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A Position Paper from the AAPS In Vitro Release and Dissolution Focus Group
Dissolution is a common characterization test used by the pharmaceutical industry to guide formulation design and to control product quality. It is often a required performance test for solid dosage forms, transdermal patches, and suspensions. Dissolution is also the only test that measures in vitro drug release as a function of time, which may reflect the reproducibility of the manufacturing process and, in some cases, the drug's in vivo performance.
Despite its wide use in pharmaceutical development and registration, there is still a lack of thorough understanding of what dissolution testing means, what it should measure, and the value it adds at various stages of drug development. There are inconsistencies, therefore, in industry practices and regulatory expectations with regard to dissolution testing. These inconsistences present even greater challenges when trying to implement quality by design (QbD), which defines the future state of dissolution, its value, method design, and links to the design space. The International Conference on Harmonization Quality Guidelines, Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System manifest the global efforts from industry and regulators to establish a consistent quality system from a QbD perspective.
This article provides a science-based analysis of the values of dissolution testing in the drug-development continuum for common solid dosage forms. The authors focus on immediate release, modified release, extended release, and QbD systems.
Value of dissolution testing: candidate selection–Phase I
Phase I clinical studies are designed to determine the metabolic and pharmacologic actions of a particular drug in humans, the side effects associated with increasing dosage, and, if possible, early evidence of efficacy. To achieve these goals, the dosage form should have adequate bioavailability to ensure that the drug is delivered to the site of preferred action. At this stage, dissolution testing can be used to:
One intended use for the dissolution test is to reflect the in vivo behavior of the pharmaceutical product. Thus, dissolution testing can be used to guide the selection of API properties as well as the toxicology and Phase I formulations for evaluation in animals and humans. Dissolution methods that use a medium that mimics human GI fluid should be investigated and used to probe in vivo–in vitro correlations and relationships (IVIVC and IVIVR). In cases where IVIVC can be difficult (e.g., when the in vivo behavior is controlled by several other factors), dissolution or disintegration testing can still add value as a quality-control tool for batch release, batch-to-batch consistency, and stability monitoring.
Drug substance characterization
Defining an appropriate drug substance form with suitable physicochemical properties is important for formulation development. Drug-substance properties are chosen to balance formulation stability, processibility, and bioavailability. Drug-substance properties (e.g., particle size, intrinsic dissolution, crystal properties) can have an impact on dosage-form bioavailability. Dissolution testing is a useful tool for screening drug-substance salt forms with different crystal forms and particle sizes. Biorelevant gastrointestinal (GI) media such as simulated gastric fluid (SGF) and fasted-state simulated small-intestinal fluid (FaSSIF), should be considered at this stage to elucidate where the drug will be solubilized and the potential for supersaturation or precipitation of drug substance in the GI tract (1). These methods provide the basis for toxicology formulation and Phase I formulation design.
The availability of drug substance is limited at this early stage. Small-volume dissolution using a very small quantity of the drug, therefore, can provide helpful information. Commercial availability of fiberoptics-integrated small-volume dissolution (microdissolution) apparatus has made quick drug-release assessment possible (2). Dissolution of the free form and different salts in various pH media can help in salt selection. The salt or free base that gives the optimum dissolution rate, amount dissolved, and a favorable or minimum precipitation rate is generally chosen. Observations of the dissolution behavior of the drug substance provide important clues that can facilitate formulation selection and development. If the drug particles aggregate or float, for example, and do not dissolve, the use of surfactants or a wet granulation process may be used to overcome the problem.
Toxicology formulation selection
The earliest drug-product formulation is often developed for toxicological studies in animals where repeated dose toxicity studies are conducted before human Phase I clinical trials. The aim of the toxicity study is to obtain sufficient exposure of the animal to the drug substance and its metabolites.
In general, formulations at this stage of development should be simple, consisting of, for example, a solution, suspension, or API in a capsule. Typical studies include pharmacokinetic (PK) research of salt versus base, solution versus suspension, a comparison of various salts, and an assessment of dose linearity. For the toxicological study, the high dose is selected to enable identification of the target organ toxicity; the systemic exposure achieved should be a significant multiple of the anticipated clinical systemic exposure. Biopharmaceutics Classification System (BCS) Class II and IV compounds with extremely low solubility often have limited or less than dose proportional exposure at high doses (3). Small-volume or even large-volume dissolution testing serves as a valuable tool for toxicology formulation selection. Common formulation approaches include the use of different salt forms; addition of surfactant, cosolvent, or lipid vehicle; or use of amorphous API with crystallization inhibitor. Dissolution should be conducted with media at a gastrointestinal pH relevant to the animal species. Animal studies with these early formulations provide an important opportunity to understand the in vivo behavior of the drug substance and provide early insight into formulation development choices.
