Recommendations from the workshops

EDQM: 50 YEARS OF LEADERSHIP IN THE QUALITY OF MEDICINES
- PAVING THE WAY FOR THE FUTURE International Conference 6-8 October 2014, Strasbourg, France
Summary of workshops
and recommendations for the future
1. Experiences with Ph.Eur. monographs
Overall, the different stakeholders provided very positive feed-back on their
experience with the use of Ph.Eur. monographs and general chapters. They
very much appreciate the provision of harmonised European standards,
facilitating Marketing Authorisation Applications for the industry and assessment
by authorities. The Ph.Eur. is perceived as being close to its users and working
in partnership with both individual manufacturers as well as associations.
Processes are transparent and user-friendly, decisions are based on consensus.
Recommendations:
In the development of future monographs on complex substances and
compounds, the Ph.Eur. will need to strike the right balance between flexible
and rigorous standards. While the Ph.Eur. already provides for the use of
alternative methods, provision of guidance on their cross-validation against
compendial methods would be most helpful. New scientific and regulatory
developments will need to be reflected in a timely manner, requiring input and
support by stakeholders. Monographs will also need frequent revisions to cover
the impurity profiles of emerging synthetic routes. Earlier availability of
reference standards would be appreciated to facilitate testing of methods
published for consultation. Finally, stakeholders encouraged the Ph.Eur. to
continue pursuing harmonisation/convergence with other Pharmacopoeias with
the ultimate aim of generating global standards.
2. Quality by Design (QbD)
The Ph.Eur. already provides a framework for the application of QbD in its
General Notices and a number of specific chapters. Accordingly, it does not
represent a barrier or disincentive to the implementation of QbD and the use of
innovative technologies, either today or in the future, as there are different
means of complying with the requirements of Ph.Eur. monographs – regardless
of whether a traditional or QbD approach has been selected to ensure the
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quality of a substance/product. However, the use of alternative methods could
be further facilitated by the provision of additional tools for the verification of
method performance to ensure that discriminatory power remains on the same
level.
QbD for analytical methods: from a regulatory point of view, the application of
QbD for analytical methods is still in its infancy and not broadly
implemented/accepted. In any case, Ph.Eur. methods remain the reference
methods for regulators. While the term “Analytical Target Profile” has been
introduced in the context of discussion on QbD for analytical methods, it is
independent from the technology that is used and equally applies to the
traditional approach – any analytical method should be fit to serve its purpose
and developed with this goal in mind. However, the application of QbD
principles to the development of analytical procedures may generate a better
understanding of their performance, eg their robustness. To gain broader
experience in this field, it would be advisable to start with easier methods
before moving on to more complex ones. However, the quality of analytical
methods should be seen together with the quality of the product and its
manufacturing process, including good control of suppliers. More information
and experience are needed before a common practice on the application of
analytical QbD principles can be agreed – and reflected in the Ph.Eur.
3. Finished Product Monographs
In a globalised world and with increased demand for generics, the development
of monographs on chemically-defined finished products is undisputed and their
added value recognised. They will facilitate assessment of marketing
authorisation applications and make it easier to compare and test medicinal
products on the market. However, as for active substances, the presence of a
finished product monograph will not replace the need to submit the respective
quality documentation as part of the marketing authorisation application in
Module 3. In addition, the applicant will need to demonstrate the suitability of
the monograph to adequately control the quality of the product in the MAA. For
the time being, FPMs are developed following the P4 procedure, that is for
products still under patent and by a group of experts solely consisting of
regulators.
The workshop identified the dissolution test as the main critical issue. The
current proposal foresees that while a dissolution test is proposed in the
monograph for relevant dosage forms, its suitability will be assessed in the
licensing procedure (“unless otherwise justified and authorised”). Participants
agreed that it needs to be discriminatory.
Participants also requested that monographs be harmonised between the
different pharmacopoeias; they asked for more communication on the principles
of elaboration or revision, eg in the case of different API forms. Finally, industry
pleaded for more involvement in the discussion related to the elaboration and
revision of finished product monographs.
