EU Expt Ext Lech

European Regulatory Perspectives and
Expectations for Safety Qualifications of

Extractables and Leachables
David R Jones
(david.jones@mhra.gsi.gov.uk)
Senior Scientific Assessor
(Pharmacotoxicologist),
Licensing Division, Medicines and Healthcare
products Regulatory Agency, UK)
PDA Extractables and

Leachables Forum 2005
ANY OPINIONS EXPRESSED IN THIS
PRESENTATION ARE MY OWN, ARE
NOT NECESSARILY SHARED BY OTHER
ASSESSORS AT THE MHRA, AND CAN
NOT BE CONSIDERED TO BE MHRA OR
EU POLICY

Topics to be Covered
Background and Guidelines

What EU Regulators Expect
How and When Advice from the Regulators
should be Sought
Questions

Background and Guidelines

The MHRA
The MHRA is the executive agency of the

Department of Health safeguarding public health by
ensuring that all Medicines and Medicinal Devices on
the UK market meet appropriate standards of safety,
quality and efficacy.
The MHRA carries out pre-marketing assessment of
the medicine's safety, quality and efficacy before a
decision is made on whether the product should be
granted a marketing authorisation.

I can give you a European perspective.
I cannot give you THE European Perspective.
Regulations of drugs in Europe is quite unique!!

The EU
The European Union (EU) is a family of democratic

European countries, committed to working together for
peace and prosperity.
It is not a State intended to replace existing states, but
it is more than any other international organisation.

The EU
The EU is unique in that Member States have set up

common institutions to which they delegate some of their
sovereignty.
This pooling of sovereignty is also called “European
integration”.

The EU
On 1 May 2004 large parts of Eastern and Western

Europe were reunited in peace and democracy as 10 new
countries joined the European Union.
The EU now consists of : Austria, Belgium, Cyprus, Czech

Republic, Denmark, Estonia, Finland, France, Germany,
Greece, Hungary, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Poland, Portugal, Slovakia, Slovenia,
Spain, Sweden, The Netherlands and the United Kingdom

The EU
The enlarged EU of 25 countries and 454 million

people will expand even further in 2007, when
Bulgaria and Romania join.
The EU is one of the largest pharmaceutical
markets in the world!

The EMEA
The European Medicines Agency (EMEA) is a decentralised

body of the European Union. It has its headquarters in
London.
The EMEA is NOT the European equivalent of the FDA (yet)
The EMEA works as a network, bringing together the

scientific resources of the Member States to ensure the
highest level of evaluation and supervision of medicines in
Europe.

The Regulatory Scene in the EU
for Pharmaceutical Products
There are 25 Member States in the EU.

Each Member State has its own National Regulatory
Authority.
The EMEA does not conduct any assessments.
The EMEA acts as Project Managers for Centralised
Procedures.
The CHMP is comprised of one expert from each
Member State.

The Regulatory Scene in the EU
The Regulatory process for pharmaceuticals in the

EU has many weaknesses.
It also has many strengths - a huge “pool” of

scientists to call upon.
Someone always seems to know something about any

subject ☺

EU Guidelines
The Annex to Directive 2001/83/EC as amended by

Directive 2003/63/EC came into force in UK law on 31
October 2003 and states:
The particulars and documents which must accompany
applications for marketing authorisation…
1. Qualitative particulars
… any relevant data concerning the container … together
with details of devices with which the medicinal product
will be used or administered.

EU Guidelines

EU Guidelines
Extraction studies should be performed where the

plastic material is used as a primary packaging
material for liquid and semi-solid preparations and is
not described in …EU pharmacopoeia.

EU Guidelines
The aim of extraction studies is to determine which

component of the material may migrate into the
dosage form.
The studies typically involve exposing a sample of the
material to an appropriate solvent system at extreme
conditions to increase the rate of extraction.
Acceptance criteria for each extractable should be
listed.

EU Guidelines
Leachables should be monitored during stability

studies under normal and accelerated conditions..
Migration studies may be omitted if the

theoretically calculated maximum amount of
individual leachable substance that may be
present in the formulation leads to ppm levels
demonstrated to be toxicologically safe in
respect to the route of administration.

EU Guidelines
For plastic materials used for container closure

systems of oral preparations toxicological data should
be provided, if the material and/or additives are not
described in pharmacopoeia and have not been
approved for use for packaging for food.

EU Guidelines
For plastic materials and/or additives not described

in pharmacopoeia and used for parenteral or
ophthalmic products, toxicological information is
required, even if the material and/or additives are
normally approved for use in food packaging.

