Oral Dosage Form Performance Tests: New Dissolution Approaches

No Heading The performance test is one of a series of tests that compose the specification in a United States Pharmacopeia (USP) dosage form monograph. For an orally administered, nonsolution dosage form, it is usually satisfied by either a dissolution or disintegration procedure. Dissolution acceptance criteria are usually set in private negotiations between an applicant and a regulatory agency. With information about this private agreement and other information provided in a sponsors Request for Revision to USP, the USPs Council of Experts elaborates a public dosage form monograph. Based on the relationship between the regulatory decisions and the Request for Revision, the USP dissolution procedure links to a regulatory judgment about bioavailability and bioequivalence and, ultimately, to a judgment about safety and efficacy. The current dissolution procedure and acceptance criteria are perceived as having worked well over the years and are generally accepted. This article discusses new approaches that merit consideration. These approaches focus on a) explicit use of hypothesis testing, b) use of parametric tolerance intervals, c) improved ways to set dissolution acceptance criteria, and d) a more flexible protocol to assess conformity. Application of the proposed approaches may better assess, manage, and communicate both manufacturer and consumer risk for dissolution testing.     

Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution

Abstract

This article reviews the current legislative requirements for risk assessment of combined exposure to multiple chemicals via multiple exposure routes, focusing on human health and particularly on food-related chemicals. The aim is to identify regulatory needs and current approaches for this type of risk assessment as well as challenges of the implementation of appropriate and harmonized guidance at international level. It provides an overview of the current legal requirements in the European Union (EU), the United States and Canada. Substantial differences were identified in the legal requirements for risk assessment of combined exposure to multiple chemicals and its implementation between EU and non-EU countries and across several regulatory sectors. Frameworks currently proposed and in use for assessing risks from combined exposure to multiple chemicals via multiple routes and different durations of exposure are summarized. In order to avoid significant discrepancies between regulatory sectors or countries, the approach for assessing risks of combined exposure should be based on similar principles for all types of chemicals. OECD and EFSA identified the development of harmonized methodologies for combined exposure to multiple chemicals as a key priority area. The Horizon 2020 project “EuroMix” aims to contribute to the further development of internationally harmonized approaches for such risk assessments by the development of an integrated test strategy using in vitro and in silico tests verified for chemical mixtures based on more appropriate data on potential combined effects. These approaches and testing strategies should be integrated in a scientifically based weight of evidence approach to account for complexity and uncertainty, to improve risk assessment.     

Moving beyond the comprehensive in vitro proarrhythmia assay: Use of human‐induced pluripotent stem cell‐derived cardiomyocytes to assess contractile effects associated with drug‐induced structural cardiotoxicity

Drug‐induced cardiotoxicity is a potentially severe side effect that can adversely affect myocardial contractility through structural or electrophysiological changes in cardiomyocytes. Human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) are a promising human cardiac in vitro model system to assess both proarrhythmic and non‐proarrhythmic cardiotoxicity of new drug candidates. The scalable differentiation of hiPSCs into cardiomyocytes provides a renewable cell source that overcomes species differences present in current animal models of drug toxicity testing. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative represents a paradigm shift for proarrhythmic risk assessment, and hiPSC‐CMs are an integral component of that paradigm. The recent advancements in hiPSC‐CMs will not only impact safety decisions for possible drug‐induced proarrhythmia, but should also facilitate risk assessment for non‐proarrhythmic cardiotoxicity, where current non‐clinical approaches are limited in detecting this risk before initiation of clinical trials. Importantly, emerging evidence strongly suggests that the use of hiPSC‐CMs with cardiac physiological relevant measurements in vitro improves the detection of structural cardiotoxicity. Here we review high‐throughput drug screening using the hiPSC‐CM model as an experimentally feasible approach to assess potential contractile and structural cardiotoxicity in early phase drug development. We also suggest that the assessment of structural cardiotoxicity can be added to electrophysiological tests in the same platform to complement the Comprehensive in vitro Proarrhythmia Assay for regulatory use. Ideally, application of these novel tools in early drug development will allow for more reliable risk assessment and lead to more informed regulatory decisions in making safe and effective drugs available to the public.     

A Generalized Pivotal Quantity Approach to the Parametric Tolerance Interval Test for Dose Content Uniformity Batch Testing

The Food and Drug Administration (FDA) has proposed a parametric tolerance interval test (PTIT) for batch-release testing of inhalation devices. The proposed test examines dose uniformity based on several inhalation units from a batch, with two observations per unit. An underlying assumption is that the observations are a random sample from a univariate normal distribution. Because there are two observations per unit, it may be more appropriate to model the data as stemming from a bivariate normal distribution. We take a bivariate approach and use generalized confidence interval methodology to derive a parametric tolerance interval for the distribution of doses within a batch. We then use Monte Carlo simulation to compare results based on this bivariate approach with those based on the FDA-proposed PTIT.     

