1Dissolution Technologies, Hockessin, DE, USA
2Bristol-Myers Squibb, New Brunswick, NJ, USA
3AbbVie, North Chicago, IL, USA
4Pfizer, Groton, CT, USA
5Sotax, Westborough, MA, USA
The AAPS In Vitro Release and Dissolution Testing (IVRDT) Focus Group had a Face-to-Face (F2F) Meeting on November 19, 2015, hosted by Bristol- Myers Squibb in New Brunswick, NJ. Xujin Lu (Bristol- Myers Squibb) was the Chair of the Organizing Committee, and the other members were Nikoletta Fotaki (University of Bath), Marie DiMaso (Corealis Pharma), and Vivian Gray (V. A. Gray Consulting).
The objective of the meeting was to have IVRDT Focus Group members engage in discussion stimulated by talks on hot topics and to hear summaries of the programs presented at the recent AAPS Annual Meeting.
The first talks were presented visually via Web conference by three USP speakers who gave an overview and updates on Compendial Dissolution and Drug Release Testing. Margareth Marques first spoke on the revisions to USP General Chapter Dissolution <711> and USP General Chapter Disintegration and Dietary Supplements <2040> that involve the use of additional enzymes and instructions when an incompatible surfactant is used with enzymes during the two-tier testing. These revisions have been thoroughly discussed in the last two years and are due to become official in May of 2016. She also mentioned a newly proposed monograph on hard gelatin capsules and a new USP Dissolution Methods Database. Erika Stippler followed with a report on the planned collaborative study on vibration. The aim of the study is to understand conditions of environmental vibration that prevail in typical dissolution laboratory settings. Vibration data will be collected over a continuous and successive time period of up to 20 days in each lab. Measurements will be conducted according to a protocol, and USP will evaluate the measurements. Accelerometer and acquisition software will be provided. About 10 labs have shown interest in participating in the study. It is planned to begin in early 2016. The third USP speaker was William Brown. His topic was the Performance Verification Test (PVT) and the USP collaborative study. He first described dissolution test variability. The purpose of the PVT is to allow a laboratory to compare its dissolution results with ranges established in a USP collaborative study. A lab could identify if its dissolution results are unusual or outside the limits of the collaborative study. He went on to describe sources of variability that the PVT could capture. He also invited the Focus Group members to encourage their companies to participate in the collaborative study.
After the USP speakers, Gregory Martin (Complectors Consulting) gave the presentation “Review of the FDA Draft Guidance on Dissolution Testing and Specifications for Class 1 and 3 Drugs.” He presented a review for the FDA draft guidance Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms Containing Biopharmaceutics Classification System Class 1 and 3 Drugs. Published in August 2015, this draft guidance has the potential to become a very valuable asset for industry, providing clarity and specific guidance for the covered drug products. In September 2015, the IVRDT Focus Group conducted an in-depth review of the draft. Greg summarized the comments from the focus group combined with his personal study. According to the Biopharmaceutics Classification System (BCS), drug substances are separated into four categories based on their aqueous solubility and intestinal permeability. This guidance focuses on those drugs in BCS Class 1 and 3, which are classified as high solubility/high permeability and high solubility/low permeability, respectively. Due to their high solubility, these drugs are considered to pose relatively low risk for drug product performance for conventional oral dosage forms. The guidance proposes standard dissolution test conditions and specification acceptance criteria based on the assessment of the lower risk. Greg indicated that there are a variety of potential options for dissolution method conditions (apparatus, agitation rate, medium, time points), resulting in a significant effort to select the conditions and evaluate many different combinations of the conditions. The process of proposing specification criteria has often involved significant negotiations as part of the regulatory submission process. With this guidance, the FDA has reduced the expectations, and the effort required for these activities may also be significantly decreased.
In this presentation, Greg summarized the draft guidance and comments:
- What are the eligibility requirements?
- What are the standard dissolution test conditions?
- What are the standard specification criteria?
- What if I want to replace dissolution testing with disintegration?
- What is not addressed in the guidance?
- What are the concerns with the guidance?
