understand and learn our expectations WHO draft Guidance on Good Data and

Record Management Practices, and other guidelines (e.g. MHRA);

Set realistic and achievable expectations Monitor process capabilities Provide necessary resources Reduce pressure and possible source of error Adoption of Quality Culture within the

company; Design a system to improve detection of

errors/changes; Training of personnel on computerised

systems and review of electronic data.

How to establish and run Good Data Management Practices

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There was no de-duster and metal detector for compression machines; The scoops for transferring granule to the vibratory sieve were in a very

poor condition and had uncleanable recesses in the welding; The blender seal was in a poor condition and staff had been using

sealing tape to contain leakage; Some punches were stored unprotected in a drawer due to inadequate

locations in frame. There was therefore a risk that tips could crash and it was noted that some punches appeared to have attrition damage;

Not all dust collector extracts could be properly adjusted. There was a build-up of residues and the some of the flaps were jammed.

There was no enough water to perform cleaning of equipment No non-return valves were installed in nitrogen supply pipelines to

prevent backflow. There was no integrity test (such as spark test) performed for glass-

lined reactors as part of the initial equipment qualification and preventive maintenance program.

Design, Maintenance and Cleaning of Equipment

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Aim to have closed processes & equipment whenever appropriate.

Always aim to have equipment which minimizes risk of errors, permit effective cleaning and maintenance.

Always ensure parts of the production equipment that come into contact with product are not reactive, additive or absorptive.

Equipment, especially if non-dedicated should be cleaned according to validated cleaning procedures.

Remember, one of the most important processes in a pharmaceutical plant is often assigned to the lowest paid staff…. CLEANING

Reduce Risks of Cross-contamination by better Design of Processes, Maintenance & Cleaning of Equipment

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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

RECOMMENDATIONS

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IN SUMMARY

1. Collaborative and risk management principles are applied to ensure efficient use of available resources i.e. WHO listed authorities 2. WHO-PQ evaluation results show that there are still a lot of poor manufacturing practices out there. 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. Results show that WHO-PQP has made tremendous contribution in this respect.

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Thank you for your attention!