| Slide 1 of 18 26 November 2009 Prequalification: Inspection Activities Prequalification Programme: Priority Essential Medicines WHO Prequalification

| Slide 1 of 18 26 November 2009

Prequalification: Inspection Activities

Prequalification Programme: Priority Essential Medicines

Prequalification Programme: Priority Essential Medicines

WHO Prequalification of Generic Medicines approved by Stringent Regulatory Authorities

Presented by

Mr. Deus K Mubangizi

Technical Officer

[email protected]

Organization of prequalification inspections and applied standards



In this presentation:In this presentation:

Inspection activities wrt WHO-PQ Mission, Strategy and Process

Scope of inspection activities: FPPs, APIs, BE/CROs, QCLs

Norms and standards used

Risk-based approach to inspections

Use of inspection reports from other NMRAs

Inspection frequency, duration and scheduling

Inspection process

Classification of deficiencies

Conclusions following an inspection:– Acceptable level of compliance– Conclusion on level of compliance awaits CAPAs– Unacceptable level of compliance

Results and transparency: WHOPIRs and NOCs on website



Inspection Activities and scope wrt PQ Mission & Strategy

Inspection Activities and scope wrt PQ Mission & Strategy

Prequalification Programme aims to make quality priority medicines available for the benefit of those in need through:

– Evaluation of a dossier of product quality, safety and efficacy information

– inspection of• manufacturing sites for FPPs and APIs,• BE studies/CROs,• QCL (National or independent)

– building national capacity for sustainable manufacturing and monitoring of quality medicines.



USPBP

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Prequalification Programme: International norms, standards and guidelines used in inspection activitiesPrequalification Programme: International norms, standards and guidelines used in inspection activities

Other guidelines e.g. ICH, ISO

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Risk based approach to inspections Ref: SOP 401.1: Inspection Frequency and Scheduling

Risk based approach to inspections Ref: SOP 401.1: Inspection Frequency and Scheduling

Inspections are scheduled on a risk basis, 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)



Prequalification Programme: Use of Inspection reports from other NMRAsPrequalification Programme: Use of

Inspection reports from other NMRAs An inspection by the PQP may be omitted when other acceptable evidence of

GMP compliance is provided by the FPP or API manufacturer.

An inspection by another acceptable organization, such as a PIC/S member country, or the US FDA, may be considered in lieu of a PQP inspection when:

– The inspection was conducted within the last 2 years, and The scope of the inspection covered the specific FPP or API in question, and The FPP or API manufacturer submits a copy of the last inspection report for

review by the PQP. (During the review, the inspectors will determine whether the inspection was comprehensive, covered the relevant areas appropriate to the product in question and that the inspection report supports the final outcome in accordance with WHO GMP).

– Irrespective of the above, the PQP reserves the right to inspect any FPP or API manufacturer if considered necessary.

Whether inspected by the PQP or GMP compliance is based on an inspection by another acceptable organization, on-going GMP compliance will be confirmed by WHO.



Guide to Manufacturer Risk ClassificationRef: SOP 401.1: Inspection Frequency and Scheduling

Guide to Manufacturer Risk ClassificationRef: SOP 401.1: Inspection Frequency and Scheduling

PRODUCT TYPE / ACTIVITY

RELATIVE RISK CATEGORY

CRITICALHIGHMEDIUMLOW

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 INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME

(1 of 2)


(1 of 2)

API

Manufacturer

Present in Product(Ref. Nos.)

