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For nearly a decade, APIC's European API
Conference has been held annually and meanwhile become the most important
event for European API manufacturers interested in GMP- and regulatory
topics. The 9th APIC/CEFIC Conference, which was held in the Czech capital
from 9-11 October 2006,
attracted again more than 230 participants from all parts of Europe.
Renowned representatives from industry and authorities, among them speakers
from FDA, EDQM and the French supervisory authority, informed about the
latest requirements on the GMP-compliant manufacture of APIs and current
trends in connection with marketing authorisations for medicinal products.
 In his opening speech, APIC's President, Matt Moran, talked about
the various challenges faced by the European API industry today. Against the
background of European legislation and Far Eastern competition, the
association's activities assume additional significance. The focussed
dialogue with the authorities, in which the urgent questions and problems of
API manufacturers are addressed, represents one important element of APIC's
work.
The series of presentations was started by Dr Katrin Nodop from the
European registration authority EMEA. Against the background of current
GMP requirements on API manufacture as laid down in the EC-GMP Guide and the
corresponding EC Directives, Dr Nodop explained which situations can trigger
the inspection of an API manufacturing plant by the competent supervisory
authority. Two important documents published by EMEA describe these
inspection-triggering situations as well as the expectations of audits,
including those contracted out to external specialists (Third-Party Audits):
the "Inspection Triggers" Guideline and the "Questions and Answers on
Audits" document. Due to global ways of distribution, inspectors have to pay
special attention to the transport chain between the manufacturing site of
the API and the place where it is used or processed. Dr Nodop emphasised
that the only valid means to check the criterion of GMP-compliant API
manufacture and to prove this compliance to the supervisory authority is a
GMP audit conducted (or - in the case of a Third-Party Audit - initiated) by
the manufacturing authorisation holder (MAH). It is not enough to refer to a
"self-assessment" audit conducted by the API manufacturer.
The newly established EudraGMP Database is meant to become the most
important tool for the best possible information exchange between the
authorities of the EU Member States. This database contains information on
manufacturing authorisations, GMP certificates, GMP histories as well as
inspection plans for audits of sites in third countries. It is the purpose
of this database to provide the supervisory authorities with an instrument
for effectively planning their inspections by avoiding unnecessary double
audits and by enabling the fastest possible information exchange up to quick
call-back campaigns in the case of impending danger through unsafe APIs. A
first release for a test run was scheduled for the end of 2006; the near
future will show how well this database facilitates the inner-European
dialogue between supervisory authorities.
A comprehensive overview on the life cycle model of process validation in
API manufacture as seen by the American supervisory and registration
authority was presented by Grace McNally, FDA. Each of the 4 phases
of the life cycle of process validation focuses on one activity - design,
confirm, monitor, assess - and is characterised by the corresponding
increase in information on process variables, analytical data, product
specifications and process deviations as well as optimisation opportunities
according to trend analyses. In any case, the FDA expects an API
manufacturer to acquire sufficient knowledge about the manufacturing process
based on a comprehensive database prior to marketing the product. Here, the
early development stage of a process plays an important role. The FDA
considers later attempts to adapt and optimise the process after placing the
product on the market to be critical.
The implementation of "Quality by Design" from the FDA's viewpoint was
the subject of the presentation given by Dr Moheb Nasr, FDA. This
principle has crucial benefits for both the API manufacturer and the
authority, said Dr Nasr. This became clear in his comparison between the
hitherto practised method and the "desired state" reached through consequent
implementation of the "Quality by Design" principle. This approach includes
systematic, multivariate experiments in the early development stage (the
"Design Space"), a robust manufacturing process controlled by
process-analytical technologies (PAT) as well as a risk-based control
strategies. Ideally, this enables a "real-time release" (RTR) of batches
without quarantine period. A cost-benefit analysis shows that, whereas at
first an increase in investments has to be expected, the desired state will
result in significant cost reduction, among others due to the fact that
process changes within the design space can be made without major regulatory
efforts. Dr Nasr emphasised that the FDA welcomes any attempts to implement
this principle in the development of new products and that it is open and
willing to co-operate constructively with the companies that decide to adopt
this course.
EDQM Director Dr Agnès Artiges gave a lecture on new developments
regarding the CEP procedure and explained the EDQM's programme to assess
APIs destined for the European market. One important pillar of the CEP
procedure is the inspection programme developed by EDQM. Within the
framework of this programme, an audit is conducted on the site of the API
manufacturer to check whether the production technology found there actually
corresponds to the CEP dossier. The most frequent complaints during such
audits are inconsistencies in documentation and records as well as
deficiencies in quality management, material management and process
equipment. In the meantime, about 90 manufacturing sites in 22 different
countries - among them China, India, Mexico and Canada - were audited. In 12
cases the CEP was suspended due to critical deviations; in only 2 cases the
CEP could be restored after re-inspection. Another pillar of the
surveillance of API quality is the network of Official Medicines Control
Laboratories (OMCLs). There are already approximately 85 of these public and
independent laboratories in over 35 countries, which are involved in a large
number of projects and e.g. take part in collaborative testing for monograph
and reference substances or analyse counterfeits. The threat constituted by
a growing number of counterfeited APIs led the EDQM to bring an initiative
into being that includes a specific EDQM-OMCL procedure and is also
supported by APIC. This procedure is meant to regulate the intensive
information exchange between the EDQM, the competent national OMCL and the
API manufacturer; at the same time the conclusion of a confidentiality
agreement signed by EDQM and OMCL protects the know-how of the manufacturer.
According to Dr Artiges, this procedure will make an important contribution
to defending the European Market from inferior substances in the near
future.
The industrial perspective on GMP- and registration-related topics was
illustrated by 9 representatives from the pharmaceutical and API industry
during the plenary sessions.
