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

WHO GMP and API Inspections
QUALITY OF PHARMACEUTICAL
INGREDIENTS
WHO Prequalification Programme: Priority
Essential Medicines
WHO GMP and API Inspections


Presented by
Mr. Deus K Mubangizi
Technical Officer
mubangizid@who.int

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Slide 2 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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

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Slide 3 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
WHO Prequalification: Inspection activities
Prequalification
WHO route SRA* route
Dossier Q/E GMP/GCP
Innovators Generics
Simplified procedure
PQ PQ
PQ
*Stringent Regulatory
Authority
APIs,
FPPs
BE/CROs

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Slide 4 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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
Data verification data manipulation, falsification, (validation,
stability, clinical, bioanalytical)
Quality control (QC, BAL, NQCL, IQCL)

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Slide 5 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
Guide to Manufacturer Risk Classification
Ref: SOP 401.1: Inspection Frequency and Scheduling
RELATIVE RISK CATEGORY
PRODUCT TYPE / ACTIVITY
LOW MEDIUM HIGH CRITICAL
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

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Slide 6 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN
THE WHO PREQUALIFICATION PROGRAMME
(1 of 2)
API
Manufacturer
Number of Products Present in Product
(Ref. Nos.)
Risk Score Risk = 1 Risk = 2 Parameter
N Y Polymorphism 1
High Low Solubility in water 2
Not complex Complex Synthesis 3
Low risk High Risk Solvents 4
Low risk High Risk Impurities 5
N Y Sterile 6
N Y Fermentation 7

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Slide 7 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN
THE WHO PREQUALIFICATION PROGRAMME
(2 of 2)
Risk Score Risk = 1 Risk = 2 Parameter
Low High Toxicity 8
Low risk High Risk Activity/potency 9
Low risk High Risk Particle size 10
Other property consideration 11
Positive Negative
Site compliance information
(WHO/EDQM/USFDA/Other)
12
Total Risk Score
General remarks:
Compliant
Outcome Last inspection date
Not Compliant
High
Inspection prioritization Medium
Low

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Slide 8 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
Guide To Inspection Frequency (in months)
Ref: SOP 401.1: Inspection Frequency and Scheduling
GMP Compliance Rating:
RISK
CATEGORY
:
Unacceptable
Acceptable:
Basic Satisfactory Good
Determine on a case by
case basis
12 18 24 Critical (C)
Determine on a case by
case basis
15 20 30 High (H)
Determine on a case by
case basis
18 24 36 Medium (M)
Determine on a case by
case basis
24 36 48 Low (L)

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Slide 9 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
Inspection Duration Guide (on-site days)
Ref: SOP 401.1: Inspection Frequency and Scheduling
RISK
Manufacturer Size
L M H C L M H C
Re-inspection Initial Inspection
2 3 3 4 3 3 4 5 Large
2 2 3 3 3 3 4 4 Major
2 2 2 3 2 3 3 4 Standard

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Slide 10 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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

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Slide 11 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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.

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Slide 12 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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

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Slide 13 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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.

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Slide 14 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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).

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Slide 15 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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_assura
nce/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. 39
th
Report.
Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 3.
http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf



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Slide 16 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
Prequalification Programme: norms, standards and
guidelines used
WHO guidelines for sampling of pharmaceutical products and
related materials. 39
th
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. 40
th
Report.
Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 2.
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf
Supplementary GMP guidelines: validation. 40
th
Report. Geneva,
WHO, 2006 (WHO TRS, No. 937), Annex 4.
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf
Good Practices for National Pharmaceutical Control Laboratories.
36
th
Report. Geneva, WHO, 2002 (WHO TRS, No. 902), Annex 3.
http://whqlibdoc.who.int/trs/WHO_TRS_902.pdf#page=37
USP
BP
Ph. Eur.
Ph. Int.
Other
guidelines
e.g. ICH, ISO

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Slide 17 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
Prequalification Programme: norms,
standards and guidelines used
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.

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Slide 18 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
WHO 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

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Slide 19 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
WHO GMP for APIs / ICH Q7
Key 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.

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Slide 20 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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 : Introduction

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Slide 21 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
WHO GMP and Inspection of API manufacturers
Increasing GMP requirements

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Slide 22 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
Main issue : How to define the API SM ?
Only flow chart
GMPs do not
apply
Detailed description
GMPs apply
Competent
Authorities
Industry
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)


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Slide 23 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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.

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Slide 24 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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: Scope

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Slide 25 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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 ICHQ7As concepts

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Slide 26 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
Change 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 control
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 ICHQ7As concepts

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Slide 27 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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).
Review of some ICHQ7As concepts
Personnel (section 3)
Appropriate and regular GMP training
periodically assessed (ICH 3.12)

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Slide 28 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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)

Review of some ICHQ7As 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

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Slide 29 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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.
Review of some ICHQ7As concepts

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Slide 30 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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)
Review of some ICHQ7As concepts

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Slide 31 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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
Review of some ICHQ7As concepts

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Slide 32 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
Review of some ICHQ7As concepts
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 density
3. Tap density

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Slide 33 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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 ICHQ7As concepts
Reprocessing or reworking for intermediates or APIs
which do not conform to standards or specifications

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Slide 34 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
Review of some ICHQ7As concepts
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 specs
3. Adequate testing
5. Use documented
1. No approved procedures
2. Specs carry over impurities
3. Not adequately tested
4. Use not documented

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Slide 35 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
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 ICHQ7As 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

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Slide 36 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
ICHQ7A : 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

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Slide 37 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
WHO GMP and Inspection of API manufacturers

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Slide 38 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
WHO GMP and Inspection of API manufacturers
2002 - 2009
Vietnam (1)
S. Korea (1)
China (9)
India (34)
2002 to 2009

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Slide 39 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
WHO GMP and Inspection of API manufacturers
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

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Slide 40 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
WHO GMP and Inspection of API manufacturers
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

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Slide 41 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
WHO GMP and 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

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Slide 42 of 43 29 - 30 March 2010, Beijing, China
WHO GMP and API Inspections
WHO GMP and 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
Cross
contamination
Batch records
SOPs
Material
Management
Cleaning
Labeling

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