EU Guidelines Formalised Risk Assessment for Ascertaining ......(2015/C 95/2) • Article 46(f) of...
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EU Guidelines
Formalised Risk Assessment for Ascertaining the Appropriate
GMP for Excipients of Medicinal Products for Human Use
(OJ 2015/C 95/02)
IPEC EUROPE ‘HOW-TO’
DOCUMENT
Kaat Bracquiné
Sr. Manager Quality & Regulatory April 27th, 2016
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•
Delivering high-quality, innovative dosage forms and solutions
for the healthcare industry to turn their compounds into better medicines and nutritionals.
• Sr. Manager Quality and Regulatory
Capsugel Hard Capsule excipient business unit
• Since long IPEC member
My Profile – Kaat Bracquiné
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Content
• Background
• Excipient GMP - EU Legislative Journey
• EU Guideline – Excipient GMP (2015/C 95/2)
• IPEC EUROPE ‘HOW –TO’ DOCUMENT
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Content
• Background
• Excipient GMP - EU Legislative Journey
• EU Guideline – Excipient GMP (2015/C 95/2)
• IPEC EUROPE ‘HOW –TO’ DOCUMENT
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Background
Market Context
• Challenges of globalized
supply chain leading to
updated regulation
• Industry trend towards
Quality By Design for
pharmaceutical
developments
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Background
Excipient Sourcing
Excipient Origin
Animal
Mineral
Plants
Chemical
Manufacturing
Process
Diverse Quality
Systems
• Dedicated process or
not ?
• Complex process or
simple blend ?
• Chemical substance
or mixture ?
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Background
Excipient Risk?
Traceability
& Supply Chain
Safety
& Integrity
Functionality
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Content
• Background
• Excipient GMP - EU Legislative Journey
• EU Guideline – Excipient GMP (2015/C 95/2)
• IPEC EUROPE ‘HOW –TO’ DOCUMENT
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Excipient GMP
EU Legislative Journey
2001 2004 2011
GMP for Medicinal Products
Directive 2001/83/EC
GMP for Active Ingedients
(API)
Directive 2004/27/EC
GMP for Excipients
Directive 2011/62/EC
(Falsified Medicines Directive)
EU GMP chapter 5
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Excipient GMP
EU Legislative Journey
Falsified Medicines Directive
API &
Excipients
Internet sales
Safety
features
Supply chain
& GDP GMP for excipients
introduced under
formalized risk
assessment
Deadline
March
2016
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Content
• Background
• Excipient GMP - EU Legislative Journey
• EU Guideline – Excipient GMP (2015/C 95/2)
• IPEC EUROPE ‘HOW –TO’ DOCUMENT
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EU Guideline
Excipient GMP (2015/C 95/2)
• Article 46(f) of Directive 2011/62/EU requires all Manufacturing
Authorisation Holders (MAHs) to verify that the excipients they use are
made according to appropriate GMP.
• EC published guideline on how to do this on 19 March 2015 (OJ
2015/C 95/02) becoming effective 21 March 2016.
• The objective of the guideline is to assure patient safety through the
evaluation of risks, and application of suitable GMPs
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EU Guideline
Excipient GMP (2015/C 95/2)
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EU Guideline
Excipient GMP (2015/C 95/2)
Linked to Source
Origin
o TSE, Viral/micro contamination,
sterility
o Impurities (aflatoxines, pesticides)
o Process carry-over: Residual
solvents, catalysts
Manufacturing
o Process/product carry over:
Impurities
Stability
o Stability parameters
o Environmental / Storage / Transport
conditions
Supply Chain
o Complexity
o Packaging integrity
Linked to Use and Function
– Pharmaceutical form and use?
– Excipient function?
– Excipient proportion in medicinal product?
– Daily intake?
– Known quality incidents?
– Composition?
– Impact on critical quality attributes?
RISK
CONSIDERATIONS
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Content
• Background
• Excipient GMP - EU Legislative Journey
• EU Guideline – Excipient GMP (2015/C 95/2)
• IPEC EUROPE ‘HOW –TO’ DOCUMENT
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1. Introduction
2. Preamble
3. The Risk Assessment Process
4. Risk mitigation activity including communication
with the Suppliers
5. Residual risks resolution (e.g. Excipient risk
classification)
6. Triggers for risk review
How To Document Structure
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CHALLENGES WITH THE GUIDELINE
• Quality systems applied during the manufacture of pharmaceutical excipients
are diverse and generally based on the material’s intended use which may not
be primarily as a pharmaceutical excipient.
