A comprehensive analysis of selected medicines collected from private drug outlets of Dhaka city, Bangladesh in a simple random survey.

Comprehensive data are needed to prevent substandard and falsified (SF) medicines as they pose a major risk to human health. To assess the quality of selected medicines, samples were collected from random private drug outlets of Dhaka North and South City Corporation, Bangladesh. Sample analysis included visual observation of the packaging, authenticity of the samples, legitimacy and registration verification of the manufacturer, physicochemical analysis, and price. Chemical analysis of the samples was performed using a portable Raman spectroscopy and high-performance liquid chromatography according to the pharmacopoeia. Several discrepancies were noted in the visual observation of samples. Among the 189 collected samples of esomeprazole (ESM), cefixime (CFIX), and amoxicillin-clavulanic acid (CVA-AMPC), 21.2% were confirmed to be authentic, 91.3% manufacturers were confirmed legitimate, and 2.1% of all samples were unregistered. Chemical analysis of the samples revealed that 9.5% (95% CI 5.7-14.6) of samples were SFs. Falsified samples and quality variation in the same generic branded samples were both detected by Raman spectroscopic analysis. Overall, sample prices were satisfactory relative to the international reference price. This study documents the availability of poor-quality medicines, demonstrating the need for immediate attention by the national medicine regulatory authority.

Pharmaceutical Compounding: a History, Regulatory Overview, and Systematic Review of Compounding Errors.

INTRODUCTION: Medications are compounded when a formulation of a medication is needed but not commercially available. Regulatory oversight of compounding is piecemeal and compounding errors have resulted in patient harm. We review compounding in the United States (US), including a history of compounding, a critique of current regulatory oversight, and a systematic review of compounding errors recorded in the literature. METHODS: We gathered reports of compounding errors occurring in the US from 1990 to 2020 from PubMed, Embase, several relevant conference abstracts, and the US Food and Drug Administration "Drug Alerts and Statements" repository. We categorized reports into errors of "contamination," suprapotency," and "subpotency." Errors were also subdivided by whether they resulted in morbidity and mortality. We reported demographic, medication, and outcome data where available. RESULTS: We screened 2155 reports and identified 63 errors. Twenty-one of 63 were errors of concentration, harming 36 patients. Twenty-seven of 63 were contamination errors, harming 1119 patients. Fifteen errors did not result in any identified harm. DISCUSSION: Compounding errors are attributed to contamination or concentration. Concentration errors predominantly result from compounding a prescription for a single patient, and disproportionately affect children. Contamination errors largely occur during bulk distribution of compounded medications for parenteral use, and affect more patients. The burden falls on the government, pharmacy industry, and medical providers to reduce the risk of patient harm caused by compounding errors. CONCLUSION: In the US, drug compounding is important in ensuring access to vital medications, but has the potential to cause patient harm without adequate safeguards.

What to consider for a good quality PDE document?

For the handling of active pharmaceutical ingredients (APIs) and production of medicinal products in shared facilities, the European Medicines Agency (EMA) has introduced the determination of permitted daily exposure (PDE) values to provide limits for cross-contamination. APIs have a desired pharmacological effect in the patient who intendedly uses a certain medicinal product. However, this effect is undesired in a patient that receives this API unintendedly as a cross-contamination of another medicinal product. In particular, for approved APIs for human use, a multitude of data is available on the pharmacological activity as well as adverse effects, which have to be taken into account in PDE setting. Thus, the setting of PDEs for APIs needs a structured scientific evaluation of all properties and identification of the most critical effect, which is the basis for PDE calculation. In this publication, we provide guidance on points for consideration when setting PDEs for APIs, or when evaluating the quality of documents describing the derivation of PDEs received, e.g. by third parties.

Official control of plant protection products in Poland: detection of illegal products.

Market presence of illegal and counterfeit pesticides is now a global problem. According to data published in 2012 by the European Crop Protection Association (ECPA), illegal products represent over 10% of the global market of plant protection products. Financial benefits are the main reason for the prevalence of this practice. Counterfeit and illegal pesticides may contain substances that may pose a threat to the environment, crops, animals, and humans, inconsistent with the label and registration dossier. In Poland, action against illegal and counterfeit plant protection products is undertaken by the Main Inspectorate of Plant Health and Seed Inspection (PIORiN), the police, the prosecution, and the pesticide producers. Results of chemical analyses carried out by the Institute of Plant Protection - National Research Institute Sosnicowice Branch, Pesticide Quality Testing Laboratory (PQTL IPP-NRI Sosnicowice Branch) indicate that a majority of illegal pesticides in Poland are detected in the group of herbicides. Products from parallel trade tend to have the most irregularities. This article describes the official quality control system of plant protection products in Poland and presents the analytical methods for testing pesticides suspected of adulteration and recent test results.

