Industry's View on Using Quality Control, Biorelevant, and Clinically Relevant Dissolution Tests for Pharmaceutical Development, Registration, and Commercialization

Accepted Manuscript Industry’s View on Using Quality Control, Biorelevant and Clinically Relevant Dissolution Tests for Pharmaceutical Development, Registration and Commercialization Haiyan Grady, David Elder, Gregory K. Webster, Yun Mao, Yiqing Lin, Talia Flanagan, James Mann, Andy Blanchard, Michael J. Cohen, Judy Lin, Filippos Kesisoglou, Andre Hermans, Andreas Abend, Limin Zhang, David Curran PII:

S0022-3549(17)30717-7

DOI:

10.1016/j.xphs.2017.10.019

Reference:

XPHS 967

To appear in:

Journal of Pharmaceutical Sciences

Received Date: 27 August 2017 Revised Date:

12 October 2017

Accepted Date: 13 October 2017

Please cite this article as: Grady H, Elder D, Webster GK, Mao Y, Lin Y, Flanagan T, Mann J, Blanchard A, Cohen MJ, Lin J, Kesisoglou F, Hermans A, Abend A, Zhang L, Curran D, Industry’s View on Using Quality Control, Biorelevant and Clinically Relevant Dissolution Tests for Pharmaceutical Development, Registration and Commercialization, Journal of Pharmaceutical Sciences (2017), doi: 10.1016/ j.xphs.2017.10.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Industry’s View on Using Quality Control, Biorelevant and Clinically Relevant Dissolution Tests for Pharmaceutical Development, Registration and Commercialization

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Haiyan Grady,1 David Elder,2 Gregory K. Webster,3 Yun Mao,4 Yiqing Lin,5 Talia Flanagan,6 James Mann,6 Andy Blanchard,7 Michael J. Cohen,7 Judy Lin,8 Filippos Kesisoglou,4 Andre Hermans,4 Andreas Abend,4 Limin Zhang,9 David Curran10 1

Pharmaceutical Sciences, Takeda Development Center Americas Inc., One Takeda Parkway, Deerfield, IL, 60015, USA David P Elder Consultancy, Hertford, Hertfordshire, SG14 2DE, UK 3 Research and Development, AbbVie Inc., North Chicago, IL 60064, USA 4 Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc., West Point, PA 19486, USA 5 Analytical Development, Biogen Inc., Cambridge, Massachusetts, 02142, USA 6 Pharmaceutical Technology and Development, AstraZeneca R&D, Macclesfield, Cheshire, UK. 7 Worldwide Research and Development, Global Chemistry and Manufacturing Controls, Pfizer Inc, Eastern Point Road, Groton, Connecticut, 06340, USA. 8 Biologics Technical Development and Manufacturing, Novartis, East Hanover, New Jersey, 07936, USA 9 Drug Product Science and Technology, Bristol Myers Squibb Company, New Brunswick, New Jersey, 08903, USA 10 Analytical Sciences and Development, GlaxoSmithKline, King of Prussia PA 19406 USA

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ABSTRACT: This paper intends to summarize the current views of the IQ Consortium Dissolution Working Group, which comprises various industry companies, on the roles of dissolution testing throughout pharmaceutical product development, registration, commercialization, and beyond. Over the past 3 decades dissolution testing has evolved from a routine and straightforward test as a component of end-product release into a comprehensive set of tools that the developer can deploy at various stages of the product life cycle. The definitions of commonly used dissolution approaches, how they relate to one another and how they may be applied in modern drug development and life cycle management is described in this paper. Specifically, this paper discusses the purpose, advantages and limitations of quality control (QC), biorelevant (BR), and clinically relevant (CR) dissolution methods.

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biorelevant, clinically relevant,

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Key words: dissolution, quality pharmacokinetics

drug release,

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This article was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader research and development community.

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INTRODUCTION

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Recent trends indicate a proliferation of descriptors for dissolution methods that are linked to in vivo behavior, including such terms as biorelevant, biopredictive and clinically relevant. These terms are often used interchangeably and inconsistently in the literature. It is important to align the industry with regulators on standard terminology in order to foster scientific collaboration and promote consistent regulatory submissions. The purpose of this article is twofold: first, to propose an alignment of terminology, and second, to describe the function and applicability of each type of these methods in pharmaceutical product development and quality control, including potential benefits and limitations.