• Adjusting current quality systems to the “pharmaceutical quality systems”
outlined in the guidelines may be problematic:
1. Guidance does not provide definitions
2. Different dosage forms, different Users different requirements
IPEC Europe members, including representatives from both Suppliers and
Users of excipients have prepared this “How to document” to help
Manufacturing Authorisation Holders comply with the new Guidelines
• Its role is to illustrate how excipient suppliers can facilitate the risk assessments
and other steps needed for compliance.
• Use of this document should support a quick and efficient implementation and
avoid duplication of work in the industry.
‘HOW-TO’ DOCUMENT 1. Introduction & 2. Preamble
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WHAT’s NEW?
• Risk processes are already applied in the industry
• The EU Guidelines (2015/C 95/02) have not introduced new or
higher requirements where Quality Management Systems are
compliant with e.g. IPEC-PQG GMP Guide 2006, EXCiPACT or
NSF/IPEC/ANSI-363 2014 standards
Excipient Users:
• The tools and insights in the ‘How-to’ document will help to proactively address this new GMP compliance assessment.
CURRENT SOPs
Risk Management
Supplier Qualification
NEW
EU Guidelines
(2015/C 95/02)
GAP
ANALYSIS
‘HOW-TO’ DOCUMENT 1. Introduction & 2. Preamble
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Data gathering (EU guideline sections 2.3 & 2.4)
1. Internal
i. Supplier quality records
ii. Audits
2. External
i. Excipient Information Package (EIP)
ii. Certifications
iii. Supply Chain information
iv. Composite excipients
Formal communication with supplier
‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
ANNEX II
Data gathering
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‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
ANNEX II
Data gathering
• Overview of available tools which can
be gathered from the excipient
manufacturer for the various sources
and origins (animal, mineral,
vegetable, synthetic), and the areas of
considerations listed in the EU
Guidelines (OJ 2015/C 95/02 - § 2.3).
• Various legislative references do not
directly apply to excipients, but are
listed where excipients are part of the
finished product assessment.
• Where judged relevant, legislative
references applicable to food are listed
in conjunction with the medicinal
products references.
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Risk assessment preparation
Excipient classification / grouping
• Users have a large selection of excipients in use for different dosage
forms with different functionality
• Categorizing can significantly reduce the risk assessment workload
• Categorizing according to route of administration / functionality /
origin
• Overall benefit of categorization is to assist in identifying which
excipients need to be formally assessed as a priority to ascertain the
appropriate GMP
Supplier Performance
History of supply
‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
ANNEX IV
Excipient
Categorization
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‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
ANNEX IV
Excipient
Categorization
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Risk identification and evaluation
• Identify and evaluate the potential risk factors
• Ensure the risk factors are clearly characterise severity, probability and
detectability and their likely impact on product quality/performance.
• Risk scoring. Some possible examples;
o Linear: 1, 2, 3, 4
o Exponential: 1, 2, 4, 8
o Logarithmic: 1, 10, 100, 1000
o Self-made:1, 3, 7, 10
• Scoring range aligned to different levels of risk (e.g.
Low/Medium/High), and subsequently to different levels of GMP.
• The identified risks should be correlated with the GMP principles that
mitigate or control the risks.
‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
ANNEX VI
Risk Scoring
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‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
Reminder
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Risk profile determination
• Is the determined minimum level of GMP provided by the
Supplier?
– Gap analysis
• The Suppliers risk profile determined as a result of the gap analysis should provide an initial risk rating.
‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
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Risk Output
Supplier Control Strategy
Risk Mitigation
‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
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Risk output • Risk rating: Excipient + Manufacturer + Usage of the excipient, based on the
outcome of the risk evaluation e.g.
i. High / Medium / Low
ii. Minimal / Moderate / Severe
iii. Ascending numerical value
iv. Critical / Non Critical
• The output from the formalised risk assessment should be fully documented and contain:
i. Residual risk
ii. Remediation/Mitigation Plan
iii. Communication (post-assessment) to the Supplier
‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
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‘HOW-TO’ DOCUMENT ANNEX V
Reference Table
GMP Principles
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Risk review and monitoring
• New risk factors identified should be considered and
included as part of the ongoing periodic risk review
• A process for revisiting and refreshing the risk rating.