'Worth the test?' Pragmatism, pill testing and drug policy in Australia.

BACKGROUND: Recent deaths of young Australian music festival attendees from 'party-drug' overdoses have sparked debate about the effectiveness of drug policies. Australia is widely lauded for its harm minimisation approach to drugs, and yet, over the last 30 years, it can be argued its policies have been fragmented, sometimes inconsistent and contradictory. The present article examines the root of this inconsistency, using it as a foundation to advocate for drug policy reform. In keeping with the goals of the National Drug Strategy to promote policy innovation, there is an opportunity to learn from international studies which have shown promising findings in the reduction of party-drug use and its harms through application of pill testing. METHOD: This paper evaluates Australia's National Drug Strategy and pill testing through a lens of pragmatism, to determine whether there is space for testing practices in contemporary policy. Specifically, the paper analyses current drug policy literature and research studies, examining a range of key drug use indicators, social and political debate and research evidence. RESULTS: The need for policy reform, attitudinal and cultural shifts and development of stronger cross-sectoral partnerships is highlighted, to ensure a rational and logical approach that genuinely tackles drug policy-making and strategy from a broad public health perspective. CONCLUSIONS: Using a theoretical frame of pragmatism and drawing from national and international research evidence, this paper recommends the integration of pill testing into Australia's harm minimisation strategy.

Recent Regulatory Trends in Pharmaceutical Manufacturing and their Impact on the Industry.

The pharmaceutical industry is one of the most regulated industries in Switzerland. Though the concept of good manufacturing practises (GMP) was implemented for chemical production in the early 1990s, the rules and regulations for our industry are in constant evolution. In this article we will highlight the impact of these changes to the industry using three recent guideline up-dates as examples: the implementation of ICH Q3D 'Guideline for elemental impurities', the EU-GMP Guideline Part III Chapter 'Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities' from 01. June 2015, and the new guidelines to data integrity such as 'PIC/S 041-1 Good Practices for Data Management and Integrity in regulated GMP/GDP environments'. These examples show how scientific approaches help to modernize the control strategies for our products and increase product quality for a better patient safety. The requirements of data integrity regulations are also of interest to industries and universities not working under GxP requirements as they also support the business to improve data quality (traceability) for patent applications, and reduce risk of data falsification.

Population Exposure to Phthalate-containing Drugs.

Phthalates are known endocrine disruptors. Not commonly recognized, phthalates are used as excipients in a number of drug formulations. We aimed to describe the sale of phthalate-containing drugs in Denmark from 2004 to 2015. National data on annual sale of medications (tablets only) were accessed from medstat.dk. Data from the Danish Medicines Agency on phthalate content per tablet were merged with data on total sale for each active substance and drug formulation. We used the 'defined daily dose' (DDD) as the unit of sale and calculated the total amount of phthalate (mg) dispensed per 1000 inhabitants. Specific tablet content was compared with the maximum daily exposure limits defined by regulatory agencies for diethyl phthalate (DEP) and dibutyl phthalate (DBP) of 4.0 and 0.01 mg/kg/day, respectively. Use of phthalate-containing drugs in Denmark was common. We found 154 drug products containing five different phthalates. Two low-molecular-weight phthalates and three high-molecular-weight phthalates were identified, with a total sale of 59.4 and 112 DDD per 1000 inhabitants per day during the study period, respectively. The highest amount of DBP was found in multi-enzymes (24.6-32.8 mg per DDD) and mesalazine (12.5-26.4 mg per DDD). Budesonide, lithium and bisacodyl also exceeded the DBP exposure limit of 0.01 mg/kg/day. Other drugs had high levels of DEP, although not exceeding the exposure limit. Sales of phthalate-containing drugs in Denmark from 2004 to 2015 were substantial, and phthalate exposure from several products exceeded the regulatory exposure limit introduced in 2014.

The regulatory framework for preventing cross-contamination of pharmaceutical products: History and considerations for the future.