HISTORICAL VIEW AND THE DRIVING FORCE FOR RECENT EVOLUTION

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The purpose and expectations of the quality control (QC) dissolution test for immediate release (IR) products and associated criteria for dissolution data evaluation, such as specification(s) have been evolving. It has been widely accepted that dissolution is the only batch release test that monitors the rate and extent of in vitro drug release and this test is often used as a surrogate to ensure consistent in vivo performance1,2. Historically, the focus of developing a QC dissolution test was on obtaining acceptable variability (as per International Conference on Harmonization ICH Q2(R1) guidelines3) while at the same time achieving some discrimination against changes in process parameters, all within a reasonable time. The underlying assumption was that, if batches of drug product showed ‘sameness’ in the selected dissolution test, they would result in similar in vivo performance vs. the batches used in pivotal clinical studies and thereby, the link to safety and efficacy would be maintained. Dissolution profiles either obtained in the proposed QC method or in multi-media dissolution as required by SUPAC were used to assess product sameness either in development or to justify post approval changes.

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Dissolution testing first became widely utilized with the development of standardized (USP apparatus 1 and 2) tests in the 1970s and with the adoption of dissolution guidances by the United States Food and Drug Administration (FDA) in 19974. During this time, it was fairly simple to select a test with presumed in vivo relevance, as most of the molecules under development had adequate solubility (i.e., biopharmaceutical classification system (BCS) 1 and 3)5 and employed relatively straightforward conventional tablet/capsule formulations. Simple aqueous buffers at physiologically relevant pH values, such as hydrochloric acid at pH 1.2 (0.1N HCl) or phosphate buffer at pH 6.8, were often suitable testing media and some degree of bio-relevance was achieved.6

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Over the last two decades, the number of drug candidates with poor aqueous solubility has significantly increased, with most new drug development candidates falling into BCS II class7. While these new drug substances have dramatically enhanced industry’s ability to pursue new molecular disease targets, they also provide significant formulation and process development challenges. These challenges have in part been met with substantial advancements in formulation, manufacturing and drug delivery technology to address both immediate release as well as extended release needs. Amorphous solid dispersion, lipid based formulation and particle engineering approaches are commonly deployed to deliver low soluble compounds8-10. This type of technological advancement in the pharmaceutical industry presents a significant challenge to the biopredictive power of the traditional dissolution test, as will be discussed later in this document, and has necessitated advancements in the field of dissolution to provide additional tools to predict product performance (e. g., development of biorelevant dissolution methods). Another driving force comes from within the field of dissolution development. In parallel with the desire to understand the drug performance at the molecular and cellular level, the strong interest in predicting in vivo drug release and absorption and their correlation(s) to in vitro tests is evidenced by 2

ACCEPTED MANUSCRIPT the sheer volume of scientific publications in recent years11-13. This interest has stimulated innovation in the development of new dissolution media and apparatus that mimic the human gastrointestinal (GI) tract, further understanding of dissolution mechanisms, integration of dissolution data into modeling and simulation, building correlation of in vitro testing and in vivo human studies, and combining dissolution and other analytical technologies14-18. Using multiple dissolution technologies or multiple dissolution tests in conjunction with computer modeling to facilitate formulation selection at various stages during product development has become a common practice in the pharmaceutical industry.

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Furthermore, changes in the regulatory landscape are also a driving force for the progression of dissolution methodology. The advent of Quality by Design (QbD) has renewed the focus on linking quality tests to product performance in patients. Thus, ICH Q8, “Guidance for Industry, Pharmaceutical Development” indicates that achieving the required safety and efficacy are key elements of drug product quality19. A number of presentations from the FDA and industry have therefore highlighted the importance of building “clinical relevance” into the QC dissolution test, and a few approaches for achieving this goal have been suggested20-22. Within the concept of QbD, the demonstration of clinically relevant dissolution methodology and specifications can be used, when appropriate, to link the acceptable product variability measured by a dissolution test to the clinical performance.

DEFINITIONS FOR DIFFERENT DISSOLUTION METHODS

Many different dissolution terms seem to be used interchangeably, while at the same time being open to different, often ambiguous interpretations. To minimize this confusion, we propose a new set of definitions: 1) QC Dissolution Method; 2) Biorelevant Dissolution Method; and 3) Clinically Relevant Dissolution Method.

