IPEC e-newsletter - Excipients Insight July/August 2018 - 31-08-18

 

Inside this issue

     

Focus on co-processed excipients

With new active pharmaceutical ingredients being developed, including both small and large molecule drugs, pharmaceutical manufacturers need new excipients to increase options for formulation, processing and delivery of medicines. However, high development costs and stringent regulatory requirements mean that few new chemical entity (NCE) excipients have reached the market in recent years.

One alternative to developing NCE excipients is to create co-processed excipients (CPEs), which provide a means whereby new excipient functionality can be introduced without the time and economic constraints relating to the introduction of novel excipients. From just a handful of examples a few years ago there are now dozens commercially available, and it’s expected that the number will continue to grow.

CPEs are a combination of two or more excipients obtained by physical co-processing – for example co-drying, spray drying, granulation, extrusion, and high-shear dispersion – that does not lead to chemical change (the formation of covalent bonds), but present functionalities that are not achievable through simple blending of the individual excipients. The enhanced functionality afforded by CPEs presents opportunities for improved drug product manufacturability, performance, stability and bioavailability.  For instance, CPEs have been used in quick-dissolving oral tablets to improve the mechanical strength of the dosage form, and others have been developed for optimum performance of a specific manufacturing process such as direct compression.

CPEs can provide improved functionality-related characteristics and enhanced properties, with minimal safety data burden as they are typically composed of substances already evaluated for safety. From a regulatory perspective, the CPE should be assessed as a whole and not as a simple blend, and risk assessment should be scientifically based and evaluated on a case-by-case basis. It is well recognised that they may require different quality controls to simple excipient mixtures, and the user of any CPE is responsible for assuring its fitness for purpose, and that the CPE and its components are manufactured to acceptable standards of good manufacturing practice (GMP).

Last year, IPEC Europe and IPEC-Americas jointly published a guide for excipient makers and users on CPEs, offering best practice advice and voluntary guidance to assist their development, manufacture and use.

The guide facilitates communication between excipient users and suppliers regarding the safety information required for regulatory filing for a product containing a novel co-processed excipient. For excipient manufacturers, it covers areas such as analytical method development, stability and safety considerations, including ‘safety bridging’ (in other words making a case for a CPE based on the safety and toxicology of the individual components) and risk analysis. For users, it looks at the CPE technical data package, regulatory and safety considerations, manufacture, fitness for purpose, and supply.

Meanwhile, IPEC has also developed an independent safety evaluation procedure for new or novel excipients that assesses safety bridging arguments to existing data in a bid to minimise the need for new safety studies.

Despite the advantages to producers, most co-processed excipients are not found in official monographs, which is holding back their use in the market.  Pharmacopoeias are however working on new CPE guidance, and specifically the development of monographs for CPEs will facilitate the use of these excipients by pharmaceutical manufacturers. Among the initiatives in play, the European Directorate on the Quality of Medicines & Healthcare (EDQM) is developing a general monograph on CPEs, which it says is intended to help excipient suppliers, pharma manufacturers and quality assessors work to a common definition and terminology, and define which quality controls are necessary based on the “particularities” of CPEs. The current definition in the monograph is fairly closely aligned to that used in the IPEC guide.

IPEC guide definition: “A co-processed excipient is a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing, and without significant chemical change. However, in some instances, formation of necessary components may occur, such as in-situ salt formation.”

EDQM proposed definition: “A co-processed excipient is any combination of 2 or more excipients, obtained by a well-defined, suitable physical process introducing intended functionalities that cannot be achieved through simple blending. If one or more excipients are added by simple blending to a co-processed excipient, the resulting product is not considered as a co-processed excipient. The composition of a co-processed excipient is defined and appropriate limits around the nominal percentage content of each component are determined based on the capability of the manufacturing process and the test method used.”

The first draft of the general monograph was developed in 2015 and revised two years later, with the second version out for public comment until the end of 2017. In particular, EDQM was seeking feedback on whether it is necessary to differentiate CPEs from simple blends and to confirm intended functionalities both during development and at batch release, or during development only.

The agency held a meeting in March to discuss that feedback and is considering the way forward – i.e. to either submit the monograph to the Ph. Eur. Commission for adoption or continue discussions on possible revisions with stakeholders. Meanwhile, the US Pharmacopeia (USP) has a guideline in place for introducing CPEs into the National Formulary but this is currently set for revision in the organization’s fiscal year 2019 work plan.

 

 

 

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