Logfile No 6a – April 2008 Maas & Peither AG - GMP Publishing
Annex 2, Background and Con-
EU GMP Guideline Annex 2 sultation
- Open Meeting - The current version of Annex 2 dates
Manufacture of Biological from the 1990's and was to provide
Medicinal Products supplementary guidance to the EU
GMP Guide, now known as Part I,
By Stephen Brown, Vivalis
with Jim Lyda, PDA Europe GMP for Medicinal Products. Follow-
ing a review of the GMP Guide, GMP
February 19 in Budapest saw a su- Annex 18 (consisting of the harmo-
perb example of industry / regulator nized ICH Q7 standard) became GMP
information exchange to the benefit Part II3, covering drug substance or
of all. The occasion was the open Active Pharmaceutical Ingredients
meeting to discuss the draft revision (APIs). A concept paper4 was then
of Annex 2 of the European GMP1, published giving notice on the intent
specifically Annex 22. About 50 dele- to revise Annex 2. The draft revision
gates took part in the discussion on was published for public consulta-
the proposed draft, including the tion in November 2007, with a con-
regulator delegation consisting of sultation deadline of March 14, 2008.
Emer Cooke, Head of Inspections
Sector, EMEA; Ian Rees, MHRA In- The open meeting was facilitated by
spector & rapporteur of the Annex 2 Hannelore Willkommen, and
drafting group; and Paul Har- opened with a presentation by Emer
greaves, MHRA Senior Inspector. Cooke describing the structure of
European GMP, how guidance is de-
Note to readers: The open meeting veloped, and how Annex 2 fits in.
described in this PDA report was an The EMEA considers that Parts I and
adjunct to the overall consultation II of the GMP guide are wholly com-
process and does not replace any patible and can be applied to
part of it. The discussion and ex- biologicals manufacture. Annex 2 is
change of views should help stake- intended to provide supplementary
holders better focus on key issues guidance to both Parts I and II of the
when submitting their comments. GMP Guide, modifying certain de-
There will be no official report on tails as appropriate.
the open meeting. This PDA report is
not an official record or transcript. Ian Rees next reviewed the devel-
Rather, it reflects the tone and opment of draft Annex 2 within the
substance of the open meeting as Inspectors Working Group (IWG).
interpreted by the authors. Read- Since the original Annex 2 was pub-
ers should use caution making lished, there have been many ad-
vances in science, manufacturing and
any regulatory or compliance in-
testing technologies. In addition, the
terpretations based on this infor-
range of product types today is sig-
mation.
nificantly greater than compared to
the 1990's. Draft Annex 2 has been
reformatted into Part A (General
Guidance) and Part B (Specific Guid-
Authors: Stephen Brown (Vivalis) Jim Lyda (PDA Europe)
V2 © Maas & Peither AG - GMP Publishing
Logfile No 6a – April 2008 Maas & Peither AG - GMP Publishing
ance on Selected Product Types). A special products, e.g. tissue engi-
key purpose of the revised Annex is neered products.
to take into account legislative There was some feeling that Annex 2
changes for Advanced Therapy Me-
contains prescriptive guidance re-
dicinal Products5, the Tissue and Cells garding process controls and risk is-
Directive6, the advent of QRM, and
sues (environmental, biohazard, bio-
new guidance on somatic cellular
safety), and that the Annex should
therapy and gene therapy. Addi- not address non-GMP issues such as
tional input on Tissue Engineered environmental and personal safety,
Products (TEPs) is being sought. and registration. There was concern
There is possibility of another public that draft Annex 2 is not “forward
consultation, on the TEPs section or looking” and does not fully embrace
the whole annex, before the end of current international manufacturing
2008. A publication date for the final quality concepts (ICH Q8, Q9 and
version of Annex 2 has yet to be set. Q10, QbD, PAT, etc.). As a result, the
Annex could stifle innovation, for
Summary of Industry Presenta-
example, by interpretations requir-
tions ing dedicated equipment for certain
The program then moved in the in- product types. In this context, a
dustry views with presentations from number of presenters raised con-
four European industry and profes- cerns that draft Annex 2 should not
sional associations (EFPIA & EVM – be applicable to clinical supply/IMP
Anita Derks; EBE – Lothar Hart- development and manufacturing.
mann; PDA – Jim Lyda) and three The industry is moving towards
major biopharmaceutical companies multi-product facilities. The potential
(F. Hoffmann La Roche – Volker consequences to industry, in terms of
Lenz; Novo Nordisk – Brigitte Holst; dedicated equipment and facilities,
& Genentech – Mary Sliwkowski). could be much higher operating
There were a number of common costs and significant capital costs.
