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 (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; 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.

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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 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 , including the some designing and manufacturing their own analytical USP and (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.

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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 (and draft monographs for FP/salmeterol combinations) cover both delivered dose uniformity (DDU) testing and APSD measurement. Figure 1: Glass sample collection apparatus is specified in place of the standard dose uniformity sampling apparatus for inhalation powders (left) and for inhalation aerosols (right) The equipment specified is very similar to that detailed in the general chapters, with the Andersen Cascade Impactor (ACI) specified for APSD measurement. This is one of two cascade impactors routinely used for OINDP characterisation, the other being the Next Generation Impactor.

However, in some areas, unique pieces of equipment are specified, including: ●● Glass sample collection apparatus specifically for DDU testing of inhalation aerosols ●● Glass sample collection apparatus specifically for DDU Figure 2: The modified induction port specified for APSD measurement necessitates the use of a modified testing of inhalation powders ACI pre-separator for inhalation powders (left) and a modified ACI inlet cone for inhalation aerosols (right) ●● Modified induction port to be used with the ACI for all APSD measurements ●● Modified version of the ACI pre-separator (for inhalation powders only) ●● Modified version of the ACI inlet cone (for inhalation aerosols only)

Like the glass sample collection apparatus for inhalation powders, the modified induction port specified in all five monographs for APSD measurement has an inlet geometry similar to that of the Glass Twin Impinger (GTI), indicative of its heritage (13). However, Guidance and Monographs Product-specific USP monographs it is manufactured from either are in place for FP and salmeterol aluminium or 316 stainless steel, to FDA product-specific draft as follows: match the impactor. Mouthpiece guidance is now available for adapters designed for the GTI can be a number of active ingredients ●● FP inhalation aerosol used to interface the induction port routinely used to treat asthma and (MDI delivery) (2013) (19) with the device, while an O-ring-less COPD. These include salbutamol ●● FP inhalation powder tapered exit enables interfacing (albuterol) (15), budesonide (16), (DPI delivery) (2013) (20) with the ACI. The modified versions FP/salmeterol (17) and, new this ●● Salmeterol inhalation powder of the ACI pre-separator and inlet year, ipratropium bromide (18). (DPI delivery) (2014) (21) cone – for inhalation powders and This guidance references test inhalation aerosols respectively equipment outlined in the general Further draft monographs covering – accommodate the modified chapters of the USP. FP and salmeterol in combination, induction port.