ICH Guidelines
Q3 – Impurities in New Drug Products

USP 28 : Chapter <87> Biological
Reactivity Tests, In Vitro
<381> Elastomeric Closures for Injections

<661> Containers
<1031> The Biocompatibility of Materials Used in
Drug Containers, Medical Devices, and
Implants
<1046> Cell and Gene Therapy Products
<1151> Pharmaceutical Dosage Forms – Aerosols

USP 28 Chapter <88> Biological
Reactivity Tests, In Vivo
<161> Transfusion and Infusion Assemblies and

Similar Medical Devices
<381> Elastomeric Closures for Injections
<661> Containers
<1031> The Biocompatibility of Materials Used in
Drug Containers, Medical Devices, and
Implants
<1046> Cell and Gene Therapy Products
<1151> Pharmaceutical Dosage Forms – Aerosols

ISO
ISO 10993 parts 1 to 19 – Biological Evaluation of

Medical Devices.
ISO 8871 – Elastomeric Parts for Aqueous

Parenteral Preparation.

Extractables & Leachables

Extractable – Chemical entity that migrates from

plastic/rubber under appropriate solvent,
temperature and time conditions.
Leachable – Chemical entity that migrates from

plastic/rubber under “normal” conditions of use or
during stability studies.

Why are these important?

May be toxic!!
May interfere with medical diagnostic test.
May interfere with drug product assay.
May react with one or more drug product
components.

• Not usually an issue with oral formulations

• Often a major issue for Inhalation and
Ophthalmic formulations
• Can also be a problem with Parental formulations
• No formal Regulatory guidance available
• Issues can affect Marketing Approval

What EU Regulators
Expect

Each application must contain enough information
to show that the plastic/rubber material is
suitable for its intended use.
Type and extent of data will depend on dosage
form and route of administration.

General Approach
• Identify extractables and/or leachables

• Review any available toxicology/safety data
• Conduct SAR assessment if necessary
• Conduct toxicology studies if necessary
• Conduct safety assessment based upon
maximum expected daily human exposure

General Approach
When toxicology data used to support proposed

specifications Safety margins should be calculated
based upon NOAEL dose and theoretical maximum
exposure.
Generally speaking, most EU regulators don’t like

“fixed” safety margins, but will defer to “case by
case”.

General Approach
Some qualification can be incorporated into standard

toxicity tests, especially is use “aged” product. Certain
degree of re-assurance if no unexplained toxicity!
Drug batches can be analysed for leachable levels

General Approach
Local toxicity and immunotoxicity are seen as

potentially the major “toxicity” issues with
extractables and leachables.

General Approach
New EU guideline on genotoxic impurities.

Chemicals with negative genotoxicity and carcinogenicity
data are OK!
Chemicals that have no genotoxicity or carcinogenicity
data are OK if they lack structural alerts.
Chemicals with structural alerts are OK if conducted
genotoxicity studies are negative.
For known carcinogens, carcinogenicity risk (inhalation)
should be < 10-6

General Advice
• Select materials to limit the number and level of

potential leachables.
• Use pre-extraction methods to lower potential
exposures.
• Submit clear rationale to support safety of
proposed product specifications.
• Seek scientific advice if necessary.

Scientific Advice

Pre-Application Scientific Advice for
Human Medicinal Products by MHRA
Previously, advice meetings at the Agency were

informal, no written advice was given and it was free.
In response to requests from Industry, written advice

is now supplied following receipt of written questions
with the company’s own position and following a face-
to-face meeting.

Fees for this advice will be applicable.
Advice given by MHRA cannot account for future

changes and developments in scientific knowledge or
regulatory requirements.

Scientific advice can be requested during any stage of
the initial development of the medicinal product and
also during the pre-submission period for a variation to an
existing Marketing Authorisation.

Scientific advice can be requested whether or not
existing guidelines are in place.
In cases where a company chooses to deviate from

guidance available, it is particularly important for
companies to seek scientific advice from MHRA.

The question(s) posed by the company should be as
precise and clear as possible.
These should address specific issues concerning:
quality aspects (e.g. the chemical, pharmaceutical and

biological testing necessary to demonstrate the quality
of a medicinal product), non-clinical aspects and/or
clinical aspects.
Advice on Regulatory procedures can also be given.

Full details can be found on our Web site:
www.mhra.gov.uk

CHMP Scientific Advice
23 September 2004
EMEA/CHMP/SAWP/69686/04
Supersedes CPMP/6648/02
Mandate, Objectives and Rules of Procedure of

the Scientific Advice Working Party (SAWP)

The EU’s SAWP provides scientific advice for medicinal
products for human use and protocol assistance for
orphan medicinal products.
The aim is to facilitate access of medicinal products to

patients in optimising Research and Development,
reducing uncertainties in regulatory outcomes and
accelerating time for approval of a Marketing
Authorisation Application.