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QC Dissolution Method

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The purpose of a QC dissolution method is to detect variations during routine product manufacturing and/or changes during product storage that might negatively impact product performance. Depending on the product, these variations may be related to API, raw materials, or other critical attributes specific to the manufacturing process. For example, the QC dissolution method should be able to identify product that has been under- or over- granulated, under- or overcompressed, or product wherein there have been meaningful changes in the critical attributes of the API, (e.g., particle morphology), or of key excipients, e.g., surfactants, granulation aids, disintegrants, lubricants, etc., as defined in the SUPAC guidance (1995)23. Additionally, a QC method needs to be robust and simple such that it can be run in a typical QC environment. Accordingly, for the majority of IR and MR drug products, QC dissolution is performed with conventional USP apparatus 1 or 2, under conditions that were established throughout product development. These conditions specify the pH of the dissolution medium, the level of synthetic surfactants, if required, temperature, medium agitation or any additional critical step(s) necessary to ensure reliable data. A critical aspect of the QC dissolution method is the demonstration of the appropriate level of discriminatory power of the method, as will be discussed below.

Biorelevant Dissolution Method The purpose of a biorelevant dissolution method is to attempt to model the different physiological environments that the drug will experience within the gastrointestinal tract, with the overall goal of guiding formulation selection and optimization, although it is important to note that this does not necessarily infer that the method will be predictive of clinical outcomes. Such methods are effective in screening drug dissolution behavior in media that model different in vivo environments (e.g., 3

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gastric, intestinal, colonic), or those that model the influence of food (i.e., fed vs. fasted state). They can also be helpful in modeling the effects of proton pump inhibitors (PPIs) or dosing to achlorhydric patients, or the effect of drug precipitation. Biorelevant dissolution methods commonly utilize nonstandard experimental conditions and/or setups, such as physiologically relevant media (e.g., SGF, FaSSif, FeSSiF, etc.), non-sink conditions, biphasic media (i.e., including an immiscible layer such as octanol to mimic permeability), and multiple compartmental apparatuses, or they mimic a combination of dissolution and drug absorption24. The terms “biorelevant” and “biopredictive” dissolution methods are frequently used interchangeably. As stated above, a biorelevant method may or may not be able to predict the outcome of an in vivo experiment.

Clinically Relevant Dissolution Method

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A clinically relevant dissolution method is established by linking in vitro dissolution data as obtained by any particular methodology with in vivo PK performance data, creating an in-vitro in-vivo correlation or relationship (IVIVC or IVIVR). With an established in vitro-in vivo-correlation, the clinically relevant dissolution method becomes predictive of in vivo drug release in human. Often times, it is not feasible to establish a full PK correlation; however, the method can be used to ensure consistent clinical performance via a demonstrated pharmacokinetic safe space. Both the QC and biorelevant dissolution methods discussed earlier in this section may be clinically relevant as long as they can demonstrate some elements of IVIVC/R25. It should be noted that these different definitions are not exclusive to each other. As shown in Figure 1, all three methods individually may be able to confirm or predict the in vivo performance of a drug and they may even converge into one method which is biopredictive. On the other hand, one can envision that a QC method is clinically relevant, but the biorelevant methods one used in development may not be suitable for implementation as a QC method, because the method lacks robustness or does not meet local and global expectations (i.e., full release within 60 min).

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The interrelationship between these terminologies is shown in Figure 1

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QC, biorelevant, and clinically relevant dissolution methods may be three distinct methods for distinct purposes as shown by the largely non-overlapping portions in Figure 1. Traditionally, a QC method would be used in late stage development for release of clinical batches and testing of registration stability testing. Once the product is approved QC dissolution methods are used for product release as a measure to confirm the product consistency. A biorelevant method which might use traditional dissolution equipment, with the substitution of a physiologically relevant dissolution medium, may be used in early formulation development. Dissolution in multiple pHs may also be considered an early version of biorelevant dissolution testing and is currently used to assess formulation and process changes within the SUPAC and equivalent international frameworks. The concept of clinically relevant dissolution method was introduced within the context of QbD and proposed to further the understanding of process and formulation variations on PK parameters, ultimately assuring only “good” product is released, and unacceptable product is rejected. However, one can envision that all three methods have some degree, or even complete, overlap. In the hypothetical case shown here of the center in Figure 1, a single method condition could meet the requirements for a biorelevant method (i.e. SGF as the dissolution media), a QC method (i.e. USP 2, with 50 rpm, a robust method that is globally acceptable) and a clinically relevant method (i.e., the method is either confirming or predictive of human PK).

