WHO Prequalification Programme: Priority
Essential Medicines
WHO API GMP Inspections
Presented by
Mr. Ian Thrussell
Head of Inspections
WHO
thrusselli@who.int
In this presentation:
•
•
•
•
WHO-PQ: Inspection activities
WHO-PQ: Norms and standards
WHO-GMP for APIs and ICH Q7
WHO-PQ API inspections: Observed trends and
deficiencies
• Conclusions
Inspection of API manufacturing
sites: put in perspective.
• Chris Joneckis, Ph.D., senior adviser for chemistry,
manufacturing and controls (CMC) issues: USFDA, noted
that:
– "quality, safety and effectiveness must be designed and built
into the product. Quality cannot be inspected or tested into
the finished product."
• http://www.entrepreneur.com/tradejournals/article/154459079.html
• Ensuring the quality of the API greatly contributes to
achieving the objective of building the quality, safety and
efficacy into the product.
– Inspection of API manufacturing sites is to assess compliance with
Good Manufacturing Practices, and to verify data submitted in
product dossiers and APIMFs.
3
http://www.who.int/medicines/areas/quality_safety/en/
WHO Prequalification: Inspection
activities
*Stringent Regulatory
Authority
APIs,
FPPs
BE/CROs
Prequalification: Inspection
Processes
‰ By a team of qualified and experienced inspectors
WHO representative (Qualified inspector small team of 6 with almost a
hundred years of GMP inspection experience – all have had senior
regulatory experience 2/3 with so called SRAs)
Inspector from well-established inspectorate (e.g. EEA, Pharmaceutical
Inspection Cooperation Scheme countries – PIC/S)
National inspector/s invited to be part and/or observe the inspection
Observer from recipient/developing countries (nominated by DRA of the
country)
‰ Scope:
‰ Compliance with guidelines: GMP (FPP and API (ICHQ7)), GCP, GLP
Î Data verification –
ÎIn accordance with dossier submitted
ÎData manipulation, falsification, (validation, stability, clinical, bioanalytical)
‰ Quality control (QC, BAL, National QCL, IQCL)
‰ Normally announced but some are NOT
9
9
9
9
Prequalification Programme: Use of Inspection
reports from other NMRAs
•
•
•
An inspection by the PQP may be omitted when other acceptable evidence of GMP
compliance (Report + CAPAs) is provided by the FPP or API manufacturer.
An inspection by another acceptable organization, such as a PIC/S member country,
or US FDA or EU, may be considered in lieu of a PQP inspection when:
– The inspection was conducted within the last 2 years, and
Î The scope of the inspection covered the specific API in question, and
Î The FPP or API manufacturer submits a copy of the last inspection report
for review by the PQP. (During the review, the inspectors will determine
whether the inspection was comprehensive, covered the relevant areas
appropriate to the product in question and that the inspection report supports
the final outcome in accordance with WHO GMP).
– Irrespective of the above, the PQP reserves the right to inspect any API
manufacturer if considered necessary (specific product issues).
Whether inspected by the PQP or GMP compliance is based on an inspection by
another acceptable organization, on-going GMP compliance will be confirmed by
WHO (also using update information from other NMRAs).
Extensive collaboration with regulators
•
•
•
Not duplicating work done by stringent regulatory authorities
• Recognition of inspections by other parties
• Joint inspections with PIC/S members
• SRA approval of new and generic products – abridged procedure
• US FDA tentative approvals – based on confidentiality agreement including in the
PQ products list
• European Medicines Agency (EMA) – Art 58 … and beyond
• Collaboration with EDQM, in particular in the area of APIs (confidentiality
agreement to be signed)
Active participation and involvement of National Regulatory Authorities
• SRA experts
• Regulatory authority experts from less resourced settings
Joint Inspections
• In February WHO joined Programme to rationalise international GMP inspections
of active pharmaceutical ingredients/active substances manufacturers
• http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/02/WC500
123489.pdfFebruary 2012
•
8
Number of inspections performed by WHO Pre‐
qualification Programme
60
50
40
FPP
API
CRO
QCL
total
30
20
10
0
2005
2006
2007
2008
2009
2010
WHO GMP and Inspection of API
manufacturers
35
• Most API inspections were
conducted in India followed
by China.
