WHO Prequalification of Team Introduction to medicines

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WHO Prequalification of Team Introduction to medicines
WHO Prequalification of Team
Introduction to medicines inspections
technical updates
Deusdedit K. Mubangizi
Group Leader, Inspections
WHO Prequalification Team
[email protected]
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UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
In this presentation:
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Role of WHO-PQT towards MDGs.
Inspectorate within new WHO-PQT within EMP/RHT
How to get inspection Information on the website
Risk-based inspections
Use of inspection reports by other authorities.
Triggers for the inspection.
Statistics
Worrying trends
Best approaches to responding to inspection observations.
Upcoming guidelines
How to contact the inspection team.
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UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
• WHO-PQ contributes to the
Millennium Development
Goals (MDGs):
• Eight international
development goals that 192
United Nations member states
and at least 23 international
organizations have agreed to
achieve by the year 2015
4. Reduce child mortality
5. Improve maternal Health
6. Combat HIV/AIDs, Malaria
and other diseases
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
3
Structure of Department of Essential Medicines & Health Products
Essential Medicines
and Health Product
[EMP]
Policy, Access and Use
[PAU]
Technologies Standards
and Norms
[TSN]
Regulation of
Medicines and other
Health Technologies
[RHT]
Regulatory Systems
Strengthening
[RSS]
Public Health,
Innovation and
Intellectual Property
[PHI]
Prequalification Team
[PQT]
Safety and Vigilance
[SAV]
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UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
Structure of the Prequalification Team
Prequalification
Team
Coordinator’s
office
Vaccines
Assessment
Medicines
Assessment
Diagnostics
Assessment
Inspections
Technical
Assistance/Labs
Administrative team
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UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
The inspection Team
Ian Thrussell
Senior Inspector
Deus Mubangizi
Group Leader, PQT Inspections
Being
processed
OHSE, Sabine
Diagnostics
Stephanie Croft
CROs/CRM
Sun Jinglin, China (has left)
Rotational Fellow, China/India
Vimal Sachdeva
Training/FPP/RH
Xingyu Chen Iveta Streipa-Naumane
APIs/Complaints QMS/Statistics/QCLs
Kate Kikule, EAC/NDA-UG
Rotational Fellow, AFRICA
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
Vacant
Vaccines
Ana Garcia Miguel
Secretary
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http://apps.who.int/prequal/assessment_inspect/info_inspection.htm#2/
Selected GMP topics for manufacturers and GMP inspectors
Nairobi, May 9-12, 2011
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1.2 Risk based approach to inspections
Ref: SOP 401.1: Inspection Frequency and Scheduling
> Inspections are scheduled on a risk basis, taking into account all
known factors that could affect quality, safety and efficacy,
including the following:
– results of previous WHO inspections
results of inspections by other National Regulators
– type of APIs, products and dosage form manufactured or - activities
performed
recalls or complaints since last inspection
results of product testing
– significant changes within the manufacturer, e.g. changes to key
personnel, buildings, equipment, products etc.
– any other relevant information (e.g. variations)
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
WHO-PQT-Rx: Use of Inspection reports from other NMRAs
- SOP 424.1 Desk Review
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 FPP or API
Is comprehensive and supports the final outcome.
PQP reserves the right to inspect the FPP/API manufacturer – as long as product
is active in WHO-PQP.
on-going GMP compliance will be confirmed by WHO
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UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
22/09/2014
WHO-PQ Inspections
> Eligibility for WHO-PQ inspections:
– companies that are producing or intend to produce
products invited under EOIs and
• have either submitted dossiers to WHO-PQ for assessment. or
• that demonstrate a serious intention to submit dossiers to
WHO-PQ for assessment within an acceptable period.
> Trigger for inspection:
– Only following submission of the product dossier.
> Target:
– within 6 months of dossier acceptance for assessment
and preferably after 1st round of assessment.
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
10
22/09/2014
Exceptions to the general rule
> Companies producing certain high priority products:
– pre-inspection PRIOR to PQ submission to expedite access and assessment of
products by early identification of GMP gaps and implementation of
improvements in GMP.
• Currently only DMPA Injection in the RH EOI eligible on acceptance for rolling submission.
> Under WHO-PQ/ Nigeria-NADFC joint special project:
– declared intention/commitment to build a regional capacity in certain essential
medicines.
• Compliance with GMP declared via pre-inspection WHOPIR on WHO-PQ website.
> Certain manufacturers of certain priority medicines of critical interest
outside the EOI:
– at the request of the relevant Disease Programmes of WHO, e.g. NTDs.
> Delayed at the request of the manufacturer:
– persistent requests for a delay or a refusal of an inspection may be considered
grounds to stop assessment, and ultimately to reject the application.
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
11
22/09/2014
Clearing misconceptions
> Pre-visits by personnel working with WHO providing technical
advice are not inspections.
> Demonstration visits performed by WHO PQT Inspectors as part
of training organised by or supported by WHO PQT cannot be
used to declare GMP compliance.
– These are usually targeted on very specific training needs
and rarely cover all aspects of GMP guidance.
– Although feedback will be provided to companies who
volunteer to host these visits, they should not be considered
or represented as WHO inspections
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
12
WHO-PQT-Rx: Target Inspection Timelines
> First inspection: 6 months from dossier acceptance for
assessment or from site confirms it is ready.
> Routine inspection: ± 3 months from due date.
> Notification: 1 – 2 months before inspection.
> Onsite days: 3 – 5 days.
> Report: 30 days from last date of inspection.
> CAPAs: 30 days from receipt of report (max 2 rounds,
comprehensive, on CDs and not hard copies)
> Closing of inspection: 6 months from inspection.
