Testing Inhaled Generics

Generic Bioequivalence Testing Inhaled Generics By Mark Copley New product-specific FDA guidance and USP monographs support at Copley the development of popular inhaled products. This article reviews their Scientific value in the rapidly growing generic sector Central to the development of a monographs for inhaled products, Ensuring Efficiency new generic product is the need to which closely detail appropriate demonstrate bioequivalence (BE) testing for off-patent active The number of generic in order to confirm pharmaceutical ingredients. The FDA and USP are submissions to the FDA has equivalence to the reference labelled discrete, independent bodies, so risen exponentially over the last drug (RLD) being replicated. Such there is no obligation to adhere decade or so, with substantial evidence is typically supplied in the to USP monographs as part of a expansion in the generic sector form of in vitro and in vivo test data. submission process, even though – in particular in India, where In vitro tests are usually the first step it is common practice to do so to annual growth rates remain in and preferable to the manufacturer reduce the risk of inadequate excess of 25% (5). A stated aim from the perspective of ease, cost data provision. of publishing product-specific and speed, but choosing a testing guidance is to streamline the strategy that yields suitable data is Monographs describe the tests process of providing support also important. required to “ensure the substance with the design of BE studies, as a is of the appropriate strength, way of improving efficiency (1). For certain widely used pharma quality and purity” (3), and provide Furthermore, better quality products, the FDA has released a standard that can be used by submissions have the potential product-specific guidance to the FDA to assess compliance to reduce the burden of regulatory support the generic submission and by manufacturers to guide assessment without increasing risk. process; drugs for administration testing strategies. Product-specific by the inhaled route are no monographs may therefore be For generic developers, time to exception. This follows a signalled helpful to ensure efficient generic submission is crucial, with the policy change in June 2010 to development; however, in certain potential prize of a 180-day actively provide guidance for the instances, they point to the use of exclusivity period in certain demonstration of BE for specific test equipment that is not included circumstances (6). Guidance on products, rather than simply dealing in the USP general chapters. how to design BE studies is, with requests for information therefore, valuable in ensuring an on demand (1). Designed to In this article, we examine the drivers efficient development process facilitate generic drug product for developing product-specific that will result in data which can availability, this guidance helps the tests and explore the reasons why robustly satisfy regulatory generic industry to “identify the they may call for the use of unique requirements. While it does not most appropriate methodology equipment. A key focus are new appear that it is mandatory to for developing drugs and USP monographs specified for follow the guidance, the ease and generating the evidence needed fluticasone propionate (FP) and reduced risk of doing so makes to support ANDA salmeterol, plus draft monographs it likely that such an approach Keywords (Abbreviated New for these two active ingredients in will be relatively attractive. In Drug Application) combination. These additions reflect summary then, product-specific approval” (2). activity to develop generic versions guidance has benefits for both the Bioequivalence of Flovent®/Flixotide®, Serevent® regulators and generic developers Inhaled route In addition to and Advair®/Seretide® respectively, alike – a happy confluence of Product-specific guidance this guidance, the latter of which – though now interests that perhaps helps to USP monographs there are now a off-patent – has proven notoriously explain the steadily increasing growing number of difficult to replicate and continues number of products covered by Aerodynamic particle product-specific US to command around $6 billion in successive guidance releases over size distribution Pharmacopeia (USP) annual sales (4). the past few years. 22 Innovations in Pharmaceutical Technology Issue 55 iptonline.com Key generic targets in the inhaled the active ingredient(s) a patient One way of approaching in vitro area include drugs routinely will receive under representative testing within this context is used for asthma and chronic delivery conditions – and the therefore to duplicate the test obstructive pulmonary disease aerodynamic particle size equipment and method used in (COPD). As the global incidence of distribution (APSD) of that dose. the development of the original respiratory illness rises, delivering APSD influences deposition product, rather than to introduce safe, efficacious and inexpensive behaviour in the pulmonary the complicating factor of treatment is becoming increasingly system, and is used to assess comparing results generated using important, with governments the likelihood of a drug being a different set-up. This approach seeking to control and contain delivered successfully to the reduces the risk that the data spiralling healthcare costs. Many target region within the lung. generated – such as delivered dose, generics are destined for home impactor drug mass-per-stage or markets in developing countries, The test equipment and methods fine particle dose – are influenced but the overall potential export defined in the USP general chapters by the equipment type or test market for generics is sizeable. have evolved over a number of method used, and hence reduces Overall, across all pharma product years, and represent the view of the burden associated with method types, around 40% of generic drugs experts and stakeholders with validation and specification setting. and over-the-counter products regard to current best practice. used in the US are now produced This raises the question of how test Monographs, unlike general by India, making FDA approval methods introduced in the product- chapters, typically include the name essential (7). specific USP monographs differ and, of an ingredient or preparation, indeed, why do they do so? and their development often Factors for Testing begins with the manufacturers of For an ANDA submission, the that product drafting a document The general FDA guidance and defining goal is to demonstrate BE for consideration by the wider USP chapters relating to orally to an RLD, essentially reproducing community (3). This heritage is inhaled and nasal drug products the performance that ultimately often particularly visible in product- (OINDPs) are defined in terms led to regulatory approval for the specific monographs, which tend of their applicability to certain original product. The fact that to include hitherto proprietary test product types: dry powder patents generally expire after 20 methods that are derived in some inhalers (DPIs), metered dose years dictates that the development way from those originally deployed. inhalers (MDIs), nebulisers and work associated with the RLD is Although these are broadly similar nasal sprays (8,9,10). Key tests likely to have been carried out to those detailed in the general include the measurement of some time ago, often prior to the chapters, there are in certain cases delivered dose – the amount of definition of current test methods. some important differences. The Evolution of Inhaled Product Testing The use of inhalers to deliver drugs via the lung is far newer pioneering organisations. As a result, some proprietary than traditional methods of drug delivery, such as oral solid equipment found its way into the resulting chapters, but dosage, which means the test methods associated with their some did not. Companies remained free to validate their development and with quality control are too. The first own test methods using preferred equipment, and some inhalers were commercialised in the 1950s, 60s and 70s, continue to do so, even today. predominantly by large pharma companies like 3M, AstraZeneca, GlaxoSmithKline and Sanofi (or their The general pharmacopoeia chapters for OINDP testing predecessors). Ensuring the safety and efficacy of these continue to evolve, reflecting on-going development and products was essential for their introduction, so these understanding, and the requirements of the market. companies led the way in evolving new test methods, with As a result, all the relevant pharmacopoeias, including the some designing and manufacturing their own analytical USP and European Pharmacopoeia (Ph Eur), are not fully equipment to meet requirements (11-13). harmonised. For example, there is an MDI content uniformity apparatus unique to the British Pharmacopoeia The need to move towards more standardised testing for testing pressurised inhalers (14). The additional need to grew with the establishing market, and pharmacopoeial ensure consistent quality during the complete product general chapters were subsequently established from the lifecycle adds to the complexity of refining the general 1980s onwards, supported by expertise within the chapters to ensure best practice. 24 Innovations in Pharmaceutical Technology Issue 55 iptonline.com In some areas, unique both aerosol and powder, have also been proposed (22,23). pieces of equipment are The monographs for FP and specified salmeterol

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