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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 Zyl | September 20092 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van ZylHead of Inspections
Prequalification of Medicines Program
World Health OrganizationGeneva
Dr AJ van Zyl | September 20093 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 20094 |
Prequalification
Vision
Mission
Through – evaluation and inspections– Building national capacity for sustainable manufacturing and monitoring of
quality medicines.
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 20095 |
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.
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 20096 |
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.
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 20097 |
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.
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 20098 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 20099 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200910 |
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".
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200911 |
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 Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200912 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200913 |
Expert Committees
Norms and standards
Including GMP for APIs, excipients, FPPs
GCP
HVAC
Water etc
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200914 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200915 |
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).
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200916 |
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).
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200917 |
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).
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200918 |
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).
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200919 |
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 manufacturers
Dr AJ van Zyl | September 200920 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturersIncreasing GMP requirements
Dr AJ van Zyl | September 200921 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200922 |
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)
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200923 |
Scheduling of inspections
HIV/AIDS, Tuberculosis, Malaria, Influenza
SOP – risk management principles
Risk associated with each API determined– Identified possible risks
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200924 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
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
Dr AJ van Zyl | September 200925 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
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)
Dr AJ van Zyl | September 200926 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
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
Dr AJ van Zyl | September 200927 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
CountryMajorObservationsDiseaseManufacturer 2007
India04HIVA
India310HIVM
Korea09HIVS
India323TBS
China010Mal/HIVS
2007
Dr AJ van Zyl | September 200928 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200929 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200930 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
CountryMajorObservationsDiseaseManufacturer 2008
India443TBBIndia11HIV/ MalCChina22MalGChina27MalGIndia233MalIIndia620TBLIndiaInvestigationTBLIndia19TBMIndia10Investigation
(38)HIVM
India28HIVMChinaInvestigationHIVSChina11MalZ
2008
Dr AJ van Zyl | September 200931 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
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
Dr AJ van Zyl | September 200932 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200933 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200934 |
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).
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200935 |
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)
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200936 |
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.
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200937 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
CountryMajorObservationsDiseaseManufacturer2009
India724TBB
India323HIVM
Vietnam615TBS
2009
Dr AJ van Zyl | September 200938 |
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 Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200939 |
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
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200940 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Dr AJ van Zyl | September 200941 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
0
2
4
6
8
10
12
Inspections
2002200420052006200720082009
Number of inspections per year
Dr AJ van Zyl | September 200942 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
0
5
10
15
20
25
30
35
Countries inspected
IndiaChinaSouth KoreaVietnam
Dr AJ van Zyl | September 200943 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
0
50
100
150
200
250
300
2002 2004 2005 2006 2007 2008 2009
Inspections
Total numberobservationsAve numberobservations
Dr AJ van Zyl | September 200944 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
0
5
10
15
20
25
30
35
2002 2004 2005 2006 2007 2008 2009
Number of sites
Ave numberobservations
Dr AJ van Zyl | September 200945 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
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
Dr AJ van Zyl | September 200946 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
0123456789
10
Major deficiencies
CrosscontaminationBatch records
SOPs
MaterialManagementCleaning
Labeling
Dr AJ van Zyl | September 200947 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
0
1
2
3
4
5
6
7
Insepctions
ARVMALTB
2007 - 2009
Dr AJ van Zyl | September 200948 |
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:
Dr AJ van Zyl | September 200949 |
Transparency – Inspection outcomes on the web
Dr AJ van Zyl | September 200950 |
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
Dr AJ van Zyl | September 200951 |
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
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
Dr AJ van Zyl | September 200952 |
Thank you for your attention