WHO GMP and Inspection of API manufacturerspharmexcil.com/data/uploads/WHO_GMP_AJVANZYL.pdf · WHO...

Dr AJ van Zyl | September 20091 |

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

Quality of

Active Pharmaceutical Ingredients

Hotel Taj Krishna, Hyderabad,

India

5 – 7 September 2009



Dr AJ van ZylHead of Inspections

Prequalification of Medicines Program

World Health OrganizationGeneva

[email protected]


In this presentation:

Introduction and history of Prequalification

WHO GMP and ICH Q7

API inspections– SOP for scheduling and risk management– Prequalification of APIs

Observations– 2002 - 2009

Trends and discussion



Prequalification

Vision

Mission

Through – evaluation and inspections– Building national capacity for sustainable manufacturing and monitoring of

quality medicines.



Strategy

Apply unified standards of acceptable quality, safety and efficacy.

Comprehensively evaluate the quality, safety and efficacy of medicinal products, based on information submitted by the manufacturers, and inspection of the corresponding manufacturingand clinical sites.

Prequalify quality control laboratories of pharmaceuticals.

Build the capacity of staff from national regulatory authorities, quality control laboratories, and from manufacturers or other private companies, to ensure medicines quality.



Key output

The list of prequalified medicinal products used for HIV/AIDS, malaria, tuberculosis and for reproductive health produced by the Programme is used principally by United Nations agencies — including UNAIDS and UNICEF — to guide their procurement decisions. But, the list has become a vital tool for any agency or organizationinvolved in bulk purchasing of medicines, be this at country level, or at international level, as demonstrated by the Global Fund to Fight AIDS, Tuberculosis and Malaria.



About the Prequalification Programme

Established in 2001

Managed by the World Health Organization (WHO)

Facilitate access to medicines

Supported by UNAIDS, UNICEF, UNFPA and the World Bank as a concrete contribution to the United Nations priority goal of addressing widespread diseases in countries with limited access to quality medicines.



Any manufacturer can apply - provided the medicines are on the invitation for Expression of Interest (EOI)

Present extensive information on the product (or products) submitted (dossier)

– all ingredients used– finished products e.g. stability, in vivo bioequivalence study

Teams of assessors evaluate all the data presented

Open its manufacturing sites to an inspection teams

If all meet the specified requirements - the product linked to this manufacturing site and company are added to a list hosted by WHO on a public web site



All product and manufacturing site requirements – on the web site

list of prequalified medicines and their manufacturers

Assessment teams include experts from national regulatory authorities

Requalification after five years, or earlier, if needed

Random quality control testing of prequalified medicines that have been supplied to countries

Complaints, investigations, routine inspections



The availability of quality, safety and efficacy of medicines is a major concern of WHO.

WHO mandated:– set norms and standards, – develops guidelines– advises Member States on issues related to quality assurance of medicines in national and

international markets.

WHO assists countries in building national regulatory capacity through networking, training and information sharing.

Work is endorsed and supported by Member States through World Health Assembly resolutions. The Prequalification Programme is part of these activities and mandate.

In 2002 and in 2004, the International Conference of Drug Regulatory Authorities (ICDRA), made up of more than 100 national medicines regulatory authorities, made a formal recommendation that "WHO should continue the Pre-qualification Programme of medicines for priority disease programmes, particularly for HIV/AIDS, malaria and tuberculosis".



Current Invitations for submission of an Expression of Interest

HIV/AIDS - 8th Invitation for EOI [pdf]

Malaria - 7th Invitation for EOI [pdf]

Tuberculosis - 8th Invitation for EOI [pdf]

Reproductive Health - 3rd Invitation for EOI [pdf]

Influenza - 2nd Invitation [pdf]

Zinc - 1st Invitation [pdf]




WHO GMP and ICH Q7






Expert Committees

Norms and standards

Including GMP for APIs, excipients, FPPs

GCP

HVAC

Water etc



Introduction and history

Manufacturers and CROs– WHO norms and standards including Good Manufacturing

Practices (GMP), and Good Clinical Practices (GCP) and Good Laboratory Practices (GLP) as appropriate.