Number of Products

ParameterRisk = 2Risk = 1Risk Score

1PolymorphismYN

2Solubility in waterLowHigh

3SynthesisComplexNot complex

4SolventsHigh RiskLow risk

5ImpuritiesHigh RiskLow risk

6SterileYN

7FermentationYN




(2 of 2)


(2 of 2)

ParameterRisk = 2Risk = 1Risk Score

8ToxicityHighLow

9Activity/potencyHigh RiskLow risk

10Particle sizeHigh RiskLow risk

11Other property consideration

12Site compliance information (WHO/EDQM/Other)

NegativePositive

Total Risk Score

General remarks:

Last inspection dateOutcomeCompliant

Not Compliant

Inspection prioritization

High

Medium

Low



Guide To Inspection Frequency (in months)Ref: SOP 401.1: Inspection Frequency and Scheduling

Guide To Inspection Frequency (in months)Ref: SOP 401.1: Inspection Frequency and Scheduling

RISKCATEGORY

:

GMP Compliance Rating:

Acceptable:

UnacceptableGoodSatisfactoryBasic

Critical241812Determine on a case by

case basis

High302015Determine on a case by

case basis

Medium362418Determine on a case by

case basis

Low483624Determine on a case by

case basis



Inspection Duration Guide (on-site days)Ref: SOP 401.1: Inspection Frequency and Scheduling

Inspection Duration Guide (on-site days)Ref: SOP 401.1: Inspection Frequency and Scheduling

Manufacturer Size

RISK

CHMLCHML

Initial InspectionRe-inspection

Large54334332

Major44333322

Standard43323222



Inspection SchedulingInspection Scheduling

Initial inspections: are scheduled at a suitable time to avoid delaying product prequalification (max 180 days after dossier accepted).

Routine re-inspections: are scheduled so that the inspection is conducted within the period 3 months before and 3 months after, the due date.

– The due date for re-inspection is determined immediately after each inspection based on manufacturer risk classification and GMP compliance rating.

– Maximum validity of compliance status – 3 years

Special inspections: (e.g. to investigate a complaint or reasons for product failure) may be conducted at any time.

Follow-up inspections: (to close out deficiencies from the last inspection) may be conducted if deemed necessary.

– If a special or follow-up inspection is conducted, the timing of the next routine re-inspection is re-determined on a case by case basis.



Prequalification: Inspection ProcessesPrequalification: Inspection Processes

By a team of qualified and experienced inspectorsWHO representative (qualified inspector)

Inspector from well-established inspectorate (Pharmaceutical Inspection Cooperation Scheme countries – PIC/S)

National inspector/s invited to be part of the team but have NO decision making power (different GMP standards, potential conflict of interest)

Observer from recipient/developing countries (nominated by DRA of the country)

Scope: Compliance with guidelines: GMP, GCP, GLPData verification – data manipulation, falsification, (validation,

stability, clinical, bioanalytical) Quality control (QC, BAL, NQCL, IQCL)



Definition and classification of deficiencies 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– Major Observation– Minor or Other Observation



Further considerations for classificationFurther considerations for classification

1. Classification of an observation is based on the assessed risk level and may vary depending on the nature of products manufactured, e.g. in some circumstances an example of an "other" deficiency may be categorized as "major".

2. A deficiency that was reported at a previous inspection and not corrected may be reported in a higher classification.

3. One-off minor lapses or less significant issues are usually not formally reported, but are brought to the attention of the manufacturer during the inspection.



Conclusion following an inspection:Conclusion following an inspection:

When there are "other" observations only:– considered to be operating at an acceptable level of compliance with WHO GxP.– 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 GxP 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, GCP, GLP guidelines.– Another inspection will be required



Prequalification Programme:Transparency - WHOPIRs and NOCs

Prequalification Programme:Transparency - 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.



ConclusionsConclusions

For PQP of generics approved by SRA, we shall largely rely on positive inspection outcome by SRAs - but reserve the right to inspect

Risk management principles are applied when:– scheduling inspections– conducting inspections– closing out inspections

Inspections are conducted according to written SOPs:– No bias or subjectivity – each deficiency is referenced to a guideline,

standard or norm.– No surprises in the report - Feedback is given every day and at the end

of the inspection.

Participation of NRAs in providing co-inspectors and observers is good for:

– Tapping into international skills– Ensuring transparency Facilitating ownership – possible faster national

penetration– Contributing to capacity building

Documents

| Slide 1 of 18 26 November 2009 Prequalification: Inspection Activities Prequalification Programme: Priority Essential Medicines WHO Prequalification