Assessing the Relevance of Solution Phase Stress Testing of Solid Dosage Form Drug Products: A Cross-Industry Benchmarking Study

Stress testing (also known as forced degradation) of pharmaceutical products has long been recognized as a critical part of the drug development process, providing foundational information related to intrinsic stability characteristics and to the development of stability-indicating analytical methods. A benchmarking study was undertaken by nine pharmaceutical companies and the Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária, or ANVISA) with a goal of understanding the utility of various stress testing conditions for producing pharmaceutically-relevant chemical degradation of drugs. Special consideration was given to determining whether solution phase stress testing of solid drug products produced degradation products that were both unique when compared to other stress conditions and relevant to the formal drug product stability data. The results from studies of 62 solid dosage form drug products were compiled.  A total of 387 degradation products were reported as being observed in stress testing studies, along with 173 degradation products observed in accelerated and/or long-term stability studies for the 62 drug products.  Among these, 25 of the stress testing degradation products were unique to the solution phase stress testing of the drug products; however, none of these unique degradation products were relevant to the formal stability data. The relevant degradation products were sufficiently accounted for by stress testing studies that included only drug substance stressing (in solution and in the solid state) and drug product stressing (in the solid state). Based on these results, it is the opinion of the authors that for solid dosage form drug products, well-designed stress testing studies need not include solution phase stress testing of the drug product in order to be comprehensive.     

Pharmaceutical technology, biopharmaceutics and drug delivery

The 40th annual international conference of the Korean Society of Pharmaceutical Sciences and Technology on Pharmaceutical Technology, Biopharmaceutics and Drug Delivery was held on 2-3 December 2010 in Jeju Special Self-Governing Providence, Korea, to celebrate its 40th anniversary. A comprehensive review of a wide spectrum of recent topics on pharmaceutical technology, biopharmaceutics and drug delivery was presented. Invited lectures and poster presentations over 2 days were divided into six parallel sessions covering areas such as biotechnology, biopharmaceutics, drug delivery, formulation/manufacture, regulatory science and frontier science. Among these, there were two sessions related to regulatory science and biopharmaceutics that were co-sponsored by the Korea Food and Drug Administration. In fact, this conference provided an opportunity for many investigators to discuss their research, collect new information and to promote the advancement of knowledge in each pharmaceutical area. This conference report summarizes the keynote podium presentations provided by many distinguished speakers, including Gordon L Amidon of the University of Michigan.     

Prodrugs: effective solutions for solubility, permeability and targeting challenges

This 2-day inaugural conference on prodrugs was presented by Pharmaceutical Education Associates and covered recent developments in prodrug techniques to solve delivery and targeting issues in drug discovery and development. The speakers were drawn from industry and academia, and the conference was attended mostly by researchers working in the pharmaceutical and biotechnology industries. A number of topics were presented at the conference, from basic prodrug design and functional group considerations to drug metabolism involving cytochrome P450 enzymes, from increasing water solubility, bioavailability, permeability and stability to tumor targeting, from the development of new anti-inflammatory agents to anti-HIV agents, and from the use of transporters and receptor-mediated endocytosis in prodrug delivery to the use of gene therapy for enzyme delivery to cancer cells and tissues. Several case studies were presented including improved pharmaceutical products in the clinic and at various stages of development.     

Japan-Specific Key Regulatory Aspects for Development of New Biopharmaceutical Drug Products

Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies.     

The Degradation Map Process – A Tool for Obtaining a Lean Stability Strategy in Drug Development

Stability is fundamental when exploring a drug candidate's potential as a drug product. During the pharmaceutical industry drug development process information regarding stability and degradation are captured in different departments, e.g. from discovery to operations, and will be included in the overall control strategy. With a profound understanding of a drug candidate's degradation chemistry, a science and risk based approach in progressing a lean stability strategy is possible. This case study present a clear and visible concept to facilitate a lean stability strategy by the use of degradation maps and describes a process for how these can be used during drug development. The understanding of possible and/or observed degradation pathways will guide the design of the drug product and stability studies in development. A degradation map displays degradation pathways with short comments on the reaction/mechanism involved. The degradation map process starts with a theoretical degradation map. The map is updated as the drug project progresses, preferably after forced degradation experiments, after compatibility studies and finally when the late stage formulation is set. The degradation map should be used to capture information of intrinsic chemical properties of the active pharmaceutical ingredient (API) and can thereby be used to mitigate stability issues. The map is foremost a cross-functionally available tool collecting and visualizing stability information throughout the development process, and as such a valuable tool to efficiently develop a lean stability strategy.     

