Developing Clinically Relevant Dissolution Specifications (CRDSs) for Oral Drug Products: Virtual Webinar Series.

A webinar series that was organised by the Academy of Pharmaceutical Sciences Biopharmaceutics focus group in 2021 focused on the challenges of developing clinically relevant dissolution specifications (CRDSs) for oral drug products. Industrial scientists, together with regulatory and academic scientists, came together through a series of six webinars, to discuss progress in the field, emerging trends, and areas for continued collaboration and harmonisation. Each webinar also hosted a Q&A session where participants could discuss the shared topic and information. Although it was clear from the presentations and Q&A sessions that we continue to make progress in the field of CRDSs and the utility/success of PBBM, there is also a need to continue the momentum and dialogue between the industry and regulators. Five key areas were identified which require further discussion and harmonisation.

The Use of Physiologically Based Pharmacokinetic Analyses-in Biopharmaceutics Applications -Regulatory and Industry Perspectives.

The use of physiologically based pharmacokinetic (PBPK) modeling to support the drug product quality attributes, also known as physiologically based biopharmaceutics modeling (PBBM) is an evolving field and the interest in using PBBM is increasing. The US-FDA has emphasized on the use of patient centric quality standards and clinically relevant drug product specifications over the years. Establishing an in vitro in vivo link is an important step towards achieving the goal of patient centric quality standard. Such a link can aid in constructing a bioequivalence safe space and establishing clinically relevant drug product specifications. PBBM is an important tool to construct a safe space which can be used during the drug product development and lifecycle management. There are several advantages of using the PBBM approach, though there are also a few challenges, both with in vitro methods and in vivo understanding of drug absorption and disposition, that preclude using this approach and therefore further improvements are needed. In this review we have provided an overview of experience gained so far and the current perspective from regulatory and industry point of view. Collaboration between scientists from regulatory, industry and academic fields can further help to advance this field and deliver on promises that PBBM can offer towards establishing patient centric quality standards.

Current Approaches for Dissolution Similarity Assessment, Requirements, and Global Expectations.

This report summarizes podium presentations and breakout sessions from the second day of the 2019 M-CERSI workshop on In Vitro Dissolution Similarity Assessment in Support of Drug Product Quality: What, How, and When? Presenters from the U.S. Food and Drug Administration (FDA), Health Canada (HC), European Medicines Agency (EMA), Brazilian Health Surveillance Agency (ANVISA), and the pharmaceutical industry shared experiences/concerns with dissolution profile similarity assessment supporting minor/moderate Chemistry, Manufacturing and Control (CMC) changes. Members from regulatory agencies explained that dissolution profile similarity testing is only part of the overall assessment of the acceptability of the proposed changes; decisions are usually made based on aggregate weight of evidence. Scientific shortcomings of f2 were highlighted but no proposal on how to replace it was made. Controlling dissolution timepoint variability and application of pairwise batch-to-batch comparisons (PBC) of dissolution profiles caused considerable debate. Several industry participants suggested increased sample sizes to raise confidence in decision-making and to avoid PBC. They proposed identification of a single mathematical method with predefined acceptance criteria and suggested that dissolution timepoint selection should follow EMA and HC guidance. A majority of meeting attendees favored applying clinically relevant dissolution specifications (CRDS) and dissolution safe space to determine the impact of minor/moderate CMC changes as opposed to dissolution profile similarity assessment via statistical methods. Day 2 of the workshop highlighted the need and opportunities for global harmonization including variability, timepoint selection, role of CRDS, and statistical methods to address the ambiguity globally operating pharmaceutical companies are currently facing.

Understanding In Vivo Dissolution of Immediate Release (IR) Solid Oral Drug Products Containing Weak Acid BCS Class 2 (BCS Class 2a) Drugs.

