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Dissolution and Translational Modeling Strategies Enabling Patient-Centric Drug Product Development: the M-CERSI Workshop Summary Report

  • Andreas Abend
  • Tycho Heimbach
  • Michael Cohen
  • Filippos Kesisoglou
  • Xavier Pepin
  • Sandra Suarez-Sharp
Meeting Report Theme: Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development
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  1. Theme: Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development

Abstract

On May 15th–17th, 2017, the US FDA and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) held a workshop at the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI), to discuss the role of dissolution testing and translational modeling and simulation in enabling patient-centric solid oral drug product development. This 3-day event was attended by scientists from regulatory agencies, pharmaceutical companies, and academia. The workshop included podium presentations followed by breakout session discussions. The first day of the meeting focused on the challenges in dissolution method development and the role of dissolution testing throughout drug product development. On the second day, approaches to establish a link between in vitro testing and in vivo drug product performance (e.g., systemic exposure) were presented. Overall success rates and challenges in establishing IVIVCs via traditional and modern physiologically based pharmacokinetic (PBPK) modeling and simulation approaches were discussed. Day 3 provided an opportunity to discuss the expectations for establishing clinically relevant drug product specifications (CRDPS). It was recognized that understanding the impact of formulation and process variations on dissolution and in vivo performance is critical for most drug products formulated with poorly soluble drugs to ensure consistent product performance. The breakout sessions served as platforms for discussing controversial topics such as the clarification of dissolution terminology, PBPK model development and validation expectations, and approaches to set CRDPS. The meeting concluded with a commitment to continue the dialog between regulators, industry, and academia to advance overall product quality understanding.

KEY WORDS

clinically relevant specifications dissolution IVIVC/IVIVR PBPK modeling and simulations safe space 

SUMMARY OF WORKSHOP PROCEEDINGS

The University of Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI) hosted a 3-day dissolution and translational modeling and simulation workshop1 in May 2017 at the University of Maryland, Baltimore campus. The meeting discussed the challenges and opportunities related to solid oral drug product development with an emphasis on establishing clinically relevant specifications. Scientists from industry, academia, and regulatory agencies presented state-of-the-art techniques and strategies for dissolution method development, as well as the regulatory application of clinically relevant dissolution methods to enable enhanced drug product development and understanding. Discussions focused on current approaches and challenges to establish a link between quality attributes, in vitro testing, and in vivo (clinical) drug product performance (e.g., systemic exposure). This link is essential and is a key component of patient-centric drug product development and the setting of specifications that are clinically relevant. In general, the meeting was structured such that scientific and regulatory background information was presented in the morning, followed by highly interactive breakout sessions in the afternoon with focus on specific questions that were posed in advance of the meeting.

Motivation to hold a 3-day meeting emanated from the recognition that pharmaceutical drug product development has become increasingly challenging over the past two decades. This challenge is in part due to the higher proportion of poorly soluble compounds, more complex dosage forms, and the desire to incorporate Quality by Design (QbD) principles. In addition, traditional tools such as in vitro dissolution testing continue to evolve from a routine product quality test into a powerful tool to guide formulation selection and process scale-up development. Recent advances in PBPK absorption modeling and simulation hold the promise to further close the gap between in vitro testing and in vivo performance. As such, the roles of biopredictive in vitro dissolution methods (e.g., based on PBPK absorption modeling and simulation) and in vitro-in vivo correlations/relationships (IVIVCs/IVIVRs), to enhance drug product understanding and to support drug product development including the setting of specifications, were central topics. Several pharmaceutical companies are already implementing these novel approaches during drug product development, to reduce the need to perform in vivo formulation studies in animal models or even for in-human pharmacokinetics (PK) studies. However, how pharmaceutical companies use these tools strategically during drug product development, their applicability to establishing final specifications for quality control purposes for commercial product, and in justifying post-approval changes, still requires further discussion and refinement.

