Dissolution Method Development for Fixed-Dose Combination Drug Products – Challenges and Strategies

• Bristol-Myers Squibb

Abstract

Development of a single dissolution method to assess in-vitro release rate of multiple components in a fixed-dose combination (FDC) drug product often presents challenges due to differences in the physicochemical properties of the active pharmaceutical ingredients (API), dose and the release mechanism of the components. A single dissolution method approach is desirable from an analytical testing efficiency and cost saving perspective, however, it may not always be achievable. In this article, we will discuss challenges one may face when developing a single dissolution method for FDC drug products along with strategic approaches on developing robust dissolution methods with meaningful discriminating ability for FDC products in the context of quality-by-design (QbD).

Introduction

A fixed-dose combination (FDC) drug product is a formulation of two or more active ingredients combined in a single dosage form in certain fixed doses. The FDC formulation could contain two or more marketed drugs, a new investigational drug in combination with an approved drug or two or more novel (not previously marketed) entities. FDC drug products are often used to target single or multiple disease areas and offer therapeutic or clinical advantages over the respective single entity drug products, such as enhanced efficacy (amoxicillin+clavulanic acid)¹, improved patient compliance via reduced pill burden², synergistic therapeutic effect (Aggrenox^®)³, minimal potential for abuse (Suboxone^®)⁴ and improved safety/ tolerability (Arthrotec^®)⁵. FDC drug products also provide simplified dosing and may reduce prescription cost for patients. It is an effective way for pharmaceutical companies to extend proprietary rights and marketability of their products.

The formulation and dosage form design for FDC products can be complicated by potential drug-drug interaction, drug-excipient interaction, formulation stability and bioavailability concerns, size of the dosage form and drug release rate requirements⁶. Various formulation strategies have been successfully employed and reported in literature to address these challenges. Commonly used approaches include multiple active pharmaceutical ingredients (APIs) formulated into monolithic tablets (multiple APIs co-exist in a single formulation), multilayer tablets (distinct layers of formulated active) or activecoated tablets⁷.

Dissolution method development for FDC products is an evolving process that coincides with the drug product formulation and process development. One of the primary roles of the dissolution method during early stage of development is to provide an in-vitro release assessment of the potential risk of Bioequivalence (BE) failure. A BE study is normally required by health authority (HA) to compare the rate and extent of absorption of each therapeutic moiety in an FDC product (containing two or more already marketed drugs) with the rate and extent of absorption of each therapeutic moiety administered concurrently as separate single-ingredient products⁸. Biopharmaceutical tools such as in vitro dissolution, biorelevant dissolution and solubility studies, in silico absorption modeling, and preclinical in vitro studies can be helpful in understanding the critical parameters that affect formulation bioperformance. Dissolution testing can also help identify drug-drug and drug-excipient interactions (incompatibilities) as well as any physical changes (API form, co-crystal formation, etc.) that may occur as a result of cogranulation. At the early stages of the development, dissolution methods are used to evaluate/rank in vitro release and stability of different prototypes with the goal of identifying lead formulations for further development. As product development progresses into late-stage, the objective is to develop a dissolution method that is capable of discriminating critical formulation and manufacturing process changes and detecting API critical material attribute changes. If possible, efforts should be made to establish the relationship between in vitro dissolution and in vivo pharmacokinetic profile to allow in vivo performance prediction from an in vitro dissolution curve, thus accelerating the development of drug products. At the registrational stage of development and beyond, the main objective of the dissolution method is to provide quality control and verify product consistency. The dissolution test can also be used to assess post-approval changes and support biowaiver of new formulations or lower strengths of the same formulation. For a FDC drug product, it is possible to acquire biowaiver for one or more active ingredient(s) while performing BE studies for the other active ingredient(s).

Dissolution method development for FDC drug products may be challenging due to differences in physicochemical properties of the active ingredients (e.g., form, pH-solubility profile and pH dependent stability profile) which could prevent the selection of a common dissolution medium. In addition, large dose disparity (e.g., a low dose component in combination with a high dose component), differing release mechanisms (e.g., an immediate release in combination with an extended release or a modified release) could also present challenges for development of a single dissolution method to assess in vitro release of multiple components in a combination drug.

In this article, we will discuss general considerations and challenges one may face when developing a single dissolution method for FDC drug products, along with strategic approaches on developing robust dissolution methods with meaningful discriminating ability in the context of quality-by-design.