Statistical evaluation for stability studies under stress storage conditions.

During the pharmaceutical development of a new drug, it is necessary to select as soon as possible the formulation with the best stability characteristics. The current International Commission for Harmonisation (ICH) regulations regarding stability testing requirements for a Registration Application provide the stress testing conditions with the aim of assessing the effect of severe conditions on the drug product. In practice, the well-known Arrhenius theory is still used to make a rapid stability prediction, to estimate a drug product shelf life during early stages of its pharmaceutical development. In this work, both the planning of a stress stability study to obtain a correct stability prediction from a temperature extrapolation and the suitable data treatment to discern the reliability of the stability results are discussed. The study was focused on the early formulation step of a very stable drug, Mitonafide (antineoplastic agent), formulated in a parenteral solution and in tablets. It was observed, for the solid system, that the extrapolated results using Arrhenius theory might be statistically good, but far from the real situation if the stability study is not designed in a correct way. The statistical data treatment and the stress-stability test proposed in this work are suitable to make a reliable stability prediction of different formulations with the same drug, within its pharmaceutical development.     

Pharmaceutical impurities: regulatory perspective for Abbreviated New Drug Applications

Impurities in drug substances and drug products have been important regulatory issues in the Office of Generic Drugs by having significant impact on the approvability of Abbreviated New Drug Application (ANDAs). This review begins with a discussion of ANDAs and its similarity/differences with NDAs, highlighting the importance of control of pharmaceutical impurities in generic drug product development and regulatory assessment. An overview of the FDA draft guidance documents "ANDAs: Impurities in Drug Substances" and "ANDAs: Impurities in Drug Products" are provided. This introduces the identification and qualification procedures for ANDAs and approaches to the establishment of acceptance criteria for both drug substance and drug product. Case studies included in this review illustrate the proposed pathway for determination of impurities and their acceptance criteria, based upon the general principles of these guidances.     

Risk Management in the Pharmaceutical Product Development Process

“The manufacture and use of a drug product, including its components, necessarily entail some degree of risk.”—International Conference for Harmonization (ICH) Q9. This paper examines the role of risk management in pharmaceutical product development in the context of patient safety and drug efficacy. Its objective is to contribute to building a common understanding of this quality risk management among the various functional groups involved in developing, testing, manufacturing, and approving of drug products within pharmaceutical companies and regulatory agencies. Selected aspects of drug substance and drug product development are used to demonstrate principles of risk management in action and presented as case studies.     

Best Practices for Drug Substance Stress and Stability Studies During Early-Stage Development Part I—Conducting Drug Substance Solid Stress to Support Phase Ia Clinical Trials

Regulatory guidances for drug stability testing during early development stages lack specifics. Consequently, companies either conduct more stability studies than necessary just to avoid regulatory questions or perform insufficient stability work resulting in regulatory questions and delays in drug development. Hence, there exist a pressing need and a great opportunity for pharmaceutical companies to share drug stability testing practices, rationales, and regulatory experiences for the early stages of development. This paper describes a quick, streamlined solid stress practice to support drug development from pre-clinical to Phase Ia Clinical Trials. By subjecting a few grams of drug substance to high temperature and high humidity (e.g., 70?°C/75?% RH, in open and closed containers, for three weeks) and to the ICH Q1B confirmatory photostability testing condition, the initial DS retest period and the initial shelf life of powder for oral solution can be reliably extrapolated, and a bulk packaging choice is made. In addition, the solid stress results can be used for multifaceted purposes. The solid stress practice offers a quick turnaround in obtaining adequate stability information for new drug development and achieves an optimum balance between risk and cost for Phase Ia clinical development.     

Evaluation of the microbial growth potential of pharmaceutical drug products and quality by design

The microbial growth potential of a pharmaceutical drug product refers to the ability of microorganisms to survive and proliferate in the product. Each drug formulation possesses a different potential for supporting or inhibiting microbial growth. Understanding this microbial growth potential can have a significant effect on the development and design of the drug manufacturing process. This article describes how this attribute can exert this effect on manufacturing process development and design through real examples and case studies obtained from the regulatory review of new drug and biologics license applications. In addition, this article describes how understanding the microbial growth potential of a pharmaceutical drug product is an element of the Quality by Design paradigm and how this understanding can simplify the drug development process and lead to better process design. LAY ABSTRACT: The microbial growth potential of a pharmaceutical drug product refers to the ability of microorganisms to survive and proliferate in the product formulation. Each drug product formulation possesses a different potential for supporting or inhibiting microbial growth depending on its components. Understanding this microbial growth potential can have a significant effect on the development and design of the drug manufacturing process. This article describes how this attribute can affect manufacturing process development and design through real examples and case studies obtained from the regulatory review of new drug and biologics license applications. In addition, this article describes how understanding the microbial growth potential of a pharmaceutical drug product is an element of the Quality by Design paradigm and how this understanding can simplify the drug development process and lead to better process design.     