The SAWP encourages Applicants to engage, as early as
possible, in ongoing dialogues with the EU on the
development of their product.

The SAWP brings an integrated view on quality,
nonclinical and clinical safety and efficacy, relating to
the development of medicinal products and orphan
medicinal products to the CHMP for adoption.
This also includes follow-up advice given with a view to

optimise the development of medicinal products and
orphan medicinal products.

The SAWP also provides opportunities to Applicants to
discuss with other regulatory agencies their global
development programmes, in particular with the FDA.
This should follow a request from the Applicant to the

EMEA to arrange such parallel advice procedure.

The EMEA and the FDA
EMEA and FDA Implementation Plan for

Confidentiality Arrangement
Doc. Ref: EMEA/93356/2004
The EMEA and FDA have published the implementation

plan for their confidentiality arrangement.

This details the information and documents the two

agencies will exchange and the process for monitoring the
implementation of the plan itself.
The plan applies to all products that fall within the remit
of the EMEA and FDA.

The plan includes both regular and ad hoc exchange of

information, including information on pre-authorisation
and post-authorisation applications, inspections and
guidance documents.
An exchange programme for staff of both agencies is
also foreseen.

A key part of the plan is a pilot programme for

companies to obtain parallel scientific advice from the
two agencies.
The programme includes a mechanism for the EMEA,
FDA and companies to exchange views on scientific
issues during the development phase of new medicinal
products.
The parallel advice programme will in particular focus
on important breakthrough drugs.

The expected advantages from such interactions

are increased dialogue between the two agencies
and sponsors from the beginning of the lifecycle of
a new product, a deeper understanding of the bases
of scientific advice, and the opportunity to optimise
product development and avoid unnecessary testing
replication or unnecessary diverse testing
methodologies.

Parallel scientific advice meetings will focus primarily

on specific questions or issues involving the
development of a medicinal product on which the
sponsor desires to have further scientific input from
both EMEA and FDA.
Usually, the sponsor will be included as part of the

meeting. In addition, the two agencies will usually hold
a pre-meeting just with each other in order to discuss
further the issues posed by the sponsor.

Prime candidates for parallel scientific advice

under this pilot will be important or breakthrough
medicinal products, especially if the product is
being developed for indications for which
development guidelines do not exist or, if guidelines
do exist, EMEA’s and FDA’s guidelines differ

Any Further Questions ?
Please Feel Free to Contact the MHRA If You

Have Any Further Queries:
Telephone: 020 7084 2000
Address: 1 Nine Elms Lane, London, SW8 5NQ
Home Page: www.mhra.gov.uk


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European Regulatory Perspectives and

Expectations for Safety Qualifications of

PDA Extractables and

PDA Extractables and

Background and Guidelines

PDA Extractables and

PDA Extractables and

The MHRA is the executive agency of the

PDA Extractables and

I cannot give you THE European Perspective.

Regulations of drugs in Europe is quite unique!!

PDA Extractables and

The European Union (EU) is a family of democratic

PDA Extractables and

The EU is unique in that Member States have set up

PDA Extractables and

On 1 May 2004 large parts of Eastern and Western

The EU now consists of : Austria, Belgium, Cyprus, Czech

PDA Extractables and

The enlarged EU of 25 countries and 454 million

PDA Extractables and

The European Medicines Agency (EMEA) is a decentralised

The EMEA works as a network, bringing together the

PDA Extractables and

There are 25 Member States in the EU.

PDA Extractables and

The Regulatory process for pharmaceuticals in the

It also has many strengths - a huge “pool” of

Someone always seems to know something about any

PDA Extractables and

The Annex to Directive 2001/83/EC as amended by

PDA Extractables and

PDA Extractables and

Extraction studies should be performed where the

PDA Extractables and

The aim of extraction studies is to determine which

PDA Extractables and

Leachables should be monitored during stability

Migration studies may be omitted if the

PDA Extractables and

For plastic materials used for container closure

PDA Extractables and

For plastic materials and/or additives not described

PDA Extractables and

Q3 – Impurities in New Drug Products

PDA Extractables and

<381> Elastomeric Closures for Injections

PDA Extractables and

<161> Transfusion and Infusion Assemblies and

PDA Extractables and

ISO 10993 parts 1 to 19 – Biological Evaluation of

ISO 8871 – Elastomeric Parts for Aqueous

PDA Extractables and

PDA Extractables and

Extractable – Chemical entity that migrates from

Leachable – Chemical entity that migrates from

PDA Extractables and

Why are these important?

PDA Extractables and

• Not usually an issue with oral formulations

PDA Extractables and

PDA Extractables and