Attack on Sunscreens Continues.

The Food and Drug Administration (FDA) was required to issue and put into effect a final sunscreen monograph by November 26, 2019. On March 27, 2020, President Donald Trump signed into effect H.R. 748, the "Coronavirus Aid, Relief, and Economic Security Act" (CARES). This bill eliminated the November 2019 requirement. The CARES Act includes legislative reforms that modernize the way over-the-counter (OTC) monograph drugs are regulated in the United States. Under this Act, sunscreens will be considered generally recognized as safe and effective (GRASE), if they meet conditions newly defined by the FDA. In addition, the FDA is required to issue a proposal to revise the sun-screen requirements for GRASE not later than 18 months after enactment and will sunset by the end of the fiscal year 2022. The CARES Act also addresses the requirement for a new drug application (NDA).1-7.

Perspectives on updates, clarifications and controversies in chromatographic assay guidance for bioanalytical method validation from major regulatory agencies and organizations.

Bioanalysis, a key supporting function for generating data for pre-clinical and clinical studies in drug development, is under the regulation of local agencies as well as global organizations to ensure the data integrity and quality in submission. As major regulatory agencies and organizations, the US Food and Drug Administration, the European Medicines Agency and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use have been updating their industry guidance for bioanalytical method validation, to keep up with the development new modalities, technologies and regulations. This article summarizes the recent updates and any clarifications and controversies triggered by those updates. Perspectives and recommendations are given based on our own experience as well as commonly accepted practice in the bioanalytical community.

The Case for Disclosure of Biologics Manufacturing Information.

Ten years after the enactment of the Biologics Price Competition and Innovation Act (BPCIA), competition in biologics markets remains scant and far from sufficient for lowering prices of biologics to the level of 80-90% price drops seen in generic drug markets. This reality is not a result of one or two cardinal reasons, but many. If lowering the price of biologics is the goal and competition is the means by which we seek to achieve that goal, then there does not seem to be a quick fix to address all of the many impediments to competition that plague biologics markets. Yet, certain changes to how the Food and Drug Administration (FDA) evaluates and approves biologics may go a long way toward the creation of meaningful competition in biologics markets. One such change would be making original biologics' manufacturing information available to follow-on manufacturers. As recognized by several commentators, access to biologics manufacturing information is key to increasing competition in biologics markets. Without access to such information, making follow-on biologics is difficult and expensive, if not outright impossible. This is expected to be especially true for the highly anticipated class of interchangeable biologics, none of which has been approved by the FDA to date. Yet, it has long been the position of the brand-name pharmaceutical industry (Industry) that biologics manufacturing information is proprietary and, thus, may not be shared. Congress has subscribed to the Industry's position, prohibiting the FDA from disclosing regulatory filings submitted by developers of original biologics, including manufacturing information, to third parties. That prohibition not only undermines competition in biologics markets, but is also wasteful, potentially unethical, and poses unnecessary risks to the health and safety of patients. This article makes the case for FDA sharing of original biologics manufacturing information with follow-on biologics developers. It is informed by the similar legal and commercial circumstances in the area of pesticides and the regulatory regime established by Congress in the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), which is administered by the Environmental Protection Agency (EPA). The article reviews the FIFRA regime, including its upholding as constitutional by the United States Supreme Court, and then examines its applicability to the area of biologics. The article concludes with a proposal for a similar regime to be incorporated into the pathway for approval of follow-on biologics as a means of increasing competition in biologics markets.

Personalized Medicine and Medicinal Chemistry: Toward a Legal Framework in the European Union.

In the last few years, the fields of Medicinal Chemistry and especially the ones related to the so-called Personalized Medicine, have received a great attention. Significant investment and remarkable researches surround the matter; however, not all those promising advances are reaching patients as quickly as they should. The absence of an adequate regulatory framework could be of no help. The complete and/or massive sequencing of individual genomes faces many ethical-legal challenges. Some of them are access to Personalized Medicine; the treatment of a large volume of sensitive information and the use of tools produced by "big data" systems in clinical care or in predictive models. In addition, the legal protection of personal data related to health, the exercise of autonomy by patients, closely related to the regulation regarding clinical trials, are seriously involved. Our purpose of this work is to review the regulations of the European Union, in an attempt to contribute to a better understanding of the legal framework for the implementation and development of health systems based on Personalized Medicine.

Reverse Engineering the 1-Month Lupron Depot®.