The importance of patient-centric drug product development is recognized by regulatory agencies, industry, and academia (1,2). To support this development strategy, it is important to develop methodologies that can accurately and unambiguously characterize in vivo systemic exposure from in vitro drug product performance. In this respect, dissolution testing is a critical tool, as it is the only in vitro test that probes the extent and rate of in vivo drug product release, which, in many cases (especially for modified release formulations and for drug products comprising of biopharmaceutics classification system (BCS) 2 or 4 compounds), is crucial to confirm consistent in vivo drug product performance. Developing dissolution methods that meet these expectations can be challenging. Scientists today have the choice to select dissolution tests from a variety of different traditional (i.e., described in the United State Pharmacopeia (3) or equivalent compendia) and non-traditional experimental approaches (i.e., triple compartment (4), etc.) that best “fit” and describe the in vivo drug product performance. These tests are strategically deployed internally by many companies throughout drug product development; however, the experimental conditions often require adjustments based on the needs of a particular program. Hence, while the intent of these methods is geared towards drug product performance understanding, the choice of experimental conditions may vary from company to company. In addition, the number of presentations and publications in the field of dissolution technology has steadily increased over the years, leading to some confusion because of inconsistent use of terminology. Specifically, technical terms (Table I) such as “biorelevant,” “biopredictive,” “clinically relevant,” or “discriminating” may have different meanings for scientists from different companies. Adding the views of regulatory scientists, who may judge understanding and quality from a different scientific perspective, unintentionally further contributes to the “terminology bewilderment.”
Table I

Definition of Frequently Used Terminology in this Manuscript

Terma

Definition

Clinically relevant

The term “clinically relevant” implies the establishment of a link between drug product quality attributes (e.g., in vitro dissolution, purity, etc.), CMAs/CPPs, and in vivo performance (e.g., systemic exposure).

Safe space – or bioequivalent space

Boundaries defined by in vitro specifications (i.e., dissolution or other relevant drug product quality attributes), within which drug product batches are anticipated to be bioequivalent to one another, or less optimally, but still possible, bioequivalent to the pivotal clinical batch (es). Drug product specifications are expected to be set within these boundaries.

Biorelevant dissolution method

A set of testing conditions for monitoring in vitro dissolution designed to closely mimic a relevant biological fluid and a physiological environment.

Biopredictive dissolution method

A set of testing conditions for which in vitro dissolution profiles are capable of predicting pharmacokinetic profiles. These are typically based on classical or mechanistic IVIVC.

Clinically relevant dissolution specifications

A set of in vitro dissolution testing conditions and acceptance criterion (ia), that can identify and reject drug product batches that are not expected to be bioequivalent to clinical pivotal product batches.

CRDPS

CRDPS are those specifications that demonstrate consistent in vivo drug product performance (i.e., efficacy and safety). These specifications are established to identify and accept only drug product batches that are bioequivalent to clinical pivotal product batches.

Discriminating dissolution specifications

A set of in vitro dissolution testing conditions that, along with the acceptance criterion (ia), are able to differentiate drug products manufactured under target conditions vs. drug products that are intentionally manufactured with meaningful variations (i.e., formulation and manufacturing variants) for the relevant manufacturing variables (e.g., drug substance particle size, compression force, tablet hardness, etc.).

QC Dissolution Specification

A set of in vitro testing conditions and acceptance criterion (ia) intended to ensure that a drug product adheres to a defined set of quality criteria that meet the requirements established by regulatory agencies.

IVIVC

A quantitative relationship validated based on a method of analysis conforming to current regulatory expectations, which links in vitro release to in vivo exposure.

IVIVR

A relationship which fails the aforementioned definition (for an IVIVC) and has no regulatory application unless a safe space is stablished (e.g., when combined with bracketing approach).

IVIVE

In vitro to in vivo extrapolation, in the context of PBPK absorption modeling and simulation refers to the quantitative transposition of experimental results or observations made in vitro to predict the systemic exposure provided the PBPK absorption model has been adequately validated (e.g., able to adequately predict failed BE batches).