The dissolution data can supplement the animal PK data as well. For instance, highly variable animal PK data with less variable dissolution data may indicate a metabolic or physiological cause. In the absence of dissolution data, one may suspect physicochemical properties such as uneven distribution of drug in the formulation or aggregation to be the cause.
Phase I formulation development
Salt selection, excipient compatibility, and formulation concepts for the first administration of a drug to humans are studied during Phase I. Dissolution serves as a useful tool in the variant selection process and in the stability assessment of the formulation. During this phase, however, every attempt must be made to lay a foundation for QbD principles, IVIVC, and IVIVR. The BCS classification of the drug should be established and serve as a guide for the selection of an appropriate dissolution test or surrogate test(s). A surrogate test can supplement dissolution data and potentially replace dissolution testing after enough developmental data are collected that demonstrate the surrogate test to be an equally good or better indicator of product performance.
If an extended-release formulation is the objective for a BCS I or BCS III compound, IVIVC should be attempted for different dissolution-rate formulations and in vivo data. For immediate-release (IR) formulations, initial dissolution testing should be performed in SGF, simulated intestinal fluid (SIF), and in pH 1.2, 4.5, and 6.8 buffers. If the amount of drug released is greater than 85% in 15 min and the stability of the formulation is favorable under stressed storage conditions, disintegration should be used as the test method of choice (4).
For BCS II and IV compounds, initial dissolution should be performed in media of different pH. Addition of surfactants and use of biorelevant dissolution media may also be considered. For acidic drugs, dissolution may be performed in pH 4.5–7.5 buffers with surfactants, if necessary, to choose an appropriate medium. For basic drugs or salts, the dissolution may be performed in pH 1–2 buffers with surfactants, if necessary. A two-step dissolution may be performed to determine if and at what rate the base precipitates at higher pH medium (5). In this case, a slower precipitation rate is preferred as it may provide enough of a window for absorption to occur.
Value of dissolution testing: Phase II clinical development
During Phase I of clinical development, sufficient information about the pharmacokinetics of an investigational drug is obtained to permit the design of scientifically valid Phase II studies. The dosage form and its unique specifications are, in most cases, not finalized in early Phase II studies. One of the aims of Phase II studies, however, is to define the dosage form that will be tested in Phase III studies. At this stage of development, a dissolution test can be used to:
For a dissolution test to be valuable in linking the formulation with efficacy and performance characteristics, establishment of IVIVC or IVIVR is crucial. The IVIVC or IVIVR dissolution method can then serve as a guide for the development of a meaningful quality control method, which will occur in Phase III clinical development. Figure 1 summarizes the different approaches that can be undertaken to establish either IVIVC or IVIVR. A basic relationship might be found between API properties and PK data (see Figure 1, Level 1). This relationship can be in the form of a rank order or can be modeled mathematically (6) In the second level, deconvolution of PK data might be used to establish IVIVC or IVIVR. The relationship can be achieved by correlating the fraction of dose dissolved versus the fraction of dose absorbed, estimated by deconvolution. In most cases, however, this correlation requires that the absorption process is dissolution controlled. For IR products, this approach mostly fails or, in some cases, requires a scale factor between in vitro and in vivo data (7). For extended-release products, there is a high probability of establishing IVIVC. When IVIVC cannot be established using deconvolution, convolution-based models should be used (see Figure 1, Level 3). Convolution-based approaches use models such as the Advanced Compartmental Absorption and Transit (ACAT) model or other PK models to predict the oral performance of a dosage form (8). In vitro data are used in these models to predict the plasma time curves. Such a prediction, if established by using the appropriate parameters, is a Level A correlation (9).
Figure 1. (FIGURES ARE COURTESY OF THE AUTHORS.)
Determination of IVIVC and IVIVR is a continuous effort throughout development. It requires input of data, including human PK levels and pharmacodynamic properties, food effects, API properties (BCS), and dosage-form information (i.e., excipient properties). Computer tools such as "GastroPlus" (Simulations Plus, Lancaster, CA), "PDx-IVIVC" (GloboMax, Hanover, MD), and "WinNonlin" (Pharsight, Mountain View, CA) can be used to develop IVIVC and IVIVR.