General Considerations of FDC Dissolution Method Development

To help ensure that each manufactured lot of drug product will release all active ingredients at an appropriate rate, dissolution is normally monitored as part of the drug product specification. Some general considerations when developing a dissolution method for a FDC drug product are provided as follows:

Single Dissolution Method

Ideally, a single method is desirable to monitor dissolution of all the active components in a FDC formulation. Significant savings in resource (such as people and money) and quicker turnaround could be observed and are advantageous to studies such as long-term stability study (LTSS), site specific stability study (SSS), and commercial release testing when high volume of samples are required to be analyzed in a short period of time.

Target Method Profile

In general, efforts should be made to provide a gradual dissolution profile for at least one of the actives, with percent dissolved less than 85% at the 15-minute time point to allow for f2 calculation9. The method should provide complete dissolution for all actives with no less than 95% dissolved at the final sampling point. It is desirable that the method can provide discriminating capability to meaningful formulation/process changes (i.e., ± 10-20% change to the specification ranges of these variables) with limit set for each active in the drug product. It is essential that the method is sufficiently rugged and reproducible for daily quality control (QC) operation, capable of being transferred between laboratories and testing in the stability programs.

Strategic Approaches in Dissolution Method Development

Dissolution method development for FDC products can be challenging due to dose disparity, differing release mechanisms (Immediate Release vs. Extended Release), divergent pH solubility and pH dependent stability of multiple components. Strategic approaches are necessary when developing dissolution method and can be summarized as follows:

1. The registrational dissolution methods that have been approved for the respective single entity drug products (if available) can be used as a starting point for the dissolution method development of the FDC product.
2. Drug-Drug interactions and Drug-Excipient interactions should be thoroughly evaluated during FDC dissolution method development (e.g., medium selection) to ensure that the presence of two or more drugs does not affect the dissolution performance of each other in a combination product.
3. When a Biopharmaceutical Classification System (BCS) Class I/III API is combined with a BCS Class II/IV API, the discriminating power for BCS Class II/IV drug should take precedence over BCS Class I/III drug since the bioavailability of BCS Class I/III drug may not be dissolution rate dependent.
4. If all the components in a FDC drug product are BCS Class I/ III, a disintegration test may be qualified as a surrogate for the dissolution test provided the presence of two or more drugs does not affect the FDC dissolution performance.
5. Significant degradation during dissolution is undesirable as it introduces bias in dissolution results. Efforts should be made to avoid the pH and/or buffer species that could trigger degradation and to select a common medium that affords both sufficient solubility and stability.
6. If a single entity dissolution method is capable of discriminating meaningful variations of most relevant manufacturing variables or material attributes, it is expected that FDC dissolution method provides similar discriminating capability for that entity if the formulation and process design of the FDC product and the respective single entity products are similar.
7. The effect of meaningful changes to proposed FDC product’s relevant manufacturing variables and material attributes on dissolution rates should be thoroughly evaluated during formulation and process development studies using batches made with, for example, different API particle sizes, tablet hardness, compression force, film coating weight gain (if any), and other relevant attributes and process parameters.
8. If in vitro-in vivo correlation (IVIVC) or in vitro-in vivo relationship (IVIVR) is presented in one or more of the single entity method(s), it is expected that the dissolution method condition/profile of the combination drug product match that (those) of the respective single entity method(s)/ profile(s) in order for the correlation to remain valid.

Quality-by-Design for Dissolution Method Development of FDC Drug Products

In order to develop a meaningful dissolution method, it is desirable to conduct the method development in the context of Qualityby- Design (QbD). QbD is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and control based on sound science and quality risk assessment^10-12. The QbD approach for dissolution method development is a process of identifying the target method profile, performing risk assessment to form a method development strategy, identifying risks associated with critical method parameters, defining analytical method design space and/or operating range, and developing an analytical method control strategy with an ultimate goal to achieve a discriminating and robust dissolution method that reflects drug product quality.

The target method profile consists of requirements of desired dissolution profile and specification for each component. It also addresses the requirement of method discriminating capability and robustness. For example, for immediate release FDC products, a desired dissolution profile and specification could consist of a requirement of dissolution profile with percent dissolved less than >85% at 15-minute time point (except for BCS I/III drugs it is desired to dissolve 85% at 15 min for bio-waiver purposes), percent dissolved more than 75% (Q) in 30 minutes and no less than 95% dissolved in 60 minutes. The method should be discriminating to meaningful formulation/process changes (i.e., ± 10-20% change to the specification ranges of these variables) for at least one active component, and RSD of n=6 vessels from run to run should be less than 10% at time-points prior to specification and less than 5% at specification time-point and beyond for all active components.