PBPK absorption modeling

Physiologically based pharmacokinetic absorption models include ACAT (Advanced Compartmental Absorption Transit) and ADAM (Advanced Dissolution, Absorption, and Metabolism) as well as other mechanistic models which mimic physiological conditions and incorporate dissolution information while accounting for relevant physicochemical and physiological factors leading to a prediction of systemic exposure versus time.

aThe terms in this table were extensively debated during the breakout sessions which will be reported in more detail as part of additional workshop proceeding’s publications in the near future

In these regards, this workshop was designed to reach consensus on the use of terminology, to clarify the utility of dissolution and modeling/simulation approaches, when and how they can be used, to delineate additional tools, and to discuss novel, still evolving approaches for developing dissolution methods to:
  1. (1)

    Facilitate formulation development and to enhance in vivo performance risk management throughout a product’s life cycle

     
  2. (2)

    Demonstrate rewards and challenges with oral absorption modeling and translational biopharmaceutics PBPK tools

     
  3. (3)

    Support the development of emerging formulation and manufacturing process technologies

     

The Role of Dissolution Testing Throughout Drug Product Development

Dissolution testing has been used for decades in pharmaceutical drug product development and applied as a quality control (QC) test to release commercial product. While typical QC dissolution tests measure the rate and extent of drug substance release in vitro, their use as reliable predictors of drug product in vivo performance is not warranted until scientifically justified (5,6). Accordingly, the meeting started with a presentation emphasizing this dilemma within the context of patient-centric product development and product quality assurance and the importance of multidisciplinary efforts (7). In the proceeding presentation, a brief overview of the evolution of traditional and novel dissolution methodologies that are currently in use was shown (8). This presentation also briefly touched on the different viewpoints of industry and regulators on the use of dissolution in development and for product quality control. Subsequent presentations showcased in more detail the application of different types of dissolution methods for different purposes at various stages of drug product development. For example, in the early stages of development, the use of dissolution at the solubility limit of the active pharmaceutical ingredient (API) can be used to rank order formulation prototypes (9).

As clinical development advances and the formulation and process are improved, many pharmaceutical companies rely on biorelevant dissolution testing to assess special patient population needs (e.g., achlorhydria, drug-drug interactions associated with proton pump inhibitors) or potential food effects. These can often be assessed by performing in vitro trials under a variety of conditions mimicking the physiological environment to which the drug product will be exposed upon ingestion (10). The experimental conditions frequently include elaborate instruments and set-ups, complex dissolution media, and sample preparation techniques that may be difficult to replicate in a routine laboratory. Nevertheless, the value of biorelevant dissolution testing in increasing the likelihood of establishing an in vitro-in vivo link was also discussed.

Once a drug product advances into late-stage clinical development, the impact of formulation and manufacturing process variations on drug product in vitro performance is typically assessed. The in vitro dissolution approaches applied here may include the tests deployed earlier, but the immense numbers of experiments commonly performed at this stage, which are aimed at establishing a robust design space, may make the use of these complex methods impractical. On the other hand, it is at this stage in product development where the capability of the dissolution method to precisely guide process scale-up is critical. Effective dissolution methods employed at this stage of development should identify changes that would be predicted to have significant impact on the drug product in vivo performance, based on sound scientific principles and prior knowledge relevant to the formulations under study. This would help to ensure that only drug product with consistent in vivo performance is released for pivotal clinical trials and to minimize the risk for the company to negatively impact the quality of the clinical data.

To ensure that a dissolution method is adequately discriminating, many pharmaceutical companies carefully examine the mechanism of drug product in vitro release under a variety of experimental conditions. These experiments are used to elucidate which steps of the dissolution mechanism, e.g., tablet disintegration, granule disintegration, or API particle dissolution, are relevant to the overall dissolution process. Once the dissolution mechanism is understood within this context, and the initial experimental conditions are identified, formulation and process variants are tested and their impact on dissolution is assessed. This information, which is often supported by several dissolution testing conditions, such as low agitation speed, and in multiple pH media, are then used to further optimize the QC dissolution method. The final method conditions are then used in late-stage drug product development for release of pivotal clinical batches and to monitor drug product performance over the anticipated shelf life. The justification of the method conditions, as well as the results from clinical batch release, and eventually registration stability data, is filed to the regulatory agencies to propose the final drug product specifications. Dissolution methods need to show discriminating ability to formulation and process variants. However, if the method is overly discriminating, it may flag process and formulation changes that do not impact drug product in vivo performance and therefore, may unnecessarily restrict the manufacturing process. Likewise, methods that lack discriminating ability may allow the release of non-conforming batches which may pose efficacy/safety concerns.