Figure 2 shows a flow chart detailing when IVIVR or IVIVC can be established and when it is unlikely that a differentiation between formulations and their in vivo behavior can be found. A drug might be either dissolution or absorption controlled (10). Any formulation changes should be assessed according to the drug's impact on either the dissolution or absorption properties. The impact on absorption, however, is normally assessed in vivo and in vitro screening tools then must be developed to assess excipient effects on the absorption.
Figure 2. (FIGURES ARE COURTESY OF THE AUTHORS.)
If the dissolution of an API is slower than its absorption in the GI tract (this typically occurs for BCS II drugs), then the API's behavior is similar to an extended-release dosage form. A critical study to consider in this case would be dissolution testing with different drug-substance particle sizes. If the dissolution rate is controlled by particle size, IVIVC or IVIVR may be attempted. If a drug dissolves quickly from the dosage form, however, as for most IR products and absorption is the time-limiting factor, then IVIVC or IVIVR will not be possible using conventional deconvolution-based correlation between dissolution data and PK parameters. In such cases, only convolution-based computer simulations should be attempted by predicting the observed plasma levels.
A number of modeling programs are being used in drug-release studies (e.g., Simulations Plus' "DDDPlus" and "GastroPlus"). These programs may allow prediction of the effects of formulation changes on dissolution and absorption behavior. Such models can predict how absorption might be affected by factors such as API particle size and may result in the development of a more relevant dissolution method.
With the challenges associated with IVIVC, especially for IR dosage forms, IVIVR should be increasingly leveraged to support design-space development. IVIVR can be manifested in two general cases: (1) in vivo performance can be tuned by in vitro dissolution; and (2) dissolution guarantees in vivo performance. In the former case, dissolution has been used to guide formulation and process development and is linked to the product and process design space. The latter case may be more valuable in the future for those drug-development paradigms in which conventional IVIVC and IVIVR are not likely or are impossible to achieve. To ensure that dissolution guarantees in vivo performance, one needs to consider the dissolution method design and drug absorption rate (ADME—absorption, distribution, metabolism, and excretion). The dissolution at least should be mapped over the entire range of physiological pH. The method conditions should mimic the in vivo environment where the drug is likely to be absorbed (11).
Understanding dissolution and its mechanism should be integral to any method development. BCS provides a scientific foundation for dissolution and its role in the drug-absorption process (12). The dissolution process generally consists of disintegration and drug-particle solubilization. Dissolution is a general test and reflects on properties of the formulation and API (see Figure 3). In most cases for oral IR or controlled-release dosage forms, however, the rate of dissolution is controlled by specific formulation or API properties, and these properties can be monitored by specific tests and controlled either in the raw materials or during the manufacturing process using process analytical technology (PAT) tools. From a QbD perspective, the dissolution test adds limited value in these cases and should be eliminated from product-release testing.
Figure 3. (FIGURES ARE COURTESY OF THE AUTHORS.)
Value of dissolution testing: Phase III clinical development
The primary objectives of Phase III development are to provide clinical supplies, generate formulation and manufacturing process knowledge for regulatory submission and approval, and help prepare for a successful, commercial product launch. To achieve these goals, it is necessary to optimize and finalize robust API and drug-product manufacturing processes, initiate long-term stability studies, and conduct pivotal bioequivalence/bioavailability (BE/BA) studies bridging Phase II and III clinical supplies and commercial product. Ideally, in vitro drug-product performance tests such as dissolution or related techniques (e.g., disintegration) should serve as a surrogate for in vivo bioavailability and as a predictor of the product's clinical performance. Development of a dissolution method may warrant significant and exhaustive evaluation of dissolution profiles in multiple apparatus and media. When process is controlled within the design space, a dissolution test may not be needed for a finished-product specification or may be replaced by other surrogate tests based on the understanding of the dissolution mechanism in Phase II clinical development. Improvements to the dissolution test method, including replacement with an appropriate surrogate test, may occur after product commercialization.
