Transcript Essential Medicines Policies, WHO, Geneva. Technical Briefing Seminar: 2011 Prequalification Programme: Priority Essential Medicines WHO-PQ INSPECTIONS Presented by Deus K Mubangizi Technical Officer [email protected].

Essential Medicines Policies,
WHO, Geneva.
Technical Briefing Seminar: 2011
Prequalification Programme: Priority Essential Medicines
WHO-PQ INSPECTIONS
Presented by
Deus K Mubangizi
Technical Officer
[email protected]
WHO-PQP Inspections
In this presentation:
• Procedures and standards used for WHO-PQP
inspections
• WHO-PQ Inspections: avenues for capacity building and
collaboration
• Observed deficiencies during Inspection of:
– FPP and API manufacturers + QC Labs
– Contract Research Organizations (CROs)
• Summary and conclusion
2
WHO Prequalification: Inspection
activities
*Stringent Regulatory
Authority
Prequalification
WHO route
Dossier Q/E
APIs,
FPPs,
BE/CROs,
QCLs
GMP/GCP
PQ
SRA* route
Innovators
Generics
Simplified procedure
PQ
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Prequalification Programme: Use of
Inspection reports from other NMRAs
 Inspectorates whose reports are recognized:
√ PICS member inspectorates
√ EU (EDQM + EMA)
√ USFDA – new member of PICS
 What GMP evidence to submit:
– SMF – Up-to-date
– Inspection report - conducted NMT 2 years
• + CAPAs to deficiencies + final conclusion
– Product Quality Review – not more than 1 year old
 Review of the report:
 scope covered the specific API
 Is comprehensive and supports the final outcome.
 PQP reserves the right to inspect the API manufacturer – as long as
product is active in WHO-PQP.
 on-going GMP compliance will be confirmed by WHO
√ Desk review may only be use once in every 5 years.
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Prequalification: Inspection Processes
 By a team of qualified and experienced inspectors
WHO representative (qualified inspector)
Inspector from well-established inspectorate (Pharmaceutical
Inspection Cooperation Scheme countries – PIC/S)
National inspector/s invited to be part and observe the
inspection
Observer from recipient/developing countries (nominated by
DRA of the country)
 Scope:
 Compliance with guidelines:
GMP for API and FPP sites,
GCP for CROs,
GLP for FPP/API factory QCL, CRO-BAL, NQCL, IQCL
Data verification – data manipulation, falsification,
(validation, stability, clinical, bioanalytical)
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Risk-based approach in:
definition and classification of deficiencies
• Deficiencies are descriptions of non-compliance
with GMP requirements.
• A distinction is made between deficiencies as a
result of: – a defective system or,
– failure to comply with the system.
• Deficiencies may be classified as:
– Critical Observation – potential risk harm to the user
– Major Observation – major deviation from GMP/GCP
– Minor or Other Observation – departure from good
practice
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Risk-based approach in:
Conclusion following an inspection
• When there are "other" observations only:
– considered to be operating at an acceptable level of compliance with WHO
GMP.
– The manufacturer is expected to provide CAPAs.
– CAPAs are evaluation and followed up during the next routine inspection.
• When the are "other" and a few "major" observations:
– compliance with WHO GMP/ICHQ7 is made after the CAPAs have been
assessed.
– CAPAs for majors to include documented evidence of completion.
– CAPAs paper evaluated ± an on-site follow up inspection.
• When there are "critical" or several "major" observations:
– considered to be operating at an unacceptable level of compliance with
WHO GMP/ICHQ7 guidelines.
– Another inspection will be required
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Information put in public domain - available for
use by NMRAs: WHOPIRs and NOCs
• These are published in response to the WHA Resolution WHA57.14
of 22 May 2004, which requested WHO, among other actions:
– "3. (4) to ensure that the prequalification review process and the results
of inspection and assessment reports of the listed products, aside from
proprietary and confidential information, are made publicly available;"
• A WHO Public Inspection Report (WHOPIR) reflects a positive
outcome after an inspection
• A Notice of Concern (NOC) is a letter reflecting areas of concern
where the non-compliances require urgent attention and corrective
action by the manufacturer or research organization.
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Prequalification Programme: International norms,
standards and guidelines used in inspection activities
to ensure wide applicability
USP
BP
Ph. Eur.
