32 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 P h a r mTe c h . c o m
Pharmacopoeia Compliance Series
guage in t he Ph. Eur. Genera l Notices (11) t hat states
a n a lternat ive met hod may be used instead of one in
t he Ph. Eur., prov ided t he a lternative met hod ensures
compliance with the monograph and the use of the a l-
ternative method has gained the "agreement of the com-
petent aut horit y," meaning approva l by t he European
regulatory agencies. In the authors' experience, no other
pharmacopoeia or regulatory agencies mandate this pri-
or-approval before the alternative method can be used
to replace a method in the pharmacopoeia. In the case
of the publication of a new Ph. Eur. monograph, where
a monograph did not prev iously exist, t his regulator y
approval for a company to continue using the previously
approved met hod in Europe rat her t ha n a met hod in
the new Ph. Eur. monograph is necessary, even though
the company had previously received approval for their
method in Europe. In essence, the currently approved
method is now considered an alternative method to that
in the Ph. Eur. monograph.
For the drug substance, there is another way to ensure
European regulatory agreement to use methods other than
those listed in the corresponding Ph. Eur. monograph. The
procedure for "Certification of Suitability to the Mono-
graphs of the European Pharmacopoeia" (CEP), described
on the European Directorate for the Quality of Medicines and
HealthCare (EDQM) website (12), provides for a centralized
assessment of applications describing the manufacture and
quality control of drug substances to facilitate and simplify
exchanges between regulators and industry to ensure compli-
ance with the Ph. Eur. and therefore with the requirements of
the relevant EU legislation. The procedure complements and
bridges the Ph. Eur. monograph and the submission of a mar-
keting authorization dossier for a drug product. Also as noted
on the EDQM website, CEPs are recognized by the signatory
parties of the Ph. Eur. Convention and are also recognized by
many other countries around the world, including Canada,
Australia, New Zealand, Tunisia, and Morocco.
Conclusion
Compliance with compendial standards is a legal and regu-
latory requirement in those countries and regions in which
the pharmacopoeia is applicable and is essential to ensure
continued availability of medicines to patients. However,
compliance is complicated when there are differences be-
tween compendial requirements and approved drug prod-
uct registrations. Challenges may arise in the elaboration
of monographs by the pharmacopoeia, when differences
emerge in the tests, methods, and acceptance criteria—rang-
ing from minor to significant—between the monographs
and registrations.
These differences must be addressed to ensure ongoing
compliance. Options include the addition of more quality
testing or updates to product registrations to bridge any gaps.
For method differences, the choices are limited, as expressed
in the "MARK" principle: Merge, Add, Replace, or Keep. To
achieve compliance decisions that meet both regulatory and
compendial requirements, dialogue is needed between im-
pacted stakeholders in a company, including quality, regu-
latory, compendial affairs, and many others. Aligning on an
implementation strategy and maintaining communication
throughout the execution of the plan are essential to achieve
the best compliance outcome for the company.
Acknowledgment
The authors gratefully acknowledge the contribution of
Susan J. Schniepp for her technical review and helpful sug-
gestions during the preparation of this series of articles.
References
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PT
Compliance is complicated
when there are differences
between compendial
requirements and approved
drug product registrations.