In vivo drug dissolution kinetics of BCS Class 2a IR solid oral drug products remains largely unknown. An understanding to what extent the solubility influences in vivo dissolution is needed to design appropriate in vitro dissolution methods. In this study, nonsteroidal anti-inflammatory drugs (NSAIDs) are used to investigate the in vivo dissolution of BCS Class 2a drugs based on numerical deconvolution analyses. The PK data were obtained from published literature or drug applications submitted to the FDA. It has been hypothesized that the in vivo drug dissolution rate would likely correlate to the solubility of NSAIDs in the media at gastrointestinal pH. Our findings show a short lag time of absorption (Tlag), comparable to the liquid gastric emptying time and independent of the solubility and formulation. In Vivo drug dissolution of NSAIDs was generally rapid and complete within the regular drug residence time in the small intestine while multi-phase absorption was observed in some subjects for all the NSAIDs. The comparisons of in vivo drug dissolution rate, which was characterized by in vivo dissolution half-life (Thalf), indicate that solubility has a minimal impact on in vivo drug dissolution rate for NSAIDs. Gastric emptying regulated by migrating motor complex (MMC) under fasted state most likely governs drug dissolution and absorption of NSAIDs. For BCS Class 2a IR solid oral drug products, large variability of gastric emptying and MMC as well as the strong driving force of intestinal absorption probably outweigh the impact of solubility on drug in vivo dissolution.

Applications of Physiologically Based Biopharmaceutics Modeling (PBBM) to Support Drug Product Quality: A Workshop Summary Report.

This report summarizes the proceedings for Day 3 of the workshop titled "Current State and Future Expectations of Translational Modeling Strategies toSupportDrug Product Development, Manufacturing Changes and Controls". From a drug product quality perspective, patient-centric product development necessitates the development of clinically relevant drug product specifications (CRDPS). In this regard, Physiologically Based Biopharmaceutics modeling (PBBM) is a viable tool to establish links between in-vitro to in-vivo data, and support with establishing CRDPS. The theme of day 3 was practical applications of PBBM to support drug product quality. In this manuscript, case studies from US FDA, EMA and pharmaceutical industry on applications of PBBM in drug product quality are summarized which include 1) regulatory agency's perspectives on establishing the safe space and achieving study waivers, 2) model-informed risk assessment on the effects of acid reducing agents, bridging of dissolution methods, food effect, and formulation selection, and 3) understanding clinical formulation performance. Breakout session discussions focused on four topics - 1) terminologies related to physiologically based modeling in support of drug product quality, 2) regulatory harmonization on evidentiary standards, 3) CRDPS approaches and 4) bridging between biorelevant and quality control (QC) dissolution methods.

In vitro Approaches to Support Bioequivalence and Substitutability of Generic Proton Pump Inhibitors via Nasogastric Tube Administration.

Administration of proton pump inhibitors (PPIs) through nasogastric tubes may present risks. If the PPI drug products are not prepared properly, clogging or obstruction of nasogastric tubes can pose a safety concern. In addition, the integrity of the enteric coating of the drug product may be damaged resulting in reduced bioavailability of the active moiety. From the perspective of administration of generic PPIs when compared to the reference drug product, differences in formulation can potentially result in a greater relative risk for the generic drug product. As part of the assessment of bioequivalence, the Office of Generic Drugs (OGD) has developed a suite of in vitro testing to compare the delivery of the generic and reference products via nasogastric tubes. These in vitro tests assess essential attributes associated with the likelihood of clogging and maintenance of the enteric coating. These in vitro tests include studies evaluating sedimentation, granule size distribution, drug recovery, and acid resistance. One of the challenges is that while the administration of PPIs through nasogastric tubes is common in clinical practice, this issue is not uniformly addressed in the FDA approved label of the reference drug products. This paper discusses the design and rationale for in vitro testing of PPI formulations with respect to bioequivalence via nasogastric tube administration and in addition, it summarizes commonly occurring deficiencies in the in vitro nasogastric tube testing of 14 recent Abbreviated New Drug Applications (ANDA) submitted for five generic PPI drug products.

Statistics on BCS classification of generic drug products approved between 2000 and 2011 in the USA.