Industry's View on Using Quality Control,Biorelevant, and Clinically Relevant Dissolution Tests for Pharmaceutical Development,Registration, and Commercialization

This article intends to summarize the current views of the IQ Consortium Dissolution Working Group, which comprises various industry companies, on the roles of dissolution testing throughout pharmaceutical product development, registration, commercialization, and beyond. Over the past 3 decades, dissolution testing has evolved from a routine and straightforward test as a component of end-product release into a comprehensive set of tools that the developer can deploy at various stages of the product life cycle. The definitions of commonly used dissolution approaches, how they relate to one another and how they may be applied in modern drug development, and life cycle management is described in this article. Specifically, this article discusses the purpose, advantages, and limitations of quality control, biorelevant, and clinically relevant dissolution methods.     

A European perspective on alternatives to animal testing for environmental hazard identification and risk assessment

Tests with vertebrates are an integral part of environmental hazard identification and risk assessment of chemicals, plant protection products, pharmaceuticals, biocides, feed additives and effluents. These tests raise ethical and economic concerns and are considered as inappropriate for assessing all of the substances and effluents that require regulatory testing. Hence, there is a strong demand for replacement, reduction and refinement strategies and methods. However, until now alternative approaches have only rarely been used in regulatory settings. This review provides an overview on current regulations of chemicals and the requirements for animal tests in environmental hazard and risk assessment. It aims to highlight the potential areas for alternative approaches in environmental hazard identification and risk assessment. Perspectives and limitations of alternative approaches to animal tests using vertebrates in environmental toxicology, i.e. mainly fish and amphibians, are discussed. Free access to existing (proprietary) animal test data, availability of validated alternative methods and a practical implementation of conceptual approaches such as the Adverse Outcome Pathways and Integrated Testing Strategies were identified as major requirements towards the successful development and implementation of alternative approaches. Although this article focusses on European regulations, its considerations and conclusions are of global relevance.     

Parametric Two-Stage Sequential Quality Assurance Test of Dose Content Uniformity

The United States Pharmacopeia (USP) content uniformity sampling acceptance plan consisting of a two-stage sampling plan with criteria on sample mean and number of out-of-range tablets is the standard for compendium. It is, however, often used mistakenly for lot quality assurance. In comparison to the Japan Phamacopeia (JP) procedure, USP procedure is less discriminative between lots with on-target mean and small variance and lots with off-target mean and large variance. The new European Pharmacopeia (EP) and USP harmonized test adopted a tolerance interval approach. But the “no-difference zone” criteria modification for off-target products make the approaches biased in favor of off-target products. We propose a parametric tolerance interval procedure to test a two-sided specification that is equivalent to the test of two one-sided hypotheses. Testing against a lower specification is to assure that the drug product is not under-dosed for the sake of efficacy. On the other hand, testing against an upper specification is to assure that the drug product is not over-dosed for the sake of safety. The operating curves of the proposed procedure are compared with those of the USP test to illustrate the difference in acceptance probability against the mean and variance of the lot.     

REACH,non-testing approaches and the urgent need for a change in mind set

The objectives of REACH cannot be achieved under the current risk assessment approach. A change in mind set among all the relevant stakeholders is needed: risk assessment should move away from a labor-intensive and animal-consuming approach to intelligent and pragmatic testing, by combining exposure and hazard data effectively and trying to group chemicals (category approaches). The focus should be on reducing the overall uncertainties of 30,000 chemicals while acknowledging the existence of the uncertainty paradox: reducing uncertainty in the assessment of individual chemicals following the classical chemical-by-chemical approach as we have in previous decades will result in a prolongation of uncertainty for the entire group of 30,000 chemicals as a whole. With the first REACH registration deadline (2010) rapidly approaching, a mind set change is urgently needed. We can speed up the regulatory acceptance process, starting with the maximum use of currently available exposure and hazard data, tools and models. Optimal use should also be made of experimental exposure and hazard data generated under REACH. Only such an approach will make it possible to obtain a sufficient level of information within the time frame of REACH. A much more intensive dialogue between stakeholders is necessary.     

The Posterior Probability of Passing a Compendial Standard,Part 1: Uniformity of Dosage Units

A compendial standard is a function of data generated by one or more quality testing procedures. Since the data are sampled from an underlying distribution, the probability of passing a compendial test (Pa) can be expressed as a function of the distribution's model parameters. Applying Bayesian methodology to such a function, we show how to compute the posterior distribution of Pa and other quantities of interest. We apply this methodology to the USP<905> compendial standard and illustrate the importance of considering interbatch variance. We show that the operating characteristics of this Bayesian approach depend on the underlying model parameters almost exclusively through the population Pa and use this to develop a simple univariate procedure to determine the number of batches needed for a process qualification. We note some advantages of this Bayesian approach compared to current approaches. To show the simplicity of the approach and encourage its use, example R and WinBUGS code are provided.     