Cross-contamination in multi-product pharmaceutical manufacturing facilities can impact both product safety and quality. This issue has been recognized by regulators and industry for some time, leading to publication of a number of continually evolving guidelines. This manuscript provides a historical overview of the regulatory framework for managing cross-contamination in multi-product facilities to provide context for current approaches. Early guidelines focused on the types of pharmaceuticals for which dedicated facilities and control systems were needed, and stated the requirements for cleaning validation. More recent guidelines have promoted the idea of using Acceptable Daily Exposures (ADEs) to establish cleaning limits for actives and other potentially hazardous substances. The ADE approach is considered superior to previous methods for setting cleaning limits such as using a predetermined general limit (e.g., 10 ppm or a fraction of the median lethal dose (LD50) or therapeutic dose). The ADEs can be used to drive the cleaning process and as part of the overall assessment of whether dedicated production facilities are required. While great strides have been made in using the ADE approach, work remains to update good manufacturing practices (GMPs) to ensure that the approaches are clear, consistent with the state-of-the-science, and broadly applicable yet flexible enough for adaptation to unique products and situations.

Development of the risk-based, phased-in approach for the international harmonization of the regulation of container closure systems for drugs in Taiwan.

The main concern for container closure systems of drugs is to ensure suitability for the intended use which is associated with issues regarding protection, compatibility, safety, and performance. Among various concerns, leachables may pose a safety hazard to patients, while risks might vary depending on the dosage form and the administration route. Stringent regulatory authorities such as the European Medicines Agency and the United States Food and Drug Administration have established risk-based regulatory requirements and published corresponding guidelines to facilitate implementation. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes every effort to harmonize with international regulations and to strengthen protection of public health through regulatory controls. The aim of the present study was to investigate the regulatory framework and policies set by stringent regulatory authorities. The strategy proposed for the development of an eventual guideline was sent to the Taiwan Food and Drug Administration for decision. A risk-based, phased-in approach which was extensively discussed in the expert committee was proposed. The approach proposed herein could also serve as a starting point which is worth considered by other countries in which international harmonization is in process.

Regulatory and quality considerations for continuous manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium.

This paper assesses the current regulatory environment, relevant regulations and guidelines, and their impact on continuous manufacturing. It summarizes current regulatory experience and learning from both review and inspection perspectives. It outlines key regulatory aspects, including continuous manufacturing process description and control strategy in regulatory files, process validation, and key Good Manufacturing Practice (GMP) requirements. In addition, the paper identifies regulatory gaps and challenges and proposes a way forward to facilitate implementation.

Meeting Report: 2013 PDA Virus & TSE Safety Forum.

The report provides a summary of the presentations and discussions at the Virus & TSE Safety Forum 2013 organized by the Parenteral Drug Association (PDA) and held in Berlin, Germany, from June 4 to 6, 2013. The conference was accompanied by a workshop, "Virus Spike Preparations and Virus Removal by Filtration: New Trends and Developments". The presentations and the discussion at the workshop are summarized in a separate report that will be published in this issue of the journal as well. As with previous conferences of this series, the PDA Virus & TSE Safety Forum 2013 provided again an excellent opportunity to exchange information and opinions between the industry, research organizations, and regulatory bodies. Updates on regulatory considerations related to virus and transmissible spongiform encephalopathy (TSE) safety of biopharmaceuticals were provided by agencies of the European Union (EU), the United States (US), and Singapore. The epidemiology and detection methods of new emerging pathogens like hepatitis E virus and parvovirus (PARV 4) were exemplified, and the risk of contamination of animal-derived raw materials like trypsin was considered in particular. The benefit of using new sequence-based virus detection methods was discussed. Events of bioreactor contaminations in the past drew the attention to root cause investigations and preventive actions, which were illustrated by several examples. Virus clearance data of specific unit operations were provided; the discussion focused on the mechanism of virus clearance and on the strategic concept of viral clearance integration. As in previous years, the virus safety section was followed by a TSE section that covered recent scientific findings that may influence the risk assessment of blood and cell substrates. These included the realization that interspecies transmission of TSE by blood components in sheep is greater than predicted by assays in transgenic mice. Also, the pathogenesis and possibility of productive TSE infection of cell substrates were considered, and cell-based assays that may be suitable for use in TSE clearance studies were discussed. The current report provides an overview about the outcomes of the 2013 PDA Virus & TSE Safety Forum, a unique event in this field.

[Official experimental testing of biomedical products. Regulatory frame and importance of for quality, safety and efficacy]. / Staatliche experimentelle Produktprüfung von biomedizinischen Arzneimitteln. Regulatorischer Rahmen und Bedeutung für die Qualität, Sicherheit und Wirksamkeit.