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THE EVOLVING ROLE FOR THE QUALITY CONTROL (QC) DISSOLUTION TEST

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Today, the dissolution test still remains as an important quality control test in the pharmaceutical industry, for batch release and monitoring stability. The use of dissolution testing as a quality control tool is common practice and, despite some minor differences, there is general consensus on requirements for this test from regulatory agencies globally. This is likely attributable to the fact that testing apparatus are standardized and the experimental approaches are limited and covered in guidances, which are well aligned. Most QC dissolution methods use common standard testing procedures, such as USP apparatus 1 or 2, 500 to 900 mL of aqueous buffer as medium with adequate sink conditions, and rotation speeds of 50 – 75 rpm for apparatus 2 and 50 – 100 rpm for apparatus 1. However, new challenges have been added to this traditional QC role in recent years. The most significant changes are related to using dissolution as QbD tools and the desire for clinically relevant dissolution methodology.

Dissolution Testing in Product Development

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Many drug product manufacturers have integrated enhanced product and process understanding into their development strategy. As a result, various dissolution approaches (e.g., biorelevant and QC methods) are utilized to understand the impact of critical process parameters on the extent and rate of drug release. In the early stages of development, biorelevant dissolution, often developed inhouse and based on prior knowledge/best practices, may be used to guide formulation and process selection. A QC dissolution test can be developed simultaneously, based on the API physicochemical properties and proper selection of dissolution parameters. The sensitivity of the QC dissolution test to key process and formulation parameters is evaluated during these stages of development. The evaluation of the results drives the decision for the final QC dissolution method. Typically, before entering clinical Phase 3, product development focuses on the systematic assessment of formulation and process parameters. This is done with the aim of consistently producing a product that has equivalent safety and efficacy as compared to the batches used in Phase 3 pivotal trials. As a result, the dissolution method conditions used in this development stage are either finalized or nearly finalized as the future regulatory QC method. Experiments performed during process scale-up provide a good opportunity to evaluate the quality of the dissolution methods, such as robustness and discrimination power, which is defined by the method sensitivity to variations in critical process parameter(s) and critical material attribute(s).

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Dissolution Testing and Clinical Relevance

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Clinically relevant dissolution specifications (CRS) can be a critical enabler of enhanced product understanding. The emphasis on CRS emerged after the roll-out of QbD. In order to justify the desired process “design space”, demonstrating adequate bioperformance is critical. Dissolution is the only analytical tool to evaluate adequate bioperformance in the absence of in vivo studies. However, there is a concern that the dissolution test may not have adequate sensitivity to identify when process variants, especially those made at the edges of the proposed process design space, are truly meeting the desired in vivo performance. The dissolution method (QC or biorelevant) can be overly discriminatory and hence constrict the process design space, or the method may be insensitive and thus support operating conditions that could lead to product release that is not meeting quality. To address this ambiguity in the dissolution method, exploring the relationship between process variants and bioperformance was proposed. With this relationship established, the underpinning in vitro dissolution method that can distinguish between product made under various process conditions has clinical relevance. Several authors have suggested approaches for defining the link between the dissolution test and in vivo performance22,26. Clinically relevant specifications can be established via traditional bioavailability (BA) studies or they may be established via modeling and simulations. The outcome of these in vivo or in silico PK studies 5

ACCEPTED MANUSCRIPT can be twofold: if the differences in the observed in vitro dissolution profiles of formulation variants also lead to differences in in vivo performance, an in vitro in vivo correlation/relationship (IVIVC/R) may be developed; if there is no difference in clinical pharmacokinetics for formulation variants exhibiting different in vitro performance, which is often the case27, then, a ‘safe space’ can be defined within which bioequivalence is assured.

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An in vivo study may not always be required, such as for IR drug products meeting the BCS 1 or 3 criteria. It is generally accepted that any product meeting the biowaiver testing criteria will have suitable performance in patients5. For products meeting these criteria, clinically relevant dissolution methods and acceptance criteria are already defined in the guidance, which can also be used for QC purposes. The draft FDA guidance on dissolution testing for BCS Class 1 and 3 products seeks to make the link between the BCS biowaiver criteria and QC release testing5.

Understanding the Constraints of the Standard QC Dissolution Method

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For the most part, QC dissolution relies on standard dissolution apparatus, commonly used buffers as media, and standard medium volumes. These parameters induce fundamental constraints that can limit the biopredictive power of the QC method and are, in general, related to the composition of the medium, the overall difficulty in mimicking the multiple compartments of the GI tract, the inability to account for permeability, and the hydrodynamics of the dissolution apparatus. Understanding these constraints can guide researchers to select an appropriate method based on product characteristics.