The 1-month Lupron Depot® (LD) encapsulating water-soluble leuprolide in poly(lactic-co-glycolic acid) (PLGA) microspheres is a benchmark product upon which modern long-acting release products are often compared. Despite expiration of patent coverage, no generic product for the LD has been approved in the USA, likely due to the complexity of components and manufacturing processes involved in the product. Here, we describe the reverse engineering of the LD composition and important product attributes. Specific attributes analyzed for microspheres were as follows: leuprolide content by three methods; gelatin content, type, and molecular weight distribution; PLGA content, lactic acid/glycolic acid ratio, and molecular weight distribution; mannitol content; in vitro drug release; residual solvent and moisture content; particle size distribution and morphology; and glass transition temperature. For the diluent, composition, viscosity, and specific gravity were analyzed. Analyzed contents of the formulation and the determined PLGA characteristics matched well with the official numbers stated in the package insert and those found in literature, respectively. The gelatin was identified as type B consistent with ~ 300 bloom. The 11-µm volume-median microspheres in the LD slowly released the drug in vitro in a zero-order manner after ~ 23% initial burst release. Very low content of residual moisture (< 0.5%) and methylene chloride (< 1 ppm) in the product indicates in-water drying is capable of removing solvents to extremely low levels during manufacturing. The rigorous approach of reverse engineering described here may be useful for development of generic leuprolide-PLGA microspheres as well as other new and generic PLGA microsphere formulations.

Current regulatory requirements and practical approaches for stability analysis of pharmaceutical products: A comprehensive review.

Different regulatory guidelines recommend establishing stability profile of pharmaceuticals at the time of drug development. The expiry date, retesting period and storage conditions of active drugs or products are established through stability analysis. Several regulatory guidelines exist for stability testing of pharmaceuticals. Mostly, ICH stability guidelines are followed in practice. This guideline recommends to validate stability indicating method using forced degradation samples that contains all possible degradation impurities. ICH guidelines provide general recommendations for inclusion of stability indicating parameters in a stability testing protocol. However, those guidelines do not provide specific requirements and experimental methodology to be followed for stability studies. Due to this gap, often confusion arises in the scientific community in designing stability testing protocol. Therefore, significant variations are observed in reported literature in selection of stability indicating parameters. Procedural dissimilarity amongst reported stability studies is also evident. This review discusses the regulatory guidelines and procedures to follow in performing stability testing of pharmaceuticals. Scope of this review also includes recommendations on practical approaches for designing stability testing protocol to fulfill current regulatory requirements for drug substances and their formulations.

10 years EU regulation of pediatric medicines - impact on cardiovascular drug formulations.

INTRODUCTION: Child-appropriate drug formulations are mandatory for an efficient and safe drug therapy in children. Since the implementation of supportive legislations development of novel drug formulations has significantly been enforced despite the fact that children are a heterogeneous group of patients with varying needs according to age, maturation and disease. AREAS COVERED: In this review, recent advances and current strategies are evaluated how to overcome the specific hurdles in pediatric drug development. For cardiovascular diseases as an example, EMA's decisions on pediatric investigation plans (PIPs) have been evaluated. New developments with innovative platform technologies such as mini-tablets and orodispersible preparations have been identified indicating a clear shift from liquid preparations to small-sized solid (multiparticulate) or orodispersible dosage forms. Reasons for this shift of paradigm are discussed. EXPERT OPINION: Innovative platform technologies for solid drug dosage forms such as mini-tablets, orodispersible tablets or film preparations will continue to conquer the pharmaceutical market. Still, there are some major issues to be resolved, e.g. how to ensure quality of the new dosage forms and dose accuracy in flexible dosing, but the governmental incentives will continue to accelerate development of pediatric medicines and will bridge the still existing gaps in the near future.

Using Data Exclusivity Grants to Incentivize Cumulative Innovation of Biologics' Manufacturing Processes.

The pharmaceutical market is divided into two types of compounds: small-molecule chemical compounds and large-molecule biologics. Due to biologics' molecular sizes and the current scientific state of biologics manufacturing, manufacturing facilities and processes require frequent reassessment to ensure production of safe, pure, and potent therapeutics. Manufacturers utilize patent and drug regulatory law to protect their investments and simultaneously signal where innovation and investment are lacking. The current four- and twelve-year regimented structures of the Biologics Price, Competition, and Innovation Act do not keep pace with scientific development; biologics manufacturing processes drift with time, and if a manufacturer can obtain a higher degree of process control, then it should not feel restricted to wait until their exclusivity period lapses. Currently, the FDA rarely grants market exclusivity privileges for manufacturing process improvements alone; hence, manufacturing processes--or at least large portions thereof--are typically withheld as trade secrets or strategically claimed within companion composition claims. As a result, significant opportunity exists in regulatory framework to incentivize the research and development of biologics manufacturing processes. By creating a one- to four-year data exclusivity extension opportunity, manufacturers will feel more comfortable reinvesting their returns on investment towards manufacturing efficiency, and manufacturers can capitalize on the complex-molecule nature of their biologic.

Medicines for Pediatric Patients-Biopharmaceutical, Developmental, and Regulatory Considerations.