强制降解试验在药物研发中的应用

目的 阐述强制降解试验研究现状,汇总各强制降解试验基本条件,为药物研发提供借鉴和参考。方法 汇总实际工作和文献中药物降解基本方法,分析药品注册申报各阶段对降解研究的要求。结果 现阶段各国监管机构没有提出统一明确的强制降解试验条件,药物的降解条件与药物分子结构及制剂处方相关。结论 强制降解研究可以帮助确定药物的降解途径并解析降解产物,为药物安全性和毒理学研究提供支持,也为稳定性指示分析方法、药物处方、包装选择和储存条件的开发提供支持。从药物研发早期到后期,强制降解需要不断完善。     

Non-clinical Post-Marketing Commitments for newly licenced pharmaceuticals

There are clear minimum requirements for non-clinical (toxicology) studies which are needed prior to human exposure to a potential new pharmaceutical and additional studies are needed in an ongoing manner to support clinical development and marketing [ICH, 2009. ICH M3(R2) Non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (CPMP/ICH/286/95). Adopted June 2009, effective December 2009.] The pharmaceutical industry is under increasing pressure to reduce costs and reduce, refine and replace the use of animals, as far as possible. Hence any increase in regulatory requirements for non-clinical safety data could have a significant impact both on the economic and ethical considerations of drug development. It is, therefore, of interest that further non-clinical studies are required by the Regulatory Authorities for a small but increasing proportion of drug product applications at the marketing approval/data review stage. These studies are known as Post-Marketing Commitments (PMCs).     

Clinical pharmacogenomics: applications in pharmaceutical R&D

Within the pharmaceutical industry, the application of clinical pharmacogenomics promises to enhance the discovery of drug response markers, reduce the size and expense of clinical drug trials and provide a new tool for addressing regulatory approval issues. Today, pharmacogenomics is primarily applied early in clinical drug development by prospective genotyping in Phase I trials, to ensure that a subject population is representative with respect to drug metabolism phenotypes. The banking of genetic material from later stage trials for retrospective studies on drug response is becoming more frequent, but is not yet standard in the industry. This article provides an overview of the driving forces that are encouraging pharmacogenomic strategy development in the pharmaceutical industry, and the significance of polymorphisms in drug metabolizing enzymes (DMEs) and target proteins.     

Establishing bioequivalence for inhaled drugs; weighing the evidence

INTRODUCTION: During drug development and product life-cycle management, it may be necessary to establish bioequivalence between two pharmaceutical products. Methodologies to determine bioequivalence are well established for oral, systemically acting formulations. However, for inhaled drugs, there is currently no universally adopted methodology, and regulatory guidance in this area has been subject to debate. AREAS COVERED: This paper covers the current status of regulatory guidance on establishing the bioequivalence of topically acting, orally inhaled drugs, the value and limitations of in vitro and in vivo bioequivalence testing, and the practical issues associated with various approaches. The reader will gain an understanding of the issues pertaining to bioequivalence testing of orally inhaled drugs, and the current status of regulatory approaches to establishing bioequivalence in different regions. EXPERT OPINION: Establishing bioequivalence of inhaled drug products involves a multistep process; however, methodologies for each step have yet to be fully validated. Our lack of understanding about the relationship between in vitro, in vivo and clinical data suggests that in most cases, unless there is a high degree of pharmaceutical equivalence between the test and reference products, consideration of a combination of preclinical and clinical data may be preferable to abridged approaches relying on in vitro data alone.     

Manufacturer's drug interaction and postmarketing adverse event data: what are appropriate uses?

Governmental agencies overseeing pharmaceutical products use a risk/benefit approach to analyse data and make regulatory decisions. Comprehensive public dissemination of the safety profile of pharmaceutical products is part of an overall strategy for reducing risk associated with the use of any medical product. In the US, reports of postmarketing surveillance of approved drugs are in the public domain. Some, but not all, of the information in drug interaction studies is available to the public through the Freedom of Information Act (FOIA). However, there are concerns over the misuse of these data for commercial or other gain. The need to protect intellectual property and foster innovation in drug development, and concerns of legal liability are often cited as reasons to limit full public access to data from drug development studies. In contrast, intellectual freedom. public safety, and a mandate for transparent decision-making processes by regulatory agencies are issues that support open access to these data. Ultimately. concern for the public safety justifies open access to postmarketing surveillance data, and to a lesser degree, data regarding drug interactions in marketed products, and should outweigh the potential loss of competitive advantage by pharmaceutical companies.     

