0157 ipec opmaak ctp - IPEC Europe

July 2004
Editorial
Contents
Editorial ......................................................... 1,2
IPEC Europe membership 2004 ......................... 2
Internet site update ........................................... 2
Regulatory Intelligence Network ....................... 3
GMO legislation in Europe ................................ 3
Good Distribution Practices ............................... 4
Excipient Masterfile system in Europe ............. 6,7
Seminar and Annual Meeting 2005 ................... 7
Henk de Jong elected as Vice-Chair of the EP .... 8
Meetings and Congresses ................................. 8
International Pharmaceutical Excipients
Council Europe
Adrian Bone
Chairman IPEC Europe
Eli Lilly & Company Ltd
Kingsclere Road
Basingstoke
Hampshire RG21 6XA
United Kingdom
Tel +44-1256 401021
Fax +44-1256 401161
E-mail: bone_Adrian_l@lilly.com
Evert Izeboud
Executive coordinator to IPEC Europe
Kerkweide 27
2265 DM Leidschendam
The Netherlands
Tel +31-70-320 9894
Fax +31-70-320 3759
E mail: eizeboud@worldonline.nl
Internet: http://www.ipec.org/europe.htm
Time flies by....
This third edition of the IPEC Europe newsletter in
2004 indicates that already half the year has
gone! Soon holidays will start and there is still so
much to do. But time has not been wasted. The
IPEC Committees have been working hard and
progress is evident, many presentations have been
given, position papers written, meetings have
been held with various regulatory bodies to
represent the “Excipient interests” , and much
more. You can find the results of this hard work
in this IPEC newsletter which provides an update
on the activities of the GDP and the Regulatory
Network Committees. It gives insight into the
latest developments of EU legislation on
genetically modified organisms and last but not
least, an IPEC perspective on the “hot” subject of
the need for a European Pharmaceutical Excipient
Master File system.
We are more than happy that also in this edition
we can introduce the company Chr. Hansen.
Getting new members is the lifeline of our
organisation. They further strengthen our position
vis-à-vis the governmental bodies with whom we
interact . A significant and balanced member list
provides an organisation such as IPEC with the
credibility it needs. With the ambitious target that
has been set, it is hoped that this new ‘recruit’ will
not be the last one for this year.
A special goal is to find new members located in
the countries recently joining the EU.
Since personal endorsement is still the best
advertisement, the Board would like to ask all of
you to mention IPEC at any opportunity you have
in the near future to possible new candidates
from those countries.
(to be continued on page 2)

( Continued from page 1)
The energy that has been put into establishing the
new regulatory network has clearly paid off. The
representatives active in this group have kept
track of new or revised legislation impacting
excipients and are now ready to provide a first
update on the progress that has been made and
providing highlights on significant regulatory
events in this period. With all the changes going
on in the international pharmaceutical environment,
it becomes nearly impossible for a single
excipient supplier to keep track of the all the
developments in the international regulatory field.
With its regulatory network IPEC has added a
powerful tool to help its members to stay up-todate
and to safeguard the interest of the Excipient
industry in particular. And as you will read, the
first success is there.
In these busy times it is good to know that
working together within IPEC really saves time,
work and avoids sleepless nights. Enjoy the
coming holidays!
Herman Ermens
IPEC Europe Membership 2004
Recently the Board welcomed the Danish
company Chr. Hansen A/S as a full IPEC Europe
member. The representative of this new member
company is Mr Sven Laulund. Below is a summary
of the membership profile of Chr. Hansen.
Membership Profiles
Chr. Hansen A/S
The company was founded in 1874 by the Danish
pharmacist Christian D.A. Hansen who made a
number of biotechnological discoveries that
revolutionized the production of wholesome dairy
products. Today the company is part of the international
Chr. Hansen Group, which develops,
produces and markets pharmaceuticals, natural
food ingredients, as well as diagnostics for specific
allergic disease management and other product
solutions for human and animal health
The mission of Chr. Hansen is to improve the
quality of food and health for people all over the
world - using effective, well-documented
ingredients, processes and technology.
