Good Manufacturing Practices:
WHO Inspections
Tony Gould
(Slides provided by Dr Andre van Zyl)
Inspections
To get started:
 Risk assessment (SOP)
 Scheduling
 Preparation
 Announce inspection
 Provide tentative inspection plan
 Inspect, prepare inspection report
 Review corrective action
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PQ Workshop, Abu Dhabi | October 2010
Inspections
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)
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Current trends in Inspections
RELATIVE RISK CATEGORY
Guide to
Manufacturer
Risk Classification
PRODUCT TYPE / ACTIVITY
CRITICAL
HIGH
MEDIUM
LOW
Finished Products:
Sterile finished products
Non-sterile finished products
X
X
APIs:
Sterile APIs
Nonsterile APIs where there is a
special risk (e.g. isomerism,
polymorphism, special risk of harmful
impurities, etc)
X
X
Other nonsterile APIs
QC Laboratories
CROs
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X
X
X
APIs
Why inspect?
 Quality
– Heparin
• Baxter – 2008, more than 80 deaths in USA
• Investigated – FDA (GMP – sourcing of starting material, lack of control)
– Nelfinavir, Lopinavir /Ritonavir
• Roche – 2008, global recall of batches
• genotoxic substance (GMP, cleaning of tanks)
• Morphic forms
 European law – FPP manufacturer's responsibility
– Self, contracted party, DRA
 Rationalization, economy
– Initially mostly in Europe – now Asia (India and China) – control?
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API
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)
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WHO GMP for APIs – ICH Q7
 II. QUALITY
MANAGEMENT
 III. PERSONNEL
 IV. BUILDINGS AND
FACILITIES
 V. PROCESS
EQUIPMENT
 VI.
DOCUMENTATION
AND RECORDS
 VII. MATERIALS
MANAGEMENT
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 VIII. PRODUCTION AND
IN-PROCESS
CONTROLS
 IX. PACKAGING AND
IDENTIFICATION
LABELING OF APIs AND
INTERMEDIATES
 X. STORAGE AND
DISTRIBUTION
 XI. LABORATORY
CONTROLS
 XII. VALIDATION
API
 XIII. CHANGE CONTROL
 XIV. REJECTION AND RE-USE OF
MATERIALS
 XV. COMPLAINTS AND RECALLS
 XVI. CONTRACT MANUFACTURERS
 XVII. AGENTS, BROKERS, TRADERS,
DISTRIBUTORS,
REPACKERS, AND RELABELLERS
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Increasing GMP requirements
WHO GMP and Inspection of API manufacturers
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PQ Workshop, Abu Dhabi | October 2010
APIs
Why inspect?
 Variations
 Change manufacturers and suppliers
 Different specifications, route of synthesis, impurity profile
 Stability, re-test dates vs expiry dates
 Incomplete dossier, DMF, APIMF
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PQ Workshop, Abu Dhabi | October 2010
API
Examples of observations of non-compliance in 2007
Batch records and SOPs
 Before steps were processed… a complete centrifugation operation before actual
operation;
 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
 Risk of cross contamination
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PQ Workshop, Abu Dhabi | October 2010
API
Examples of major non-compliances (2009)
 Quality management
– Lack of knowledge and experience
– Deviations not reported
– Change control incomplete
 Documentation
– Recording of operations, also not reflecting all steps and full of errors
– Incomplete process validation
 Materials management
– Sampling (number of samples, release date before manufacturing date)
– Storage and use - FIFO
 Buildings and facilities
– Water systems; HVAC – poor design and controls
– equipment cleaning – show product residue after cleaning, equipment
cleaned in outside environment
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PQ Workshop, Abu Dhabi | October 2010
Inspection of API manufacturers
35
30
25
Number of sites
20
15
Ave number
observations
10
5
0
2002
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2004
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PQ Workshop, Abu Dhabi | October 2010
2006
2007
2008
2009
Inspection of API manufacturers
2007 -2009. Inspections (disease areas)
and number of observations
Areas of non-compliance
40
10
35
9
30
8
7
25
TB
HIV/AIDS
MAL
20
15
6
5
2
0