Discussion in this section focuses on where dissolution testing can add value to Phase III development. These areas include the use of dissolution testing for:
Process development and optimization
During Phase III development, QbD approaches can be used to optimize and finalize the drug-product formulation and manufacturing processes. Compared with conventional development approaches, QbD is primarily devoted to increasing the mechanistic understanding of a formulation and its manufacturing processes, their relationship to product quality attributes, and ultimately, their impact on the safety and efficacy of the product. When a QbD approach is selected, robust product formulation and manufacturing processes should be designed to achieve desired product performance and also relate to desired clinical performance. When the product performance can be appropriately characterized by in vitro dissolution (or a surrogate) test, the dissolution test can be a powerful tool. In the latter case, the dissolution test may use multivariate analysis to evaluate parameters that can affect drug-product performance, thus assisting in the identification of critical quality attributes and critical process parameters.
From the process knowledge generated through the development that includes, among other things, potential relationships between dissolution and other quality attributes, a design space can be established, whereby drug-product performance can be ensured through the proper control of relevant material attributes and process parameters (13). For example, drug product performance can depend on variables such as API particle distribution, excipients, and tablet hardness. For certain changes to formulation and processes, in vivo BE studies may not be needed. When IVIVC or IVIVR can be established, dissolution methods or related techniques (e.g., disintegration) and acceptance criteria are established to provide continued assurance for product clinical performance.
For IR dosage forms containing BCS I or III compounds, disintegration, single-point dissolution, and other rationalized surrogate tests are adequate to ensure drug-product performance because most process changes should have little or no impact on the in vivo drug release. Dissolution may have little value for rapidly dissolving IR dosage forms and should be replaced by disintegration for performance testing. Changes to the formulation and process within the design space should not impact the drug product's in vivo performance and thus do not require in vivo BE studies. PAT or other surrogate tests may be adequate to ensure product performance or enable real-time release of the product.
For IR dosage forms containing BCS II or IV compounds, in vitro dissolution could be limited by API solubilization or properties of the formulation. Dissolution profiles in various pH media should be evaluated during development. Once a correlation is established between dissolution and API physical properties that affect solubilization such as particle-size distribution and polymorphism, controlling the physical properties or using a disintegration test may be sufficient to ensure product performance. Although it is not realistic to clinically test all the tablets produced during the establishment of the design space, for IR dosage forms containing BCS II compounds, IVIVC or IVIVR could be established to link the in vitro dissolution and in vivo performance. Within the design space, changes to formulations and processes do not require in vivo BE studies if supported by IVIVC or may not require in vivo BE studies if supported by IVIVR.
With lack of IVIVC, certain changes to formulations and processes within or beyond a design space still may not require in vivo BE studies if the products demonstrate similarity of dissolution profiles in physiologically relevant pH media. For IR dosage forms containing BCS IV compounds, changes to formulations and processes within the design space may not require in vivo BE studies because establishment of IVIVC is not expected. Changes beyond the design space, however, are more likely to require in vivo BE studies and should be decided on a case-by-case basis.
For modified-release solid oral dosage forms, dissolution testing should be performed appropriately to establish IVIVC or IVIVR. The established correlation or relationship should be incorporated into the product's design space. It is anticipated that QbD principles will play an important role in modifed-release dosage forms because dissolution will likely be a critical quality attribute for drug-product performance.
Application of dissolution in demonstrating bioequivalence
During Phase III development, formulation changes may involve API morphology, particle-size distribution, excipients, film-coating, dose adjustment, and tablet shape. These changes may have an impact on in vivo drug release and in vitro dissolution of the dosage form, potentially impacting the bioavailability of the API. A dissolution test could be acceptable in lieu of an in vivo BE study depending on the BCS characteristics of the drug compound and depending on changes that affect the formulation and design space.
For IR dosage forms containing BCS I or III compounds, in vivo BE studies may not be needed for changes in formulation, manufacturing site, or scale when the product exhibits rapid dissolution (i.e., not less than 85% dissolved within 30 min for BCS I compounds [10,14] or not less than 85% within 15 min for BCS III compounds ), provided that the drug substance does not have a narrow therapeutic index and excipients do not significantly affect drug absorption. Dissolution tests are typically performed in various dissolution media with a pH range of 1–6.8, similar to physiological fluids in the human GI tract (15, 16).
For IR dosage forms containing BCS II compounds, in vivo BE studies may not be needed to demonstrate bioequivalence once IVIVC is established because, in most cases, in vivo drug release may be the rate-limiting step in drug absorption. IVIVC is expected if in vitro dissolution is similar to the in vivo dissolution rate, unless the product dose is very high (3).