Chr. Hansen is specialized in developing and
manufacturing excipients for solid dosage forms
(coatings), phytonutrients and probiotics.
Food supplements containing phytonutrients are
a convenient way of enhancing the intake of
essential nutrients normally coming from fruits
and vegetables to maintain good health.
Probiotics may help maintain and restore a
healthy balance of the intestinal flora and may
have a positive influence on immunity.
The New IPEC Europe Internet site
Evert Izeboud
During the second quarter of 2004, progress was
made in the work progamme of IPEC Europe’s
Communication Committee. With the assistance
of a professional designer and website builder an
Internet site was set up in conformance with
IPEC Europe’s new house style. The new site can
be considered as a nice example on what can be
achieved with teamwork.
On 13 July 2004 the public domain of the new
site was “transferred” to the host server of IPEC
Europe at PharmWeb in Manchester (United
Kingdom); the member area and the section
used for publication of the results of Committee
work will move on 23 July 2004.
The task of ‘cleaning’ outdated documents from
the site and finding an appropriate solution for
archiving will be undertaken.
Your coordinator/ webmaster will keep you
updated on further developments.
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IPEC Europe’s Regulatory
Intelligence Network (RIN)
Adrian Bone
At the IPEC Europe Annual Meeting in Cannes at
the start of 2004, the re-launch of this sub-group
was announced and since then on a monthly
basis, contact has been made with ‘regulatory’
representatives of several member companies. The
names can be found in Mr Adrian Bone’s
presentation given during the Annual Meeting in
January 2004 (IPEC Europe Internet site).
The RIN’s intent is to share with and gather
information on new or revised legislation
impacting pharmaceutical excipients from the
perspective of users, manufacturers and
distributors. Thus we can ensure awareness of
changes and where appropriate seek to influence
requirements to the best advantage of the
Membership.
So, four months later, and hereafter every three
months, it’s time to give the readers of this newsletter
an update on progress and any significant
events. Whilst many items were discussed some
have more indirect impact, affecting activities
which relate to aspects of a manufacturer’s
business other than pharmaceutical excipients.
Hopefully, this information is useful and as always
your feedback on the value of this would be most
appreciated to improve this service.
What is sometimes frustrating is that awareness
comes only when legislation has become
effective...our goal is to try to ensure that we
receive notice of these, if and when they are
issued for consultation, and therefore, we have a
chance to influence their content. The idea is that
when such draft documents are issued, IPEC
Europe will generate a position paper, possibly in
collaboration with other associations, to submit to
the body proposing the new rules etc..
Probably the most notable success this year
concerns the French draft order on GMPs for Raw
Materials for pharmaceutical purposes. Just before
Christmas IPEC Europe submitted major concerns
on the French draft order Basically this draft
requested full GMP, similar to API’s for all
excipients used in pharmaceuticals in France.
Apparently our comments have been accepted
and the draft has been withdrawn and will be rewritten
to apply only to API’s and certain highrisk
excipients (e.g. gelatin). This brings it in-line
with requirements in the rest of Europe and is a
great success!!! The new draft has not yet been
published but the original has been withdrawn.
Many thanks to those who helped to reach this
satisfactory conclusion.
Another significant item to note is that as a result
of the 2001 review of EU pharmaceutical
legislation, that in the case of certain excipients,
there will be an obligation for manufacturers of
medicinal products to use only excipients that
have been manufactured in accordance with
GMP. To which excipients this will apply and
what the GMP requirements will be, have yet to
be defined but will be included in a later
Commission Directive. IPEC Europe will ensure
that as much assistance as is possible is provided
to the EMEA, referencing the already developed
GMP guidelines for excipients.