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Historically, the most commonly used media in QC laboratories were water or buffers at pH 1.2, 4.5 or 6.8 with or without surfactants to simulate gastric fluid (SGF, pH 1.2) and intestinal fluid (SIF, pH 6.8)28. However, these common media are not compositionally similar to biological gastric or intestinal fluids, showing differences in buffer types, ionic strength and the presence/absence of enzymes or surfactants (e.g., bile salts). The QC dissolution test using USP 1 or 2 may simulate only one gastrointestinal environment, such as the stomach or one section of the intestine. While in human, a drug product experiences various pH environments as it passes through the GI tract.

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Solubility and permeability typically work together in a synergistic fashion within the small intestine29,30. For highly permeable compounds, the drug can be rapidly absorbed and removed from this dynamic in vivo system facilitating further dissolution. In contrast, the standard dissolution test is a static system, although there have been attempts to change the pH of the medium as a function of time and even to introduce a dissolution-permeation system31-33. For BCS 2 compounds with low solubility and high permeability, dissolution in standard dissolution apparatus could significantly underestimate in vivo dissolution where the drug can be absorbed and removed from the intestinal compartment. The USP Apparatus 4 open loop setting allows running a pH gradient system to mimic the human GI. Other USP apparatus also provide more flexibility in using multiple media or altering agitation, versus apparatus 1 and 2. The most commonly used dissolution apparatus is USP 2 (paddle). This is poorly designed from a hydrodynamic perspective and exhibits elevated levels of variability. A FDA sponsored study, which looked at the hydrodynamics and mixing of apparatus 2 using computational fluid dynamics (CFD) showed significant differences in the flow and shear rate at different positions along the bottom of the vessel34. These conclusions were also substantiated by other researchers35,36. There is a “dead zone” immediately underneath the paddle, and consequently, the tablet/capsule position may be a critical factor to the dissolution results, leading to increased variability. Over the years, there have been several attempts to address these intrinsic design flaws, e.g. PEAK vessels37, tilted vessels38, crescent shaped spindles39, “mega” paddle40, metal strips41, permanent in-line probes acting as baffles42, and the off centre paddle43. However, none of these approaches have gained general

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The standard QC dissolution medium volume is 900 mL. While appropriate for a QC test, this volume has limited in vivo relevance; fasted human gastric volumes are more likely to be about 250 mL after ingestion of a glass of water (and considerably less in the resting state), with the same volumes being typically found in the small intestine, i.e., a total volume significantly less than 900 mL29. Interestingly, two recent FDA guidelines have recommended the use of 500 mL of medium for highly soluble drugs5,44. However, the industry’s reaction has generally not been supportive of this aspect of the guidance, based on the absence of alignment with EMA/PMDA requirements (≥ 900 mL) and concerns that the hydrodynamic mixing efficiencies will likely be very different with a reduced volume of medium when using the standard USP apparatus 1 or 2.

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The rotational speeds of the basket or paddle apparatus were intended to mimic the peristaltic motion exhibited by the stomach and small intestine. However, the actual mixing forces observed within the stomach are not necessarily represented by either the basket or paddle at standard operational speeds, i.e., 100 rpm for baskets and 50-75 rpm for paddles45. Attempts have been made to remedy this using the dissolution stress tester46. This device is designed to simulate the physical conditions of the gastrointestinal tract passage experienced by a modified release dosage form. The simulation includes the pressure force exerted by GI motility, shear stress forces generated during phases of GI transport (e.g. passage through the pylorus) and the intermittent contact with intestinal fluids while the dosage form is located in an intestinal air pocket. There is a power law relationship between the stirring rate and observed dissolution rate47. Drug products that contain large amounts of insoluble excipients can be expected to form a cone at the bottom of the vessel; while this phenomenon is irrespective of the solubility of the drug, the impact will be more significant for poorly soluble drugs38. This situation can be addressed by adjusting rotation speed or using PEAK vessels. However, increasing rotation speed may potentially sacrifice discrimination. Furthermore, the application of PEAK vessels is somewhat limited by their non-compendial status, which is perceived to indicate lack of regulatory acceptability, and the absence of a recognized mechanical calibration procedure.