For the eligibility, this guidance is scoped for immediaterelease dosage forms intended to be swallowed, such as tablets and capsules, but not for chewable and orally disintegrating dosages. It is for the BCS Class 1 or 3, with the drug substance highest dose soluble in 250 mL or less over the pH range of 1-6.8. It does not apply to narrow therapeutic index drugs or to rapid analgesic or rescue medications. For the standard dissolution test conditions, the draft guidance recommends that a fixed agitation speed, fixed volume, and fixed medium be used rather than ranges, which are found in the 1997 guidance. The overall impact of making specific recommendations rather than providing ranges can be to reduce the amount of work necessary to identify the final conditions. This guidance also defines a standard specification criterion, which is a benefit that requires fewer time points and data to be collected and less negotiation with the FDA when the standard criterion is appropriate. A tighter requirement for BCS Class 3 (Q = 80% in 15 min) is stated, which provides better assurance that the bioavailability of the drug is not limited by the dissolution, but that the rate-limiting step for drug absorption is gastric emptying. It is very interesting that replacement of dissolution testing with disintegration is addressed in this guidance. It is recommended that disintegration can be used in lieu of dissolution if the product has been shown to meet a specification of Q = 80% in 15 min. This approach is much less complicated that the current guidance.
It was pointed out during Greg’s presentation that no recommendations are provided for those products that will not meet the recommended specifications. In those cases, presumably the scientists will revert to the 1997 guidance and continue according to the paradigm prior to the issuance of this new guidance. Would those be similar to the recommendation for Class 2 and 4 drug substances and presumably also for drug substances or drug products that do not fall within the scope of eligible products? Meanwhile, both the new draft guidance and the 1997 guidance are silent with respect to the analytical finish for the dissolution testing. The expectation is that the analytical finish will be suitable for its intended use (e.g., sufficiently specific, accurate, and precise over the range of interest). In addition, several concerns have been raised and further clarifications are expected from the agency, including why there is a requirement for the drug substance to be chemically stable for 24 h, how “normal” and “large” quantities of excipients in the dosage are defined, and what are the expectations for discriminatory ability. An intensive discussion followed this presentation even though comments were collected during the review conducted in September by the IVRDT Focus Group. It is expected that this guidance will make significant impact when it is implemented.
The topic of “Practical Approach for Developing Dissolution Methods to Support Clinically Relevant Specifications” was presented by Jian-Hwa Han (AbbVie). His presentation discussed the optimal deliverables of a typical dissolution method. After years of discussion and debate on so-called biorelevant dissolution testing methods, the industry still has a hard time finding the right direction for developing dissolution methods that can support clinically relevant specifications. This presentation consolidated the working strategies and concepts from industry and academia through the discussions of the biorelevant subteam within IVRDT.Due to the in vitro dissolution testing limitations, there is no generic biorelevant dissolution method that can predict in vivo performance for a board range of drug products. In other words, no biorelevant dissolution method can exist without proving clinical relevancy.
A dissolution test to support clinically relevant acceptance criteria cannot be developed by the analytical dissolution group alone. It has to be a strong collaboration among analytical, formulation, and PK groups. The method development activities will follow development phasedependent strategies. The framework aligns with QbD concepts. The formulators may have to specially prepare some “unordinary samples” to see the impact from CMAs (critical material attributes) or CPPs (critical process parameters) on drug release behavior both in vivo and in vitro. The PK group designs biostudies and collects clinical data to establish the target profiles for the studied product and also collects the in vivo data for those unordinary samples for assessment. The analytical group selects the most appropriate dissolution testing conditions to match the “target dissolution profile” and compares the dissolution profiles of those unordinary samples to set the relevant specification. The efforts need strong links among multiple functional groups and good collaboration. The teams work together to consolidate all the findings and define the manufacturing “control space” (control strategy) to assure the quality of the product.
“Applying CQA Principles to Dissolution Method Development and Formulation Selection,” presented by Danna Mattocks ( Tergus P harma), w as a s ummary o f the outcome from the IVRDT CQA subteam discussions. The focus point of this presentation was to apply Quality by Design principles routinely to build quality into the dissolution test method. The first step is to identify the product CQAs (critical quality attributes), and this has to be a cross-functional collaboration among analytical, formulation, and biopharmaceutics groups. Typical examples of common formulation and manufacturing CQAs were presented. The use of suitable biorelevant dissolution techniques should be encouraged for formulation/process development, product understanding, identification of CQAs, and clinical continuity for all oral products.
For designing the test (i.e., method development strategy), it is needed to keep it in mind that the final QC method should be discriminatory based on product CQAs and optimized for the final formulation. The analytical CQAs (or CMAs, critical method attributes) need to be explored and identified for reliable and consistent method performance. A flowchart for identifying CMAs of typical formulations was presented. The consideration for other special cases/formulations (e.g., multicomponent, low potency, hydrophobic matrices products, and product with absorption issues) was also mentioned. This presentation was not considered a guiding reference but rather an initiative for further communications for improvement/refinement on this approach. IVRDT is seeking out expertise from wider AAPS membership.