The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Essential Medicines to determine the distribution of BCS Class 1, 2, 3, and 4 drugs in Abbreviated New drug Applications (ANDA) submissions. To categorize solubility and intestinal permeability properties of generic drugs under development, we used a list of 61 drugs which were classified as BCS 1, 2, 3, and 4 drugs with certainty in the World Health Organization Model List of Essential Medicines. Applying this list to evaluation of 263 ANDA approvals of BCS drugs during the period of 2000 to 2011 indicated 110 approvals (41.8%) for Class 1 drugs (based on both biowaiver and in vivo bioequivalence studies), 55 (20.9%) approvals for Class 2 drugs, 98 (37.3%) approvals for Class 3 drugs, and no (0%) approvals for Class 4 drugs. The present data indicated a trend of more ANDA approvals of BCS Class 1 drugs than Class 3 or Class 2 drugs. Antiallergic drugs in Class 1, drugs for pain relief in Class 2 and antidiabetic drugs in Class 3 have received the largest number of approvals during this period.

Controlled release of modified insulin glargine from novel biodegradable injectable gels.

The objective of this study was to investigate the duration of biological effects of modified insulin glargine released from a novel biodegradable injectable gel in type II diabetic Zucker diabetic fatty (ZDF) rats. Modified insulin glargine was purified from the marketed formulation by process of dialysis followed by freeze-drying, and the purity was confirmed by the single peak, corresponding to insulin glargine in the HPLC chromatogram. To determine and to compare the biological activity of purified insulin glargine with marketed formulation, it was suspended in isotonic saline solutions and administered subcutaneously to ZDF rats at a dose of 10 IU/kg of insulin and the blood glucose levels were measured. The blood glucose levels of ZDF rats after a subcutaneous injection of a suspension of purified insulin glargine decreased below 200 mg/dL within 2 h and remained at this level up to 6 h, then steadily raised above 400 mg/dL in 12 h. Insulin glargine particles were loaded into a novel biodegradable injectable gel formulation prepared from a blend of polylactic-co-glycolic acid (PLGA) and biocompatible plasticizers. Approximately 0.1 mL of insulin glargine-loaded gel prepared with PLGA was administered subcutaneously to the ZDF rats, and blood glucose levels were measured. The PLGA gel formulations prepared with insulin glargine particles had duration of action of 10 days following a single subcutaneous injection. The addition of zinc sulfate to the formulations prepared with purified insulin glargine particles further slowed down the drop in blood glucose concentrations.

Dissolution testing for generic drugs: an FDA perspective.

In vitro dissolution testing is an important tool used for development and approval of generic dosage forms. The objective of this article is to summarize how dissolution testing is used for the approval of safe and effective generic drug products in the United States (US). Dissolution testing is routinely used for stability and quality control purposes for both oral and non-oral dosage forms. The dissolution method should be developed using an appropriate validated method depending on the dosage form. There are several ways in which dissolution testing plays a pivotal role in regulatory decision-making. It may be used to waive in vivo bioequivalence (BE) study requirements, as BE documentation for Scale Up and Post Approval Changes (SUPAC), and to predict the potential for a modified-release (MR) drug product to dose-dump if co-administered with alcoholic beverages. Thus, in vitro dissolution testing plays a major role in FDA's efforts to reduce the regulatory burden and unnecessary human studies in generic drug development without sacrificing the quality of the drug products.

A randomized, open-label, controlled trial of gabapentin and phenobarbital in the treatment of alcohol withdrawal.

Gabapentin was compared with phenobarbital for the treatment of alcohol withdrawal in a randomized, open-label, controlled trial in 27 inpatients. There were no significant differences in the proportion of treatment completers between treatment groups or the proportion of patients in each group requiring rescue medication for breakthrough signs and symptoms of alcohol withdrawal. There were no significant treatment differences in withdrawal symptoms or psychological distress, nor were there serious adverse events. These findings suggest that gabapentin may be as effective as phenobarbital in the treatment of alcohol withdrawal. Given gabapentin's favorable pharmacokinetic profile, further study of its effectiveness in treating alcohol withdrawal is warranted.