• A process for monitoring the effectiveness of the risk control
activities.
The overall risk assessment and its constituent part must
not be considered as a one-off exercise and must be
considered as a live document subject to review as and when changes are made internally and externally
‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
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Risk mitigation or reduction
• Risk assessment outcome;
Can be accepted, therefore no further action is required
Reduced with the aid of a control strategy
Requires avoidance, in which case termination of the
supply chain is the only action
• Risk reduction strategy to reduce or control the potential
failures – with clearly defined actions for the User and/or
Supplier
• Residual risk must be clearly defined based on the agreed
mitigations
‘HOW-TO’ DOCUMENT 3. Risk Assessment Process
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Risk Mitigation Plan / Control Strategy
addresses gaps identified from
the risk assessment in co-operation
with the Supplier. This may be
achieved by means of:
1. Quality Improvement Plan
(QIP)
2. Training
3. Audit / Corrective And
Preventive Actions (CAPA)
4. Escalation
5. Modification to the
User/Supplier agreement (e.g.
Quality Agreement,
Commercial agreement,
etc…)
‘HOW-TO’ DOCUMENT 4. Risk Mitigation activity
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• The EU Guidelines (OJ 2015/C 95/02) do not introduce any new GMP or GDP
requirements for excipient Suppliers and Distributors who are already compliant with certain appropriate standards e.g.
• IPEC-PQG GMP Guide
• EXCiPACT GMP and GDP standards
• ANSI/IPEC/NSF 363-2014 US national standard.
• Any risk assessment result that suggests a higher level GMP (e.g. ICH Q7) than
the current expectations should be re-examined to confirm the outcome.
• Contradictory requirements for an excipient could arise for example when the
User applies the same excipient in multiple drug products resulting in being
classified differently
• Another situation could occur when a Supplier provides the same excipient to
multiple customers and when the Users then respond with different risk
mitigations (which would come from the different risk classifications).
‘HOW-TO’ DOCUMENT 5. Residual Risk Resolution
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Multiple results for an excipient – Users conundrum
• Mitigations required entirely “in house” (i.e. applied by the User)
• Segregation of the deliveries of one excipient into different internal grades
Multiple results for an excipient – Suppliers conundrum
• Different customers request different requirements for the same material
• Segregation of production volumes and quality systems, for example:
1. Production/Testing Controls
2. Quality System Controls
Think carefully what mitigating actions you take – time, resource and
costs
• In the worst case scenario where no agreement can be reached then the
relationship between the Supplier and User may cease. This would have to be
an extraordinary conclusion
‘HOW-TO’ DOCUMENT 5. Residual Risk Resolution
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• Listed in the EU Guideline (OJ
2015/C 95/02 – § 4.1)
• Supplemented in the Document
• For significant changes:
Users will have to revisit their risk
assessment
If these are now revised to
require greater levels of
assurance then this has to be
communicated to the
Supplier.
• User must communication the
rationale of conclusions to Supplier
• In all cases however, it is very clear
that the risk assessment is a “living
document”
‘HOW-TO’ DOCUMENT 6. Triggers for Risk Review
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And finally as a
reminder……………..
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Identify excipient(s) for risk
assessment
References: 2.3 i-x
Collate all relevant data/information from internal & external sources
References: 2.3 i-x; 2.4 i-viii
Perform excipient risk assessment
using the most appropriate tool
References: 2.2
Generate risk rating for excipient from assessment References: 2.5
Use excipient risk rating to define the required minimum GMP
standard & controls/mitigations for the assessed excipient References: 2.6 i-xvi
Assess the excipient supplier site Quality standards (production &
distribution) against the identified minimum GMP standard &
controls/mitigations for the excipient References: 3.1
Identify the gaps (if any) at the supplier site
References: 3.1, 3.2
Perform risk assessment for supplier site including information from the
gap analysis
References: 3.4
Generate a risk rating for the supplier site
References: 3.4
Select a control strategy for the supplier site appropriate to the
supplier site risk rating
References: 3.5
Periodic reviews of risk assessments, excipient risk rating, excipient (GMP) standards, and
supplier site risk rating
References: 4.1 i-viii
Confirm existing risk control/mitigation at the supplying
site under assessment References: 3.4
ANNEX I
Overall Process Flow
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Thank you for your attention!