This commentary reflects current developments in pediatric medicine. The underpinning legislation in both Europe and the United States has led to the initiation of an increased number of clinical trials in the pediatric population, but there are still a number of outstanding issues within this field. These include the differences in the physiology between adults and the very heterogeneous nature of pediatric patients. There is an ongoing scientific debate on the applicability of a Pediatric Biopharmaceutical Classification System to define when waivers for bioequivalence studies can be supported by in vitro dissolution. However, a challenge is that in vitro models should adequately mimic the physiology of different pediatric age-groups and dose definition is another critical aspect. There is a tendency for off-label use of established adult medicines, resulting in increased adverse events and decreased efficacy in the target population. Recent advances in physiologically based pharmacokinetic modelling may be used to provide valuable input into these discussions, but there are currently still many knowledge gaps. It is encouraging that there is a global recognition of these deficiencies and substantial funding in the field of basic research is being provided, for example, within Europe the Innovative Medicines Initiative consortium.

Laboratory-based testing to evaluate abuse-deterrent formulations and satisfy the Food and Drug Administration's recommendation for Category 1 Testing.

The US Food and Drug Administration (FDA) considers the development of abuse-deterrent formulations of solid oral dosage forms a public health priority and has outlined a series of premarket studies that should be performed prior to submitting an application to the Agency. Category 1 studies are performed to characterize whether the abuse-deterrent properties of a new formulation can be easily defeated. Study protocols are designed to evaluate common abuse patterns of prescription medications as well as more advanced methods that have been reported on drug abuse websites and forums. Because FDA believes Category 1 testing should fully characterize the abuse-deterrent characteristics of an investigational formulation, Category 1 testing is time consuming and requires specialized laboratory resources as well as advanced knowledge of prescription medication abuse. Recent Advisory Committee meetings at FDA have shown that Category 1 tests play a critical role in FDA's evaluation of an investigational formulation. In this article, we will provide a general overview of the methods of manipulation and routes of administration commonly utilized by prescription drug abusers, how those methods and routes are evaluated in a laboratory setting, and discuss data intake, analysis, and reporting to satisfy FDA's Category 1 testing requirements.

Moving toward a paradigm shift in the regulatory requirements for pediatric medicines.

Over the past two decades, there has been growing concern over the lack of proper medication for children. This review attempts to evaluate the current progress of EU Pediatric Regulation made since 2007. The lack of properly evaluated pediatric medication has for long been a source of concern in the European Union. The drugs that were used in the past were often not properly evaluated, and dosage was arbitrarily calculated. Therefore, it was necessary to establish the Pediatric Regulation (EC no. 1901/2006) in the EU which would mandate research for pediatric drugs. Current legislations in place not only require mandatory research by pharma industry but also have guidelines to direct the quality of pediatric research performed. The main aim of this regulation was to advance high-quality research and development of pediatric drugs, thereby increasing the availability of safe and effective drugs for children. It also aimed to improve the information available on existing pediatric drugs. It has been 9 years since the pediatric regulation was framed. The pharma industry now sees pediatric research as an integral process of development. Drug companies which develop plans for a new drug, new form of drug, new indication, or new route of administration for adults are obliged to integrate in their development plan similar research for pediatric populations as well. CONCLUSION: It is hoped that the implementation of the current legislation will be reflected better in the future by the marketing of better and safer drugs for the pediatric population. The upcoming assessment to the European Commission in 2017 will further inform us on the impact after 10 years implementation of the legislation. What is Known: • The lack of properly evaluated pediatric medication has for long been a source of concern in the European Union. • Therefore, it was necessary to establish the EU Pediatric Regulation which would mandate research for pediatric drugs. What is New: • It has been 9 years since the pediatric regulation was framed, and the teething problems are slowly being overcome and the regulation is being used with increasing confidence. • As the Regulation is due for revision in 2017, this paper gives a current perspective on the impact of the regulation on availability and access to medicine for children.

Scientific and Regulatory Considerations in Solid Oral Modified Release Drug Product Development.

This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patient-focused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance. The use of various biopharmaceutics tools that link the CQAs to a predictable and reproducible clinical performance for patient benefit is emphasized. Product and process understanding lead to a more comprehensive control strategy that can maintain product quality through the shelf life and the lifecycle of the drug product. The overall goal is to develop MR products that consistently meet the clinical objectives while mitigating the risks to patients by reducing the probability and increasing the detectability of CQA failures.

Regulatory Experience with In Vivo In Vitro Correlations (IVIVC) in New Drug Applications.

