Slide 1 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
WHO Prequalification Programme: Priority Essential Medicines
WHO GMP and API InspectionsMr. Deus K Mubangizi
Technical [email protected]
Slide 2 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
In this presentation:
• WHO-PQ API inspections
– Norms, standards, procedures and process
– Risk-based approach and transparency
• WHO-GMP for APIs: review of some concepts
• WHO-PQ API inspections: Observed trends and review of some deficiencies
• Summary and conclusions
Slide 3 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Inspection of API manufacturing sites:
put in perspective.
• Chris Joneckis, Ph.D., senior adviser for chemistry, manufacturing and controls (CMC) issues, noted that:– "quality, safety and effectiveness must be designed and built
into the product. Quality cannot be inspected or tested into the finished product."
• http://www.entrepreneur.com/tradejournals/article/154459079.html
• Ensuring the quality of the API greatly contributes to achieving the objective of building the quality, safety and efficacy into the product. – Inspection of API manufacturing sites is to assess compliance
with Good Manufacturing Practices, and to verify data submitted in product dossiers and APIMFs.
Slide 4 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
WHO 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
Slide 5 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Prequalification 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).
Slide 6 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Prequalification: Inspection Processes
� By a team of qualified and experienced inspectors
�WHO 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
� WHO GMP for APIs: Annex 2, WHO TRS957, 2010: http://whqlibdoc.who.int/trs/WHO_TRS_957_eng.pdf#page=144
�Data verification – data manipulation, falsification, (validation,
stability, clinical, bioanalytical)
� Quality control (QC, BAL, NQCL, IQCL)
Slide 7 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Guide to Manufacturer Risk ClassificationRef: SOP 401.1: Inspection Frequency and Scheduling
�CROs
�QC Laboratories
�Other non-sterile APIs
�
Non-sterile APIs where there is a special risk (e.g. isomerism, polymorphism, special risk of harmful impurities, etc)
�Sterile APIs
APIs:
�Non-sterile finished products
�Sterile finished products
Finished Products:
LOWMEDIUMHIGHCRITICAL
RELATIVE RISK CATEGORY
PRODUCT TYPE / ACTIVITY
Slide 8 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN
THE WHO PREQUALIFICATION PROGRAMME
(1 of 2)
Number of
Products
Present in
Product
(Ref. Nos.)
Manufacturer
API
NYFermentation7
NYSterile6
Low riskHigh RiskImpurities5
Low riskHigh RiskSolvents4
Not complexComplexSynthesis3
HighLowSolubility in water2
NYPolymorphism1
Risk ScoreRisk = 1Risk = 2Parameter
Slide 9 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN
THE WHO PREQUALIFICATION PROGRAMME
(2 of 2)
Total Risk Score
PositiveNegative
Site compliance information
(WHO/EDQM/USFDA/Oth
er)
12
Other property consideration11
Low riskHigh RiskParticle size10
Low riskHigh RiskActivity/potency9
LowHighToxicity8
Risk ScoreRisk = 1Risk = 2Parameter
Low
Medium
High
Inspection prioritization
Not
Compliant
CompliantOutcomeLast inspection date
General remarks:
Slide 10 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Guide To Inspection Frequency (in months)Ref: SOP 401.1: Inspection Frequency and Scheduling
Determine on a case by case basis
243648Low (L)
Determine on a case by case basis
182436Medium
(M)
Determine on a case by case basis
152030High (H)
Determine on a case by case basis
121824Critical (C)
BasicSatisfacto
ryGood
Unacceptable
Acceptable:
GMP Compliance Rating:RISK
CATEGORY:
Slide 11 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Inspection Duration Guide (on-site days)Ref: SOP 401.1: Inspection Frequency and Scheduling
22232334Standard
22333344Major
23343345Large
Re-inspectionInitial
Inspection
LMHCLMHC
RISKManufacturer
Size
Slide 12 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
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
Slide 13 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Further 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.