Risk assessment is a process of determining the quantitative or qualitative value of risk associated with method development strategy and method performance. Prior to initiation of a method development, a risk assessment to define which active ingredient(s) in the FDC product or what factors should take primary consideration for method development and method alignment should be performed. Factors such as potential drug-drug and drug-excipient interactions, solubility and solution stability of multiple components under various method conditions should be evaluated as part of the risk assessment. An Ishikawa diagram that lists all the variables pertaining to APIs and drug product characteristics that could drive the FDC dissolution method development strategy is helpful for decision making. An example Ishikawa diagram that illustrates the thought process behind the formation of a FDC method development strategy is provided in Figure I.

 Figure 1. Risk Assessment of Dissolution Method Development Strategy (Ishikawa Diagram)

Risk assessment also includes identifying potential risk factors that could critically impact the robustness and discriminating capability of the method. This assessment classifies risks in groups related to instrumentation, materials, methods (e.g., sample preparation and calculation), chemicals and reagents, measurements, human factors, and environmental issues (e.g., vibration, laboratory temperature, relative humidity, and light)^13,14. Failure Mode and Effect Analysis (FMEA)¹⁵ could be used as an effective tool in identifying potential critical factors, impact of failures and cause of failure, and ranking the risks so that poor method performance could be proactively prevented. Risk assessment to identify the failure mode of method performance could be performed throughout the lifecycle of the method development, from method validation, method transfer, and long term stability study to commercial quality control testing for continuous improvement purpose.

The effect of critical method parameters on method robustness and discriminating capability can be identified through Design-of- Experiment (DOE) studies using high risk factors as variables. There are multiple DOE designs (e.g. Full Factorial, Fractional Factorial, Plackett-Burman, Central Composite, Box-Behnken and D-Optimal) that are available, which can be chosen based on the study intent (e.g. main effect and/or the interaction of effects). By varying significant percentage of method parameters such as medium composition, pH, surfactant concentration, agitation speed, mobile phase composition etc., the critical method parameters that could impact method robustness and discriminating capability can be identified.

Based on the results and the interpretation of the DOE studies, an analytical method design space and operating range can be obtained. Analytical method design space refers to a multidimensional combination of method parameters that has proved to provide a dissolution method that is discriminating to meaningful formulation/ process changes yet robust enough for daily QC operation. The benefits include providing regulatory flexibility for a dissolution method while assuring the product quality. For dissolution method of a combination drug, the design space should be a common range of parameters that ensures the dissolution performance of all active ingredients.

Analytical method control strategy is developed based upon risk assessment and failure mode detected during method development and validation, stability sample testing and technology transfer. Method variables that could critically impact the dissolution and analytical method performance (e.g., HPLC) should be documented in the method and controlled in dissolution testing to assure that the method performs as intended (meet target method profile) on a routine basis and reflects the true dissolution performance of FDC drug products. For example, if dissolution release of one or more components is sensitive to the testing environment, such as vibration, it should be controlled or removed/ minimized from the testing environment. Ultimately, analytical method control strategy is developed to insure the quality of the drug products.

Procedure of Developing Dissolution Method for FDC Products

Dissolution method development for FDC products requires thorough evaluation of background information of each API and their drug products (both single entities and FDC) as they are the cornerstone of the method development strategy and method parameter selection. Typical background information that should be collected prior to dissolution method development and is vital to the overall development strategy is listed in Table I. The selection of medium pH, surfactant and surfactant concentration (if necessary), apparatus and agitation speed should be adequately justified using development batches.

Table 1. Background Information

Selection of Dissolution Medium

Ideally, dissolution tests should use a physiologically relevant medium, one that can be correlated to the in vivo performance such as route of drug administration and in vivo environment (physiologically and conditionally similar)¹⁶, and/or a scientifically justified dissolution medium (e.g., pH, composition), one that can help discriminate changes in critical material attributes or manufacturing variables (quality control purpose). A thorough evaluation of physicochemical properties of each API such as pHsolubility, solution stability, potential drugdrug or drug-excipient interaction across physiological pH range should be carried out prior to establishing the medium. A desired dissolution medium should provide sufficient sink, where saturation solubility of a drug in the dissolution medium is at least three times more than the drug concentration [17] to enable complete dissolution release of all actives, yet (along with agitation conditions) affording rates slow enough to allow f2 calculations for at least one component. The medium from the regulatory-endorsed single entity dissolution method can be used as a starting point. Several factors that play important roles in developing the dissolution medium are summarized below:

Medium pH

Medium pH should be selected based on the consideration of pKa, pH-solubility profile and solution stability of each API in physiological pH range of 1.2-6.8. The goal is to select a pH that affords the sink condition for all actives with no or minimal amount of surfactant added and no or minimal degradation occurred. If all the active ingredients are BCS class I or III, select a pH that provides a slower dissolution release to enable discriminating capability of the method.

If FDC formulations contain both BCS I/III and BCS II/IV active ingredients, one may select a pH that meets the sink condition for the BCS II/IV, as dissolution is likely to be the ratelimiting step for bioavailability of BCS II/IV. If multiple BCS II/IV compounds have divergent pH solubility profiles and pH dependent solution stability, evaluation of multiple media to identify a common medium that accommodates solubility and stability of multiple components is encouraged. For example, Huang et.al¹⁸ revealed that dissolution method development for clopidogrel/ pravastatin bilayer tablets was a challenge as clopidogrel was most soluble and stable in aqueous solution at low pH whereas pravastatin sodium rapidly degraded due to lactonization and oxidation. Conversely, at a neutral pH and higher, pravastatin sodium was most soluble and stable, but clopidogrel bisulfate underwent hydrolysis and racemization. A pH range of 4.5-6.8 was found to be suitable for the solubility requirement of pravastatin and stability of both components. With addition of 2% CTAB in dissolution medium, the sink requirement for clopidogrel was met and a discriminating and robust FDC dissolution method was achieved.

Surfactant

Although non-sink dissolution media may be used to guide formulation development, for a QC dissolution method, if sink requirement for one or more of the FDC component(s) cannot be met, surfactant can be added in dissolution medium to enhance the solubility of that (those) component(s). Multiple solubility studies with different types of surfactant may be necessary to aid the selection of the most effective agent (achieves the desired solubility with the least amount added for the component that is the least soluble). Solubility study should be performed on each API, and carried out at 37 °C with various levels of surfactant concentration in desired pH. For Japan filing, a justification for not using SLS or Tween-80 should be provided if a surfactant other than these two is selected¹⁹.

Ionic Interaction

The effect of selected counter ion and buffer ionic strength of dissolution medium on dissolution release should be evaluated for each active component during dissolution method development. It is recommended to avoid the use of anionic surfactants such as sodium laurel sulfate (SLS) in dissolution medium with a cationic drug such as metformin hydrochloride to prevent dissolution slow down that was induced by surfactant-API interaction²⁰. It is also recommended to avoid the use of a medium pH that could introduce API-excipient interaction in dissolution testing, such as pH 4.5 and 6.8 for formulation containing croscarmellose sodium (CCS) and a weak base such as brivanib alaninate²¹. In the cases where incomplete dissolution release was observed due to interactions between APIs or excipients observed at the layer interface of the multilayer tablets, a root cause investigation should be carried out, and change of formulation or process may be necessary to overcome the issue.

Selection of Apparatus and Agitation Speed

Selection of dissolution apparatus and agitation speed requires thorough evaluation of dissolution hydrodynamics, shape and size of the dosage unit and formulation design of the FDC product. The criteria for selecting apparatus and agitation speed can be summarized as follows:

1. Evaluation of paddle and basket apparatus at multiple speeds should be performed using desired dissolution medium to ensure proper hydrodynamics in dissolution vessels is achieved so that a gradual but complete dissolution profile at the final sampling point can be obtained for at least one or more components²².
2. Any coning should be minimized so that it does not affect the dissolution of FDC product artificially. The coning effect can be verified by collecting dissolution samples at infinite point at a higher agitation speed, and is confirmed if additional release is observed. If coning artifact is observed in FDC dissolution, basket apparatus or paddle with increased agitation speed may be evaluated.
3. For dosage units that may float or “stick” to the vessel wall, use of sinkers may be necessary. The criterion of selecting proper sinker is minimal vessel-to-vessel variability. If variation of the release rate is due to tablet orientation (e.g. Multilayer tablets) in dissolution vessel, proper sinker or different apparatus (e.g. basket with proper mesh size) may be evaluated.
4. A flow-through apparatus (USP IV) dissolution may be employed to aid formulation development of low solubility products, as it can improve the sink condition through open-loop configuration. For FDC drug products that have very rapid dissolution for each API, where discriminating capability of the method cannot be achieved by USP apparatus I or II, USP IV can be explored in order to achieve gradual dissolution profiles. Justification should be provided to health authorities if USP IV dissolution is selected as a quality control method.