To address this dilemma, regulatory agencies and several pharmaceutical companies have advocated the demonstration of “clinical relevance” in the registered dissolution method. One of the objectives of the first day of the workshop was to refine dissolution-related terminology (Table I) which was widely debated during the breakout sessions. The applicability of clinically relevant drug product specifications, including dissolution specifications—especially their regulatory implications—was discussed in-depth on day 3.

Within the context of enhanced formulation, manufacturing process, and in vivo drug product performance understanding, the need for end-product dissolution testing was debated. For some highly soluble and very rapidly dissolving products, the use of dissolution surrogates such as disintegration and tablet hardness is already accepted (11), but the concept of surrogates for dissolution approaches (e.g., multivariate models) should be recognized as an opportunity for any drug product with adequate (e.g., enhanced via clinical relevance) process understanding and in-process controls. In addition, the end-product release paradigm for production batches may not be necessary in a continuous manufacturing process environment, highlighting a desire for companies to advance enhanced product/process understanding, while linking in-process controls to in vivo performance (12). Examples of product dissolution reinforced either by process analytic tools (PAT) or/and by empirical correlation of process parameters/material attributes with in vitro dissolution rates demonstrated their utility to support continuous manufacturing (13). Moreover, these approaches should also be considered for implementation in traditional batch production as well.

The Need for Establishing the In Vitro-In Vivo Link

The overall value of various dissolution testing methodologies in drug product development to enable formulation candidate selection, formulation, and process development, as a key enabler of robust manufacturing control strategies and ultimately, as a quality tool for product release, has been generally recognized. However, a clear linkage of the dissolution methodology and associated acceptance criteria (specifications) to the assurance that the drug product released to patients will meet the safety and efficacy attributes that were established during pivotal clinical studies is often missing in regulatory submissions. At a minimum, understanding the impact of formulation and process variations on in vitro dissolution and in vivo PK is critical for most drug products formulated with poorly soluble drug substances to ensure consistent in vivo drug product performance.

Attempts to establish a link between in vitro release and in vivo exposure should be undertaken early during drug product development. These efforts consist of introducing deliberate variations in potentially critical material attributes (CMAs) and process parameters (CPPs) to prototype clinical formulations, and correlating in vitro dissolution profiles of these formulations with their observed clinical systemic exposure. These endeavors typically lead to the identification of a “safe space” (Table I), within which product and process design spaces can be justified and clinically relevant drug product specifications can be proposed. Through this level of product and process understanding, manufacturers should be able to justify appropriately substantiated ranges of operating conditions and gain flexibility throughout the life cycle of the drug product. Demonstrating manufacturing consistency comparable to the pivotal clinical batches may be an acceptable basis for providing a risk-based approach to assure consistent in vivo performance. However, in the absence of an in vitro-in vivo link, developers accept the risk of being challenged on the selection of the proposed specifications and a potential delay in regulatory approval. This may result in the implementation of tight dissolution specifications and running routine manufacturing under very stringent controls, bearing an increased risk of product quality investigations, or even unnecessary product discards.

Day 2 of the workshop focused on discussing and addressing the challenges industry and regulators are facing in establishing this essential link between the in vitro and in vivo performance (14). Traditional tools used in biopharmaceutics, such as dissolution testing and bioavailability (BA)/bioequivalence (BE) measures, can be employed to evaluate the clinical outcomes related to changes in the CMAs and CPPs. However, conducting BA/BE studies for every formulation/manufacturing change with respect to the clinical formulation is impractical and would pose unnecessary burden on the pharmaceutical industry. In addition, this may unnecessarily require more volunteers to be enrolled in costly clinical trials submitting them to undue safety risks. A novel approach in human PK study design using stable isotopes was proposed (15) as one potential path (under certain circumstances) to overcome the challenge of high subject numbers. This approach could be useful in early clinical development, when the inter- and intra-subject PK variability is still being explored. It was emphasized that without this knowledge, determining an appropriate number of patients for a BA/BE study is challenging, and studying a wide range of formulation and process variables would be difficult to justify, both from a scientific and practical perspective.

