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Good Manufacturing Practices:
WHO Inspections
Tony Gould(Slides provided by Dr Andre van Zyl)
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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
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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
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Current trends in Inspections
Guide toManufacturer
Risk Classification
RELATIVE RISK CATEGORY
PRODUCT TYPE / ACTIVITY
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
http://www.api.polpharma.pl/files/(x6urq7udbXZt2WxVgFSTskWh2rGie51teGaebYyAZF65XZermaFib5yAZaGlXXdlXWhbnqWrpHRsaXlg0KKKaG2g)/pl/defaultgalerie/248/6/1/884434863.jpg8/13/2019 1 5 PQ Inspections
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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 lawFPP manufacturer's responsibility Self, contracted party, DRA
Rationalization, economy Initially mostly in Europenow Asia (India and China)control?
http://www.api.polpharma.pl/files/(x6urq7udbXZt2WxVgFSTskWh2rGie51teGaebYyAZF65XZermaFib5yAZaGlXXdmXWhUmqWtp3FkaH9klJyTrVReww)/pl/defaultgalerie/248/6/1/1446610592.jpg8/13/2019 1 5 PQ Inspections
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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)
http://www.api.polpharma.pl/files/(x6urq7udbXZt2WxVgFSTskWh2rGie51teGaebYyAZF65XZermaFib5yAZaGlXXdmXWhUl6Kqo3dla3lqlJyTrVReww)/pl/defaultgalerie/248/5/1/1113271838.jpg8/13/2019 1 5 PQ Inspections
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VIII. PRODUCTION AND
IN-PROCESSCONTROLS
IX. PACKAGING ANDIDENTIFICATIONLABELING OF APIs ANDINTERMEDIATES
X. STORAGE ANDDISTRIBUTION
XI. LABORATORYCONTROLS
XII. VALIDATION
WHO GMP for APIsICH Q7
II. QUALITYMANAGEMENT
III. PERSONNEL
IV. BUILDINGS ANDFACILITIES
V. PROCESSEQUIPMENT
VI.DOCUMENTATION
AND RECORDS
VII. MATERIALS
MANAGEMENT
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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
http://www.api.polpharma.pl/files/(x6urq7udbXZt2WxVgFSTskWh2rGie51teGaebYyAZF65XZermaFib5yAZaGlXXdmXWhUmaiwpnVra39olJyTrVReww)/pl/defaultgalerie/248/5/1/1379557896.jpg8/13/2019 1 5 PQ Inspections
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WHO GMP and Inspection of API manufacturers
Increasing GMP requirem ents
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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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Examples of observations of non-compliance in 2007
Batch records and SOPs
Before steps were processed a complete centrifugation operation before actualoperation;
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 30minute as required in the BMR equipment logbook no entry
The SOP cleaning of centrifuge bag was incompleteNo evidence of: dedicated bags
labeling of storage drums
Also for fluid bed bags
Risk of cross contamination
API
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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; HVACpoor design and controls
equipment cleaningshow product residue after cleaning, equipmentcleaned in outside environment
API
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Inspection of API manufacturers
0
5
10
15
20
25
30
35
2002 2004 2005 2006 2007 2008 2009
Number of sites
Ave numberobservations
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Inspection ofAPI manufacturers
0
5
10
15
20
25
30
35
40
Ave (total) obs per
site
Ave (Major)
TB
HIV/AIDS
MAL
2007 -2009. Inspec tion s (dis ease areas)and number of observat ions
0
1
2
3
4
56
7
8
9
10
Major deficiencies
MaterialsManagement
SOPs
Cleaning
Batch records
Labeling
Crosscontamination
Areas of n on-compl iance
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Inspection of API manufacturers
Summary of trends
Number of inspections between '05 and '099 to 12. Low numberin 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 lowernumber of major non compliances at malaria manufacturers
Observations relating to material management, SOPs anddocuments, cleaning
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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 reportcorrectiveaction
Inspection of FPP manufacturers
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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 laboratoryspecifications, reference standards,
methods of analysis, validation and qualification
Inspection of FPP manufacturers
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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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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
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PQR Not done annually Not all data reported including starting materials, commitments, variations
Trends not reviewed / discussedresults 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 ...
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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 ...
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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
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Reworking materials / products: GMP allows in exceptional cases - reworks were done on a
routine basis.
Inappropriate authorization for the reworks including no priorauthorization 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 OOSinvestigation.
Reworked batches were not subjected to additional testing
including stability studies
Only one of all the reworked batches was subjected to stabilitytesting according to the stability plan.
FPP
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Inspection of FPP manufacturers
Inspections by country
0
5
10
15
20
25
China Egypt India Morocco South Africa
Country
Numberofsites
2008
2009
Co-inspectors by country
0
2
4
6
8
10
12
14
Austr CH Es Fr Hu UK WHO SA DEN
Country
Numberofsites
2008
2009
Total
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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
Numberofobservations
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
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Inspections of Contract Research Organizations
(CROs)
New York Times 2007
Clinical sites: Normally over 2 days
Started 2004 -Covers all aspects ofGCP and GLP
Ethical considerations, Protocol,Volunteers etc
Data verificationidentified
misrepresentation of data
Clinical part
Clinic, Pharmacy and relatedareas, data verification
Bio-analytical part
Laboratory and data verification
Statistical analysis
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I ti f C t t R h
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Also:
Guidance for Indus try
B io-analyt ical Method Validat ion
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)
f
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Inspections of
Contract Research Organizations (CROs)
Clinical Part of the study
Protocol, Ethics committee
Volunteers
Informed consent
Source data and CRFs
B io-analyt ical part of the study
Sample management
Method val idat ion and samp le analys is
I ti f
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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 independentset up by sponsors
Manipulation of data
No source data / records available (CRO and Sponsor)
I ti f
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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 CROclaims 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
I ti f C t t R h
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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 notreal
I ti f
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Inspections of
Contract Research Organizations (CROs)
Example: Numerous improper manual integrations were notedby the inspectors for QC samples.
Such integrations were found both for the method validation and forthe trial phase. These integrations were corrected during theinspection by one staff member under control of one inspector.
The status of the results of several QC samples was affected bythese improper manual integrations
Taking these corrected results into consideration the results ofsubjects No. 5 and 20 should be rejected:
subject No. 5: results were only obtained for 4 of the 6 QC samples and the results of2 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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I ti f
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Recent observations included unreliable data such as:
Discrepancies between electronic raw data files and data submittedin study reports for assessment;
Improper manual integration of chromatograms observed duringinspections even as "no manual integration" was reported;
Differences in chromatogram peak areas between the electronicraw data files and the printouts submitted to the WHO;
Batches that fail when data is calculated from raw data files duringinspections (e.g. for QC samples) even as these batches were
presented as "passing" with values different from those actuallyobtained during subject sample analysis;
Inappropriate bio analytical method validation.
Inspections of
Contract Research Organizations (CROs)
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Number of inspections
0
10
20
30
40
50
60
2005 2006 2007 2008 2009
FPP
APICRO
QCL
total
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Thats all