Other items that were generated within the
network are more ‘for information’ and have
been distributed to your RIN contact. But again,
please let us have your feedback on what you
would like to know. Also if you would like to be
part of this group or make contributions, you are
most welcome!
Genetically Modified Organisms
EU legislation
For food applications only!
Evert Izeboud
The strictest rules and regulations on GM labelling
in the world are in force in the European Union,
extending mandatory labelling requirements to
countless food products in the supermarkets and
resulting in an extensive paper trail for the food
industry.
Under the new rules, all foods which contain or
consist of GMOs or which are produced from
GMOs will have to be labelled regardless of the
presence of GM material in the final product.
(to be continued on page 4)
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(continued from page 3)
In addition to this obligation, food additives,
which are manufactured with raw materials
derived from GMO, even up to the fifth
generation, have to be considered as GMOderived
and thus within the scope of the GMO
legislation.
A glucose syrup, for example, derived from
starch, that in turn is derived from a GM maize,
will have to be labelled as such. It is evident that
such obligations are going beyond the objective
of the GMO legislation.
The new rules from Brussels - (EC) 1830/2003 on
the Traceability and Labelling of GMOs and (EC)
1829/2003 on Genetically Modified (GM) Food
and Feed - find their source in the right of the
consumer to be adequately informed . The rules
are set up to bring choice to the consumer - if
they see ‘GM ingredient’ on the label they can
decide to buy, or not.
The European Commission has been under
intense pressure from the biotech industry and
the US to end the EU’s de facto moratorium on
GMs. The new rules on GM labelling open the
way for an ultimate end to the ban and the
introduction of new GM food crops into the
European food chain.
Under the new rules, a threshold of 0.9 per cent
will apply for the accidental presence of GM
material, below which labelling of food or feed is
not required. But for the CIAA, the threshold
versus derivative slant of the law could leave the
door open to confusion for the consumer reading
the label.
While the food industry prepares itself to create a
mountain of paperwork, the start of the chain -
the GM seed industry - must also be in line with
the new rules. While the food industry will have
to label GM food products in Europe, in fact food
manufacturers have been reluctant to use GM
ingredients knowing that ultimately it did not
make sound business sense in a climate where the
European consumer remains suspicious of
genetically modified foodstuffs.
But it is not just European food manufacturers
who will be affected by the new rules. Companies
from the US - where the use of GM ingredients is
much more widespread - are also subject to the
regulations if they wish to do business in the
European Union.
Good Distribution Practices
for Excipients
- Current status of international development
and committee activities -
1. International development
Since January 2004 IPEC Europe Good
Distribution Practice (GDP) Committee has been
working on a guidance document which will be
an interpretation of the Good Trade and
Distribution Practice Guidelines for
Pharmaceutical Starting Materials (GTDP) of the
World Health Organisation (WHO). This WHO
document was published early this year
(http://www.who.int/medicines/strategy/
quality_safety/trs917ann2.pdf). It is defining a
standard which should be applied to the supply
chain for excipients (handling, trading
warehousing, repackaging, transportation etc.) to
ensure full traceability and to prevent
contamination and cross-contamination while
bringing starting materials from original
manufacturers downstream to the end user. It has
been recognised by WHO that a significant
volume of these products are supplied by
distributors to the final user. In November 2003
and May 2004 Frank Milek had meetings in
Stuttgart and Geneva with the responsible people
for GTDP at WHO, namely Sabine Kopp and
Lembit R‰go . WHO has committed to support
this IPEC activity and indeed they welcomed the
fact that IPEC will provide such a “How-to-do”
document which supports the implementation
and use of WHO GTDP principles by distributors
of excipients. WHO promised to send a key-note
speaker to an IPEC launch event where this
document will be presented to industry and
regulatory bodies.