Geoffrey Grove (Sotax) presented a summary of the dissolution technology subteam including a discussion of two open projects that the team is addressing: the dissolution vessel physical dimensions and the design of a paddle for biphasic dissolution. Regarding the dissolution vessel physical dimensions review, he reported that the subteam, which includes technology manufacturers from Agilent, Distek, Hanson, QLA, and SOTAX as well as a number of participants from pharmaceutical companies, has discussed the impact that vessel physical dimensions currently have on dissolution results. Regarding one aspect of the vessel physical dimensions, the inner diameter, the point was made that the current specification of 98-106 mm is not always quite so large and that this specification is larger than what the manufacturing community currently needs. The subteam is considering a study to look at this as well as other parameters to see whether a tightening of the specification could be accomplished and recommended to the USP. The team has met with and discussed this idea with the USP, and the USP has offered to have one of its in-house statisticians review the results of the future study. The subteam is also interested in including results for higher precision vessels typically made by vacuum forming. Currently there is no definition for what criteria define and differentiate a higher precision vessel, and the subteam is also beginning to discuss this topic. Regarding the design of a paddle for use in biphasic dissolution, the subteam is currently planning a feasibility study to determine the relationship between using paddles of different sizes versus running biphasic dissolution with no paddle stirring the upper organic layer. The results of this feasibility study may turn into a poster for the next AAPS annual meeting.
A presentation by Kailas Thakker (Tergus Pharma) focused on “Changing Regulatory Environment for IVRT Testing of Semisolid Formulations.” In vitro release testing, the methodology originally developed and primarily used for solid oral dosage forms, has expanded to a variety of “novel” or “complex” dosage forms including semisolids as drug delivery becomes more complex. She indicated that, based on her experience in Tergus over the last four years, IVRT has become a critical tool to understand the release characteristics of semisolid dosage forms with respect to a quality by design approach to product development. IVRT plays the role of a performance test for semisolid dosage forms to confirm the consistency in manufacturing. It is also required by SUPAC-SS to be used instead of clinical trials for certain levels of post-approval changes, as well as in biowaivers for generic products.
Dr. Thakker introduced the new USP Chapter <1724> Semisolid Drug Products—Performance Tests that recently became official. It describes the performance test of semisolid products, the apparatus to be used, guidance in developing IVRT with respect to the selection of key parameters, and recommendations on validation attributes and test parameters that should be validated. For topical dosage forms, three types of apparatus have been suggested by the chapter including vertical diffusion cell, the immersion cell, and the flow-through cell (USP 4). Different apparatus and procedures have different characteristics that are often specific to the dosage form category, formulation type, or even an individual product. The principal of the performance test is to determine the diffusion of active ingredient from the semisolid matrix across a membrane into an appropriate medium that should represent the clinical use of semisolid dosage form as closely as possible. The vertical diffusion cell has been a standard system in the industry and well applied to the study of semisolid drug formulations at Tergus. After she described the design of the vertical diffusion cell and its operation parameters, Dr. Thakker presented details on IVRT method development, method validation, and varieties of applications of IVRT methods during the development cycle.
During development of reproducible and robust IVRT methods for semisolid drug products, factors from both the API and formulation can affect drug release and need to be considered (e.g., the particle size of the API, the pH of API, the incorporation and solubility of API in semisolid matrix, the presence of emollients and penetration enhancers, the compatibility of excipients with API and with environmental agents such as moisture, gases). Formulation attributes such as viscosity, spreadability, overall pH, moisture content, and even the manufacturing process and site, can affect the drug release. Based on the experience at Tergus, hydrophobic petrolatum-based ointments present a substantial challenge to developing reproducible IVRT methods; the diffusion coefficients of hydrophobic molecules in solution are extremely low and the drug substance in suspension adds an additional challenge. In addition, many other considerations may be needed to allow greater drug release, including extended-release time frames (>24 h), surfactant-based receptor fluids, high ionic strength receptor fluids, solvent systems stronger than typical hydroalcoholic mixtures, membrane soaking with IPM or other solvents, membranes with greater pore sizes, and increased temperatures in the receiving chambers. According to Dr. Thakker, a number of unique and successful approaches to develop reproducible and robust IVRT methods have been established at Tergus for challenging semisolid drug products.