4. Impurities
Monograph specifications are based on specifications approved by European
licensing authorities and reflect the quality of approved products on the
European market. Indeed, batch results at release and end of shelf-life are
taken into consideration during monograph elaboration or revision. Ph.Eur.
monographs provide a high degree of transparency: they list specified and
unspecified impurities and indicate the list of impurities controlled by each
method.
A close collaboration with industry is crucial to obtain all necessary information
on impurities as well as necessary samples. Implementation of the recently
adopted guideline on specifications for antibiotics still poses a number of
problems. In order to be successful, the right balance between the
requirements of assessors (“regulatory science”) and practical feasibility for the
industry needs to be found.
The Ph.Eur. Commission has developed a strategy for the implementation of
the new ICH Guideline on elemental impurities (ICH Q3D), which will mostly
apply to finished products. In the Ph.Eur., reference to the current “Heavy
Metals” chapter 2.4.8 will be deleted from individual monographs, unless they
cover veterinary use only. In addition, chapter 5.20 will be revised to replace
the current verbatim reproduction of the EMA Guideline on the specification
limits for residues of metal catalysts or metal reagents by the new harmonised
ICH guideline. Chapter 2.4.20 will also be revised accordingly. Stakeholders
expressed their need for support in the implementation of this new guideline.
5. Pharmacopoeial Harmonisation
While a globalised supply chain and markets clearly demand pharmacopoeial
harmonisation, local and regional needs have to be acknowledged. In addition,
different regulatory environments of the pharmacopoeias and different cultures
pose specific challenges in this context.
In order to make the best use of limited resources and time available, the
pharmacopoeias should prioritise topics for harmonisation and harmonisation
processes. As regards the work of the Pharmacopoeial Discussion Group (PDG),
users would benefit from a more transparent process. In this context, the
establishment of a common website rather than the current three individual
websites of the participating pharmacopoeias would be helpful.
The bilateral prospective API harmonisation pilot was very much appreciated,
but participants felt it was time for a final evaluation and decision on
whether/how to proceed with this initiative – should it be continued, continued
with a different procedure or stopped? Overall, there was great interest in
continuing and opening up to further APIs and excipients. Finally, all
participants clearly supported the facilitation of global harmonisation of
pharmacopoeial standards through the development of Good Pharmacopoeial
Practices under the auspices of the WHO.
6. Biologicals
Overall, users are supportive of the existing General chapters and General
monographs on biologicals. However, for specific products or classes of
products, a need for flexibility versus details was identified, and similarly for
robust versus advanced technologies.
Application of the P4 procedure was considered a two-phase learning approach:
to start, it was considered necessary to evaluate users’ needs and elaborate
monographs on innovator products. As a follow-up, as biosimilars emerged,
further evolution and standardising of the thinking would be required. To be
successful, close collaboration between pharmacopoeias, industry and
regulators was necessary.
Compared to monographs on chemically defined substances, biologicals require
more flexible monographs and the challenge is how to translate this flexibility
into working reality. A first step was the work conducted by the P4 Bio Working
Party on recombinant FIX products.
There is also a need for further harmonisation within the Ph.Eur., for example
as regards approaches for glycan analysis.
In drafting monographs for biologicals, it has to be borne in mind that a
monograph should not only be suitable for one specific material; biosimilars
have lots of common aspects – even if they do not constitute identical
molecules.
In the field of advanced therapy medicinal products (ATMPs), the Ph.Eur. is
considered useful by both developers and assessors. However, product-specific
monographs for ATMPs are far from being a reality today.
7. Certification
The Certification of suitability (CEP) procedure is a well-established system for
the assessment of pharmaceutical substances and for inspections of API
manufacturers. It is beneficial for both authorities and industry, it helps to save
resources, facilitates harmonisation/convergence in assessment and inspection
practices and is an excellent platform for exchanging knowledge between
authorities.