Slide 14 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
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 for APIs.
– 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 for APIs 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 for APIs guidelines.
– Another inspection will be required
Slide 15 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
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.
Slide 16 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
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/q
uality_assurance/production/en/index.html
• WHO GMP for APIs: Annex 2, WHO TRS957, 2010:http://whqlibdoc.who.int/trs/WHO_TRS_957_eng.pdf#page=144
• 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
Slide 17 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
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.
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf
• Supplementary GMP guidelines: validation. 40th
Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 4.
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf
• WHO Good Practices for Pharmaceutical Quality Control Laboratories. 44th Report. Geneva, WHO, 2010 (WHO TRS, No. 957), Annex 1.
http://whqlibdoc.who.int/trs/WHO_TRS_957_eng.pdf#page=95
USPBP
Ph. Eur.Ph. Int.
Other guidelines
e.g. ICH, ISO
Slide 18 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
WHO GMP for APIs = ICH Q7same numbering of sections
WHO GMP for APIs = ICH Q7same numbering of sections
• I. INTRODUCTION
• 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
Slide 19 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
WHO GMP for APIs: Key definitions
• 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.
Slide 20 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
• From what point does WHO GMP for APIs start to be applied ?– WHO GMP for APIs applies from the point at which
production of the API begins – the point at which the API starting material is introduced in the API manufacturing process”.
– Some indications are provided in Table 1 of WHO GMP for APIs.• 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.
WHO GMP for APIs: Introduction
Slide 21 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Increasing GMP requirements
Slide 22 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Main issue : How to define the API SM ?
Only flow chart
GMPs do not
apply
Detailed description
GMPs apply
Competent
Authorities
Industry
API SM
RM (solvent, catalyst, reagent, filtration aid,
decolorizing agent, chromatography phase, etc.)
C, H, O, N SM (Intermediates)n Active substance
crude
Active substance
(pure)
Slide 23 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Application of WHO GMP for APIs
• Companies should decide at which point WHO GMP for APIs 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.
Slide 24 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Designation of API starting material
• API starting material:
– Is incorporated as a significant structural fragment into
the structure of the API.
– it is obtained by commonly known procedures.
– it is a compound whose name, chemical structure,
chemical and physical characteristics, properties and
impurity profile are well defined
– it is commercially available
– at least two synthetic steps are required between the
starting material and the API.
Slide 25 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Incorporated as a significant structural fragment into the structure of the API.
• Example of Zidovudine: β-thymidine versus
sodium azide
β-thymidine sodium azide Zidovudine
SM??
Slide 26 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
At least two synthetic steps between the starting material and the API:For Levofloxacin: Which one is incorporated as a significant structural fragment
into the structure of the API
SM??
2 synthesis steps 2 synthesis steps Levofloxacin
Slide 27 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
At least two synthetic steps between the starting material and the API:For Artemether and Artesunate: Artemisinin versus Dihydroartemisinin
Artemisinin Dihydroartemisinin
Artemether
Artesunate
SM??
Slide 28 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
• Quality management (Chapter 2)
– 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 WHO GMP for APIs concepts
Slide 29 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
• Facilities,equipment and utilities system
– Facilities designed to prevent mix-
ups and contamination (sec 4.11)
– Precautions implemented based on
a risk assessment
– Equipment cleaning methodology
and intervals appropriate to prevent
build-up and carry-over of
contaminants (degradants)
(sec.4.15)
Review of some WHO GMP for APIs concepts
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
Slide 30 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
• HVAC systems (section 4.2)
– Adequate ventilation, air filtration and exhaust systems should be provided where appropriate (sec 4.21, 4.22)
– Qualification and appropriate monitoring and operating range limits in place (sec 4.20)
• Water (section 4.3)
– WHO potable water quality as a minimum(sec 4.31)
– Water for final isolation and purification steps for API for sterile products: test for microbial counts, objectionable counts and endotoxins (sec 4.34)
Review of some WHO GMP for APIs concepts
Slide 31 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Inspection of API manufacturers
• Cross-contamination: Centrifuge XZ1234 labelled as
clean was found with white residues between the
basket and the inner wall
• Double standards:
– Block A (announced): The status of all centrifuges was
indicated and the centrifuge cloths were brand new and
identified as dedicated to centrifuges and stages of
synthesis;
– Block B (unannounced): The status of centrifuge XZ4567
was not indicated and all the centrifuge cloths were found
to be old and not dedicated to centrifuges and stages of
synthesis.