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Product-specific guidance can be 3. USP Fact Sheet, USP Standards: Monographs. Visit: www.usp. extremely helpful in defining in vitro org/sites/default/files/usp_pdf/ test strategies EN/regulator/monograph_ backgrounder_dec_2011.pdf 4. Nisen M, The bestselling The new monographs specify The need for accurately timed prescription drugs in the the 28.3L/min version of the ACI flow control, in order to obtain the world last year. Visit: www. (Stages 0 to 7, plus filter stage) in above volumes, can be achieved qz.com/349929/best-selling- all cases, despite the fact that a using a fast-acting solenoid valve, drugs-in-the-world flow rate of 60L/min is specified for as specified in the general chapter 5. World’s pharma innovation testing powders. 60L/min and 90L/ set-up for DPI testing, which is also base moving to India, says IBEF, min modified versions of the ACI designed to ensure a constant flow Manufacturing Chemist, CPPR designed to, among other things, rate through the cascade impactor Industry/University Cooperative, restore the full cut-off diameter during testing. October 2013 range of the impactor at higher 6. FDA Guidance for Industry, flow rates, now form part of the A Crucial Role 180-day generic drug general chapter (24). However, exclusivity under the Hatch- these modified versions of the ACI, Product-specific guidance can Waxman Amendments to the although in use for some time now, be extremely helpful in defining Federal Food, Drug and post-date the equipment available in vitro test strategies that will Cosmetic Act. Visit: www.fda. when the initial development of robustly demonstrate BE and gov/downloads/drugs/.../ these RLDs was undertaken. satisfy regulatory requirements. guidances/ucm079342.pdf Product-specific monographs also 7. Munroe T and Chatterjee S, With regard to test conditions, have a role to play in ensuring Analysis: Indian pharma draws the total air volumes specified in the the consistent quality of widely more FDA scrutiny as U.S. inhalation powder monographs are: used drugs as they transition into imports rise. Visit: www.reuters. generic products. Although some com/article/2013/09/12/us- ●● 2L for DDU testing, a figure that of these call for the use of test india-drugs-analysis- is widely accepted as broadly methods that differ from idusbre98b17c20130912 reflecting the lung capacity of a those in the general chapters, 8. FDA guidance for industry typical COPD/asthma patient the equipment required is metered dose inhaler and dry ●● 3L for APSD measurement, a now readily and commercially powder inhaler drug products, figure most likely to have been available. Its use may be helpful Chemistry, manufacturing specified as a compromise, in generic development and in and control documentation, to achieve adequate volume ensuring an ongoing supply of November 1998. Visit: www.fda. changes in the ACI safe, efficacious and inexpensive gov/downloads/drugs/.../ drug products. guidances/ucm070573.pdf 9. USP general chapter 601, References Aerosols, nasal sprays, Mark Copley is the Sales Director at 1. FDA Guidance for metered dose inhalers and Copley Scientific Ltd. Prior to this, he was Technical Sales Manager and Industry, Bioequivalence dry powder inhalers Product Specialist for the company’s recommendations for 10. USP general chapter 1601, range of inhaler testing equipment. specific products. Visit: www. Products for nebulization – He also provides application support fda.gov/downloads/Drugs/ characterization tests and consultancy, runs focused training workshops GuidanceComplianceRegula 11. Mitchell JP and Nagel MW, for the inhaled drug testing sector, and sits on the toryInformation/Guidances/ Cascade impactors for the size editorial advisory panel of Inhalation Magazine. ucm072872.pdf characterization of aerosols An invited member of the European Pharmaceutical 2. FDA Guidance, Compliance and from medicinal inhalers: Aerosol Group impactor sub-team, Mark has also Regulatory Information, Product- Their uses and limitations, made recommendations to the Inhalanda working specific recommendations for Journal of Aerosol group, leading to subsequent revisions to Ph Eur generic drug development. 16(4): pp341-377, 2003 and USP monographs. He holds a Masters degree in Visit: www.fda.gov/drugs/ 12. Van Oort M and Downey B, Aerospace Engineering from the University of Bath. Email: [email protected] guidancecomplianceregula Cascade impaction of MDIs toryinformation/guidances/ and DPIs: Induction port, ucm075207.htm induction cone and

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pre-separator lid designs 16. Draft guidance on 20. New introduction: recommended for inclusion budesonide, recommended Fluticasone propionate in the general test chapter September 2012. Visit: www. inhalation aerosol, Aerosols USP 601, Stimuli fda.gov/downloads/Drugs/.../ Second supplement to to the revision process, Guidances/UCM319977.pdf USP 36-NF31, December Pharmacopoeial 22(2): 17. Draft guidance on fluticasone 2013 pp2,204-2,210, 1994 propionate; salmeterol 21. New introduction: Salmeterol 13. Collins S, Determination xinafoate. Visit: www.fda. inhalation powder, Second of emitted dose from dry gov/downloads/Drugs/ supplement to USP37-NF33, powder inhalers: An alternative GuidanceComplianceRegula December 2014 to the USP unit spray sampling toryInformation/Guidances/ 22. USP Pharm Forum 41(1) apparatus, Drug Delivery to the UCM367643.pdf fluticasone propionate and Lungs 8: pp116-120, 1997 18. Draft Guidance on salmeterol inhalation aerosol, 14. Preparations for inhalation of ipratropium bromide. February 2015 the British Pharmacopoeia, Visit: www.fda.gov/ 23. USP Pharm Forum 41(1) Content of active ingredient downloads/Drugs/ fluticasone propionate and delivered by actuation of GuidanceCompliance salmeterol inhalation powder, the valve RegulatoryInformation/ February 2015 15. Draft Guidance on albuterol Guidances/ucm436831.pdf 24. Chapter 601, Inhalation and sulfate, June 2013. Visit: www. 19. New introduction: nasal drug products: Aerosols, fda.gov/downloads/drugs/ Fluticasone propionate sprays, and powders – guidanceComplianceRegulatory inhalation powder, Second Performance quality tests, first Information/Guidances/ucm supplement to USP 36-NF31, supplement to USP 37-NF32, 346985.pdf December 2013 August 2014