Good practices in the manufacture and supply
chain of pharmaceutical starting materials are
now a key requirement in European drug
regulation. Since 1 May the European Directive
2004/27/EC is in place. This directive clearly
covers active pharmaceutical ingredients and
certain excipients with GMP requirements:
(to be continued on page 5)
4

(continued from page 4)
Article 46: The holder of a manufacturing
authorization shall at least be obliged:
f) To .... use only active substances employed as
starting materials which have been manufactured
in accordance with detailed guidelines on good
manufacturing practice for starting materials.
This point shall also be applicable to certain
excipients, the list of which and the specific
conditions of application shall be established by
a Directive...
The list of excipients is currently under
construction by European legislators where a
group of GMP inspectors from various European
countries is working on a proposal for that list. It
is planned to be published by October 2005 at
the latest. These requirements will also be
extended to the activities of distributors of
starting materials as stated in Article 46a of the
directive:
For the purpose of this directive,
manufacture ... shall include ... the various
processes of dividing up, packaging or
presentation prior to its incorporation into a
medicinal product, including repackaging or
relabelling, such as carried out by a distributor of
starting materials,...
Up to now it is not clear which GMP conditions
will have to be applied for the manufacture and
distribution of excipients. Only for active
pharmaceutical excipients have European GMP
Guidelines for the manufacture and distribution
been published (Annex 18 of EU GMP
Guidelines). These new requirements in European
legislation clearly indicate that IPEC activities on
GMP and GDP for excipients are supporting the
effected industries to comply with this regulation
and good practices.
2. Committee activities
IPEC Europe GDP Committee has already met
three times this year for two day working
sessions in order to draft the GDP Guidelines. In
January the basic format and structure of the
document was discussed and agreed upon with
IPEC Americas in a joint meeting in Cannes. In
the meantime, a first complete draft has been
created by the IPEC Europe GDP Committee and
submitted to IPEC Americas for comment. The
scope and structure of the document has been
designed to comply with IPEC Europe member’s
recommendations which the Committee collected
during 2003. After harmonization of the current
draft with the IPEC Americas GMP/GDP
Committee, the IPEC Europe membership will
again have the opportunity to comment on the
document prior to its official publication.
The document should provide a practical approach
as to how the WHO GTDP principles
should be enacted by distributors of excipients.
For the purpose of the document, “distributors”
includes all parties involved in trade and
distribution, (re)processors, (re)packagers, transport
and warehousing companies, forwarding
agents, brokers, traders, other suppliers than the
original manufacturer, etc. It applies to all steps in
the entire distribution/supply chain starting from
the point at which material is transferred outside
the control of the original manufacturer’s material
management system.
Some sections and/or sub-sections in the document
may not apply to all involved parties. To
help the user to identify the sections applicable to
specific activities there will be a Matrix of
Applicability and detailed table giving the
applicability of each chapter and sub-chapter to
particular supply chain activities. The matrix and
table will differentiate between activities
involving direct contact with excipients and
activities with non-direct contact , reflecting
different levels of risks.
Publication of the document is planned for the
end of 2004 or the beginning of 2005 at an
international launch event together with WHO.
The Committee will then plan and organize a
seminar for interested industries covering the
implication and use of the guide and its detailed
content.
The whole activity is also supported by the
Federation of European Chemical Distributors
Associations (FECC). The GMP Committee of
FECC also supports WHO GTDP principles and is
committed to use the upcoming IPEC document
to work on GDPs with their European member
companies. Frank Milek gave a presentation at
the annual congress of FECC in June 2004 on
GDP aspects of excipient supply chain and IPEC
activities. At that congress Olivier Gross from
WHO presented WHO GTDP guidelines.
(to be continued on page 6)
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(continued from page 5)
FECC GMP Committee committed to contribute
to IPEC’s launch date and seminar on Good
Distribution Practices for excipients. FECC
estimated that the majority of their member
companies are delivering excipients to the
pharmaceutical industry and therefore are
involved in the new European regulations and
these supply chain safety issues. IPEC Europe GDP
Committee will keep close contact with FECC
(www.fecc.org).