For a drug compound with pH-dependent solubility, it is still possible to demonstrate that an in vivo BE study is not necessary by performing in vitro dissolution at a higher pH (5–6.8) that is more physiologically relevant (17, 18). For example, in vivo studies may not be needed for a weak acid API that has low solubility in acid but high solubility and rapid dissolution in a pH 6.8 medium, if drug product risk for patients is deemed acceptable. The effect of excipients on solubility and subsequent in vivo drug absorption should be taken into consideration.
For IR dosage forms containing BCS IV compounds, in vivo BE studies are generally expected to demonstrate bioequivalence for changes to the formulation and manufacturing process. But in some cases, bioequivalence between lower and higher strengths of a product can be demonstrated by in vitro dissolution testing instead of in vivo BE studies if the strengths are dose-proportional and if the approach is supported by linear pharmacokinetics (16, 19).
Table I summarizes the application of dissolution or surrogate tests to demonstrate when in vivo BE studies may not be needed for IR dosage forms based on BCS and QbD principles. With the increased application of BCS and QbD approaches throughout industry, it is hoped that more scientific understanding will lead to harmonized principles regarding formulation and manufacturing process changes that do not require in vivo BE studies and are recognized by both industry and regulatory agencies.
Table 1: Application of dissolution and surrogate tests for immediate-release dosage forms based on BCS and QbD.
Utility of dissolution as a performance test for quality control
For a drug product developed using conventional approaches, dissolution testing is an important quality control tool for monitoring batch-to-batch consistency and for discriminating the impact of formulation or process changes on product performance. A quality control dissolution method for a product is specific to its dosage form. The hydrodynamics and medium can be selected to ensure batch-to-batch product consistency and be sufficiently discriminating to changes in product quality.
On the other hand, for a drug product developed using QbD approaches, dissolution may not be needed or can be replaced by related techniques such as disintegration or another surrogate test (e.g., API particle size by near-infrared spectroscopy). Both dissolution and surrogate test data may be collected for batches produced from process development, clinical-supply manufacture, intentionally produced aberrant tablets (e.g., made with over-lubricated granulation or excessive compression forces), and stability programs to justify the use of surrogate tests in lieu of dissolution for product release. Nevertheless, unless a suitable surrogate test exists, it is generally recognized that dissolution is an effective test to monitor collective changes in a product on stability that are attributed to temperature and relative humidity.
For a modified-release dosage form, quality-control dissolution method can be the same as or different from the dissolution method used during IVIVC development. If the method is different, in most cases, a quality-control method takes much less time than the development method. A correlation between the quality-control method and the development method should be established to justify the use of a quality-control method (e.g., comparable sensitivity toward critical process parameters).
Dissolution testing continues to add value throughout the drug-development continuum. It serves as a tool for characterizing an API; developing, selecting, and optimizing formulations; studying drug-release mechanisms; ensuring batch-to-batch consistency; monitoring stability; and demonstrating bioequivalence between formulations. Dissolution testing can also help link the design space and target product profile. With the increasing application of BCS and QbD approaches, the value and appropriateness of dissolution testing for a given product will need to be assessed. Dissolution may not be needed or may be replaced by a suitable related or surrogate test to control the critical quality attributes of the product. Increased scientific understanding and experiences should lead to harmonized principles recognized by both industry and regulatory agencies with regard to the continued use and value of dissolution testing.
The authors wish to acknowledge the thoughts, ideas, and comments from the In Vitro Release and Dissolution Testing Focus Group. They also wish to thank Mary Ann Quarry, PhD, for her editorial input.
Cheng Tong is a senior principal scientist at Pfizer Inc., Ruben Lozano is a principal scientist at Bristol-Myers Squibb, Yun Mao is a research fellow at Merck Co., Tahseen Mirza is a director at Novartis, Raimar Löbenberg is an associate professor at the University of Alberta in Canada, Beverly Nickerson is an associate research fellow at Pfizer Inc., Vivian Gray is president of V.A. Gray Consulting, and Qingxi Wang* is a director at at Merck Co., tel. 215.652.1302, fax 215.652.2835, firstname.lastname@example.org. All authors are part of the American Association of Pharmaceutical Scientists (AAPS) In Vitro Release and Dissolution Focus Group.
*To whom all correspondence should be addressed.
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