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PQ Workshop, Abu Dhabi | October 2010
Batch records
4
3
Ave (Major)
Cleaning
5
10
Ave (total) obs per
site
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Materials
Management
SOPs
Labeling
Cross
contamination
0
Major deficiencies
Inspection of API manufacturers
Summary of trends
 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)
 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
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PQ Workshop, Abu Dhabi | October 2010
Inspection of FPP manufacturers
To get started (FPP manufacturer):
 Product dossier submitted
 Listed as a manufacturer in a product dossier
 Assessment in progress
 Risk assessment
 Submit a SMF
 Announce inspection
 Provide tentative inspection plan
 Inspect, prepare inspection report – corrective
action
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PQ Workshop, Abu Dhabi | October 2010
Inspection of FPP manufacturers
Manufacturers: Normally over 4 days
 Covers all aspects of GMP
– Quality management, Quality assurance, Premises, Equipment, Documentation,
Validation, Materials, Personnel
– Utilities (e.g. HVAC, water) . . .
 Also data verification (dossier) including stability data, validation
(process), development batches and bio batches
 Quality control laboratory – specifications, reference standards,
methods of analysis, validation and qualification
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PQ Workshop, Abu Dhabi | October 2010
FPP
Findings
 Validation and qualification work was often incomplete
 Validation Master Plans (VMP) lacked details
 Validation policies as defined in the VMPs were not implemented
 Process validation was lacking
 Validated procedures (e.g. environmental monitoring) were lacking
 Incomplete (not detailed) qualification of HVAC, water and
computer systems
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PQ Workshop, Abu Dhabi | October 2010
FPP
Findings
 Insufficient filtration of air to production areas
– No prevention of possible cross-contamination and contamination.
 "As built" AHUs lacked components reflected in the schematic drawings,
including filters
 No qualification of sampling areas and reverse unidirectional air flow units
 Temperature and RH mapping studies incomplete, or results not applied
 HVAC systems not controlled or monitored, start up, shut down
 Filters:
– not planned, classified, tested (including installed filter leakage test), monitored
 Pressure differential gauges not controlled, including calibration and zero checks
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PQ Workshop, Abu Dhabi | October 2010
GMP ...
 PQR
– Not done annually
– Not all data reported including starting materials, commitments, variations
– Trends not reviewed / discussed – results merely reported
 Deviations
– Not reported, some are opened, new deviations opened on a deviation
– Not authorized by production manager or QA prior to implementation
– No assessment on impact, not additional testing
 Change control procedures not followed
– No assessment on impact, no routing to responsible persons
– No qualification or validation
– Wrong materials used (e.g. MOC extension of PW loop)
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PQ Workshop, Abu Dhabi | October 2010
GMP ...
 In process controls
– Some less critical ones reported
– Wrong results represented
– Even though "fail" – reported as "pass"
 Qualification
–
–
–
–
Often incomplete
Wrong sequence
Unreliable data
"approved" and signed off despite non compliance
with specifications, errors not picked up
– Computers, software, excel calculations
 Process validation
– Lacking
– Unreliable results
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PQ Workshop, Abu Dhabi | October 2010
FPP
OOS
 SOP for the reporting and investigation of Out of
Specification (OOS) results not implemented
 No record of OOS results
 In case of an OOS, re-testing was done, however, the
results were recorded on a loose piece of paper, other
sheets were not appropriately completed e.g. method
number, no of samples, LIMS number
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PQ Workshop, Abu Dhabi | October 2010
FPP
Reworking materials / products:

GMP allows in exceptional cases - reworks were done on a
routine basis.

Inappropriate authorization for the reworks including no prior
authorization by QA, authorization by production supervisors up to
7 weeks after the rework was initiated.

A rework was even initiated prior to the conclusion of the OOS
investigation.

Reworked batches were not subjected to additional testing
including stability studies

Only one of all the reworked batches was subjected to stability
testing according to the stability plan.
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PQ Workshop, Abu Dhabi | October 2010
Inspection of FPP manufacturers
Inspections by country
20
15
2008
10
2009
5
0
China
Egypt
India
Morocco
South Africa
Country
Co-inspectors by country
14
Number of sites
Number of sites
25
12
10
2008
8
6
2009
Total
4
2
0
Austr
CH
Es
Fr
Hu
Country
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PQ Workshop, Abu Dhabi | October 2010
UK
WHO
SA
DEN
Inspection of FPP manufacturers
120
100
2008 Total
80
2009 Total
60
2008 Major
40
2009 Major
20
25
23
21
19
17
15
13
11
9
7
5
3
0
1
Number of observations
Observations 2008 and 2009
Number of sites
Non compliant sites
10
Number
8
2008
6
2009
4
Total
2
0
R
H
T
M
Disease group
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PQ Workshop, Abu Dhabi | October 2010
INJ
OSD
Inspections of Contract Research Organizations
(CROs)
 Clinical sites: Normally over 2 days
 Started 2004 -Covers all aspects of
GCP and GLP
– Ethical considerations, Protocol,
Volunteers etc
New York Times 2007
 Data verification – identified
misrepresentation of data
 Clinical part
– Clinic, Pharmacy and related
areas, data verification
 Bio-analytical part
– Laboratory and data verification
 Statistical analysis
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PQ Workshop, Abu Dhabi | October 2010
Inspections of Contract Research
Organizations (CROs)
Also:
Guidance for Industry
Bio-analytical Method Validation
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Veterinary Medicine (CVM)
May 2001
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PQ Workshop, Abu Dhabi | October 2010
Inspections of
Contract Research Organizations (CROs)
Clinical Part of the study
 Protocol, Ethics committee
 Volunteers
 Informed consent
 Source data and CRFs
Bio-analytical part of the study
 Sample management
 Method validation and sample analysis
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PQ Workshop, Abu Dhabi | October 2010
Inspections of
Contract Research Organizations (CROs)
Main problems in some CROs:
 Many haven't done studies for "regulated market" submissions
 Lack of GCP and GLP regulations, requirements, enforcement and
compliance
 IEC not independent – set up by sponsors
 Manipulation of data
 No source data / records available (CRO and Sponsor)
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PQ Workshop, Abu Dhabi | October 2010
Inspections of
Contract Research Organizations (CROs)
Examples of observations

Half of the CRFs "missing"

Source data destroyed accidently by fire or "monsoon"

Sponsor claims the data were kept by the CRO, and the CRO
claims the data were kept by the sponsor

All data and retention samples destroyed as the product "expired"
– even though the submission is still under evaluation
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PQ Workshop, Abu Dhabi | October 2010
Inspections of Contract Research
Organizations (CROs)
Examples
 Half of the CRFs "missing" (at
sponsor / CRO?), source data
destroyed accidently by fire or
"monsoon", destroyed as the product
"expired"
 Out of 95 ECGs copied by the
inspectors, 43 appear to have been
recorded from the same and single
subject during a single session
 Manual integration and results not
real
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PQ Workshop, Abu Dhabi | October 2010
Inspections of
Contract Research Organizations (CROs)
Example: Numerous improper manual integrations were noted
by the inspectors for QC samples.
 Such integrations were found both for the method validation and for
the trial phase. These integrations were corrected during the
inspection by one staff member under control of one inspector.
 The status of the results of several QC samples was affected by
these improper manual integrations
 Taking these corrected results into consideration the results of
subjects No. 5 and 20 should be rejected:
– subject No. 5: results were only obtained for 4 of the 6 QC samples and the results of
2 of these 4 samples fall out of acceptance limits;
– subject No. 20: the results of both LQC samples fall out of acceptance limits..
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Example discrepancies
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PQ Workshop, Abu Dhabi | October 2010
Inspections of
Contract Research Organizations (CROs)
Recent observations included unreliable data such as:
 Discrepancies between electronic raw data files and data submitted
in study reports for assessment;
 Improper manual integration of chromatograms observed during
inspections even as "no manual integration" was reported;
 Differences in chromatogram peak areas between the electronic
raw data files and the printouts submitted to the WHO;
 Batches that fail when data is calculated from raw data files during
inspections (e.g. for QC samples) even as these batches were
presented as "passing" with values different from those actually
obtained during subject sample analysis;
 Inappropriate bio analytical method validation.
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PQ Workshop, Abu Dhabi | October 2010
Number of inspections
60
50
40
FPP
API
CRO
QCL
total
30
20
10
0
2005
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PQ Workshop, Abu Dhabi | October 2010
2007
2008
2009
That’s all…
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PQ Workshop, Abu Dhabi | October 2010