Good Manufacturing Practices (GMP)– APIs– FPPs



Agreed to revise WHO GMP for APIs – accept ICH Q7 principle text

To be tabled EC in October 2009

II. QUALITY MANAGEMENT – A. Principles (2.1).– B. Responsibilities of the Quality Unit(s) (2.2).– C. Responsibility for Production Activities (2.3). – D. Internal Audits (Self Inspection) (2.4).– E. Product Quality Review (2.5).

III. PERSONNEL – A. Personnel Qualifications (3.1).– B. Personnel Hygiene (3.2).– C. Consultants (3.3).



IV. BUILDINGS AND FACILITIES – A. Design and Construction (4.1).– B. Utilities (4.2).– C. Water (4.3).– D. Containment (4.4).– E. Lighting (4.5).– F. Sewage and Refuse (4.6).– G. Sanitation and Maintenance (4.7).

V. PROCESS EQUIPMENT – A. Design and Construction (5.1). – B. Equipment Maintenance and Cleaning (5.2).– C. Calibration (5.3).– D. Computerized Systems (5.4).

VI. DOCUMENTATION AND RECORDS – A. Documentation System and Specifications (6.1).– B. Equipment Cleaning and Use Record (6.2).– C. Records of Raw Materials, Intermediates, API Labeling and Packaging Materials (6.3).– D. Master Production Instructions (Master Production and Control Records) (6.4).– E. Batch Production Records (Batch Production and Control Records) (6.5).– F. Laboratory Control Records (6.6). – G. Batch Production Record Review (6.7).



VII. MATERIALS MANAGEMENT – A. General Controls (7.1).– B. Receipt and Quarantine (7.2).– C. Sampling and Testing of Incoming Production Materials (7.3).– D. Storage (7.4). – E. Re-evaluation (7.5).

VIII. PRODUCTION AND IN-PROCESS CONTROLS – A. Production Operations (8.1).– B. Time Limits (8.2).– C. In-process Sampling and Controls (8.3).– D. Blending Batches of Intermediates or APIs (8.4).– E. Contamination Control (8.5).

IX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES – A. General (9.1).– B. Packaging Materials (9.2).– C. Label Issuance and Control (9.3).– D. Packaging and Labeling Operations (9.4).



X. STORAGE AND DISTRIBUTION – A. Warehousing Procedures (10.1).– B. Distribution Procedures (10.2).

XI. LABORATORY CONTROLS – A. General Controls (11.1).– B. Testing of Intermediates and APIs (11.2).– C. Validation of Analytical Procedures (11.3).– D. Certificates of Analysis (11.4).– E. Stability Monitoring of APIs (11.5).– F. Expiry and Retest Dating (11.6).– G. Reserve/Retention Samples (11.7).

XII. VALIDATION– A. Validation Policy (12.1).– B. Validation Documentation (12.2).– C. Qualification (12.3).– D. Approaches to Process Validation (12.4).– E. Process Validation Program (12.5).– F. Periodic Review of Validated Systems (12.6).– G. Cleaning Validation (12.7).– H. Validation of Analytical Methods (12.8).



XIII. CHANGE CONTROL

XIV. REJECTION AND RE-USE OF MATERIALS – A. Rejection (14.1).– B. Reprocessing (14.2).– C. Reworking (14.3).– D. Recovery of Materials and Solvents (14.4).– E. Returns (14.5).

XV. COMPLAINTS AND RECALLS

XVI. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)

XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS – A. Applicability (17.1).– B. Traceability of Distributed APIs and Intermediates (17.2).– C. Quality Management (17.3).– D. Repackaging, Relabeling, and Holding of APIs and Intermediates (17.4).– E. Stability (17.5). – F. Transfer of Information (17.6). – G. Handling of Complaints and Recalls (17.7).– H. Handling of Returns (17.8).



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



WHO GMP and ICH Q7






Inspections

Done by teams of inspectors

WHO inspector plus appointed from DRA (PICS member)

Invite local inspector (DRA)

Some cases observers and technical advisors

Technical assistance (independent, no conflict of interest)



Scheduling of inspections

HIV/AIDS, Tuberculosis, Malaria, Influenza

SOP – risk management principles

Risk associated with each API determined– Identified possible risks




Guide to Manufacturer Risk Classification

RELATIVE RISK CATEGORY

LOWMEDIUMHIGHCRITICAL

Finished Products:

XSterile finished products

XNon-sterile finished products

APIs:

XSterile APIs

X

Nonsterile APIs where there is a special risk (e.g. isomerism,

polymorphism, special risk of harmful impurities, etc)

XOther nonsterile APIs

XQC Laboratories

XCROs

PRODUCT TYPE / ACTIVITY



Parameters considered:

• Polymorphism• Solubility in water• Route of Synthesis• Solvents used• Impurities• Sterile API• Fermentation• Toxicity• Activity/potency• Particle size• Other properties to be considered• Site compliance information (WHO/EDQM/Other)



0

50

100

150

200

250

300

Observations Inspections

2002 28 12003 0 02004 68 32005 264 92006 240 10

Year Observations Inspections

China: 3India: 20

2002 -2006

2002 (1)

2005 (9)

2006 (10)

2004 (3)

Average 22 – 29 observations per inspection



CountryMajorObservationsDiseaseManufacturer 2007

India04HIVA

India310HIVM

Korea09HIVS

India323TBS

China010Mal/HIVS

2007


Examples of observations of non-compliance in 2007

… a complete centrifugation operation was recorded in the batch manufacturing record (BMR) including, the starting time operation, the end time and all required details although the product had not been centrifuged yet.

… BMR was not completed, although the step was already in progress... No start time of the cooling process … no records of the temperature … for every 30 minute as required in the BMR… equipment logbook no entry…

The SOP “cleaning of centrifuge bag” was incomplete…No evidence of:– dedicated bags– labeling of storage drums

Also for fluid bed bags and to leaf filters bags

Risk of cross contamination



Responsibilities for all the steps of the batch release not appropriately controlled and recorded, although it was a critical part of the batch release procedure

No status e.g. "approved labels" fixed on the drums after batch release

Batch XX 123123 of API XYZ was not released according to the relevant procedure by QA

The qualification of the supplier of ABC (a key starting material) was not completed although material were purchased and used –with insufficient quality control performed




CountryMajorObservationsDiseaseManufacturer 2008

India443TBBIndia11HIV/ MalCChina22MalGChina27MalGIndia233MalIIndia620TBLIndiaInvestigationTBLIndia19TBMIndia10Investigation

(38)HIVM

India28HIVMChinaInvestigationHIVSChina11MalZ

2008



CountryMajorTotal number of

observations

DiseaseNumber of inspections

2008India1082TB4

India1077*HIV3

India244*Mal2

China-InvestigationHIV1

China-60Mal3

* (11) HIV and MalIndia. 9 inspections, 22 Major. China. 4 inspections, 0 Major

2008


Examples of non compliance observations in 2008

Cleaning validation - no justification for the choice of solvent used (The product was at least 10x less soluble in the chosen one opposed to that referred to in literature).

Insufficient cleaning:– Residues of product were observed in the tray drier after the

equipment went through an end of campaign cleaning– Stagnant colored liquid was observed below the ventilation

system in the drier• Even as the cleaning record of the equipment was reviewed – but no

visual inspection done



Materials management was found deficient for the following :

SOP for vendor qualification not implemented.

SOP for vendor qualification was not followed e.g. – samples from consecutive batches were not analysed, – trial batches were not done;– questionnaire was not sent, received and assessed– no audit was performed before the supplier was approved.

The supplier was audited, the outcome was "not satisfactory" – yet no corrective action was proposed or implemented by the supplier which was "approved"

Products were purchased from suppliers not included in the approved vendor list

Distributors were on the list of approved suppliers, without identification of the specific approved and qualified manufacturers



Inappropriate material handling e.g.:

The warehouse temperature was monitored but not controlled. It reached 34°C even as some materials were required to be stored in “a cool and dry place”.

Several drums were marked as sampled and approved, although the drums were still sealed.

Several drums (6) of the same approved batch of ABC were noted with a broken seal – no "sampled" label.

Labels affixed on drums were dirty, torn, and unreadable.

Nitrogen was used to flush XYZ - but there was no assurance of the quality of Nitrogen used (e.g. use of filter, quality control, vendor qualification).



Production

A housekeeper was cleaning the compacting room:– While the operation was ongoing. – Didn't follow the relevant SOP which required all materials to be

covered during the cleaning operations– Had no training in GMP or SOP

Different batches of material - including batches not supposed to be processed – were kept in the area. (The drums were identified by labels on their lids only)



The change control procedure was not implemented. For example:– The specification of the key raw material XYZ was revised. There was no

change control done for this. In addition, the analytical method implemented was not validated.