Meanwhile, CEFIC published a new revision of its
GDP Guidelines for Propylene Glycol EP/USP
which can be accessed via the internet: http://
www.landmarks.be/clients/propylene/en/. This
document is also helpful for IPEC members
involved in the manufacture, distribution and use
of that particular excipient.
July 2004, IPEC Europe GDP Committee
Frank Milek,Hedinger GmbH & Co. KG -
Chairman (Email: fmilek@hedinger.de)
Mathias Brenken
Reiner Gellrich
George Mansveld
Alexander Schoch
Tanja Twiehaus
Allan Whiston
Dow Deutschland
GmbH & Co. OHG
Cognis
Hercules Aqualon
Palatinit GmbH
Merck KGaA
Aventis
The Case for a Pharmaceutical Excipient
Masterfile (EMF) System in Europe
Michael Gross
Henk de Jong
Adrian Bone
The EMEA Guideline on Active Substance Master
File Procedure becomes effective on 31 August
2004 and addresses Master Files for active
pharmaceutical ingredient (ASMF). It provides a
mechanism for protecting confidential intellectual
property and ‘know-how’ belonging to an API
manufacturer allowing the Applicant/Marketing
Authorization holder to take full responsibility for
the medicinal product and the quality of and
quality control of the active substance (API). This
is achieved through a two-part Master File divided
into an Applicant’s (or Open) Part containing
non-confidential information and a Restricted (or
Closed) Part, which contains proprietary details
shared directly with a Competent Authority. If,
during review of the Application, the Competent
Authority determines that in order to effectively
control the quality of the API, the Applicant/
Marketing Authorization holder needs access to
information contained in the Restricted Part, the
Competent Authority may request that an
amendment to the Applicant’s Part is filed by the
API manufacturer.
Establishing a similar Master File system for
excipients in Europe would provide an important
vehicle for manufacturers of pharmaceutical,
especially novel excipients to submit information
to regulatory authorities on pharmaceutical
excipients in support of applications for Marketing
Authorization submitted by their customers.
IPEC Europe is proposing that the Master File
system in Europe is extended to pharmaceutical
excipients. There is precedence for this: in the
past the European Commission allowed the
equivalent of Master Files for excipients to be
submitted when it became necessary to replace
CFC propellants with HFA propellants (norflurane
or HFA-134a) in metered dose inhaler products.
Looking at EMF’s globally, the (US) FDA’s DMF
system includes Type IV Drug Master Files for
Pharmaceutical Excipients where all submitted
information is treated as confidential and there is
no “open” Applicants Part. In Japan, a Drug
Master File system is being constructed, and it
will include active ingredients and novel
excipients. The system should become
operational in 2005. Current European legislation
distinguishes between API and excipient
manufacturers in that the ASMF system protects
intellectual property concerning the manufacture
and control data for APIs but not for
excipients.[Note: The Treaty of Rome requires
that all groups of manufacturers are treated
equally.]
Efforts to develop new formulations to improve
manufacturability, stability or drug delivery is
dependent upon innovation in the development
and manufacture of pharmaceutical excipients.
However, the lack of protection of intellectual
property of new and novel pharmaceutical
excipients discourages this.
(to be continued on page 7)
6

(continued from page 6)
Medicinal products formulated with novel
excipients are more likely to undergo centralized
assessment by regulatory authorities and may
require more comprehensive information in their
applications. Greater detail on development,
manufacturing methods and quality assessment is
needed for new excipients and if used for the first
time in a medicinal product or by a new means of
administration, clinical and preclinical information
are also required.
To encourage the development of novel
excipients, innovative technologies and ‘knowhow’
must be protected. The pharmaceutical
market for excipients is small compared to that for
food additives and there needs to be adequate
protection of proprietary information as otherwise
they will not be economic to develop and produce.