• The number of China API
sites inspected has
increased of recent
30
25
India
China
South Korea
Vietnam
20
15
10
5
0
Countries inspected
WHO GMP and Inspection of API manufacturers
The early Years (2002 – 2009)
Number of inspections per year
12
10
2002
2004
2005
2006
2007
2008
2009
8
6
4
2
0
Inspections
•
•
API inspections have
been increasing over
time.
Most API inspections
were conducted in 2005,
2006, 2008 and 2009.
Guide to Manufacturer Risk
Classification
Ref: SOP 401.1: Inspection Frequency and Scheduling
RELATIVE RISK CATEGORY
PRODUCT TYPE / ACTIVITY
CRITICAL
Finished Products:
Sterile finished products
Non-sterile finished products
APIs:
Sterile APIs
Non-sterile APIs where there is a special risk
(e.g. isomerism, polymorphism, special
risk of harmful impurities, etc)
Other non-sterile APIs
QC Laboratories
CROs
HIGH
MEDIUM
LOW
WHO GMP and Inspection of API manufacturers
2012
• In 2012 there are a total of 27 GMP inspections
sites located in China programmed out of a total
of 79 planned inspections of (this compares to 41
scheduled sites which are in India)
• Of these 27 site inspections 22 are of API
manufacturers and 5 are FPP. (For India APIs
represent 19 API sites and 22 FPP sites).
Risk based approach to
inspections
Inspections are scheduled on a risk basis, taking into account all known
factors that could affect quality, safety and efficacy, including but not
limited to the following:
– results of previous WHO inspections
– results of inspections by other National Regulatory Agencies
– 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)
RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS
WITHIN THE WHO PREQUALIFICATION PROGRAMME
(1 of 2)
API
Manufacturer
Present in Product
(Ref. Nos.)
Number of Products
Parameter
Risk = 2
Risk = 1
Y
N
Low
High
3 Synthesis
Complex
Not complex
4 Solvents
High Risk
Low risk
5 Impurities
High Risk
Low risk
6 Sterile
Y
N
7 Fermentation
Y
N
1 Polymorphism
2 Solubility in water
Risk Score
RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS
WITHIN THE WHO PREQUALIFICATION PROGRAMME
(2 of 2)
Parameter
8 Toxicity
9 Activity/potency
10 Particle size
Risk = 2
Risk = 1
High
Low
High Risk
Low risk
High Risk
Low risk
Negative
Positive
Risk Score
11 Other property consideration
12
Site compliance information
(WHO/EDQM/USFDA/Other)
Total Risk Score
General remarks:
Last inspection date
Outcome
High
Inspection prioritization
Medium
Low
Compliant
Not Compliant
Inspection Duration Guide (on-site days)
Ref: SOP 401.1: Inspection Frequency and Scheduling
RISK
Manufacturer Size
C
H
M
L
C
Initial Inspection
H
M
L
Re-inspection
Large
5
4
3
3
4
3
3
2
Major
4
4
3
3
3
3
2
2
Standard
4
3
3
2
3
2
2
2
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
– Minor or Other Observation – departure from
good practice
Further considerations for
classification
1. Classification of an observation is based on the
assessed risk level and may vary depending on the
nature of API manufactured, e.g. in some
circumstances an example of an "other" deficiency may
be categorized as "major".
2. A deficiency that was reported at a previous
inspection and not corrected may be reported in a
higher classification.
3. One-off minor lapses or less significant issues are
usually not formally reported, but are brought to the
attention of the manufacturer during the inspection.