– Several changes and additions to the master batch manufacturing document were also not covered by appropriate change control.

The SOP on change control:– Didn't include the checks to be performed for a major change whenever

appropriate e.g.:• the impact on stability, • The need for validation or qualification,• impurity profile,• regulatory requirements,

– Was introduced without updating the corresponding forms.




CountryMajorObservationsDiseaseManufacturer2009

India724TBB

India323HIVM

Vietnam615TBS

2009


Examples of major non-compliances (2009)

Quality management– Lack of knowledge and experience,– Deviations not reported

Buildings and facilities– Water systems; HVAC – poor design and controls– equipment cleaning – show product residue after cleaning, equipment cleaned in

outside environment

Documentation– Recording of operations– Batch record not reflecting all steps and full of errors

Materials management– Sampling (number of samples, release date before manufacturing date) – Storage and use - FIFO




WHO GMP and ICH Q7









0

2

4

6

8

10

12

Inspections

2002200420052006200720082009

Number of inspections per year



0

5

10

15

20

25

30

35

Countries inspected

IndiaChinaSouth KoreaVietnam



0

50

100

150

200

250

300

2002 2004 2005 2006 2007 2008 2009

Inspections

Total numberobservationsAve numberobservations



0

5

10

15

20

25

30

35

2002 2004 2005 2006 2007 2008 2009

Number of sites

Ave numberobservations



0

5

10

15

20

25

30

35

40

Ave (total) obs persite

Ave (Major)

TBHIV/AIDSMAL

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



0123456789

10

Major deficiencies

CrosscontaminationBatch records

SOPs

MaterialManagementCleaning

Labeling



0

1

2

3

4

5

6

7

Insepctions

ARVMALTB

2007 - 2009


Transparency: WHO Public Reports (WHOPIRs and WHOPARs)

Transparency: WHO Public Reports (WHOPIRs and WHOPARs)

Aurobindo Pharma Limited, Unit - VIII Name of manufacturer

Survey N° 13Gaddapotharam (Village), IDA- Kazipally, Jinnaram (Mandal),Medak District, Andhra Pradesh- 502319India

Address

Same as abovePostal address

+91 8458 277115Telephone number

+91 8458 277114Fax number

Manufacturing and control of anti-retroviral active ingredients, including but not restricted to the manufacturing process of Zidovudine and Efavirenz..

Summary of activities of manufacturer (e.g. manufacturing, packing). Indicate dosage forms and type of products (e.g. tablets; cephalosporin containing products)

14 & 15 March 2006Date of inspection:

Prequalification ProgrammeProject:

Part 2: Summary and conclusion of the inspection.Summary:


Transparency – Inspection outcomes on the web


Consult the EOI's to see which products are in

the prequalification process

Submit a Site Master File

Prepare a product dossier in accordance with the guideline

Inspection team WHO PQ

Applicant Assessment team WHO PQ

Respond to the questions:Submit additional data

Manufacturers and CRO to take corrective and preventive actions

(CAPA's)

Assessment of additional data

Request additional data

Screen dossier. If accepted, assessment

starts

Submit product dossier and product sample

Request corrective

actions and data

Inspection of clinical site (GCP/GLP)

Inspection of FPP site (WHO

GMP)

Inspection of API site (GMP

ICH Q7)

Review and assess CAPA.

Possible follow-up inspection

Q10. When and where in the prequalification process will inspections be done?The diagram below presents a simplified presentation of the steps in the prequalification process and where inspections will take place.

___________________________________________________________________________If compliance (dossier and inspections) = prequalification (listing of product)

Maintenance (variations)

Assessment

Routine inspections, complaint

investigation etc

Sampling and testing of products -

and verification of supply of prequalified

products

WHOPAR WHOPIR

Non compliance: Notice of concern

Non compliance: Suspension



Summary

Number of inspections between '05 and '09 – 9 to 12. Low number in 2007

Highest number of inspections in India, followed by China

Observations range between 20 and 28 (low number in 2007)

Same number of inspections in areas of HIV, TB and Malaria ('07 –'09)

Lower number of observations in ARV manufacturers, but lower number of major non compliances at malaria manufacturers

Observations relating to material management, SOPs and documents, cleaning


Thank you for your attention

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