Slide 32 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
• Material management (section 7.)– At least, identity testing of each batch on a
sample representative of the batch (sec 7.30)
– Reduced testing for approved/validated
suppliers (sec 7.31)
• Past quality history
• Full analysis at least on three batches before
starting reduced-testing
• Reliability of the CoA checked at regular
intervals
– Precaution for bulk deliveries in non-dedicated
tankers (sec 7.22) – Certificate of cleaning
Testing for trace impurities, supplier audit.
Review of some WHO GMP for APIs concepts
Slide 33 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
WHO GMP and Inspection of API 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.
Slide 34 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Inspection of API manufacturers
Other examples of non-compliances
• Sampling and storage of materials
– The number of drums sampled for a consignment of 340 drums of ABC B. No. 123 as recorded on the sampling sheet (5) was less than that required by the sampling procedure (√N+1 = 19).
– ABC BN 123 was stored in an uncontrolled T° storage area (same warehouse where staff bus was parked). The recommended storage condition for this material is below 150C
– API XYZ B. No. 1111 had a release status label dated 09.02.2008 although its manufacturing date was 10.02.2008.
Slide 35 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
• Production (section 8)– Critical operations should be witnessed
or subjected to an equivalent control (sec 8.12)
– Deviations should be documented, explained and/or investigated (sec 8.15)
– Process time limits should be respected (sec 8.20)
– Conditions and duration of storage of intermediates (sec 8.21)
– In-process sampling and controls (sec 8.3)
• approved written procedures, avoid risk of cross contamination during sampling, sample integrity
Review of some WHO GMP for APIs concepts
Slide 36 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Review of some concepts of WHO GMP for APIs
• 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 size2. Blending tailings
APIs for OSDs/ Suspensions
1. Particle size distribution2. Bulk density3. Tap density
Slide 37 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
• 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
Review of some WHO GMP for APIs concepts
• Reprocessing or reworking for intermediates or APIs
which do not conform to standards or specifications
Slide 38 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Review of some WHO GMP for APIs concepts
• Recovery of Materials and
solvents (sec 14.4)
– 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 procedures2. Suitable specs3. Adequate testing5. Use documented
1. No approved procedures2. Specs – carry over impurities3. Not adequately tested4. Use not documented
Slide 39 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Inspection of API manufacturers
• Deficiencies related to recovered solvents:
– specifications for recovered solvents (Ethanol, Toluene, Ethyl acetate, Triethylamine, methanol, Isopropyl alcohol) from and reused in various stages of synthesis allowed low purity and high maximum single unknown impurity which were not justified by actual data.
• e.g. specification for recovered methanol: potency as NLT 90.0% and MSUI as NMT 10.0%, the results showed potency of NLT 98% and MSUI on NMT1%.
– No ratio for fresh to recovered solvents had been set for the above solvents based on validation data.
– No limit had been set on the number of times/cycles the above solvents could be recovered and re-used – risk of impurity build up.
Slide 40 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
• 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
Review of some WHO GMP for APIs concepts
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 testing
3. Retrospective Validation (10 - 30
batches):• Only in exceptional cases• For well established process• All batches, including failed ones
Slide 41 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Inspection of API manufacturers
• Data Manipulation:
– The calibration report for the T° sensor
supporting the “OK” status written on the
qualification report of reactor R1234 carried out in
March 2009 was requested on December 9th by
the inspector and presented the day after in the
morning. This calibration report was dated March
2009 although the form presented by the
company was effective in July 2009. Company’s
management acknowledged that this document
was created after the inspectors’ request.