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/ICHQ7.
– 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
Transparency: Information put in public
domain - 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.
– A NOC may be issued to a company but never published on the WHO Internet
Pages because the company resolves the issues promptly and in a manner
that satisfies us within the normal inspection process
Publication of WHOPIR
Publication of WHOPIR
Appeals against an NOC
• Manufacturers may appeal against notice of concern
decision by WHO-PQP
• The appeal must be based upon science and risk
• Appeal could be sent to the Head of Inspections
• Appeal could be sent to the Programme Manager
• Investigation of an appeal
• Response to appellant
24
Quality of Pharmaceutical Ingredients
29 June 2012 Shanghai
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, MA,
TB
Total
0
0
46
0
0
49
0
0
0
6
2
1
1
25
HA
TB
MA
RH
IN
D
HA, IN
Not yet Inspected
20
15
8
3
0
0
0
0
Innovators/PICS
33
3
8
5
0
0
0
0
Sites inspected - NC
1
4
1
0
0
0
0
Sites inspected - C
10
5
4
0
0
0
2
Type of API
HA, TB HA, MA
Prequalification Programme: International norms,
standards and guidelines used in inspection
activities to ensure wide applicability
•
•
•
Quality Assurance of pharmaceuticals. A compendium of
guidelines and related materials. Vol.2, GMP and inspection.
WHO, Geneva, 2007.
http://www.who.int/medicines/areas/quality_safety/quality_a
ssurance/production/en/index.html
WHO GMP for APIs: Annex 2, WHO TRS957, 2010:
http://whqlibdoc.who.int/trs/WHO_TRS_957_eng.pdf#page=
144
WHO GMP: water for pharmaceutical use. 39th Report.
Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 3.
http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf
Prequalification Programme: norms,
standards and guidelines used…
•
WHO guidelines for sampling of pharmaceutical products
and related materials. 39th Report. Geneva, WHO, 2005
(WHO TRS, No. 929), Annex 4.
http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf
•
Supplementary GMP guidelines for HVAC systems. 40th
Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex
2.
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf
•
Supplementary GMP guidelines: validation. 40th Report.
Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 4.
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf
•
Good Practices for National Pharmaceutical Control
Laboratories. 36th Report. Geneva, WHO, 2002 (WHO TRS,
No. 902), Annex 3.
http://whqlibdoc.who.int/trs/WHO_TRS_902.pdf#page=37
USP
BP
Ph. Eur.
Ph. Int.
Other
guidelines
e.g. ICH, ISO
WHO GMP for APIs / ICH Q7
Key definitions:
– API starting material (API SM): a raw material,
intermediate or an API used in the production of an API
and incorporated as a significant structural fragment
into the structure of the API. API SM can be an article
of commerce, a material purchased from one or more
suppliers under contract or commercial agreement, or
produced in-house. API SM are normally of defined
chemical properties and structure.
– Intermediate: A material produced during steps of the
processing of an API that undergoes further molecular
change or purification before it becomes an API.
ICH Q7 : Introduction
zFrom what point does ICHQ7 start to be
applied ?
– “ICH Q7A applies from the point at which production
of the API begins”.
– Some indications are provided in Table 1 of ICH Q7.
• For synthetic process, this corresponds to the
introduction of the API starting material into the
process;
• For other processes, on a case by case basis.
Increasing GMP requirements
WHO GMP and Inspection of API
manufacturers
Main issue : How to define the API SM ?
RM (solvent, catalyst, reagent, filtration aid,
decolorizing agent, chromatography phase,
etc.)
C, H, O,
N
SM
(Intermediates)n
Only flow chart
GMPs do not
apply
Competen
t
Detailed
description
API SM
GMPs apply
Active substance
crude
Active substance
(pure)
Industry
Authorities
Photo :
Application of ICHQ7
•
Companies should decide at which point ICH Q7A applies for their
processes and should have documentation to support it. GMP applies
from the declared and approved (API) SM in the registered file.