Nonanimal toxicology testing approaches for traditional and deemed tobacco products in a complex regulatory environment: Limitations,possibilities, and future directions

The evaluation of tobacco products is complex due to a multitude of factors including product diversity, limited testing standards, and variability in user behavior. Alternative approaches in current testing paradigms have limitations that generally truncate their applicability beyond screening for hazard identification; this is also true for toxicological evaluations of tobacco products. In a regulatory context, results from tobacco product toxicity assessments are extrapolated to the in vivo condition to assess human health relevance at the individual and population level. A key limitation of alternative approaches is the difficulty and uncertainty in extrapolating results to adverse outcomes relevant to chronic tobacco exposures in humans. This difficulty and uncertainty are increased when comparing toxicological outcomes between tobacco products. Given that the interpretation and quantification of differences in assay results (e.g., mutagenicity) for tobacco product comparison may be inconclusive, the predictive value of these approaches for human risk of relevant downstream pathologies (e.g., carcinogenesis) can be limited. Development and validation of fit-for-purpose alternative approaches that are predictive of human toxicity and dose response assays with adequate sensitivity and specificity for product comparisons would help advance the field of predictive toxicology.     

Translating Cell and Gene Biopharmaceutical Products for Health and Market Impact. Product Scaling From Clinical to Marketplace: Lessons Learned and Future Outlook

Cell and gene therapies have the potential to be curative for severe disease states such as cancer or incurable orphan genetic diseases. Despite the promise, there are only few such therapies available, although more are appearing in pharmaceutical pipelines. A major culprit limiting a fast translation from preclinical research to the clinic and the market is chemistry, manufacturing and control. The root cause is that most cell and gene therapies currently are personalized in form of ex vivo manipulated cells. This approach stands in sharp contrast to the population-based approach seen for small molecules and protein therapeutics. Therefore, it warrants a different approach to product manufacturing, testing, release, regulatory submissions, and product distribution. In this commentary, we highlight opportunities to solve these issues already in progress in industry and at academic institutions, but in addition call for expert contributions to a future cluster of articles in Journal of Pharmaceutical Sciences to illuminate additional solutions. Finally, we are also providing a perspective on future directions including expanding from current approaches of gene modification via viral vectors to for example gene editing, approaches that may lend themselves better toward allogenic and in vivo therapies and more typical chemistry, manufacturing and control approaches.     

Reproductive toxicants have a threshold of adversity

This paper surveys the scientific basis for the current threshold approach for reproductive hazard and risk assessment. In some regulatory areas it was recently suggested to consider reproductive toxicants under the stringent linear extrapolation risk assessment paradigm that was developed for genotoxic carcinogens. First, the current risk assessment paradigm for genotoxic carcinogens is addressed, followed by an overview of reproductive toxicology and its threshold dose approach for hazard and risk assessment, the testing procedures for assessing the reproductive toxicity of chemicals, and the derivation of conclusions on their risk assessment and Classification, Labelling and Packaging (CLP). Relevant details of testing methodologies are discussed, such as exposure time windows, parameters determined, and the coverage of the entire reproductive cycle. In addition, the dose-response relationship is considered, illustrated with several examples. It is concluded that the current risk assessment methodology for genotoxic carcinogens is a debatable worst-case scenario and that for risk assessment of reproductive toxicants the threshold dose approach remains valid.     

Parametric Two-Tier Sequential Quality Assurance Test of Delivery Dose Uniformity of Multiple-Dose Inhaler and Dry Powder Inhaler Drug Products

The delivery dose uniformity is one of the most critical requirements of dry powder inhaler and metered dose inhaler products. In 1998, the U.S. Food and Drug Administration recommended a two-tier acceptance sampling plan in the Draft Guidance of Metered Dose Inhaler and Dry Powder Inhaler Drug Products Chemistry, Manufacturing and Controls. The two-tier procedure is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity. It employed a zero tolerance criterion. In addition, it has a near-zero probability acceptance at the second tier. In this article, a two-tier sequential tolerance interval approach is proposed that is equivalent to a two-tier two one-sided testing procedure. It controls the probability of the product delivering below a prespecified effective dose and the probability of the product delivering over a prespecified safety dose.     

