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

Susanne Keitel

, 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 

 is well aligned with regulatory developments and needs, and reflects state-of-the-art technologies and requirements. 

 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. 


  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 

 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 

 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 

 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. 


  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 

 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 

 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 

, 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 

,  accessed May 9, 2014.
  2.  European Commission, Commission Directive 2003/63/EC, 


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

Articles

The European Pharmacopoeia Commission re-evaluates its policy on the development of monographs for finished drug products.

Finished Product Monographs in the European Pharmacopoeia

 traditionally collaborates closely with European regulatory authorities. The Ph. Eur. Convention specifies that member states nominate their delegates for the Ph.Eur. Commission, the governing body of the Ph. Eur.Currently, all delegations include at least one representative from a health authority who normally also serves as head of the delegation. It is not surprising, therefore, that the texts of the Ph. Eur. are much aligned with regulatory developments in its 37 member states. This is a true benefit for users, as it ensures that compliance with the legally binding Ph. Eur. standards makes it easier to obtain marketing authorizations from competent authorities throughout the continent. 


The decision of the Ph. Eur. Commission to revise its strategy regarding control of metal catalyst or metal reagent residues is a recent example of the consistency between the approaches of European licensing authorities and the Ph. Eur. This revision followed a discussion at the Committee for Medicinal Products for Human Use (CHMP), the leading EU scientific committee involved in assessing marketing authorization applications coordinated by the European Medicines Agency (EMA).

In 2008, the CHMP adopted a EU guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000). CHMP’s Safety Working Party developed this guideline in close collaboration with the Joint CHMP/CVMP Quality Working Party. It defines specification limits for 14 metal elements according to their route of administration and came into effect in September 2008 for new drug products while defining a five-year transition period for existing drug products. When it was adopted, it was intended that the requirements of the guideline would apply to existing products by September 2013 at the latest. 


  The current compendia tests on heavy metals (Chapter 2.4.8 of the 

) have been criticized by users for not being adequate and state-of-the-art for the control of all relevant metal elements. A revision of these tests, therefore, has been included on the work program of the Ph. Eur. Commission. However, as methods and specifications are linked, the commission felt it important not to proceed with a revision of the chapter until limits had been harmonized and agreed upon. At the same time, to support the implementation of the CHMP guideline in line with what has been done in the past (e.g., related to the International Conference on Harmonization [ICH] guidelines on control of impurities in active substances [ICH Q3A] or on residual solvents [ICH Q3D]), the Ph. Eur. Commission decided to introduce the CHMP guideline as a general chapter for information only, as is the case for all general chapters that are not referred to by a monograph. This was done in 

 Supplement 7.7, which came into effect in April 2013. As the final step, the commission decided at its 145

 session in March 2013 to introduce a reference to this general chapter in the general monograph “Substances for pharmaceutical use” (2034), which would make the requirements of the general chapter mandatory for all substances used in the production of medicines for the European market, regardless of whether or not they are covered by an individual monograph in the 

At the international level, in October 2009, the ICH Steering Committee endorsed a concept paper on the development of a harmonized ICH 

, a project known as ICH Q3D. Step 2b of this guideline was completed in June 2013, and the document is currently published in the EU for comments until December 31, 2013. While the limits defined in the CHMP guideline referred to previously have been used as a basis for ICH Q3D discussions, the latter has a different scope in terms of both geography (which is normal for an ICH guideline) and the elements covered, notably in that it defines limits for the so-called “big four” contaminants arsenic, cadmium, mercury, and lead among the 24 elements it deals with. At present, these are not covered by the current CHMP guideline. In addition, certain limits proposed in the current version of the ICH document differ from those that have already been implemented via the CHMP guideline in Europe. For some of the elements the limits are wider (e.g., chromium, nickel, and platinum), while for others they are stricter (e.g., copper, molybdenum, and vanadium). A certain degree of disharmony between the current European and the future ICH guideline should be noted.


  Being committed to international harmonization, European regulators and the Ph. Eur. Commission have stated from the inception of the ICH guideline that they would update their respective requirements in line with the outcome of the discussions at the ICH level. This means that the CHMP guideline would be replaced by the ICH guideline once the CHMP adopts the latter, which according to EU procedures is the final step in the implementation in the EU of an ICH guideline adopted by the ICH Steering Committee. The Ph. Eur. Commission would do the same for its general chapter on metal catalyst or metal reagent residues (Chapter 5.20). The Ph. Eur. has always been clear that it will keep the European requirements for the time being and revise the respective chapter to align them with the ICH requirements once the discussions at the ICH level have been finalized. This strategy contrasts with what has been announced by the United States Pharmacopeial Convention, which has been developing its own specification limits for elemental impurities in parallel with the ICH discussions.

In the meantime, the ICH document has reached step 2b, but some of the limits are different from the ones previously defined by European regulators and applied by the Ph.Eur. Normally, according to the CHMP guideline, the latter requirements should have become applicable to existing products as well in September 2013. Likewise, the 

. would have made these requirements legally binding for all substances for pharmaceutical use as of Supplement 8.1, which will come into force in April 2014. This would have created further disharmony for industry. To avoid this, the CHMP decided at its July 2013 meeting to postpone the application of its guideline to existing products and to await the outcome of discussions at the ICH level before taking any further measures. As an integral part of the European regulatory network and to ensure continued consistency between the policies applied by regulatory authorities and the pharmacopoeia, the Ph. Eur. Commission has decided to defer the addition of a reference to the general chapter in the general monograph “Substances for pharmaceutical use.” This should not be confused with the decision of the USP Executive Committee of Council of Experts to postpone the implementation of its respective General Chapters <232> Elemental Impurities-Limits and <233> Elemental Impurities-Procedures, which was made for different reasons.

The decision to postpone the implementation of the full scope of the CHMP Guideline on the specification limits for residues of metal catalysts or metal reagents made by the CHMP and the Ph. Eur. Commission are an excellent example of the benefits of close collaboration between regulators and the pharmacopoeia authority, not only for themselves, but also for industry. Just imagine the situation if one party had decided to defer the extension of the scope of the CHMP guideline to existing products while the other had made them mandatory. 


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

The European Pharmacopoeia Commission has decided to change its approach on elemental impurities.