Finished Product Monographs in the European Pharmacopoeia

The European Pharmacopoeia (Ph.Eur.), which is celebrating its 50th anniversary in 2014, has a worldwide reputation for its monographs on APIs and excipients. Owing to its close collaboration with European regulators, the Ph.Eur. is well aligned with regulatory developments and needs, and reflects state-of-the-art technologies and requirements.

While the Ph.Eur. includes amongst its texts a wide range of general dosage-form monographs and has taken measures to stay abreast with scientific and technical developments, for example, by fostering the implementation of quality-by-design principles and relevant modern analytical technologies, the Ph.Eur. Commission has been somewhat reluctant in the past to initiate extensive development of specific dosage-form monographs. Until recently, such monographs have only been established in certain specialized areas (e.g., for vaccines, blood products, insulin, and radiopharmaceuticals).

It has to be acknowledged, however, that there is a clear demand for these monographs. They are needed by official medicines control laboratories for their market surveillance studies; they support and facilitate the development of generic drugs, which are crucial to ensure the sustainability of today’s healthcare systems, and they may also be useful to regulatory authorities by facilitating the assessment of respective quality dossiers. Based on the feedback received from stakeholders in the context of its tri-annual scientific conference held in Prague in October 2010, the Ph.Eur. Commission has reviewed its policy. Following intensive discussions with the European Medicines Agency’s Joint CHMP/CVMP Quality Working Party, the Ph.Eur. Commission decided in 2012 to initiate a pilot phase on the feasibility of finished product monographs. A dedicated working party composed solely of representatives of licensing authorities and official medicines control laboratories was set up and assigned two tasks: to elaborate draft monographs on two finished products, one for which the API is still under patent in Europe (a so-called “single-source” product) and a second one for which generic drugs are already on the market (“multi-source” product), and to draft a guidance document to explain the rationale for finished product monographs and how to use them, intended for both regulators and the industry.

Finished product monographs
Since then, the pilot phase has concluded and the outcome was presented to the Ph.Eur. Commission for approval at its March 2014 session. Based on the commission’s unanimous decision, the draft monograph on sitagliptin phosphate tablets--a text elaborated by the working party in close collaboration with the innovator—is now published in Pharmeuropa, the Ph.Eur.’s free online-forum, for public comments (1). For this monograph, like all other monographs based on a single-source product, broad public consultation is even more important than for multi-source products to ensure that the resulting acceptance criteria and test methods are indeed robust and applicable to a wide range of products. During the elaboration of the finished product monograph, a monograph for the active substance sitagliptin phosphate monohydrate was also drafted, for which the consultation period ended in March 2014.

It is the Ph.Eur. Commission’s policy that each finished product monograph, taken as a whole, should provide a reliable basis for making an independent judgement as to the quality of the preparation. Finished product monographs will cover different formulations and strengths (whenever possible) of the same dosage form containing the same API. The Ph.Eur. Commission, as it does for all its API and excipient monographs, will only elaborate monographs on products that have been authorized in at least one of its member states and that contain an API for which a monograph has already been published in the Ph.Eur. or which is on the work program. As for all monographs, the elaboration and revision of finished product monographs will be subject to public consultation and take into account current scientific knowledge and relevant medicinal products authorized at the time.

In addition, finished product monographs, like all other API and excipient monographs, while legally binding and reflecting the state of the art, are not intended to be a “regulatory straitjacket” that stifles innovation. In line with the requirements for all compendial APIs, a full dossier will need to be submitted to the licensing authorities for a finished product covered by a Ph.Eur. monograph, detailing its composition, pharmaceutical development, manufacture, control, container/closure system, and stability. As analytical procedures may be affected by the presence of excipients and/or the manufacturing process selected, demonstration that the testing procedures described in a finished product monograph are suitable for the specific product will need to be included in the marketing authorization dossier. However, this is not an unusual requirement as any applicant referring to a compendial API has to demonstrate that the pharmacopoeial monograph is indeed capable of adequately controlling the quality of the substance, manufactured according to the submitted route of synthesis.

Regulatory requirements
The EU pharmaceutical legislation, in directive 2003/63/EC detailing the requirements of marketing authorization applications (2), already provides for a feedback mechanism between regulators and pharmacopoeia authorities in case a compendial product is not adequately controlled by the respective monograph. This provision allows assessors to make sure that the specifications for a given product are indeed adequate for the specific purpose and provides the Ph.Eur. Commission with valuable information on the need to review and potentially revise the monograph. In addition, the Ph.Eur. itself in its general notices offers much flexibility to users, from the notion of alternative methods—provided they lead to the same “pass/fail” result and are approved by the competent authority—to the possibility of using modern control strategies, including parametric release and real-time release testing or even using manufacturing flexibility, for example, that is allowed by the design space.

While the pilot phase clearly demonstrated the feasibility of developing monographs for both single-source and multi-source products, the Ph.Eur. Commission felt it would be prudent to gather more experience with single-source products and has decided to start with the elaboration of single-source monographs on products that are potential future generic drugs. This does not, however, exclude the possibility of also including multi-source products in the work program. Such a decision will be based on a critical assessment of the usefulness of having a Ph.Eur. monograph and its impact on products already on the market.

While the decision of the Ph.Eur. Commission to be more active in the field of finished product monographs will help to further broaden the scope of the Ph.Eur., it is not a change in paradigm. The same general principles for monograph elaboration will be applied as for API and excipient monographs to ensure they are of the same high scientific quality. In addition, public consultation will provide feedback from a wide range of stakeholders and contribute to the texts’ usefulness and adequacy.

Based on the promising outcome of the pilot phase and its decision to transform this into a routine work program, the Ph.Eur. Commission is looking forward to its future collaboration with sponsors who are interested in contributing to the elaboration of finished product monographs in the Ph.Eur.

References
1.  EDQM, Sitagliptine tablet monograph, Pharmeuropa, accessed May 9, 2014.
2.  European Commission, Commission Directive 2003/63/EC, Official Journal of the European Union (June 25, 2003).

About the Author
Susanne Keitel, PhD, is head of the European Directorate for the Quality of Medicines of the Council of Europe. EDQM is responsible for the European Pharmacopoeia.