Slide 42 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
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
Review of some WHO GMP for APIs concepts
Slide 43 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
– Contract manufacturers (section 16)
• Contract manufacturers should comply with
GMP (sec 16.10)
• A contract or a formal agreement should exist
between the contract acceptor and the contract
giver (sec 16.12).
Review of some WHO GMP for APIs concepts
– Personnel (section 3)
• Appropriate and regular GMP
training periodically assessed
(sec 3.12)
Slide 44 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers
Slide 45 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
0
20
40
60
80
100
120
140
No
of
sit
es
Type of API
INSPECTION STATUS OF API SITES USED IN PRODUCTS UNDER WHO
PREQUALIFICATION
Not yet Inspected 20 15 8 3 0 0 0 0 0 0 46
Innovators/PICS 33 3 8 5 0 0 0 0 0 0 49
Sites inspected - NC 1 4 1 0 0 0 0 0 0 0 6
Sites inspected - C 10 5 4 0 0 0 2 2 1 1 25
HA TB MA RH IN D HA, IN HA, TB HA, MAHA, MA,
TBTotal
Out of 126 API sites participating in PQ activities, 49 were accepted based on approval by PICS inspectorates.
Slide 46 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Most of the API sites were located in India and China and that where most of the inspections have taken place.
0
20
40
60
80
100
120
140
Num
ber of sites
Baham
as
Belg
ium
Canada
Chin
a
Fra
nce
Germ
any
India
Irela
nd
Italy
Japan
Latv
ia
Mexic
o
Neth
erlands
Port
ugal
Puert
o R
ico
Sin
gapore
South
Afr
ica
South
Kore
a
Spain
Sw
itzerland
Thailand
United K
ingdom
USA
Vie
tnam
Tota
l
Host countries of API sites
Host Countries for API Sites within the WHO Prequalification of Mediucines Programme
Not yet Inspected
Innovators/PICS
Inspected & NC
Inspected & C
Slide 47 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
The sites inspected are those producing many APIs (average 4 APIs per site) mainly for HIV/AIDS, TB and MA in that order.
APIs PER SITE
0
2
4
6
8
10
12
Inspection Status of API Sites
No o
f A
PIs
per Site
Average 4 2 1 1 2
Minimum 1 1 1 1 1
Maximum 10 2 3 5 10
Sites inspected - C Sites inspected - NC Innovators/PICS Not yet Inspected All sites
Slide 48 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
The sites inspected were the ones producing APIs used in most FPPs (average
each API site representing 21 FPPs). This demonstrates maximizing use of
available inspection resources.
NUMBER OF FPPs USING APIs FROM EACH SITE
0
10
20
30
40
50
60
70
80
90
Inspection Status of API Sites
No o
f FP
Ps p
er A
PI S
ite
Average 21 15 3 2 7
Minimum 1 2 1 1 1
Maximum 80 48 12 10 80
Sites inspected - C Sites inspected - NC Innovators/PICS Not yet Inspected All sites
Slide 49 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Trends from WHO-PQP Inspection of API manufacturers
Trends from WHO-PQP Inspection of API manufacturers
0
5
10
15
20
25
30
35
40
Ave (total) obs per
site
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
Slide 50 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Trends from WHO-PQP Inspection of API manufacturers
Trends from WHO-PQP Inspection of API manufacturers
• 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
Slide 51 of 51Meeting with manufacturers, 5 April 2011
Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland
Summary 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
• Emphasis on the risks of
– Contamination and cross contamination
– Mix-ups, build-up and carry-over of degradants
– Lack of traceability
• 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.
谢谢谢谢谢谢谢谢!!!!
ध�यवादध�यवादध�यवादध�यवाद
Dhan'yavāāāāda