| Slide 1 of 43 29 - 30 March 2010, Beijing, China WHO GMP and API Inspections QUALITY OF...

| Slide 1 of 43 29 - 30 March 2010, Beijing, China

WHO GMP and API Inspections

QUALITY OF PHARMACEUTICAL INGREDIENTS

QUALITY OF PHARMACEUTICAL INGREDIENTS

WHO Prequalification Programme: Priority Essential Medicines


Presented by

Mr. Deus K Mubangizi

Technical Officer

[email protected]



In this presentation:In this presentation:

WHO-PQ: Inspection activities

WHO-PQ: Norms and standards

WHO-GMP for APIs versus ICH Q7A

Key elements of ICH Q7A

WHO-PQ API inspections: Observed trends and deficiencies

Conclusions



WHO Prequalification: Inspection activitiesWHO Prequalification: Inspection activities

Prequalification

WHO route SRA* route

Dossier Q/E GMP/GCP Innovators Generics

Simplified procedurePQPQ

PQ

*Stringent Regulatory Authority

APIs,FPPs

BE/CROs



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 and observe the inspection

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

Scope: Compliance with guidelines: GMP (ICHQ7), GCP, GLP

Data verification – data manipulation, falsification, (validation, stability, clinical, bioanalytical)

Quality control (QC, BAL, NQCL, IQCL)



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/USFDA/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

Critical (C)241812Determine on a case by

case basis

High (H)302015Determine on a case by

case basis

Medium (M)362418Determine on a case by

case basis

Low (L)483624Determine 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



Risk-based approach in:definition and classification of deficiencies

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– Minor or Other Observation – departure from good practice



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 API 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.



Risk-based approach in:Conclusion following an inspection

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/ICHQ7.– 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/ICHQ7 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/ICHQ7 guidelines.– Another inspection will be required



Transparency: Information put in public domain - WHOPIRs and NOCs

Transparency: Information put in public domain - 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.



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 (Report + CAPAs) is provided by the FPP or API manufacturer.

An inspection by another acceptable organization, such as a PIC/S member country, or US FDA or EU, 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 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 API manufacturer if considered necessary (specific product issues).

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 (also using update information from other NMRAs).



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

ensure wide applicability

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

ensure wide applicability Quality Assurance of pharmaceuticals. A compendium

of guidelines and related materials. Vol.2, GMP and inspection. WHO, Geneva, 2007.http://www.who.int/medicines/areas/quality_safety/

quality_assurance/production/en/index.html

ICH Q7: GMP Guide for Active Pharmaceutical Ingredients, International Conference on Harmonization.http://www.ich.org/cache/compo/276-254-1.html

WHO GMP: water for pharmaceutical use. 39th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 3. http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf



Prequalification Programme: norms, standards and guidelines used…


WHO guidelines for sampling of pharmaceutical products and related materials. 39th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 4.

http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf

Supplementary GMP guidelines for HVAC systems. 40th Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 2.


Supplementary GMP guidelines: validation. 40th Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 4.


Good Practices for National Pharmaceutical Control Laboratories. 36th Report. Geneva, WHO, 2002 (WHO TRS, No. 902), Annex 3.

http://whqlibdoc.who.int/trs/WHO_TRS_902.pdf#page=37

USPBP

Ph. Eur.Ph. Int.

Other guidelines

e.g. ICH, ISO





WHO Expert Committee has revised WHO GMP for APIs at its meeting in October 2009 – adopted ICH Q7 principles.

Final editing going on but numbering of sections essentially similar to ICH Q7:

– ICH Q7 is used in the discussions that follow.



WHO GMP and ICH Q7WHO GMP and ICH Q7

II. QUALITY MANAGEMENT

III. PERSONNEL

IV. BUILDINGS AND FACILITIES

V. PROCESS EQUIPMENT

VI. DOCUMENTATION AND RECORDS

VII. MATERIALS MANAGEMENT

VIII. PRODUCTION AND IN-PROCESS CONTROLS

IX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES

X. STORAGE AND DISTRIBUTION

XI. LABORATORY CONTROLS

XII. VALIDATION

XIII. CHANGE CONTROL

XIV. REJECTION AND RE-USE OF MATERIALS

XV. COMPLAINTS AND RECALLS

XVI. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)

XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS



WHO GMP for APIs / ICH Q7Key definitions:

WHO GMP for APIs / ICH Q7Key definitions:

ICH Q7A– API starting material (API SM): a raw material, intermediate or

an API used in the production of an API and incorporated as a significant structural fragment into the structure of the API. API SM can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API SM are normally of defined chemical properties and structure.