Due to the critical role that dissolution plays in helping to understand bioavailability, it can be effectively used (e.g., with IVIVCs) to evaluate the effects of variations in drug product’s CMAs and CPPs on systemic exposure. Unfortunately, the incidence of sponsors developing a successful IVIVC has been rather low (16,17) partly due to the failure of in vitro dissolution methods used to predict in vivo performance, or the inability of traditional IVIVC approaches used to establish the in vitro and in vivo link (16). Therefore, there continues to be a critical need to establish/gain confidence in new strategies/approaches to aid in the development of clinically relevant dissolution methods, which can effectively serve as surrogates for in vivo studies. To this end, the application of stochastic deconvolution in IVIVC development was presented as one potential option (18).

Regulatory agencies have been gaining confidence in the use of PBPK absorption modeling and simulation, not only in the understanding/establishing this essential link, but also to support regulatory decision-making (19). Current PBPK models offer the possibility to conduct sensitivity analyses for parameters such as drug dose, solubility, dissolution rate, particle size, or gastrointestinal pH, to determine their impact on drug absorption or systemic drug availability. Moreover, permeability rate-limited absorption, as opposed to dissolution rate-limited absorption, can be readily identified. PBPK absorption modeling supported at least 19 NDA submissions that were reviewed by the FDA since 2009, and approximately 75% of these models were found acceptable from a biopharmaceutics perspective (14).

Several case examples from the FDA and industry, spanning all phases of drug product development and life cycle management, were presented demonstrating the value of PBPK absorption models—also known as mechanistic absorption models—to link in vitro data with systemic exposure. Briefly, absorption modeling is PBPK modeling. With PBPK absorption models, the gastrointestinal tract (GIT) is divided into multiple (usually 6–9) anatomically relevant compartments, with human physiological volumes and transit times. Drug absorption from the GIT segments occurs in a complex process resulting from the underlying mechanisms which includes release from the formulation, dissolution, precipitation, luminal degradation, permeability, metabolism, and transport (20,21). The case studies presented included the use of mechanistic absorption modeling to establish IVIVCs and, more explicitly, to assess the impact of varying API particle size on drug product in vivo performance during drug product development (22), as well as to justify API particle size and dissolution specifications for a commercial drug product (23). The advantages of mechanistic PBPK IVIVC models over classical IVIVC approaches were highlighted, especially in the potential ability to handle more complex scenarios, such as addressing the interplay of in vivo dissolution and metabolism while at the same time accounting for physiological variability, both on the absorption and systemic disposition. Approaches to integrate dissolution in PBPK absorption modeling were discussed and exemplified. These ranged from the use of direct measured data, fitted or not with a Weibull function, to a more mechanistic approach, such as the determination of Z-factor or fitting product-specific particle size distributions (24). Moreover, examples were presented where PBPK modeling and simulation was used to identify permeability rate-limited absorption, allowing for the identification of a “safe space” for dissolution profiles.

The need for gaining experience via additional examples of PBPK absorption modeling and simulation using varied inputs of dissolution data as well as developing decision trees to guide the selection of the various methods was widely recognized, especially by the regulatory agencies (25,26). In addition, current challenges and opportunities for PBPK absorption modeling in addressing clinical questions or identifying risks were emphasized (19,26) and have been recently documented (27). Specifically, the use of PBPK absorption modeling to project the absence of food effects or proton pump inhibitor interactions in early clinical development, thus informing whether additional formulation work was required, was highlighted (28,29). Lastly, current perspectives on the utility of PBPK absorption modeling and simulation as a tool to increase the success of developing biopredictive dissolution methods were reviewed (30). Although PBPK modeling and simulation hold a promise to close the gap in the establishment of an in vitro-in vivo link and allowing development of biopredictive dissolution methods, there are currently several challenges that pharmaceutical companies and regulators are facing in its implementation.