The extension of the EDMF procedure to include
pharmaceutical excipients would provide a suitable
and efficient way for relevant information to be
made available to authorities as it would enable
the presentation of complete and pertinent
information in a single dossier and facilitate a
comprehensive and consolidated assessment of
the novel excipient product. It would eliminate the
need for excipient manufacturers to re-submit the
same documentation for the review of each
marketing authorisation from multiple end-users
of the same excipient and serve to protect the
intellectual property of developers of new
excipients. This also achieves a degree of
harmonization with developers of APIs in Europe
and manufacturers of excipients in the United
States and (soon) in Japan.
Your comments, ideas and support for this
proposal would be most welcome. We
look forward to hearing from you: please
contact IPEC Europe as follows:
Adrian Bone
Chair, IPEC Europe
bone_adrian_l@lilly.com
+44(0)1256 401021
Henk de Jong
Vice Chair, IPEC Europe
hendrik.dejong@fr.netgrs.com
+33-1-5572 6178
Evert Izeboud
Executive coordinator to IPEC Europe
eizeboud@worldonline.nl
+31-70-3209894
Seminar and AGM 2005
Following the highly appreciated January event
the Board has decided to organise the January
2005 Seminar at the same venue.
IPEC Europe members are requested to
reserve the dates of 27 and 28 January, 2005
in their diaries.
The EDQM’s Certificate of Suitability system for
excipients having a monograph in the European
Pharmacopoeia is similar to a DMF, and highly
useful for well-known ingredients. However, it is
not open to biotech products and novel
ingredients.
IPEC Europe is seeking support to promote the
idea of a European Masterfile system applicable
to excipients not in the scope of the EDQM
certification scheme. We are doing this to
stimulate innovation (in formulation science/drug
delivery) and international harmonization.
Majestic Hotel, Cannes, France
7

Mr Henk de Jong elected as Vice Chair of
the European Pharmacopoeia Commission
Calendar of events 2004
It is a pleasure to announce that Professor Henk
de Jong, Vice Chair of IPEC Europe, has recently
been elected 1 st Vice-chair of the European
Pharmacopoeia Commission for the period
2004-2007.
The Presidium consists further of the Chair: Dr
Mike Morris (Irish Medicines Board, Dublin)
and the 2 nd Vice-chair Mrs. Hilda Köszegi-Szalai
(OGYI, the Hungarian agency for medicines,
Budapest).
The IPEC Europe Board would like to congratulate
Professor Henk de Jong on this very important
appointment which will undoubtedly strengthen
the constructive working relationship which exists
with the European Pharmacopoeia.
Date
July 15
September 20
October 4-6
October
November 17
November 18
Event
Board Meeting
Paris, France
Harmonisation Cie
Geneve, Switzerland
Quality on the move
EDQM Symposium
Budapest, Hungary
Board meeting
Paris, France
Tri-PEC Meeting
PDG/Tri-Pec Meeting
EDQM Conference
Quality on the Move,
Dynamics of the European Pharmacopoeia
From 4-6 October 2004, the European Directorate
for the Quality of Medicines (EDQM) will organise
an International Conference with contributions
from IPEC (Dr Undine Kettenring, Dr Chris Moreton
and Prof. Henk de Jong). The venue of the
conference is Budapest (Hungary).
IPEC Europe will further organise a promotional
programme including a display and cocktail hour.
The programme, including registration forms for
the conference and accommodation can be
downloaded from the website of the EDQM.
December 7-9 CPhI 2004
Brussels, Belgium
************************************
Next IPEC Europe Newsletter
The next Newsletter is scheduled to be
issued in the month of October 2004.
Call for text to be published
IPEC Europe members who would like to
contribute to the Newsletter are invited to
submit text electronically (maximum 1 A4)
to Mr Izeboud.
EDQM site address:
www.pheur.org
IPEC Europe on the Internet
http://www.ipec.org/europe.htm
8