•
Stringency of GMP in API manufacturing increases from early steps to
final steps
•
Advanced intermediates and crude APIs outsourced should be
manufactured in compliance with GMP
– This means that these “late intermediate and crude API”
manufacturers should be considered as contract manufacturers (Q7A
chapter 16 applicable).
•
Sterilisation and aseptic processing should be performed
according to GMP related to Sterile Pharmaceutical Products.
Inspection of API manufacturers observations
•
•
The most frequently found observations were:
– Material management
– SOPs
– Cleaning
Others included:
– Batch records
– Labelling
– Cross contamination
10
9
Cross
contamination
Batch records
8
7
6
SOPs
5
Material
Management
Cleaning
4
3
2
1
Labeling
0
Major deficiencies
•
•
•
Most deficiencies were observed in sites for TB APIs and these were the sites
with most of the major observations.
Although sites for Malaria APIs had equally high number of observations, most
of them were not major.
The sites for HIV APIs were generally in a reasonable shape.
API GMP Concepts and observations
z Quality management (Chapter 2)
– Responsibilities of the Quality Unit
– Sections 2.22-1 to 2.22-15
– Tools for surveillance, monitoring and continuous
improvement:
– Internal audits/Self inspection (section 2.4)
– Product Quality review (section 2.5)
– Complaints, returns and recall (sections 14.5 and 15)
– Change control (section 13)
Change Management
– Raw materials, specifications,
analytical methods, facilities,
support systems, equipment
(including computerized
systems), processing steps,
labelling and packaging
materials
– That can impact the quality of
the API
– Not restricted to the API plant
technical process
– Expansion and additional
shifts ARE changes
– Other activities on the site
MUST be considered
– Proposal drafted, reviewed and
approved by the appropriate
organisational unit
– Change reviewed and
approved by QU
– Classification and impact
assessment
– Evaluation and monitoring +
Notification
Facilities, equipment and utilities
system
– Facilities designed to prevent mix-ups
and contamination
– Precautions implemented based on a
risk assessment
– Equipment cleaning methodology and
intervals appropriate to prevent buildup and carry-over of contaminants
(degradants)
Critical operation with
prolonged exposure to
the environment
Non critical operation with
prolonged exposure to the
environment
Non critical or critical
operation in a closed
equipment
z HVAC systems (section 4.2)
– Adequate ventilation, air filtration and exhaust
systems should be provided where appropriate
(ICH 4.21, 4.22)
– Qualification and appropriate monitoring and
operating range limits in place (ICH 4.20)
z Water (section 4.3)
– WHO potable water quality as a minimum (ICH
4.31)
– Water for final isolation and purification steps
for API for sterile products: test for microbial
counts, objectionable counts and endotoxins.
Material management and transport
z Material management (ICH section 7)
– At least, identity testing of each batch on a sample
representative of the batch (ICH 7.30)
– Reduced testing for approved/validated suppliers
(ICH 7.31)
• Past quality history
• Full analysis at least on three batches before
starting reduced-testing
• Reliability of the CoA checked at regular
intervals
• A documented supplier audit is not required
but currently performed in the case of critical
material by API manufacturers.
– Precaution for bulk deliveries in non-dedicated
tankers (ICH 7.22)
Production
– Critical operations should be witnessed or
subjected to an equivalent control (ICH
8.12)
– Deviations should be documented,
explained and/or investigated (ICH8.15)
– Process time limits should be respected
(ICH8.20)
– Conditions and duration of storage of
intermediates (ICH 8.21)
– In-process sampling and controls (ICH 8.3)
• approved written procedures, avoid risk of cross
contamination during sampling, sample integrity
Production Blending operations (section 8.4)
• Only batches meeting
established specifications
• Expiry or retest date of
the blended batch based
on the manufacturing
date of the oldest batch
included.
