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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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 X X

Non-sterile finished products APIs:

Sterile APIs Nonsterile APIs where there is a special risk (e.g. isomerism, polymorphism, special risk of harmful impurities, etc)

Other nonsterile APIs

QC Laboratories CROs X X

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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 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:
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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

VIII. PRODUCTION AND IN-PROCESS CONTROLS

IX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES X. STORAGE AND DISTRIBUTION XI. LABORATORY CONTROLS XII. VALIDATION

V. PROCESS EQUIPMENT
VI. DOCUMENTATION AND RECORDS VII. MATERIALS MANAGEMENT

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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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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 incompleteNo evidence of:
dedicated bags labeling of storage drums

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 20 15 10 5 0 2002 2004 2005 2006 2007 2008 2009

Number of sites Ave number observations

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Inspection of API manufacturers

2007 -2009. Inspections (disease areas) and number of observations Areas of non-compliance

40 35 30 25 20 15 10 5 0 Ave (total) obs per site Ave (Major) TB HIV/AIDS MAL

10 9 8 7 6 5 4 3 2 1 0 Major deficiencies Cross contamination Batch records Labeling Materials Management SOPs Cleaning

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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

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

Number of sites

20 15 10 5 0 China Egypt India Country Morocco South Africa 2008 2009

Co-inspectors by country
14

Number of sites

12 10 8 6 4 2 0 Austr CH Es Fr Hu Country UK WHO SA DEN 2008 2009 Total

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Inspection of FPP manufacturers

Observations 2008 and 2009
Number of observations
120 100 80 60 40 20 0 2008 Total 2009 Total 2008 Major 2009 Major

11

13

15

17

19

21

23

Number of sites

Non compliant sites

10 8

25

Number

6 4 2 0 R H T M INJ OSD Disease group

2008 2009 Total

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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:
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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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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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

All data and retention samples destroyed as the product "expired" even though the submission is still under evaluation

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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 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 30 20 10 0 2005 2006 2007 2008 2009 FPP API CRO QCL total

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Thats all

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