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

•

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

Content

• Background

• Excipient GMP - EU Legislative Journey

• EU Guideline – Excipient GMP (2015/C 95/2)

• IPEC EUROPE ‘HOW –TO’ DOCUMENT

Content

• Background

• Excipient GMP - EU Legislative Journey

• EU Guideline – Excipient GMP (2015/C 95/2)

• IPEC EUROPE ‘HOW –TO’ DOCUMENT

Background

Market Context

• Challenges of globalized

supply chain leading to

updated regulation

• Industry trend towards

Quality By Design for

pharmaceutical

developments

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 ?

Background

Excipient Risk?

Traceability

& Supply Chain

Safety

& Integrity

Functionality

Content

• Background

• Excipient GMP - EU Legislative Journey

• EU Guideline – Excipient GMP (2015/C 95/2)

• IPEC EUROPE ‘HOW –TO’ DOCUMENT

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

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

Content

• Background

• Excipient GMP - EU Legislative Journey

• EU Guideline – Excipient GMP (2015/C 95/2)

• IPEC EUROPE ‘HOW –TO’ DOCUMENT

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

EU Guideline

Excipient GMP (2015/C 95/2)

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

Content

• Background

• Excipient GMP - EU Legislative Journey

• EU Guideline – Excipient GMP (2015/C 95/2)

• IPEC EUROPE ‘HOW –TO’ DOCUMENT

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

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

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

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

‘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.

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

‘HOW-TO’ DOCUMENT 3. Risk Assessment Process

ANNEX IV

Excipient

Categorization

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

‘HOW-TO’ DOCUMENT 3. Risk Assessment Process

Reminder

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

Risk Output

Supplier Control Strategy

Risk Mitigation

‘HOW-TO’ DOCUMENT 3. Risk Assessment Process

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

‘HOW-TO’ DOCUMENT ANNEX V

Reference Table

GMP Principles

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

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

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

• 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

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

• 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

And finally as a

reminder……………..

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

Thank you for your attention!