In general, use of single entity method parameters (e.g. apparatus, sinker and agitation speed) from one of the API as a starting point is highly recommended. A good practice for method development is to start with low rpm (i.e. 50 rpm paddle) and increase if coning artifact is observed. For agitation speed, typically 50 rpm or 75 rpm for paddle, 100 rpm for basket are acceptable by regulatory authorities.

Detection Method for Dissolution Sample Analysis

Typically, for FDC products, a HPLC method may be necessary for dissolution sample analysis due to challenges in selecting a unique wavelength that does not absorb other components by traditional UV-Vis technique. An isocratic HPLC method is desirable (robust, easy to operate), however gradient HPLC may be necessary to achieve a shorter run time with adequate separation of multiple components. The criteria of a desirable detection method include robust performance, short sample analysis time, simple mobile phase and diluent preparation, and simple instruments that are available globally.

For formulations that contain APIs with large dose disparity, development of two detection methods or use of a photodiode array detector may be necessary. The detection wavelength for such formulations is recommended to align with the respective single entity dissolution methods. For example, if component A is a high dose compound that has a strong chromophore whereas compound B is a low dose compound with a weak chromophore, a common detection wavelength for sample analysis may result in over saturation or unable to detect one of the components, thus separate process channels or sample analysis are warranted.

Testing Discriminatory Capability of the Method

Discriminating capability of the dissolution method is one of the most important elements that health authorities will seek during review of CMC section of new drug applications (NDA). The method discriminating capability should be evaluated early on during method development and demonstrated throughout formulation and process ruggedness studies. As part of the discriminating capability assessment, risk assessment to identify critical process parameters (CPP) and material attributes of FDC products, and evaluation of method discriminating capability on the meaningful variations of these CPP or material attributes are recommended. A risk assessment example on evaluating the discriminating capability of the method for a dry granulation process can be found in Table 2. Ideally, one should demonstrate the capability of the selected dissolution method to identify batches that may not be bioequivalent, however it may not always be achievable. In general, one should demonstrate discriminating ability of the selected dissolution method on drug product manufactured under target conditions vs. the drug products that are intentionally manufactured with meaningful variations (i.e., ± 10-20% change to the specification limit/target value of these variables) for the most relevant manufacturing variables and material attributes (e.g. drug substance particule size, compression force, tablet hardness, etc.). An f2 (similarity factor) calculation is commonly used to demonstrate the similarity between profiles. The dissolution method is considered discriminating if one or more APIs show(s) f2 < 50 between profiles²³.

Table 2. Example Risk Assessment of Dissolution Discriminating Capability

If discriminating capability of the method is demonstrated on the most relevant material attributes and manufacturing variables, the method can be considered as a quality control tool to be used in commercial and stability testing to ensure the drug product quality. It is desirable that the discriminating capability of the FDC method is comparable to that/those of the corresponding single entity dissolution method(s) if their formulation design and release mechanism are similar.

Evaluation of Method Robustness and Ruggedness

Determination of dissolution method robustness/ruggedness is essential, as a highly variable method can mislead the formulation and process development and provide incorrect information on drug product quality if dissolution is one of the critical quality attributes. A risk assessment to outline all the variables that could impact the dissolution release rate, vessel-to-vessel, instrument-to-instrument, and analyst-to-analyst variability should be performed prior to NDA method validation (prior to long term stability study). Typical variables that could impact the method robustness include but are not limited to instrument (e.g., dissolution bath, HPLC, balance etc.), reagent (e.g., chemicals, water, solvent etc.), work environment (e.g., vibration, light etc.), sampling (e.g., manual vs. auto, position of cannula etc.) and analyst (e.g., sample withdraw, instrument set up etc.).

Method robustness and ruggedness can be verified by examining small variations of critical parameters such as medium composition, pH, surfactant concentration, agitation speed, mobile phase composition, flow rate, column temperature and detection wavelength. In addition, column ruggedness (e.g. 3 lots), dissolution bath from different vendors and single point vs. profile sampling (if automation is used) should be evaluated as part of the method robustness assessment. Intermediate precision studies conducted at different sites can be used to demonstrate the method robustness performed by different analysts and instruments. The method robustness/ruggedness is demonstrated if equivalent dissolution profiles of all components are obtained between the target and the varied conditions.