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This discussion infers that it may be challenging to achieve clinical predictability with a dissolution method when using USP apparatus 1 and 2 with standard media, especially for poorly soluble compounds. The pharmaceutical industry generally welcomed the FDA’s initiative as an attempt to standardize the dissolution test methods for BCS 1 and 3 compounds, since the in vivo absorption is rarely dissolution limited for these drugs. The new draft guidance on biowaiver for BCS 1 and 3 compounds published in 2015 is also viewed as a step forward. Standardizing dissolution test methods for BCS 2 and 4 compounds, however, is much more challenging; yet it is a worthwhile effort to outline collective thinking from the industry and regulatory agencies on developing appropriate dissolution tests for low solubility compounds.

DISSOLUTION TESTING BEYOND TRADITIONAL QC The dissolution test has evolved beyond the traditional standard USP type of methods. Besides relatively standard QC dissolution methods, the dissolution test used in pharmaceutical industry today includes a variety of diverse analytical principles, instruments, media, and combinations with other technologies. It is an open field welcoming new ideas or approaches.

Biorelevant Dissolution Methods and Applications in Early Development In the field of biorelevant dissolution development, much work has been, and will continue to be, performed in trying to obtain a more holistic simulation of prevailing gastrointestinal conditions. The 7

ACCEPTED MANUSCRIPT most commonly used media in simulating different regions within the intestinal tract have been detailed in the literature48. Medium properties such as pH, osmolality, surface tension and buffer capacity have been studied extensively on many different products. Besides medium composition, hydrodynamics play a key role in establishing an IVIVC. For this reason, some biorelevant dissolution methods employ alternative apparatus in order to obtain the hydrodynamics that cannot be achieved using the standard USP apparatus 1 and 2 (see Understanding the Constraints of the Standard QC Dissolution Method). Biphasic and multi-compartmental dissolution are typically utilized. It is also common to use biorelevant media in the USP apparatus 2 dissolution system.

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One of the most important and widely adopted applications using biorelevant dissolution is in the early clinical development phase, to enable the evaluation of “clinically enabling formulations.” The term “clinically enabling formulation” is used for enhanced drug products that address the often seen, sub-optimal biopharmaceutical properties of the drug substance via various solubilityenhancing formulation strategies. Examples of these formulations are amorphous solid dispersion (ASD) tablets, soft-gel capsules (lipid-in-capsule), or conventional formulations with amorphous drug substance, high solubility meta-stable polymorphs, anhydrates, solvates, highly soluble salt forms or co-crystals. Although, such formulations are typically intended for early clinical development in humans (Phase 1/2a), the enhanced bioavailability of the drug product and the improved exposure across a wide dose range have become driving forces for taking these bio-enhanced formulations forward into later clinical development and commercialization. A physiologically-based dissolution test such as biorelevant dissolution mimics drug release in human GI tract thus can be used to assess the biopharmaceutical risk, and discriminate different types of enabling technology/formulations, in order to establish a rank order to facilitate formulation selection.

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In the absence of sufficient in vivo data, the dissolution approaches are often based on prior knowledge and conditions applied successfully in support of similar product development efforts in the past. As such, non-standard dissolution methods are used to evaluate key properties of the clinically enabling formulations, and the method conditions can be very different from those traditionally used for QC methods. For example, non-sink conditions are often employed. Gordon Amidon and co-workers recently advocated the use of a mini-gastrointestinal simulator that changes the media/pH (pH 1.2 simulated gastric fluid (SGF)/pH 6.5 simulated intestinal fluid (SIF)) to model the in vivo dissolution profiles of BCS class 2b drugs49. A research group from Roche advocated the use of a miniaturized intrinsic dissolution tool in a 96-well format that, it was claimed, was a useful tool in the screening of appropriate dissolution media as well as characterizing the intestinal release profiles of discovery/early development compounds50.

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During the early stages of product development, when clinical data are limited, animal data, biorelevant dissolution data generated from methods that model different GI regions, or fed vs. fasted states, and in silico modeling are often used to inform formulation screening or early clinical development. As development progresses, there are a large number of API and formulation composition variables to be evaluated. Biorelevant dissolution can offer more appropriate discrimination against those variables compared to standard QC methodology. In addition, the results from biorelevant dissolution are increasingly used as input to physiologically-based pharmacokinetic (PBPK) modeling tools, e.g., GastroPlus, SymCyp, etc. The modeling and early clinical data can then be used together to predict in vivo product performance51. As such, biorelevant dissolution is an important tool in the formulation and process development paradigm.