Users appreciate the clear procedures and timelines as well as overall
transparency of the Certification procedures. Where an active substance is
covered by a CEP, the level of information exchanged between the API
manufacturer (CEP holder) and the Marketing Authorisation Applicant/Holder
(MAA/MAH) varies. From an assessor’s point of view, measures should be taken
to ensure that sufficient information is shared, to enable the MAA/MAH to fulfil
their responsibility for the quality of the API and the final medicinal product.
The CEP procedure will soon face a number of new challenges, related to the
implementation of the new ICH guidelines on genotoxic and elemental
impurities (ICH M7 and ICH Q3D). The assessment of CEP applications and the
content of CEPs will need to be adapted accordingly.
Participants encouraged continued evolution of the procedure, in line with
developments in the international regulatory environment and in close
cooperation with authorities. The EDQM should further promote the procedure
and encourage additional authorities outside its member States to accept CEPs.
In addition, further contribution to international collaboration in the field of API
inspections was recommended with a view to further reducing the burden on
manufacturers (by replicate inspections), to save resources while increasing the
oversight of API manufacturers.
8. Herbals
Participants felt that there was no justification for mandatory general tests for
pesticides in essential oils and for arsenic in herbal drugs, but would prefer
consideration of individual cases.
In order to further improve TLC identification of herbal drugs and herbal drug
preparations in the Ph.Eur., HPTLC should be introduced, together with a better
description of the methods and the chromatograms, the introduction of a
system suitability test and intensity marker and pictures of sample
chromatograms. A corresponding general chapter will be published in
Pharmeuropa.
The semi-quantitative use of HPTLC may be a future concept for the quality
control of herbals but needs further discussion with stakeholders.
Furthermore, participants felt that the extensive analysis described for dried
herbal drugs was not appropriate for fresh herbal drugs. Instead, they
recommended establishing different levels of analytical requirements,
depending on the provenance of the fresh herbal drug and the methods of
processing into the herbal drug preparation. However, this does not apply to
homeopathic preparations as there are separate texts and individual
monographs.
9. Role of the OMCL Network
The network of Official Medicines Control Laboratories is based on common,
harmonised quality systems. This allows members to share work and mutually
recognise test results. While routine annual Post Marketing Surveillance
programmes (PMSs) are established in most member States on the basis of
risk-assessment and risk-based criteria, not all OMCLs have influence over their
routine PMSs. A survey was therefore recommended to gain an overview of the
bodies responsible for PMSs in the individual member States.
The collaboration between OMCLs, assessors and inspectors should be further
improved at national level to ensure the greatest mutual benefit of the
respective activities.
Feedback from the market surveillance studies conducted throughout the
network also contributes to the development and optimisation of Ph.Eur.
monographs and General chapters. In the light of the growing importance of
biosimilars, comparative testing of such products was identified as a potential
future field of activity of the network.
10.
Combating Illegal Medicines
The OMCL Network has developed effective programmes and tools to detect
counterfeit/illegal medicines. So far, they have been rarely found in the legal
distribution chain, while most cases have been identified on the illegal market.
However, the quality and authenticity of dietary/food supplements has been
identified as a significant problem which requires education of users.
The network approach taken by the Council of Europe/EDQM in the fight
against counterfeit/illegal medicines fosters cooperation which is especially
beneficial in the context of the MEDICRIME convention and the model of Single
Points of Contacts (SPOCs).
In order to be successful in this battle, it is important to raise awareness and to
develop strategies to identify harm. Feedback provided on the outcome of a
first project aimed at estimating the scale of illicit use of drugs by testing
sewage water (sewage epidemiology) was very much welcomed.
Participants recommended strengthening the legislation with respect to
medicines “disguised” as dietary/food supplements. Responding to the question
as to what role the Ph.Eur. could play in the fight against counterfeit/illegal
medicines, they felt that updated monographs with state-of-the-art methods
were important, but not the only means of detecting illegal products. The
importance of developing new approaches, such as a link to pharmacovigilance
signals was underlined.

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