Transcript
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 inspection
Provide tentative inspection plan
Inspect, prepare inspection report
Review corrective action
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PQ Workshop, Abu Dhabi | October 2010
Inspections To get started:
Risk assessment (SOP)
Scheduling
Preparation
Announce inspection 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
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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 requirem ents
WHO GMP and Inspection of API manufacturers
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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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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
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Also for fluid bed bags Risk of cross contamination
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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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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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2006
2007
2008
2009
Inspection of API manufacturers 2007 -2009. Inspec tion s (dis ease areas) a n d n u m b e r o f o b s e r v a t io n s
A r e as o f n o n - c o m p l i a n c e
40
10
35
9
30
8
SOPs
7
25 TB
20
HIV/AIDS
15
MAL
6
5
2
0
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Batch records
4 3
Ave (Major)
Cleaning
5
10
Ave (total) obs per site
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Materials Management
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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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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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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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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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
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Pressure differential gauges not controlled, including calibration and zero checks
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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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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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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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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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Inspection of FPP manufacturers Inspections by country 25 s 20 e t i s f 15 o r e b 10 m u N 5
2008 2009
0 China
Egypt
India
Morocco
South Africa
Country
Co-inspectors by country 14 s 12 e t i 10 s f o 8 r e b 6 m 4 u N
2008 2009 Total
2 0
Austr
CH
Es
Fr
Hu Country
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UK
WHO
SA
DEN
Inspection of FPP manufacturers Observations 2008 and 2009 s 120 n o i t 100 a v r e 80 s b o 60 f o r 40 e b 20 m u N 0
2008 Total 2009 Total 2008 Major 2009 Major
1
3
5
7
9
1 1
3 1
5 1
7 1
9 1
2 1
3 2
5 2
Number of sites
Non compliant site s 10 8 r e b 6 m u 4 N
2008 2009 Total
2 0 R
H
T
M
Disease group
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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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Inspections of Contract Research Organizations (CROs) Also: G u i d a n c e f o r In d u s t r y
B i o -an a l y t i c a l M e t h o d Val i d a t i o n 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 28 |
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Inspections of Contract Research Organizations (CROs) C l i n i c a l P ar t o f t h e s t u d y
Protocol, Ethics committee
Volunteers
Informed consent
Source data and CRFs
B i o -a n al y t i c a l p a r t o f t h e s t u d y
S am p l e m a n ag e m e n t
M et h o d v a l i d a t i o n an d s a m p l e a n al y s i s
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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 independent – set up by sponsors
Manipulation of data
No source data / records available (CRO and Sponsor)
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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 CRO claims the data were kept by the sponsor
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All data and retention samples destroyed as the product "expired" – even though the submission is still under evaluation
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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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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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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Number of inspections 60 50 40
FPP API
30
CRO QCL
20
total
10 0 2005
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2006
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2007
2008
2009