Limitations of Biorelevant Methods for Quality Control While it may be desirable for QC dissolution methods to have some level of bio-predictability, the use of biorelevant dissolution for quality control is typically not appropriate. One reason is that the purposes of the two types of methodologies are different. In early development, there are a large number of API and formulation composition variables to be evaluated, such as API properties, 8

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excipient type and amount, and process route. Biorelevant dissolution can offer significant advantages over QC dissolution in discriminating against those variables. In contrast, in Phase 3 and beyond, formulation composition and all these variables are essentially fixed. The focus of a QC method is to be sufficiently capable (sensitive) to ensure that the manufacturing process operates within established conditions that have historically resulted in acceptable product. Therefore, for process and manufacture changes, QC dissolution is more suitable compared to biorelevant dissolution, in spite of the fact that biorelevant dissolution methods may have been used successfully for internal evaluations to guide the formulation or process changes before or post product approval.

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Another limitation to biorelevant dissolution methods is that they are typically costly, complex, time or labor intensive, difficult to transfer or operate, and lack robustness (such as overly sensitive to testing conditions). These characteristics are often perceived as sufficiently problematic to preclude the use of a biorelevant method for routine lot release, especially since it may result in spurious outof-specification (OOS) results, which may be directly attributable to the non-robust methodology, rather than the product performance. Furthermore, typical practice for the dissolution method is to comprise sink conditions and exhibit >80% drug release at the Q time point for IR products. These requirements are essential for ensuring in vitro consistency, but can impact adversely on in vivo predictability30. In some cases, a biorelevant method should be able to provide a rank order for multiple formulations, such as comparing a crystalline tablet formulation and amorphous dispersed formulations, but may be unable to dissolve the drug >80% at a reasonable time, such as 30 minutes. This inability limits the application of such method for QC purposes.

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Due to above mentioned reasons, many biorelevant methods are used mostly for development purpose in the pharmaceutical industry. Although efforts are being made to bridge the gap between biorelevant and QC methods, it is very likely that these two methodologies will continue to play separate but important roles within product development and lifecycle with main focus of biorelevant methods during development and QC methods for routine manufacture.

Clinically Relevant Dissolution: Linking In Vitro Dissolution Data with Drug Product In Vivo Performance

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The primary focus for current QC dissolution methods is to enable later stage product development by enhancing product understanding and to be used as a quality control method for commercial product release once the product is approved. It is ideal if a QC method is clinically relevant. As mentioned above, clinical relevance can be achieved by evaluating formulation variants in clinical PK studies, linking the dissolution method(s) and results to the product safety and efficacy. Although it is a desire to fully understand the impact of critical quality attributes on the product performance in humans to better develop control methodologies in this manner, one obstacle faced by the pharmaceutical industry is that it is impractical to collect clinical data on a large set of formulation and process variants (in particular, introducing the necessary formulation/process variability to evaluate in vivo impact). Due to the resources required, only a few clinical studies are conducted to support formulation and process development in a typical drug development cycle and it is not always easy to have relevant clinical data available to guide setting of clinical relevant specifications. BCS classification system can aid in developing clinically relevant dissolutions. For BCS 1 and 3 compounds, a Q of 80% dissolved in 15 min (BCS3) and 30 min (BCS1) in 500 mL 0.01 N HCl with gentle agitation should be considered clinically relevant without actual in vivo data52. For BCS 2 and 4 compounds, establishing clinical relevance of the dissolution method would require linking in vitro dissolution data with in vivo PK data which may be challenge due to the constraints mentioned above.

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One approach to overcome this obstacle was suggested by Cook53. He recommended utilizing the information from early clinical studies in humans (Phase 1/2a), which may use both liquid and solid oral dosage forms and integrate the outputs from multiple early clinical studies with physiologically based absorption/pharmacokinetic modeling to obtain in vivo dissolution profiles. The in vitro dissolution method could then be developed using all of the available in vivo information. Another approach suggested by the authors of this paper is an integration of in vitro dissolution data. The Phase 1/2a clinical retain samples are used when the in vitro dissolution method is in the final development stage, to evaluate the relationship between the final dissolution method and the product performance in human (covering Phase 1-3). This approach may also be used to compare different dissolution conditions for the purpose of selecting the most appropriate dissolution method for quality control. Utilization of PBPK modeling and simulation tools, such as GastroPlus, can also be beneficial to help mechanistically understand the important factors for formulation performance in vivo, which can then be used to guide the development of the in vitro dissolution tests. It is also helpful to use information gleaned from any biorelevant dissolution methods used in the early stage of development to guide the development of a QC method in a later stage. This may link the QC method to the early clinical study data and help to evaluate the QC method’s discriminatory ability. Such QC methods could be further developed with additional human PK data to become clinically relevant. These QC methods may be appropriate to discriminate changes of key material attributes and process parameters that impact the in vivo performance, while also maintaining robustness for quality control and stability testing.