– Intermediate: A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API.



From what point does ICHQ7A start to be applied ?

– “ICH Q7A applies from the point at which production of the API begins”.

– Some indications are provided in Table 1 of ICH Q7A.• For synthetic process, this corresponds to the

introduction of the API starting material into the process;

• For other processes, on a case by case basis.

ICH Q7A : IntroductionICH Q7A : Introduction



WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturersIncreasing GMP requirements



Main issue : How to define the API SM ?Main issue : How to define the API SM ?

Only flow chart

GMPs do not apply

Detailed description

GMPs apply

Competent

AuthoritiesIndustry

API SM

Photo : Internet

RM (solvent, catalyst, reagent, filtration aid, decolorizing agent, chromatography phase, etc.)

C, H, O, N SM(Intermediates)n

Active substance crude

Active substance (pure)



Application of ICHQ7 Application of ICHQ7

Companies should decide at which point ICH Q7A applies for their processes and should have documentation to support it. GMP applies from the declared and approved (API) SM in the registered file.

Stringency of GMP in API manufacturing increases from early steps to final steps

Advanced intermediates and crude APIs outsourced should be manufactured in compliance with GMP

– This means that these “late intermediate and crude API” manufacturers should be considered as contract manufacturers (Q7A chapter 16 applicable).

Sterilisation and aspetic processing should be performed according to GMP related to Sterile pharmaceutical products.



Q7A does not apply to :– vaccines, whole cells, whole blood and plasma– blood and plasma derivatives (plasma fractionation)

– gene therapy APIs– bulk-packaged medicinal products– medical gases and manufacturing/control aspects specific to

radiopharmaceuticals.

Q7A does not cover :– Safety aspects for the personnel engaged in the manufacture – and environmental issues.

ICHQ7A: ScopeICHQ7A: Scope



Quality management (Chapter 2)

– Responsibilities of the Quality Unit – Sections 2.22-1 to 2.22-15

– Tools for surveillance, monitoring and continuous improvement:– Internal audits/Self inspection (section 2.4) – Product Quality review (section 2.5)– Complaints, returns and recall (sections 14.5 and 15)– Change control (section 13)

Review of some ICHQ7A’s conceptsReview of some ICHQ7A’s concepts



ChangeChange control– Raw materials, specifications,

analytical methods, facilities, support systems, equipment (including computerized systems), processing steps, labelling and packaging materials

– That can impact the quality of the API

Change controcontroll– Proposal drafted, reviewed and

approved by the appropriate organisational unit

– Change reviewed and approved by QU

– Classification and impact assessment

– Evaluation and monitoring + Notification




– Documentation (section 6)• Specifications for raw materials, intermediates, APIs, labelling and packaging

materials (ICH 6.17)• Retention period specified for production, control and distribution records

(ICH 6.13)– Contract manufacturers (section 16)

• Contract manufacturers should comply with Annex 18 (ICH 16.10)• A contract or a formal agreement should exist between the contract acceptor

and the contract giver (ICH 16.12).


– Personnel (section 3)• Appropriate and regular GMP training

periodically assessed (ICH 3.12)



Facilities,equipment and utilities system

– Facilities designed to prevent mix-ups and contamination

– Precautions implemented based on a risk assessment

– Equipment cleaning methodology and intervals appropriate to prevent build-up and carry-over of contaminants (degradants)


Critical operation with prolonged exposure to

the environment

Non critical operation with prolonged exposure to the

environment

Non critical or critical operation in a closed

equipment



HVAC systems (section 4.2)– Adequate ventilation, air filtration and exhaust

systems should be provided where appropriate (ICH 4.21, 4.22)

– Qualification and appropriate monitoring and operating range limits in place (ICH 4.20)

Water (section 4.3)– WHO potable water quality as a minimum

(ICH 4.31)– Water for final isolation and purification steps

for API for sterile products: test for microbial counts, objectionable counts and endotoxins.




Material management (section 7.)– At least, identity testing of each batch on a

sample representative of the batch (ICH 7.30)

– Reduced testing for approved/validated suppliers (ICH 7.31)

• Past quality history• Full analysis at least on three batches before

starting reduced-testing• Reliability of the CoA checked at regular intervals• A documented supplier audit is not required but

currently performed in the case of critical material by API manufacturers.