Ph. Int.
Other guidelines
e.g. ICH, ISO
http://apps.who.int/prequal/assessment_inspect/info_inspection.htm#2
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WHO-PQ offers new avenues for
collaboration in inspection
 WHO-PQ Collaborative Procedure in Inspections
–
nominated inspectors from NMRAs of selected member states
are invited to participate in WHO-PQ organized inspections and
in turn, the NMRAs is given appropriate access to outcomes of
these inspections.
• Capacity building of NMRAs inspectors.
• Facilitating use of WHO-PQ inspection results in national regulatory
environment for information and decision making.
• Facilitation of harmonization through joint inspections and sharing of
outcomes.
• Share the workload and promote avoiding duplicative inspections.
http://apps.who.int/prequal/info_general/documents/inspection/NMRAs/GUIDANCE_WHOPQM_NMRAs_CollaborativeProcedure.pdf
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Inspection observers have been from:
⃟ AFRO Region - External Observers
⃟ WPRO Region – Host country Observers
Source of Obsevers by WHO Regions: January 2008 - April 2010
40
0
35
30
25
20
36
18
15
10
10
5
8
0
2
0
0
0
0
AFRO
AMRO
EMRO
EURO
SEARO
From other country
18
10
0
0
0
WPRO
0
From host Country
8
0
0
2
0
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Medicines Prequalification Process
Expression
of Interest
Assessment
Product dossier
SMF
Inspections
Corrective
actions
Additional information
and data
Compliance
Compliance
Prequalification
Handling of
complaints
12
Monitoring
Dossier maintenance
(variations)
Zidolam-N
Zidovudine 300mg, Lamivudine 150mg
and Nevirapine 200mg tablets
• Prequalified on 23
May 2006 with
reference number
HA275
• Manufactured by
Hetero at its Unit III,
Andhra Pradesh, India
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Source of Information: MSF
12th September 2011
PHOTO by MSF
14
Alert from CHMP to MSF
Immediate Investigation
13th September 2011
• Alerted Kenya Pharmacy
and Poisons Board
– Had not been notified by
CHMP (Kenya) or MSF
(Kenya)
• Special Inspection of
Hetero Unit 3:
–
–
–
–
–
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Retention samples
Manufacturing records
Analysis records
Distribution records
Observed re-analysis of
retention samples
Findings (1)
Genuine Zidolam-N
Batch No. E10076
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Falsified Zidolam-N
Batch No. E10076
Findings (2)
ZIDOLAM-N Batch No. E100766
GENUINE
 Font style of zero the batch
number; is printed as 0.
FALSEFIED
 Font style of zero the batch
number; is printed as Ø.
 The spacing between licence  The spacing between licence
number and the batch
number and the batch number
number on the bottle label is
on the bottle label varies from
constant in all samples.
one bottle to another.
 The samples of the genuine
Hetero batch do not carry a
COIP logo.
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 Falsified samples bear the
COIP logo. (The logo is that of
a Canadian nongovernmental
organization.)
Findings (3)
• Affected batches;
– E100766, E110467, A9351, A9357, A9366
• the genuine batches E100766 and E110467 were never
supplied to the Kenyan market
• the quantities of Zidolam-N with a reference to “batch number
A9351, A9357 or A9366”, found in Kenya, exceed the quantities
manufactured, packed and dispatched by Hetero as batches
A9351, A9357 and A9366 to Kenya.
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Findings (4)
• Results of analysis by Kenya’s NQCL and Hetero:
– Intact samples comply with the manufacturers’ and with
international pharmacopoeia specifications.
– Open samples discoloured with high friability, low assay,
fungal growth: Possible poor handling by patient.
• Nature of falsification:
– Relabeling and repackaging of donated batches (whose
expiry dates are unknown) in order to divert them to the
commercial market.
– Extent and conditions under which the falsification (relabelling) was undertaken is unknown and thus the quality
of the products cannot be fully ascertained
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Actions taken
• Collaborated with Kenya authorities in conducting
investigation and taking necessary actions.
• Special inspection of the manufacturing site.
• Analysis of complaint and retention samples.
• KPPB ordered a recall of the batches.
• Issued public notices which were updated as
more information became available – careful not
to cause anxiety and fear.
20
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Lessons for the future
• Inadequate market controls and procurement
procedures:
– Diversion of donations, relabeling and repackaging.