Regulatory Applications of Clinically Relevant Dissolution Testing

The final day of the workshop focused on advancing regulatory applications of clinically relevant dissolution testing, with special focus on its role in setting clinically relevant drug product specifications (CRDPS). Within this context, CRDPS are those specifications that help in establishing consistent in vivo drug product performance (e.g., efficacy and safety) as proven by their ability to identify and reject drug product batches that are not bioequivalent. CRDPS are not limited to final drug product release specifications but, rather, include established limits for identified CMAs and CPPs as part of the manufacturing control strategy. Confirming the appropriate control strategy and final drug product specifications is critical in assuring consistent quality, efficacy, and safety (compared to the batches that were used during pivotal clinical trials) throughout the product’s life cycle (31, 32, 33).

In reality, many pharmaceutical companies still establish drug product specifications solely for quality control purposes to support the in vitro determination of identity, purity, potency, and strength of drug products and not on pre-determined clinically acceptable outcomes (e.g., systemic exposure) (31, 32, 33). For drug products where this practice is pursued, the ability of the quality control dissolution specification to ensure consistent in vivo drug product performance is questionable. Relying on this “traditional” set of specifications for quality control purposes alone, especially for BCS 2 or 4 drugs or modified release drug products, may pose a risk of “under-discriminating” specifications, whereby drug products with different—and more importantly perhaps unacceptable—in vivo performance could be released to patients (31, 32, 33). The risk of the specifications to be too narrow or “over-discriminating” also exists with this traditional approach, if the development experience has been limited to small variations in the CMAs and CPPs. This may lead to unnecessary investigation and rejection of batches that are acceptable in terms of in vivo performance. For many drug products, it is unlikely to establish clinically relevant drug product specifications without dissolution methods that increase the likelihood of developing successful IVIVCs/IVIVRs. Even if one applies a battery of different dissolution experiments under physiologically relevant conditions to probe for potential changes of in vivo performance during product development, these methods alone do not necessarily provide an in vivo link. This dilemma was recognized by regulators (31,32) and highlighted by several presenters from pharmaceutical companies. Therefore, there is an urgent need to develop a framework for the systematic approach in setting clinically relevant drug product specifications and this is one of the Center for Drug Evaluation and Research (CDER) science and research needs identified by the CDER Science Prioritization and Review Committee.

To demonstrate the substantial advantages of developing clinically relevant specifications, roadmaps towards the development of these were presented from regulatory (the European Medical Agency (EMA) and FDA) and industry perspectives (31, 32, 33). To this end, the integration of biopharmaceutics tools (such as dissolution methods and/or IVIVC/IVIVR) into drug product development is essential in setting clinically relevant specifications. The successful application of these approaches, i.e., (1) establishment of IVIVR with bracketing approach; (2) establishment of IVIVC; and (3) establishment of in vitro-in vivo extrapolation (IVIVE) via acceptable PBPK absorption modeling and simulation, is likely to provide a link between drug product quality and in vivo performance, leading to enhanced drug product understanding and potential regulatory flexibility (31,34). In all cases, it was widely discussed and agreed that drug product specifications are clinically relevant as long as the resulting dissolution profiles fall within the “safe space” defined via these approaches. In the absence of a defined “safe space,” drug product specifications are set based on the limited number of in vitro test results from batches used in pivotal clinical trials, which are likely to provide very limited regulatory flexibility. Case studies highlighting the different approaches towards clinically relevant specifications which are ideally developed prior to entering late-stage clinical development (35,36), but can also be developed prior to filing or even post-product approval (37,38), were presented. Based on the presentations, a level A IVIVC is generally considered the gold standard and often pursued for MR products (31,32,34). An IVIVR with bracketing approach or multiple level C IVIVCs highlighted the most likely outcomes for immediate release (IR) products (36) along with IVIVE (31,33,34) via acceptable PBPK absorption model and simulation. However, it was also acknowledged that in some cases, due to complex PK or no relation to product quality, specifications may need to be set based on clinical experience (38). Current differences in global perspectives on clinically relevant specifications were discussed. In this regard, it was acknowledged that while setting of specifications relative to pivotal clinical batches generally accepted globally, more uncertainties exist around application of the IVIVR/bracketing approach or IVIVEs for IR products in terms of global acceptability. Consideration for updates (e.g., FDA PBPK guidance with application to product quality) or modifications to regulatory guidance (i.e., FDA IVIVC guidance) as opportunities to further advance the development of clinical relevant specifications for the benefit of regulators, industry, and ultimately, the patient, was proposed.