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It should also be recognized that the use of dissolution testing as a regulatory quality control tool, for example in the release of clinical supplies, may not be appropriate in early stages of development, as the process and formulation may still change and hence a method to monitor product quality seems to be sufficient. Other techniques such as disintegration may be adequate and stage appropriate until the formulation and dissolution test have been developed and an understanding of its critical attributes have been understood, and clinical relevance of the dissolution test has been established.

SUGGESTIONS FOR INDUSTRY AND REGULATORY AGENCIES

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Besides advancements in dissolution development driven by the pharmaceutical industry as described above, many dissolution related topics still remain to be further explored. One such topic is how to clearly communicate between the pharmaceutical industry and regulatory agencies on the different roles of dissolution testing to find common ground for future development directions. This paper serves as a forum for IQ members to describe their view of the roles of different types of dissolution methods and also to stimulate more discussions. A few suggestions for aligning the industry and the regulatory agencies are as follows:

Enhance Biorelevant Dissolution Models Biorelevant dissolution methodologies are a major enabler of product development. They are frequently used in development as surrogates for in vivo formulation screening and they are often capable of linking in vitro and in vivo product performance. However, the biorelevant dissolution tools are typically far from adequate to meet the practical needs of the pharmaceutical industry as a robust, routine quality control tool, due to the reasons described in the section above “Limitations of Biorelevant Methods for QC Purpose”. In order to expand the utility of biorelevant methods for QC purposes, strong collaboration among industry, academia, dissolution instrument companies and regulatory agencies is needed to develop the next generation of biorelevant dissolution models. The pharmaceutical industry should continue to play an active role in the development of dissolution models and new apparatus in order to bridge the gap between academic and industrial applications.

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Although the pharmaceutical industry welcomes the concept of clinically relevant dissolution specifications, successful strategies that are practical and meet global regulatory expectations are still evolving. The pharmaceutical industry is very interested in the development of practical approaches to establish clinically relevant specifications and substantial internal resources are being invested in new product development. Linking clinical performance to in vitro dissolution tests often requires the integration of clinical and CMC development. In light of the clinically relevant dissolution concept, certain regulatory guidance documents, such as the SUPAC Guidance, may need to be re-examined for alignment with the current thinking.

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Open discussions and knowledge sharing between regulatory agencies and the pharmaceutical industry or among pharmaceutical companies is a very important step toward this goal. IQ Consortium member companies have compiled our thoughts on this topic in a publication which may serve as a base for such discussion52.

CONCLUSION

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This paper summarizes the view from IQ Consortium members, which comprise various pharmaceutical companies, on the different roles of the dissolution test for early formulation and process development purposes as well as for QC. It is generally agreed that the dissolution test is an integral part of the drug development process. The paper has provided definitions of, and explores the interrelationships between, biorelevant, clinically relevant and quality control dissolution methodologies. A quality control dissolution method is designed to detect variations during routine product manufacture and/or changes during product storage that might negatively impact product performance. The key purpose of a quality control method is to confirm lot to lot consistency of commercial product at release and over the shelf life of the product. Biorelevant dissolution attempts to model the different physiological environments that the drug will experience within the gastrointestinal tract through the use of physiologically relevant media as well as standard and/or non-standard equipment and conditions. The key purpose of biorelevant dissolution is to guide formulation development in the absence of clinical PK data. Clinical relevance is established for any type of methodology by linking in vitro dissolution data with PK performance, creating an in vitro in vivo relationship (IVIVC, IVIVR or PK “safe space”). When used as a quality control method for poorly soluble drugs, clinically relevant dissolution provides an enhanced approach to directly confirm that each batch meets the desired bioperformance standards as identified during development.

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It is the recommendation of the IQ Consortium that well-developed quality control methodology is acceptable for routine batch release and stability studies. A clinically relevant method, as linked to bioperformance, should be accepted as support for biowaiver and other post approval changes.

Figure 1: Illustration of the Relationship between Quality Control, Biorelevant, and Clinically Relevant Dissolution Methods (not to scale)

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