Reproductive toxicants have a threshold of adversity

This paper surveys the scientific basis for the current threshold approach for reproductive hazard and risk assessment. In some regulatory areas it was recently suggested to consider reproductive toxicants under the stringent linear extrapolation risk assessment paradigm that was developed for genotoxic carcinogens. First, the current risk assessment paradigm for genotoxic carcinogens is addressed, followed by an overview of reproductive toxicology and its threshold dose approach for hazard and risk assessment, the testing procedures for assessing the reproductive toxicity of chemicals, and the derivation of conclusions on their risk assessment and Classification, Labelling and Packaging (CLP). Relevant details of testing methodologies are discussed, such as exposure time windows, parameters determined, and the coverage of the entire reproductive cycle. In addition, the dose-response relationship is considered, illustrated with several examples. It is concluded that the current risk assessment methodology for genotoxic carcinogens is a debatable worst-case scenario and that for risk assessment of reproductive toxicants the threshold dose approach remains valid.     

Genetic toxicity assessment: employing the best science for human safety evaluation part IV: a strategy in genotoxicity testing in drug development: some examples.

The minimal three-test battery of the International Conference on Harmonization guideline has been in use since 1997 for the development of new pharmaceuticals (ICH, 1997). After a 10-year experience of this core battery in regulatory genotoxicity testing, everywhere the time has come for reflection about what was learned from this experience. Different aspects of genotoxicity testing are currently being debated under different organizations (HESI, 2006; IWGT, 2007; Kirkland et al., 2007). The main concerns are to develop relevant strategies and adequate complementary tests to the minimal battery, appropriate for each specific case to assess risk for humans when in vitro positive results or findings in rodent bioassays for carcinogenicity are found. In this article, an example of an in-house decision tree is shown, with some options which can contribute to the current reflections. Additionally, tools built for early genotoxicity are presented.     

From alternative methods to a new toxicology

Mechanistic toxicology has evolved by relying, to a large extent, on methodologies that substitute or complement traditional animal tests. The biotechnology and informatics revolutions of the last decades have made such technologies broadly available and useful, but regulatory toxicology has been slow to embrace these new approaches. Major validation efforts, however, have delivered the evidence that new approaches do not lower safety standards and can be integrated into regulatory safety assessments.Particularly in the EU, political pressures, such as the REACH legislation and the 7th Amendment to the cosmetic legislation, have prompted the need of new approaches. In the US, the NRC vision report calling for a toxicology for the 21st century (and its most recent adaptation by EPA for their toxicity testing strategy) have initiated a debate about how to create a novel approach based on human cell cultures, lower species, high-throughput testing, and modeling.Lessons learned from the development, validation, and acceptance of alternative methods support the creation of a new approach based on identified toxicity pathways. Conceptual steering and an objective assessment of current practices by evidence-based toxicology (EBT) are required. EBT is modeled on evidence-based medicine, which has demonstrated that rigorous systematic reviews of current practices and meta-analyses of studies provide powerful tools to provide health care professionals and patients with the current best scientific evidence. Similarly, a portal for high-quality reviews of toxicological approaches and tools for the quantitative meta-analyses of data promise to serve as door opener for a new regulatory toxicology.     

欧盟EMEA以风险为基础的抽验品种选择方法探析

目的了解欧盟药品抽验的模式和经验,对我国的评价抽验提供参考和借鉴。方法介绍了针对欧盟集中审评程序批准上市药品的抽验中,以风险为基础的抽验品种选择方法 ,对其中的风险水平量化模型以及专家意见法给予分析。结果与结论对我国的药品评价抽验具有一定的参考价值。     

Challenging the requirement for chronic fish toxicity studies on formulated plant protection products

Ecotoxicity testing of pesticide active ingredients and formulated plant protection products (PPPs) prior to their commercial use is required by authorities around the world. Such studies are important for the conduct of risk assessments to protect wildlife and the environment, but they should only be conducted when their use is scientifically justified. One test of questionable scientific merit is the chronic fish toxicity test when conducted with formulated PPPs, which is a potential requirement under European legislation: chronic exposure to the formulated product per se rarely occurs in the environment and therefore it is generally not possible to use the data from chronic formulation studies in a meaningful risk assessment. A recent survey of European crop protection companies to explore the scientific merits and regulatory drivers for chronic fish toxicity studies has shown that current practice in deciding on the need for chronic fish toxicity testing of formulated PPPs varies substantially between companies. The most commonly cited reason for conducting such studies was solely to meet regulatory requirements. We conclude that chronic formulation testing is rarely if ever scientifically justified, and recommend that the forthcoming revision of the EU Aquatic Toxicology Guidance Document takes account of this by including a requirement that justification must be provided for conducting the test, rather than the current situation where the onus is on the registrant to provide a justification for not conducting the test.