• Should be controlled and
documented – traceability
• Validation for
homogeneity following
blending
OOS batches
blended with
others to meet
specifications
1. Blending small
batches to ↑se batch
size
2. Blending tailings
APIs for OSDs/
Suspensions
1. Particle size
distribution
2. Bulk density
3. Tap density
Reprocessing or reworking for intermediates
or APIs which do not conform to standards or
specifications
z Reprocessing (s. 14.2)
– Repeating a step of the established
manufacturing process
• Crystallization, distillation, filtration,
chromatography, milling, etc
• Continuation to completes process after
IPQC in not reprocessing
• Introducing unreacted material into
reaction is reprocessing
– Included in the standard
manufacturing process if
reprocessing used for a majority
batches
z Reworking (section 14.3)
– Reason for non conformance
determined prior to any reworking
– Involves a “treatment” different from
the established one
• Recrystallization with a different
solvent
– Reworked batches to be subjected
to appropriate evaluation, testing ±
stability testing
• Concurrent validation
• Should have comparable impurity
profile
Recovery of Materials and solvents
– Reactants, intermediates or APIs
may be recovered from mother liquor
or filtrates.
– Must use approved procedures and
specifications.
– Recovered solvents may be reused
in same process or in different
process if confirmed to meet
appropriate standards.
– Fresh and recovered solvents and
reagents if confirmed their adequacy
1. No approved procedures
2. Specs – carry over impurities
3. Not adequately tested
4. Use not documented
1. Approved procedures
2. Suitable specs
3. Adequate testing
5. Use documented
Validation (section 12)
– Applies to
• Analytical methods
• Process
• Cleaning
• Computerized systems
1. Prospective validation (≥3 consec batches):
•
complete before commercial distribution
2. Current validation (≥3 consec batches):
•
•
For API produced infrequently
Batches may be released for commercial
distribution after monitoring and testing
3. Retrospective Validation (10 - 30 batches):
•
•
•
Only in exceptional cases
For well established process
All batches, including failed ones
– Validate operations critical to the quality and purity of the API
– Periodic review of validated systems
Conclusion
– GMP is a “What to do document”
– “How to do” is sometimes described
– Flexibility
– If necessary, when appropriate …
– “Should” even if it could be interpreted mostly as “must”
– Emphasis on the risks of
– Contamination and cross contamination
– Mix-ups, build-up and carry-over of degradants
– Lack of traceability
Summary and Conclusions
•
•
•
Inspection of API sites is part of the WHO-PQ procedures
International norms and standards are used during WHOPQ inspections
Risk management principles are applied when:
– scheduling inspections
– conducting inspections
– closing out inspections
•
•
Inspections of API sites has increased over time. Most of
the API sites inspected by WHO-PQ are in India and China
Deficiencies have been observed mainly in:
– Material management, SOPs, Cleaning, Batch records,
Labelling, Cross contamination
•
Most deficiencies have been observed on sites for TB and
Malaria APIs.
ధన
ా ల
谢谢！
WHO-PQP Inspections
Benefits to manufacturers:
• Inspections by international teams led by WHO.
• Standards used are internationally agreed.
• Procedures the same as most SRAs.
– Enables manufacturers to benchmark themselves against
international standards.
– Exposure to WHO inspections help manufacturers better understand
the expectations of other SRAs.
• TGF quality assurance policy requires use of their money to
by product prequalified by WHO or approved by a SRA.
– Applicants whose products are not yet prequalified or approved by a
SRA but are WHO GMP compliant may be recommended for timelimited use based on advice by an Expert Review Panel (ERP)
• Reduces inspection burden:
– results used by other NMRAs, manufacturers and procurement
agents [TGF, UNITAID, UNICEF, UNFPA, GDF, NGOs (ICRC, MSF)].
– Identified by FPP manufacturers as quality sources of APIs.
46
Quality of APIs, Tutorial
Hyderabad, 16 September, 2011