The application of IVRT methods has been beneficial during the development cycle of semisolid drug products, especially in the QbD grid to support product development. In the development phase, the IVRT is applied to the selection of an appropriate clinical candidate formulation and characterization of the dosage form. As a performance test, the robustness and discriminating ability of the IVRT method are critical, and enough data need to be generated to allow setting meaningful acceptance criteria and specifications. In the clinical phase, it is for monitoring and correlating the in vivo versus in vitro results and for further characterization of the final formulation. In the post-approval phase, it is a bioavailability/bioequivalence surrogate for justification of the changes in manufacturing site, composition, and manufacturing process. Dr. Thakker presented an actual case of the IVRT for a SUPAC-SS application. In this example, a post-approval change in formulation was made, and a new batch was manufactured after the change. Two six-cell runs were performed using the Franz cell system with a validated IVRT method. The slopes of drug release were calculated for each cell. The ratios of the slopes were further calculated and ranked. Because the results from the first-level runs did not meet the criteria, a second level of testing was triggered with four additional runs of six cells each. A total of 18 slopes for each batch was obtained, 324 T/R ratios were computed, and the ranked results fell within the criteria. The interesting IVRT presentation for the semisolid formulation attracted much attention from meeting attendees.
Dissolution testing for nonconventional dosage forms is an active area that facilitates the development of new drugs for unmet medical needs. Xujin Lu (Bristol- Myers Squibb) presented his exploratory work, “Use of Dissolution Testing in Simulated Saliva for Taste Masking Evaluation,” which focused on pediatric formulation development. It has been a regulatory requirement by both FDA and EMA to establish a pediatric study plan prior to NDA submission. But pediatric formulation development faces unique challenges. Besides ageappropriate dosing flexibility, accuracy, and safety, the palatability and patient compliance are especially important. The taste of medicines in oral dosage forms is a crucial factor that determines drug palatability. Incorporating taste-masking into the drug development process has become a general practice in the industry. A number of methodologies have been used for tastemasking, including the most popular ones using flavor enhancers and sweeteners. However, recent advances in polymer excipients have made polymer coatings an attractive choice for the purpose of taste-masking. An API coated with a functional polymer can prevent the release of unpleasant taste in the patient’s mouth and assist drug rapid release in the stomach. Selection of a suitable polymer compatible with the API requires many studies and experiments. Therefore, quick evaluation of the performance of the coated materials and the tastemasking efficiency is necessary.
Currently, evaluation of the taste primarily relies on in vivo testing using a human panel. Some in vitro methods using UV or HPLC have also been applied, but they still rely on the thresholds established by the human panel. Electronic tongue (E-Tongue) is another in vitro method designed to mimic biological taste recognition and to statistically classify the taste patterns. All these evaluations have limitations. The human panel test is time consuming and requires a specially trained panel or contractor. It has a high cost that is not economical for early formulation development and screening. The E-tongue test requires expensive instrumentation and an experienced operator. It does not test the drug release process, but tests fixed concentrations or specially prepared solutions.
In vitro release and dissolution has been explored as a fast and economic tool for characterization of taste-masked drugs in solid oral dosage forms. DI water and phosphate buffer (pH 6.8) with different volumes, incubation times, and arbitrary thresholds have been reported as the media. Studies have been conducted to evaluate the use of simulated saliva as the medium for biorelevant dissolution tests of taste-masking. In this presentation, Dr. Lu presented his research and results from testing using simulated saliva for tablets and granules samples made by using polymer-coating technology for tastemasking. He indicated that the preliminary studies and results demonstrate great potential for biorelevant in vitro dissolution for taste-masking assessment. The tastemasked drugs may behave differently in phosphate buffer and simulated saliva. As a biorelevant medium, simulated saliva mimics the condition of the drug delivery route. It can be used to enhance the predictive capability of the dissolution test. Testing for in-house coated API samples using simulated saliva provided useful information in support of the coating process development. Further study and application of the biorelevant in vitro assessment for taste-masking are anticipated so that a reliable and standardized procedure can be established.
A summary of AAPS 2015 Sunrise Session on “Systematic Design of In Vitro Testing Methods for Drug Product Development” was presented by Danna Mattocks (Tergus Pharma) for Alger Salt (GSK). The intended outcome of this session was the beginning of a dialog that would lead to agreement and better understanding between the pharmaceutical industry and regulatory agencies in terms of appropriate strategies for developing adequate test methods. It was focused on identifying strategies and best practices for developing in vitro test methods that are appropriate and will ultimately benefit the patient. Around 100 attendees participated in discussions with the speakers.
