2. 2 | PQ Workshop, Abu Dhabi | October 2010
To get started:
Risk assessment (SOP)
Scheduling
Preparation
Announce inspection
Provide tentative inspection plan
Inspect, prepare inspection report
Review corrective action
Inspections
3. 3 | PQ Workshop, Abu Dhabi | October 2010
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)
Inspections
4. 4 | PQ Workshop, Abu Dhabi | October 2010
Current trends in Inspections
Guide to
Manufacturer
Risk Classification
RELATIVE RISK CATEGORY
PRODUCT TYPE / ACTIVITY
LOW
MEDIUM
HIGH
CRITICAL
Finished Products:
X
Sterile finished products
X
Non-sterile finished products
APIs:
X
Sterile APIs
X
Nonsterile APIs where there is a
special risk (e.g. isomerism,
polymorphism, special risk of harmful
impurities, etc)
X
Other nonsterile APIs
X
QC Laboratories
X
CROs
5. 5 | PQ Workshop, Abu Dhabi | October 2010
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?
6. 6 | PQ Workshop, Abu Dhabi | October 2010
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)
7. 7 | PQ Workshop, Abu Dhabi | October 2010
VIII. PRODUCTION AND
IN-PROCESS
CONTROLS
IX. PACKAGING AND
IDENTIFICATION
LABELING OF APIs AND
INTERMEDIATES
X. STORAGE AND
DISTRIBUTION
XI. LABORATORY
CONTROLS
XII. VALIDATION
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
8. 8 | PQ Workshop, Abu Dhabi | October 2010
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
API
9. 9 | PQ Workshop, Abu Dhabi | October 2010
WHO GMP and Inspection of API manufacturers
Increasing GMP requirements
10. 10 | 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
11. 11 | PQ Workshop, Abu Dhabi | October 2010
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
API
12. 12 | PQ Workshop, Abu Dhabi | October 2010
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
API
13. 13 | PQ Workshop, Abu Dhabi | October 2010
Inspection of API manufacturers
0
5
10
15
20
25
30
35
2002 2004 2005 2006 2007 2008 2009
Number of sites
Ave number
observations
14. 14 | PQ Workshop, Abu Dhabi | October 2010
Inspection of API manufacturers
0
5
10
15
20
25
30
35
40
Ave (total) obs per
site
Ave (Major)
TB
HIV/AIDS
MAL
2007 -2009. Inspections (disease areas)
and number of observations
0
1
2
3
4
5
6
7
8
9
10
Major deficiencies
Materials
Management
SOPs
Cleaning
Batch records
Labeling
Cross
contamination
Areas of non-compliance
15. 15 | PQ Workshop, Abu Dhabi | October 2010
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
16. 16 | PQ Workshop, Abu Dhabi | October 2010
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
Inspection of FPP manufacturers
17. 17 | PQ Workshop, Abu Dhabi | October 2010
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
Inspection of FPP manufacturers
18. 18 | 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
19. 19 | 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
20. 20 | PQ Workshop, Abu Dhabi | October 2010
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)
GMP ...
21. 21 | PQ Workshop, Abu Dhabi | October 2010
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
GMP ...
22. 22 | PQ Workshop, Abu Dhabi | October 2010
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
FPP
23. 23 | PQ Workshop, Abu Dhabi | October 2010
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.
FPP
24. 24 | PQ Workshop, Abu Dhabi | October 2010
Inspection of FPP manufacturers
Inspections by country
0
5
10
15
20
25
China Egypt India Morocco South Africa
Country
Number
of
sites
2008
2009
Co-inspectors by country
0
2
4
6
8
10
12
14
Austr CH Es Fr Hu UK WHO SA DEN
Country
Number
of
sites
2008
2009
Total
25. 25 | PQ Workshop, Abu Dhabi | October 2010
Inspection of FPP manufacturers
Observations 2008 and 2009
0
20
40
60
80
100
120
1 3 5 7 9 11 13 15 17 19 21 23 25
Number of sites
Number
of
observations
2008 Total
2009 Total
2008 Major
2009 Major
Non compliant sites
0
2
4
6
8
10
R H T M INJ OSD
Disease group
Number
2008
2009
Total
26. 26 | PQ Workshop, Abu Dhabi | October 2010
Inspections of Contract Research Organizations
(CROs)
New York Times 2007
Clinical sites: Normally over 2 days
Started 2004 -Covers all aspects of
GCP and GLP
– Ethical considerations, Protocol,
Volunteers etc
Data verification – identified
misrepresentation of data
Clinical part
– Clinic, Pharmacy and related
areas, data verification
Bio-analytical part
– Laboratory and data verification
Statistical analysis
28. 28 | PQ Workshop, Abu Dhabi | October 2010
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
Inspections of Contract Research
Organizations (CROs)
29. 29 | 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
30. 30 | 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)
31. 31 | 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
32. 32 | 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
33. 33 | 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..
34. 34 | PQ Workshop, Abu Dhabi | October 2010
Example discrepancies
36. 36 | PQ Workshop, Abu Dhabi | October 2010
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.
Inspections of
Contract Research Organizations (CROs)
37. 37 | PQ Workshop, Abu Dhabi | October 2010
Number of inspections
0
10
20
30
40
50
60
2005 2006 2007 2008 2009
FPP
API
CRO
QCL
total
38. 38 | PQ Workshop, Abu Dhabi | October 2010
That’s all…