– Precaution for bulk deliveries in non-dedicated tankers (ICH 7.22)




Production (section 8)– Critical operations should be witnessed or

subjected to an equivalent control (ICH 8.12)– Deviations should be documented, explained

and/or investigated (ICH8.15)– Process time limits should be respected

(ICH8.20)– Conditions and duration of storage of

intermediates (ICH 8.21)– In-process sampling and controls (ICH 8.3)

• approved written procedures, avoid risk of cross contamination during sampling, sample integrity





Production– Blending operations (section

8.4)• Only batches meeting

established specifications• Expiry or retest date of the

blended batch based on the manufacturing date of the oldest batch included.

• Should be controlled and documented – traceability

• Validation for homogeneity following blending

OOS batches blended with

others to meet specifications

1 .Blending small batches to ↑se batch size

2 .Blending tailings

APIs for OSDs/ Suspensions

1 .Particle size distribution

2 .Bulk density3 .Tap density



Reprocessing (s. 14.2)– Repeating a step of the established

manufacturing process• Crystallization, distillation, filtration,

chromatography, milling, etc• Continuation to completes process after

IPQC in not reprocessing• Introducing unreacted material into

reaction is reprocessing– Included in the standard

manufacturing process if reprocessing used for a majority batches

Reworking (section 14.3)– Reason for non conformance

determined prior to any reworking– Involves a “treatment” different from

the established one• Recrystallization with a a different

solvent– Reworked batches to be subjected to

appropriate evaluation, testing ± stability testing

• Concurrent validation• Should have comparable impurity profile


Reprocessing or reworking for intermediates or APIs which do not conform to standards or specifications




Recovery of Materials and solvents– Reactants, intermediates or APIs may

be recovered from mother liquor or filtrates.

– Must use approved procedures and specifications.

– Recovered solvents may be reused in same process or in different process if confirmed to meet appropriate standards.

– Fresh and recovered solvents and reagents if confirmed their adequacy

1 .Approved procedures

2 .Suitable specs3 .Adequate testing5 .Use documented

1 .No approved procedures2 .Specs – carry over impurities

3 .Not adequately tested4 .Use not documented



Validation (section 12)– Applies to

• Analytical methods • Process • Cleaning• Computerized systems

– Validate operations critical to the quality and purity of the API

– Periodic review of validated systems


1. Prospective validation (≥3 consec batches):• complete before commercial distribution

2. Current validation (≥3 consec batches):• For API produced infrequently• Batches may be released for commercial

distribution after monitoring and testing3. Retrospective Validation (10 - 30 batches):

• Only in exceptional cases• For well established process• All batches, including failed ones



ICHQ7A : ConclusionICHQ7A : Conclusion

– ICH Q7A is a “What to do document” – “How to do” is sometimes described– Flexibility

– If necessary, when appropriate …– “Should” even if it could be interpreted mostly as “must”

– Emphasis on the risks of– Contamination and cross contamination– Mix-ups, build-up and carry-over of degradants– Lack of traceability



WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers



WHO GMP and Inspection of API manufacturers2002 - 2009

WHO GMP and Inspection of API manufacturers2002 - 2009

Vietnam (1)

S. Korea (1)

China (9)

India (34)

2002 to 2009




Most API inspections were conducted in India followed by China.

The number of China API sites inspected has increased of recent

0

5

10

15

20

25

30

35

Countries inspected

India

China

South Korea

Vietnam




0

2

4

6

8

10

12

Inspections

2002

2004

2005

2006

2007

2008

2009

API inspections have been increasing over time.

Most API inspections were conducted in 2005, 2006, 2008 and 2009.

Number of inspections per year




0

5

10

15

20

25

30

35

40

Ave (total) obs persite

Ave (Major)

TB

HIV/AIDS

MAL

Most observations were observed in sites for TB APIs and these were the sites with most of the major observations.

Although sites for Malaria APIs had equally high number of observations, most of them were not major.

The sites for HIV APIs were generally in a reasonable shape.

2007 -2009. Inspections (disease areas) and number of observations




The most frequently found deficiencies were:

– Material management– SOPs– Cleaning

Others included:– Batch records– Labelling– Cross contamination

0

1

2

3

4

5

6

7

8

9

10

Major deficiencies

Crosscontamination

Batch records

SOPs

MaterialManagement

Cleaning

Labeling



Summary and ConclusionsSummary and Conclusions Inspection of API sites is part of the WHO-PQ procedures

International norms and standards are used during WHO-PQ inspections

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

Inspections of API sites has increased over time. Most of the API sites inspected by WHO-PQ are in India and China

Deficiencies have been observed mainly in:– Material management, SOPs, Cleaning, Batch records, Labelling,

Cross contamination

Most deficiencies have been observed on sites for TB and Malaria APIs.

谢谢！

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