themes developed by the industry
representatives. Most frequently Requirement or Interpretation?
were issues related to the scope of There was discussion about possible
the Annex. There is overlap and industry ‘over-interpretation’ of the
some inconsistency between draft text contained in Annex 2. For ex-
Annex 2 and GMP Part II (originally ample, while there are references to
ICH Q7). There was suggestion that dedicated equipment, the text usu-
GMP Part II should be regarded as ally suggests that the use of such
the reference GMP guidance for equipment should be “considered”
API/drug substance for the vast ma- by the manufacturer. In very few
jority of marketed products. Simi- cases does the text mandate a par-
larly, GMP Part I should be limited to ticular activity or requirement. There
finished medicinal products. Annex 2 was a comment that the industry is
would then only address GMP issues frequently inferring a ‘most prescrip-
that are not yet defined, associated tive’ requirement from text that
with new technologies, or relate to clearly allows room for discretion. In
Authors: Stephen Brown (Vivalis) Jim Lyda (PDA Europe)
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Logfile No 6a – April 2008 Maas & Peither AG - GMP Publishing
other words, requirements are being dustry was not represented in this
read into the text in a manner that is open meeting.
not stated or intended.
• There was discussion regarding
Why is this so? Several participants low bioburden production of APIs
stated that, based on experience, with some industry representa-
there is an expectation that some tives citing difficulties with Euro-
inspectors will interpret the discre- pean inspectors on this subject.
tionary wording of the Annex in its The regulators advise that noth-
most rigorous interpretation as the ing in draft Annex 2 forbids low
GMP standard. In other words, while bioburden API processes
the manufacturer may see a range of
• Applicability of Annex 2 to clini-
choices in a GMP decision when
cal or IMP manufacturing should
reading the Annex, the inspectors
be clarified. Annex 2 is not spe-
frequently start at the extreme (pre-
cifically aimed at early stage clini-
scriptive) end of that range. This may
cal trials.
require manufacturers to justify
process decisions during inspections In summing-up, Emer Cooke consid-
multiple times, depending on each ered the meeting to have been a
new inspection situation. All agreed valuable exercise that has sensitized
that while European GMP can be everyone to the issues that will be
complex, there is no intention to be addressed as a result of the consulta-
over prescriptive or to stifle innova- tion process. There was a plea from
tion. the regulators that comments on
Annex 2 be submitted in a manner
Other points from the discus- useful for the redrafting process. For
sion: example, it is important to supply
• Redundancy between Annex 2, technical justifications and concise
GMP Part I and Part II is an area alternative text where changes are
that needs to be looked at again. recommended.
Finally, there were expressions of
• Today there is great diversity in
appreciation from the attendees
biotechnology products and
for the willingness of the EMEA and
technologies. These are difficult
to cover in one document, giving Inspectors to discuss this important
topic. As one observer said, “We
rise to problems of interpreta-
asked the regulators to listen, and
tion.
this is what they did. They asked us
• It is necessary to achieve consis- to listen, and we did as well. The
tent interpretation of Annex 2 meeting was worth every minute!”
between inspectors and the in-
Note: The final PDA comments on
dustry.
Annex 2 were submitted to the
• There is need to define require- EMEA on March 14. To view the PDA
ments for Tissue Engineered comments go to the PDA web site,
Products. That sector of the in- www.pda.org (regulatory affair \ regu-
latory comments\2008).
Authors: Stephen Brown (Vivalis) Jim Lyda (PDA Europe)
V2 © Maas & Peither AG - GMP Publishing
Logfile No 6a – April 2008 Maas & Peither AG - GMP Publishing
____________________________
1. Eudralex Volume 4, Good Manufacturing
Practice Part I, Annex 2: Medicinal Products
For Human And Veterinary Use.
2. Draft Annex 2 : Manufacture of Biological
Medicinal Products for Human Use, Septem-
ber 03, 2007).
3. Part II : Basic Requirements for Active
Substances Used As Starting Materials.
4. Concept Paper On The Revision Of Some
Annexes To The European GMP Guide In The
Context Of GMP For Active Substances,
EMEA/INS/GMP/147444/2005.
5. Regulation n°1394/2007/EC of the Euro-
pean Parliament and of the council of 13
November 2007 on Advanced Therapy Me-
dicinal Products.
6. Regulation n°2004/23/EC of the European
Parliament and of the council of 8 February
2006 as regards certain technical require-
ments for the donation, procurement and
testing of human tissues and cells.
Authors: Stephen Brown (Vivalis) Jim Lyda (PDA Europe)
V2 © Maas & Peither AG - GMP Publishing