– Purchase from middlemen at very low prices without
question.
– NMRA not informed promptly.
• PQ prompt reaction and coordination facilitated
quick investigation.
• Collaboration between PQ, MSF, KPPB, KNQCL
and Hetero was crucial for the success of
investigations.
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Recommendation
• Supply chain should be fully known and actions
should be taken to shorten it wherever possible
• A supply chain is no stronger than its weakest
link
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Inspection of FPP manufacturers
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Deficiencies observed during PQ Inspections
PREMISES
– Inadequate segregation.
– Illogical process flow.
– Inadequate provision for Utilities: HVAC,
water, compressed gases
• Poor design and management of
the HVAC system:
– Multipurpose plant used re-circulated air
but had no HEPA filters.
– Adequate pressure differentials: reversal
of air flow.
– No sequence of switching on and off of
AHUs of adjacent areas.
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Mix-ups
Contamination
Cross contamination
• Poor design and construction of
premises:
Deficiencies observed during PQ Inspections
MATERIALS
•
Inadequate goods and materials
management
–
–
–
–
–
–
–
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Starting materials: sourcing and
sampling – ID per container.
Packaging materials: inadequate
sampling – ISO2859 or BS6001.
Intermediate and bulk products –
holding time not set, or justified, or
respected.
Finished products: Release
procedures – no adequate review
by QA or QP.
Rejected materials and products:
not adequate segregation or
disposal.
Reagents and culture media: no
GPT, positive and negative control
Reference Standards: inadequate
standardisation, storage and use.
Deficiencies observed during PQ Inspections
QC Laboratories
IR: What not to do!
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Deficiencies observed during PQ Inspections
QUALITY CONTROL: Microbiology
• Media Preparation:
– No positive and negative control
– No separate room for media preparation
• Equipment:
– No separate autoclave for sterilization of media and
decontamination of used media.
• Environmental Monitoring:
– Inadequate exposure of plate method, adequate air sampling or
swabbing.
• Validation of Sanitising Agents: no challenge tests using
the standard stock cultures (103-104/0.1ml) in order to
ascertain the minimum dilutions to effect a kill.
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Deficiencies observed during PQ Inspections
FPP manufacturers: – sterile products
Poor aseptic techniques:
• Extensive movement of
operators in Grade A close to
the open vials.
• Vials that were not stoppered by
the machine taken from the
conveyor belt into class B area
and manually placed back into
class A to be manually
stoppered.
• Inadequate Media Fill Tests
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Environmental monitoring:
• The viable particle continuous
monitoring for Grade A zone
does not cover the whole time
period of setting up of the
equipment and the vial fillingcapping process.
• Personnel garments and gloves
were not monitored after
manufacturing operations in
grade A/B areas
Inspection of API manufacturers
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Out of 126 API sites participating in PQ activities, 49 were
accepted based on approval by PICS inspectorates and/or
ICH countries while 31 were inspected.
INSPECTION STATUS OF API SITES USED IN PRODUCTS UNDER WHO
PREQUALIFICATION
140
120
No of sites
100
80
60
40
20
0
HA
TB
MA
RH
IN
D
HA, IN
HA, TB
HA, MA
HA, MA,
TB
Total
Not yet Inspected
20
15
8
3
0
0
0
0
0
0
46
Innovators/PICS
33
3
8
5
0
0
0
0
0
0
49
1
4
1
0
0
0
0
0
0
0
6
10
5
4
0
0
0
2
2
1
1
25
Sites inspected - NC
Sites inspected - C
Type of API
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The sites inspected were the ones producing APIs used in
most FPPs (average each API site representing 21 FPPs).
Thus maximizing use of available inspection resources.