Jan Moors from Pharmaceutical BV, the Netherlands, talked about the
experiences of a generics manufacturer with the new EU legislation on active
ingredients. After the legislation had come into force, many of the
contracts with suppliers had to be revised and adapted with regard to the
new GMP requirements on APIs. With the help of specific examples he
illustrated the difficulty to access audit reports of third-country
manufacturers when medicinal products are imported. Another case he
mentioned was the problem to procure an API after the long-term supplier's
CEP was suspended as the negative result of an EDQM inspection.
How the principles of risk management described in ICH Q9 have to be
applied to an API manufacturing site, was explained by Barbara Lani from
Bracco International, Manno, Switzerland. In her lecture she presented
the factors determining the quality of a production process and used a large
number of examples to show in which way they were analysed from a risk-based
point of view and which control mechanisms were established afterwards.
In his presentation Gerry Migliaccio, Vice President Global Quality
Operations Pfizer, New York, USA, dealt with statements in the ICH Q10
Guideline on pharmaceutical quality systems. Gerry Migliaccio is also Head
of the Expert Working Group elaborating the ICH Q10 Guide. He stressed that
the "ICH Quality Trio" constituted by ICH Q8, Q9 and Q10 should not be
looked upon as separate documents; their benefits rather come to the fore
when they are seen in combination and, when applied consequently, lead to a
more effective risk management and higher regulatory flexibility, since
there are less changes and variations in the process of which the authority
has to be notified.
Dr John Berridge from Pfizer, Ramsgate, UK, described in detail the
principles of pharmaceutical development laid down in the ICH Q8 Guideline.
With the help of examples he made it clear how systematic data analysis can
help to define a multidimensional space, the "Design Space", within which
the product possesses the desired quality. In the end, the quality that was
"built into" the process design right from the start results in continual
improvement of the process. He gave an impressive example of this: the
reduction of a waste solvent quantity to the three-hundredth part of the
original volume.
In another lecture on "Quality by Design" from an industry viewpoint,
Wendy Mavroudakis from Johnson & Johnson Pharmaceutical Research and
Development, Titusville, USA, outlined how this principle can reduce
regulatory efforts. With the help of concrete examples she demonstrated what
a scientifically sound risk-based marketing dossier can look like that
includes the crucial facts relevant to process understanding and therefore
equally represents an advantage for the Regulatory Affairs department of the
pharmaceutical company and for the reviewers on the part of the authority.
Examples of the implementation of Process-Analytical Technology (PAT)
were presented by Conor McSweeney from Pfizer, Cork, Ireland.
Critical process steps and parameters, like e.g. the end point of a chemical
reaction, crystallisation or particle size, are monitored online by means of
suitable analytical technologies, and thereby, an optimisation, a greater
understanding and, ultimately, a better control of the process is achieved.
The consequences of the EU Directive, which came into force not long ago,
for an Indian API manufacturer were the lecture subject of Dr Nandkumar
Chodankar from Sekhsaria Chemicals, Mumbai, India. In a historical
excursion, he described the development of the Indian pharmaceutical and API
industry and showed how it rapidly caught up with European GMP standards in
recent years. A quickly growing number of audits by authorities, like EDQM
and FDA, and by European customers, led many companies to rethink. The
Indian API industry is experiencing a boom; however, only 300 of the
approximately 11,000 registered units are large-scale firms and account for
70% of the market share.
In his lecture, Dr Jan Smeets illuminated the significance of
impurities in APIs in connection with creating the marketing dossier.
Stricter requirements in the European Pharmacopoeia regarding impurities and
their identification force API manufacturers more and more frequently to
procure reference standards for a large number of impurities, which often
takes a lot of time and money. Dr Smeets strongly advocated a revision of
the corresponding pharmacopoeial chapters and the concept that the
registration authorities should focus more on safety-relevant facts than
merely on analytical results of the batches when judging a dossier.
Dr Mike James presented EFPIA's proposals for a revision of the
Variations Regulation in the EU, which had been forwarded to the European
Commission at the end of September 2006. Currently, notifiable changes
involve a high regulatory burden. The increasing tendency to hand in such
notifications under the Centralised System is tying up more and more
resources both on the part of the industry and on the part of the
authorities. EFPIA's suggestion for the revision of the Variations
Regulation aims at a different way of classifying or grouping the variations
("related and grouped variations") and propagates a procedure for sharing
out the tasks for medicinal products registered on a national level.
The event was rounded off by 8 parallel sessions, during which the
aspects mentioned in the lectures could be consolidated and discussed in
detail. The following topics were offered, from which the conference
participants could choose two:
- APIC Guide on Quality Management (Walter Finster, DSM Fine Chemicals,
Austria)
- Risk-Based Approach for Equipment Qualification (Sabra Seyer, Pfizer,
USA)
- Critical Quality Attributes in a Multi-Customer Environment (Dr Henri
Leblanc, Rhodia Organique, France)
- How to Establish a 6 Sigma Concept in an API Plant (Jim McKiernan,
McKiernan Associates, Switzerland)
- A New API Powder-Processing Facility – Regulatory Aspects (Dr Marten
Wiersma, Diosynth, The Netherlands)
- How to Define the API Starting Material – Case Studies (John Webster,
Pfizer, USA)
- API Dossier Requirements in Japan (Claude Becker, PCAS, France)
- Third-Party Auditing: Update on the APIC Auditing Program (Dr Thomas
Buggy, DSM Anti-Infectives, The Netherlands)
On the whole, this conference was characterised by a great willingness to
discuss matters and an openness on all sides. Thus, this event has once more
made a contribution to the mutual understanding and reinforced co-operation
between the European API industry and the supervisory and registration
authorities. The changes in the framework conditions have set other things
in motion, and the challenges for all parties concerned have grown.
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