Dissolution Profile Comparisons between Single Entity Products and FDC Product

Dissolution release comparison between single entity formulations and FDC formulation are commonly performed during formulation and process development to help identify the lead FDC prototypes and demonstrate the equivalency of formulations used at different stage of clinical studies. This information is often included in the dissolution method justification document when seeking Health Authority endorsement of the method. The comparison is typically carried out on both single entity formulations and FDC formulation using proposed FDC QC dissolution method. The f2 calculation can be used to demonstrate the similarity of profiles. A f2 value of 50 or greater (50-100) ensures the sameness or equivalence of two dissolution profiles and, thus, the in vitro performance of the two formulations. Comparable dissolution profiles between FDC formulation and the respective single entity formulations are generally expected if their formulation, process and release mechanism are similar.

Specification Setting

A discriminating dissolution method should be developed, with limits set, for each API in a FDC drug product. If dissolution method is considered a critical quality attribute, specification-sampling time point and specification value should be set to ensure the drug product quality. Dissolution specifications for FDC drug products evolve from IND (development specification) to NDA/MAA (registrational specification). At IND stage, a default single point specification of NLT 75% in 60 minutes is typically employed for immediate release (IR) APIs to ensure that the active ingredients can be readily released from drug product formulation. For extended release (ER) formulation, a multipoint specification is typically required, with limits set at the first time point to ensure that dose dumping does not occur, a midpoint as an optional control, and the last time point to ensure that drug release is complete. Specifications will evolve at phase II and beyond when BE data become available. At registrational stage and beyond, the specifications for FDC drug product release should be based upon acceptable clinical, pivotal bioavailability, and/or bioequivalence batches and primary stability batches. They should mirror the specifications of respective single entity drug products with consideration of the final dosage form, commercial packaging, and labeling requirement at the local markets. Justification should be provided if different release and shelf life specifications are used between FDC and respective single entity drug products.

The dissolution profile data from the pivotal clinical batches and primary (registration) stability batches are usually required for the setting of the dissolution acceptance criteria of the product, and the specifications should be established based on average in vitro dissolution data for each lot under study, equivalent to USP Stage 2 testing (n=12)23. The specification should be set at the first time point of a plateau where at least 80% of the drug has been released. Thus, for the component that exhibits very rapid release, it is possible to set specification on the time point earlier than 30-minutes.

Health Authority Endorsement

It is essential to communicate and seek health authority endorsement on the proposed dissolution method prior to the start of registrational stability studies (LTSS). An End of Phase II meeting or Type C meeting (if filing is in US) with Food and Drug Administration (FDA) may be required by sponsors to reach consensus on the dissolution method to be used in LTSS studies. For filings that are outside of US, local regulatory counterparts could be consulted for such purpose.

Conclusion

Dissolution method development for FDC product presents many challenges that require a systematic and strategic approach. A systematic method development in the context of QbD ensures the development of a meaningfully discriminating and robust dissolution method. A thorough evaluation of various factors (such as BCS Class, physicochemical properties, regulatory expectation, etc.) that could drive the development strategy is the cornerstone of the method development as it dictates the priorities when selecting method parameters to meet the target method profile. Risk assessment tools such as Ishikawa diagram and Failure Mode and Effect Analysis (FMEA) could be used throughout the method development process to help identify method development priorities and critical method parameters that could impact the method robustness and discriminating capability. A single dissolution method to assess the dissolution release of multiple components in a FDC product is a desirable approach from analytical testing efficiency and cost saving perspectives. A thorough evaluation of physicochemical properties of each API ensures the selection of a proper dissolution medium that enables discriminating and robust dissolution profiles. Careful selection of dissolution apparatus and agitation speed ensures proper dissolution hydrodynamics and the removal of dissolution artifact. Discriminating capability of the method should be demonstrated on the most relevant manufacturing variables and material attributes. Method robustness should be demonstrated throughout the life cycle of the method development, validation, technology transfer and quality control testing.

Acknowledgement

The authors would like to thank valuable comments from Dr. Dilbir Bindra, Dr Divyakant Desai, Dr. Frank Tomasella, Dr. Pankaj Shah and members of the portfolio teams at Bristol Myers Squibb Company.

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