The official experimental testing of biomedicinal products provides a very significant contribution to ensuring quality, safety and efficacy of these indispensable medicines. Already in the prelicensing phase or to elucidate clusters of increased adverse effects, official medicinal control laboratories are committed to perform experimental testing. The official batch release can be seen as external quality control of the manufacturer's release testing. For proficient performance in these tasks, scientific research is required, in particular on the development and refinement of test methods, and considering the continuous development of innovative biomedicinal products. This article is aimed at introducing the present thematic issue and in particular the regulatory basis of experimental product testing, and illustrates by means of several examples its great importance for the sake of the patients.

The assessment of impurities for genotoxic potential and subsequent control in drug substance and drug product.

The strategies implemented at Eli Lilly and Company to address European Medicines Agency and US Food and Drug Administration requirements governing the control of genotoxic impurities (GTIs) are presented. These strategies were developed to provide understanding with regard to the risk and potential liabilities that could be associated with developmental and marketed compounds. The strategies systematize the assessment of impurities for genotoxic potential, addressing both actual and potential impurities. Timing of activities is designed to minimize impact to development timelines while building a data package sufficient to either discharge the risk of potential GTI formation or support the implementation of a specification necessary for long-term control. This article presents the background associated with GTI control, the types of impurities that should be assessed, and the actions to be taken when an impurity is found to be genotoxic. A systematic approach to define potential degradation products derived from stress-testing studies is outlined with a proposal to perform a genotoxic risk assessment on these impurities. Finally, an Arrhenius-based strategy is proposed for a rapid assessment of the likelihood of potential degradation impurities to form in the commercial drug product formulation. Importantly, this article makes a proposal for discharging the risk of a potential GTI with supporting data.

Drug safety and efficacy impaired by quality failure.

The three main pillars of drug evaluation are quality, safety and efficacy. Each marketing authorization dossier has to demonstrate conformity with quality, safety and efficacy requirements separately. While this is justifiable, it may nevertheless lead to some important problems being overlooked. The relationship between these three aspects of a medicinal product can be of great importance. Little is said about how quality can affect safety or even efficacy. It is worth discussing these connections in order to assess side-effects appropriately and to distinguish between quality failures and real pharmacovigilance problems. Not every side-effect is a result of the drug's pharmacodynamic or pharmacokinetic properties or other therapy-related issues such as interactions. Sometimes a patient complaint is caused by substandard quality of the drug. This possibility should never be ignored in any assessment of side-effects. This paper presents a useful check-list of quality failures that can endanger drug safety.

Overall impact of the regulatory requirements for genotoxic impurities on the drug development process.

In the last decade a considerable effort has been made both by the regulators and the pharmaceutical industry to assess genotoxic impurities (GTI) in pharmaceutical products. Though the control of impurities in drug substances and products is a well established and consolidated procedure, its extension to GTI has given rise to a number of problems, both in terms of setting the limits and detecting these impurities in pharmaceutical products. Several papers have dealt with this issue, discussing available regulations, providing strategies to evaluate the genotoxic potential of chemical substances, and trying to address the analytical challenge of detecting GTI at trace levels. In this review we would like to discuss the available regulations, the toxicological background for establishing limits, as well as the analytical approaches used for GTI assessment. The final aim is that of providing a complete overview of the topic with updated available information, to address the overall GTI issue during the development of new drug substances.

Sterile products: advances and challenges in formulation, manufacturing and regulatory aspects--a regulatory review perspective.

For several decades, the FDA has undertaken many initiatives to improve the quality and safety of sterile drug products. In recent years, efforts have also been undertaken to accelerate the rate for application approval by adding earlier involvement of microbiology reviewers in drug development. Product and manufacturing process development, as well as safe use and product design, are among the elements of enhanced technical involvement. An overview of the product quality microbiology aspects for sterile drugs is provided.

Organic solvents in the pharmaceutical industry.

Organic solvents are commonly used in the pharmaceutical industry as reaction media, in separation and purification of synthesis products and also for cleaning of equipment. This paper presents some aspects of organic solvents utilization in an active pharmaceutical ingredient and a drug product manufacturing process. As residual solvents are not desirable substances in a final product, different methods for their removal may be used, provided they fulfill safety criteria. After the drying process, analyses need to be performed to check if amounts of solvents used at any step of the production do not exceed acceptable limits (taken from ICH Guideline or from pharmacopoeias). Also new solvents like supercritical fluids or ionic liquids are developed to replace "traditional" organic solvents in the pharmaceutical production processes.