> Follow-up inspection: 6 months from inspection
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UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
22/09/2014
STATISTICS: INSPECTIONS 2013
FPP SITES
API SITES
CRO SITES
QCL SITES
TOTAL
34
22
11
16
83
NEW
REINSPECTION
32
51
COMPLIANT
AWAITS CAPAs
NOT COMPLIANT
PRE-AUDITS
TOAL
49
12
16
6
83
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
14
22/09/2014
DATE REPORT SENT
Total
Number
Average
Minimum
Maximum
First Quartile, Q1
Median, Q2
Third Quartile, Q3
2013: New Sites
FPP SITES
API SITES
TOTAL
API SITES
TOTAL
Range: 0 – 148 days
Median: 28 days
COMPLIANT AWAITS CAPAs
16
7
23
6
2
8
2013: Re-inspections
FPP SITES
2883
81
36
0
148
15
28
42.5
1
2
3
Target: 30 days
NOT COMPLIANT
TOTAL
9
3
12
16
7
23
COMPLIANT AWAITS CAPAs NOT COMPLIANT TOTAL
18
15
33
13
6
18
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
5
3
8
0
6
6
18
15
33
15
22/09/2014
NEW SITES: Days from acceptance to first date of inspection
FPP+API
FPP
Total
Number
Average
Minimum
Maximum
First Quartile, Q1
Median, Q2
Third Quartile, Q3
2284
23
99
13
263
33
87
145
Total
Number
Average
1387
16
87
Minimum
Maximum
First Quartile, Q1
Median, Q2
Third Quartile, Q3
API
27
261
30.75
70
127.25
Total
Number
Average
897
7
128
Minimum
Maximum
First Quartile, Q1
Median, Q2
Third Quartile, Q3
13
263
69
130
189
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
Rage: 13 – 263 days
Median: 87 days
Target: 180 days (6 months)
Range: 27 – 261 days
Median: 70 days
Target: 180 days (6 months)
Range: 13 – 263 days
Median: 130 days
Target: 180 days (6 months)
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22/09/2014
RE-INSPECTIONS: Days from acceptance to first date of inspection
FPP+API
FPP
API
Total
Number
Average
Minimum
Maximum
First Quartile, Q1
Median, Q2
Third Quartile, Q3
92
33
3
-136
175
-23
1
27
Total
Number
Average
-208
18
-12
Minimum
Maximum
First Quartile, Q1
Median, Q2
Third Quartile, Q3
-136
103
-53
-4
26
Total
Number
Average
Minimum
Maximum
First Quartile, Q1
Median, Q2
Third Quartile, Q3
300
15
20
-48
175
-6
3
29
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
Rage: -136 – 175 days
Median: 1 day
Target: 180 days (6 months)
Range: -136 – 105 days
Median: -4 days
Target: 180 days (6 months)
Range: -48 – 175 days
Median: 3 days
Target: 180 days (6 months)
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Worrying Trends
Media is awash with NOCs, warning letters, import alerts,
statements of non-compliance, complaints, recalls, etc.
> Data integrity and falsification
– unbalanced focus on QC (quality built in – not tested in).
> « Show-case » and « shadow » industries.
> « Knee-jerk » responses to inspection observations.
> Many « Awaits CAPAs » on routine inspection:
– poor maintenance of quality systems
– work hard to pass first inspection and then go on holiday
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
18
RESPONSES TO INSPECTION OBEERVATIONS (1)
> An inspection is a sampling exercise and by consequence not all
aspects of the manufacturing process may be inspected.
– The manufacturer is encouraged to take the
information provided in the inspection report as
examples and to consider vertical and horizontal
analysis of the issues.
– nonconformities described in the report that are
designated to be of lesser degree of severity, may
increase in severity if not satisfactorily addressed
in a timely manner.
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
RESPONSES TO INSPECTION OBSERVATIONS (2)
> The manufacturer is required to submit an action plan in response
to the observations and all nonconformities noted in the final
inspection report within 30 days after receipt of the report.
> It is suggested that the action plan incorporates:
– root cause analysis (how/why did this happen),
– analysis regarding related areas (is this same issue
impacting/occurring elsewhere),
– correction (fix now) with completion dates,
– corrective action (to prevent recurrence) with completion dates
and,
– The plan for demonstration of effectiveness of the actions
taken.
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
22/09/2014
New Format for Submission of CAPAs
Name of Manufacturer
Unit number
Production Block
Physical address
Contact person(s) and email address
Date of inspection
Inspector(s)
Observations
Critical
1. a)
2. a)
Major
3. a)
4. a)
Other
5. a)
6. a)
Root cause analysis
(Additional
information may be
attached as annexes)
Correction and proposed
corrective action
(Additional information may
be attached as annexes)
The steps that have or will be
taken for the demonstration
of effectiveness of the actions
taken
Timeline
Assessment by
inspector
a)
a)
a)
a)
a)
a)
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
21
22/09/2014
Upcoming New and Revised Guidelines
> Good data management – new guidance
> Good Manufacturing Process for hazardous substances – update
> Good Manufacturing Practice for APIs (Q&As) – collaboration with
ICH IWG – update
> Supplementary guidance on GMP: validation for non-sterile
process validation and other areas – Proposal for revision
> Guidance for Inspectors on “hold-time” studies – general guidance
> Quality risk management – Q&As
> Guidance for organizations performing in vivo bioequivalence
studies – revision
> Classifications for inspection deficiencies – new guidance for
inspectors
> Model inspection report – update
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
22
HOW TO CONTACT US
谢谢!
谢谢!
UNICEF, UNFA & WHO Joint meeting with manufactures and suppliers
UN City, Copenhagen, Denmark, 22 – 25 September 2014
23

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