The speakers and presentations were Dr. Sandra Suarez (FDA/OPQ/ONDP) on “Strategies for Developing Dissolution Test Methods Fitted for Purpose—QbD Case Studies” and Danna Mattocks (Tergus Pharma) on “A Strategy for Dissolution Method Development: A Risk-Based QbD Approach.” Dr. Suarez talked about the purpose for QbD in the pharmaceutical industry, the role of QbD in developing dissolution test methods, and how to use a QbD approach to develop a design space. She stressed that using an unsuitable dissolution method could lead to defining a design space that is not fit for the purpose. She presented case studies to illustrate the advantage of integrating biopharmaceutics tools in the early phase of drug development (QbD based) and the use of in silico modeling and simulation as an aid in developing a suitable dissolution method. Ms. Mattocks presented the basic concept for dissolution method development strategy following the risk-based QbD approach. She pointed out the key elements including identification of both product and method critical attributes, systematic risk assessment, analysis of dissolution results from stretch batches, dissolution profile modeling (a case study), and implications of the DMDS.
Questions and comments at the session were: Can we have separate methods for biorelevance and for QC/ Stability? Can a biopredictive method (based on failed BE data) be used to guide in the selection of the CMAs and CPPs? How to handle supersaturation? Some participants asserted that PBPK modeling is not ready for prime time (e.g., to guide the selection of a biopredictive dissolution method) and that more research is needed to account for variability on the data. More discussion is definitely needed for all these questions.
Global regulatory requirements for dissolution profile similarity divergence are on the rise. During AAPS 2015, a sunrise session exploring “Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations?” had been held. Dorys Argelia Diaz (Pfizer), the sunrise session organizer, shared the key highlights from this session, which was designed to stimulate discussion on the regulatory requirements to meet country-specific regulatory expectations for dissolution profile similarity assessment, to present industry perspectives on challenges and opportunities, and to advance the discussion on the importance of harmonization of dissolution requirements. The rising challenge of global suitability of studies using f2 to compare dissolution profiles was discussed as well as the proliferation of countryspecific bioequivalence guidelines. Vivian Gray (V.A. Gray Consulting, Inc.) presented “In Vitro Equivalence— Is Harmonization Possible?” that focused on the necessity to harmonize dissolution guidance to enable timely access to medicines. She discussed the globally divergent regulatory requirements for bioequivalence, multipurpose dissolution guidances, and the complexity of global dissolution filing strategies, along with the impact on research, innovation, and access to medicines. She provided business case examples along with a powerful analysis of the multipurpose applicability of dissolution guidance explaining how complexity increases when referral to various guidance documents (e.g., method development, post-approval changes, biowaiver for additional strengths) is needed. She finished her presentation highlighting how the similarity f2 statistical comparison is accepted globally, but how subtle differences in country-to-country criteria and a proliferation of new countries with similarity requirement guidances are observed. Ganapathy Mohan (Merck) began his presentation with the drivers for developing a dissolution method including regulatory requirements, QC test, surrogate for in vivo release testing, and support of clinically relevant specifications. He discussed in detail specification setting as well as the current struggle associated with accelerating timelines and incomplete understanding of manufacturing processes and dissolution methods. He also highlighted the risk of not meeting f2 for post-approval changes and the significant dissolution related queries received from health authorities, especially FDA and EMA. Dr. Mohan shared a summary of dissolution queries related to specification setting Q, dissolution discriminating capability, the use of enzymes, surfactant selection and justification, rotation speed, f2 calculation, and reporting format. He concluded by emphasizing the importance of clinically relevant specifications, and encouraged a dialog toward harmonization of dissolution requirements. During the IVRDT face-to-face meeting, Dorys Diaz summarized the efforts that have been initiated to address the technical and regulatory gaps identified by the speakers. She also reported the other steps initiated toward raising awareness of dissolution guidance harmonization efforts including publications, posters, and the AAPS sunrise session. For further action, Dorys pointed to the identification of other dissolution requirements that need to be harmonized and the potential regulatory challenges that should be considered, and the initiation of collaboration among industry, academia, health authorities, and ICH.
The F2F meeting ended with a brainstorming session on the programs that the Focus Group wanted to propose for the AAPS 2016 Annual Meeting. There were 21 attendees, and the discussions were spirited and fruitful. Xujin thanked the participants and closed the meeting with the promise of another F2F in the near future.
AAPS Focus Group Speakers (left to right): Jian-Hwa Han, Greg Martin, Donna Mattocks, Dorys Diaz, Geoff Grove, Kailas Thakker, and Xujin Lu.