In the past two decades, in vitro in vivo correlation (IVIVC) has been considered an important tool for supporting biowaivers, setting dissolution acceptance criteria, and more recently in the Quality by Design (QbD) framework promoting the establishment of clinically meaningful drug product specifications using dissolution as the endpoint. Based on our review experience at the FDA, for the purposes of this article, we analyzed the current state of regulatory submissions containing IVIVC approaches and discussed the successes and failures from the perspectives of study design to methodology. In the past decade, the overall acceptance rate of the IVIVC submissions is about 40%. Moreover, the number of IVIVC studies seen in the submissions per year is not increasing. Establishing clinically meaningful drug product specifications through the linkages between the identified critical quality attributes and in vivo performance is key for developing a quality drug product. To achieve this goal, there is an imminent need for addressing the issues behind a low success rate in IVIVC development. The results from the current analysis revealed that special considerations should be taken in areas such as (1) selection of appropriate number/kind of formulations for IVIVC development/validation, (2) construction of exploratory plots to guide model building and selection, (3) investigation of the reasons of inconclusive predictability, (4) improvement on the quality and richness of the data, and (5) avoidance of over parameterization. The development and incorporation of biopredictive dissolution methods and the use of non-conventional approaches, including mechanistic/physiologically based approaches, should be explored to increase the likelihood of IVIVC success.

Standard Preparations, Limits of Potency, and Dating Period Limitations for Biological Products. Direct final rule.

The Food and Drug Administration (FDA or Agency or we) is amending the general biological products standards relating to dating periods and also removing certain standards relating to standard preparations and limits of potency. FDA is taking this action to update outdated requirements, and accommodate new and evolving technology and testing capabilities, without diminishing public health protections. This action is part of FDA's retrospective review of its regulations in response to an Executive order. FDA is issuing these amendments directly as a final rule because the Agency believes they are noncontroversial and FDA anticipates no significant adverse comments.

Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications.

Dissolution profile comparisons are used by the pharmaceutical industry to assess the similarity in the dissolution characteristics of two formulations to decide whether the implemented changes, usually minor/moderate in nature, will have an impact on the in vitro/in vivo performance of the drug product. When similarity testing is applied to support the approval of lower strengths of the same formulation, the traditional approach for dissolution profile comparison is not always applicable for drug products exhibiting strength-dependent dissolution and may lead to incorrect conclusions about product performance. The objective of this article is to describe reasonable biopharmaceutic approaches for developing a biowaiver strategy for low solubility, proportionally similar/non-proportionally similar in composition immediate release drug products that exhibit strength-dependent dissolution profiles. The paths highlighted in the article include (1) approaches to address biowaiver requests, such as the use of multi-unit dissolution testing to account for sink condition differences between the higher and lower strengths; (2) the use of a single- vs. strength-dependent dissolution method; and (3) the use of single- vs. strength-dependent dissolution acceptance criteria. These approaches are cost- and time-effective and can avoid unnecessary bioequivalence studies.

Crónica amable de la Farmacia en la España constitucional. 1978-2013 / Chronicle of Spanish constitutional pharmacy: 1978-2013

Para muchos, los primeros treinta y cinco años después de la aprobación de la Constitución Española de 1978, son un periodo demasiado próximo para abordar su estudio histórico: está en nuestra mente marcado con vivencias e imágenes sugerentes; ha conformado nuestra propia vida, y por ello tendemos a considerar que, con un mínimo esfuerzo seríamos capaces de recordar casi todo lo sucedido. Sin embargo, en ocasiones desearíamos haber tomado nota de muchos acontecimientos que hemos vivido, y que se van oscureciendo con el paso del tiempo, algo que se pretende revitalizar en esta crónica. La Farmacia, en estos años ha vivido cambios muy intensos de mano de la evolución política de nuestro país y del extraordinario desarrollo científico. Los grandes acontecimientos ya están siendo tallados por el cincel de la historia, pero hay otras pequeñas cuestiones que nos han interesado, que nos han conmovido o producido curiosidad: son la pequeña historia, la unamuniana 'intrahistoria' de la Farmacia, objeto principal de este trabajo, a las que se pone el adjetivo de 'amables', porque nada fundamental se ha perdido en la Farmacia entendida como arte científico, tal como la definiera el Rey Don Felipe IV

For many, the first thirty-five years after the adoption of the Spanish Constitution of 1978, are a time too close to address its historical study: it is in our mind marked by experiences and evocative images; He has formed our own lives, and so we tend to believe that, with minimal effort would be able to remember most of what happened. However, sometimes we would have taken note of many events that we have experienced, and become darker over time, which is intended to revitalize in this story. Pharmacy, in recent years has experienced very strong hand changes the political evolution of our country and the extraordinary scientific development. Great events are already being carved by the chisel of history, but there are other small issues that have concerned us that have moved us or produced curiosity: are the little story, Unamuno main 'inside story' of the pharmacy, the subject of this work, to which the adjective 'nice' it gets, because nothing fundamental has been lost in the pharmacy understood as a scientific art, defined as the King Felipe IV