Decisions and Key Follow-up Actions

The breakout sessions provided a prolific discussion forum for scientists involved in product development and regulatory decision-making. Attendees passionately debated how to clarify existing dissolution-related terminology and felt strongly about replacing existing terms such as “biopredictive,” “biorelevant,” and “quality control” methods with more accurate/precise terms such as clinically relevant and regulatory method, when applicable. The prevalence of non-traditional or novel in vitro dissolution methodologies in product development, not only in assessing, but also frequently in mitigating biopharmaceutical product risk, was generally recognized. However, overcoming the challenges to either use as is or to translate these often novel, non-robust methods into procedures for routine product release was highlighted as a potential opportunity to enhance confidence in the marketed product control strategy. As the use of PBPK absorption modeling has been gaining a strong foothold in product development, especially to support product quality and life cycle management, the need for clear guidance on model and software validation and verification has become evident. Despite two draft guidelines being recently published by the European Medical Agency (EMA) (39) and FDA (40), the criteria for acceptable model qualification and validation still need to be determined. This effort requires close collaboration between software developers, as well as application scientists both from industry and regulatory agencies. The meeting audience was united in their position to firmly integrate the establishment of clinically relevant dissolution specifications in drug product development and for mature products if needed. To be fully successful, opportunities for (1) discussing the key requirements in product development, (2) the critical need to understand the link between in vitro dissolution testing and in vivo performance, be it based on BCS classification system or not, (3) the use of dissolution under physiologically relevant conditions, supported by human PK data and/or PBPK modeling, and (4) the need for regulatory harmonization all need to be further propagated. Rather than creating entirely new regulatory guidance related to dissolution testing in product development and “clinical relevance” and for finished product release and post-approval change management, the audience focused on few guidance documents (e.g., FDA IVIVC guidance published in 1997 (6) and PBPK guidance published in 2016 (40)) that could potentially be updated in the near future and are supported by publications in the open literature to illustrate their successful application or limits. In addition, the use of surrogate tests for dissolution including parametric approaches, especially within the context of continuous manufacturing, was identified as a new opportunity to further enhance drug product quality understanding. As such, a series of publications which will include more detailed information on the morning presentations and afternoon breakout session discussions is planned mid-2018 up to 2020 in AAPS Journal to further build on the outcome of the 2017 M-CERSI workshop.

Footnotes

  1. 1.

    By following this link, the interested reader can access the workshop agenda and all meeting materials (presentations). Alternatively, the agenda can be found following by clicking on the following link: http://pharmacy.umaryland.edu/centers/cersievents/dissolution-and-translational-modeling-strategies/

Notes

Acknowledgments

The meeting organizers are indefinitely grateful to Drs. James Polli (University of Maryland, School of Pharmacy, Baltimore, MD), Tzuchi (Rob) Ju (AbbVie, Inc.), Mr. Evangelos Kotzagiorgis (EMA), and Ms. Ann Anonson (UM) for their tremendous efforts in helping in the organization of this workshop and to all speakers, facilitators, and scribes whose participation was key in having a very informative workshop.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest to declare.

Disclaimer

This article reflects the views of the authors and should not be construed to represent their organizations’ views or policies.

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Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Pharmaceutical SciencesMerckWest PointUSA
  2. 2.Novartis Institutes for Biomedical ResearchEast HanoverUSA
  3. 3.Pfizer IncGrotonUSA
  4. 4.AstraZeneca R&DCheshireUK
  5. 5.Division of Biopharmaceutics, Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and ResearchFood and Drug AdministrationSilver SpringUSA

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