Four decades of modern pharmacogenomics: from promise to clinical utility. World PGX Summit 2011. Boston, USA, 26-27 April, 2011

The World PGX Summit was held in Boston and preceded by a 1-day workshop. The conference aimed at assessing the current 'state-of-the art' in advanced molecular profiling strategies for increased drug development success. The topics varied from regulatory policies, pharmaceutical case examples and vendor presentations on innovative technologies. The subject is obviously closely related to personalized medicine and it was interesting to hear the perspectives from healthcare providers and subscribers. It became clear during the meeting that we are on the verge of important changes in how pharmaceutical research and development operates but also how increased costs and high unmet medical needs require new models in which pharmacogenomics can play an important role.     

Regulatory framework on bioequivalence criteria for locally acting gastrointestinal drugs: the case for oral modified release mesalamine formulations

Introduction: Bioequivalence testing for locally acting gastrointestinal drugs is a challenging issue for both regulatory authorities and pharmaceutical industries. The international regulatory framework has been characterized by the lack of specific bioequivalence tests that has generated a negative impact on the market competition and drug use in clinical practice.

Areas covered: This review article provides an overview of the European Union and United States regulatory frameworks on bioequivalence criteria for locally acting gastrointestinal drugs, also discussing the most prominent scientific issues and advances that has been made in this field. A focus on oral modified release mesalamine formulations will be also provided, with practical examples of the regulatory pathways followed by pharmaceutical companies to determine bioequivalence.

Expert commentary: The development of a scientific rationale to demonstrate bioequivalence in this field has been complex and often associated with uncertainties related to scientific and regulatory aspects. Only in recent years, thanks to advanced knowledge in this field, the criteria for bioequivalence assessment are undergoing substantial changes. This new scenario will likely result in a significant impact on pharmaceutical companies, promoting more competition through a clearer regulatory approach, conceived for streamlining the demonstration of therapeutic equivalence for locally acting gastrointestinal drugs.     

The role of degradant profiling in active pharmaceutical ingredients and drug products

Forced degradation studies are used to facilitate the development of analytical methodology, to gain a better understanding of active pharmaceutical ingredient (API) and drug product (DP) stability, and to provide information about degradation pathways and degradation products. In order to fulfill development and regulatory needs, this publication provides a roadmap for when and how to perform studies, helpful tools in designing rugged scientific studies, and guidance on how to record and communicate results.     

A Tutorial for Developing a Topical Cream Formulation Based on the Quality by Design Approach

The pharmaceutical industry has entered in a new era, as there is a growing interest in increasing the quality standards of dosage forms, through the implementation of more structured development and manufacturing approaches. For many decades, the manufacturing of drug products was controlled by a regulatory framework to guarantee the quality of the final product through a fixed process and exhaustive testing. Limitations related to the Quality by Test system have been widely acknowledged. The emergence of Quality by Design (QbD) as a systematic and risk-based approach introduced a new quality concept based on a good understanding of how raw materials and process parameters influence the final quality profile. Although the QbD system has been recognized as a revolutionary approach to product development and manufacturing, its full implementation in the pharmaceutical field is still limited. This is particularly evident in the case of semisolid complex formulation development. The present review aims at establishing a practical QbD framework to describe all stages comprised in the pharmaceutical development of a conventional cream in a comprehensible manner.     

6th Annual Bioanalysis in Clinical Research conference

The 6th Annual Bioanalysis in Clinical Research conference held recently in London, UK, targeted numerous themes of significant current interest within the discipline of bioanalysis. The conference invited a diverse speaker panel and attracted an audience consisting of researchers from the pharmaceutical industry, CROs and academia. The range of topics presented covered LC-MS and ligand-binding assays, small- and large-molecule quantification, regulatory issues and concerns and new technologies. Within the scope of LC-MS bioanalysis, presentation topics included new developments in dried blood spot technologies, the use of direct analysis MS techniques, eliminating matrix effects through direct-electron ionization MS, and the complications of developing and validating LC-MS methods for the quantitative determination of endogenous biomarkers. With respect to ligand binding, the importance of assay validation being a continuous process, extending into study analysis, was a recurrent theme in several presentations along with the hot topic of immunogenicity. Of relevance to both analytical disciplines were the presentations on regulatory topics covering the EMA guidelines on method validation and bioanalysis within bioequivalence clinical studies.