NUMBER OF FPPs USING APIs FROM EACH SITE
90
80
No of FPPs per API Site
70
60
50
40
30
20
10
0
Sites inspected - C
Sites inspected - NC
Innovators/PICS
Not yet Inspected
All sites
Average
21
15
3
2
7
Minimum
1
2
1
1
1
Maximum
80
48
12
10
80
Inspection Status of API Sites
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Deficiencies observed during PQ Inspections
API manufacturers
• The most frequently found
deficiencies were:
– Material management
– SOPs
– Cleaning
• Others included:
– Batch records
– Labelling
– Cross contamination
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10
9
Cross
contamination
Batch records
8
7
6
SOPs
5
Material
Management
Cleaning
4
3
2
1
Labeling
0
Major deficiencies
Inspections of Contract Research
Organizations (CROs)
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http://apps.who.int/prequal/
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Prequalification Programme: International norms,
standards and guidelines used in inspection activities
to ensure wide applicability
•
HANDBOOK FOR GOOD CLINICAL RESEARCH PRACTICE (GCP)
Guidance for implementation
http://whqlibdoc.who.int/publications/2005/924159392X_eng.pdf
•
Guidelines for good clinical practice (GCP) for trials on pharmaceutical
products. World Health Organization, 1995 (WHO Technical Report
Series, No. 850), Annex 3.
http://apps.who.int/prequal/info_general/documents/TRS850/WHO_TRS_850Annex3.pdf
•
Additional guidance for organizations performing in vivo bioequivalence
studies. WHO Technical Report Series, No. 937, 2006, Annex 9
http://apps.who.int/prequal/info_general/documents/TRS937/WHO_TRS_937__an
nex9_eng.pdf
•
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Guidelines for the preparation of a contract research organization
master file. World Health Organization, WHO Technical Report Series,
No. 957, 2010 Annex 7, Page 271.
http://www.who.int/medicines/publications/TRS957_2010.pdf
Other
guidelines
e.g. ICH
CRO/BE Inspections: Problems with integrity,
archiving and retrieval of documents
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CRO/BE Inspections: Inadequate data integrity
Source data either not available or authenticity
questionable:
• Source data could not be located to verify entries in VRFs
–
–
destroyed accidently by fire or rain
Sponsor claims the data were kept by the CRO, and the CRO
claims the data were kept by the sponsor
•
Two of the ECGs shown to the inspectors, bearing different
subject numbers and initials, were found to be identical.
•
Other ECGs bearing different subject numbers and initials
appear to have been recorded from a single subject. Out of
95 ECGs copied by the inspectors, 43 appear to have
been recorded from the same and single subject during
a single session
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The following images are lead III of the screening and follow-up ECGs of
volunteers AND and KRK, respectively, as copied during the inspection. They
show no difference in QRS complex morphology.
• Lead III, screening ECG, subject AND
• Lead III, follow-up ECG, subject AND
• Lead III, screening ECG, subject KRK
• Lead III, follow-up ECG, subject KRK
•
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CRO/BE Inspections: Data manipulation –
inappropriate manual integration of peaks
• Manual reintegration of peak was
done
inappropriately
and
inconsistently
for
all
peaks
inclusive internal standard
–
For some samples checked, especially QCs or
standards close or outside the 15% of their
nominal concentration, the baseline of the
chromatograms were modified manually. This was
not done appropriately and consistently for all
peaks inclusive internal standard. For modified
integration, initial integration was not available.
• No paper or electronic audit trail of
manual integration available.
• Each analytical run did not include
calibration and quality control
samples.
40
CRO/BE Inspections: Data manipulation - Identical
chromatograms had different peak areas but the same
area percent
41
Deficiencies observed during PQ Inspections
QC Laboratories: Conclusions
• Data manipulation and misrepresentation is not
acceptable to the WHO and according to the law
of most national regulatory authorities (could
result in the publication of NOC or NOS on
behalf of the WHO).
• The honest way is always the "right way".
• Good ethics are key to reliable data.
• Always prioritize data integrity – not quick batch
release at any cost.
42
WHO-PQ Inspections
Summary and Conclusions
•
•
•
•
•
•
API, FPP and CRO/BE Inspections are an important part of
the WHO-PQP evaluation and continuous monitoring process
International norms, standards and guidelines are used in
inspection activities to ensure wide applicability
Collaborative and Risk management principles are applied
to ensure efficient use of available resources
Information put in public domain - available for use by
NMRAs: WHOPIRs and NOCs
Inspection results show that there are still a lot of poor
manufacturing practices out there. Collaborative effort and
skills are needed to ensure access to medicines of assured
quality. Results show that WHO-PQP has made
tremendous contribution in this respect.
The support of NRAs in providing co-inspectors and
observers is appreciated. This is good for:
–
–
–
–
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Tapping into international skills
Ensuring transparency
Facilitating ownership
Contributing to capacity building
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