Contextual factors affecting the implementation of drug checking for harm reduction: a scoping literature review from a North American perspective.

BACKGROUND: The opioid epidemic continues to be a significant cause of morbidity and mortality in the US. In 2020, 83% of opioid-related overdose deaths were due to synthetic opioids, such as fentanyl. Drug checking services have been widely implemented as a harm reduction intervention to facilitate the identification of substances in a drug sample. There is a need to inform decision-making on drug checking technologies and service implementation. This research aims to outline contextual considerations for the implementation of a drug checking service. METHODS: A scoping review was conducted using a structured search strategy in PubMed and EMBASE. Articles were independently screened by two reviewers, and included if they were primary literature and reported on an actionable consideration(s) for drug checking services. Data elements were extracted using a standardized form, and included study design, study population, drug checking technology utilized or discussed, and main findings. RESULTS: Twenty-nine articles were selected for inclusion, and four primary areas of consideration were identified: drug checking technologies, venue of a drug checking service, legality, and privacy. Technological considerations include the need for highly accurate, quantitative results which appeal to both populations of people with drug use disorder and recreational users. Accessibility of services was identified as an important factor that may be impacted by the location, integration with other services, how the service is provided (mobile vs. fixed), and the hours of operation. Maintaining plausible deniability and building trust were seen as important facilitators to service use and engagement. Issues surrounding legality were the most frequently cited barrier by patrons, including fear of criminalization, policing, and surveillance. Patrons and stakeholders identified a need for supportive policies that offer protections. Maintaining anonymity for patrons is crucial to addressing privacy-related barriers. CONCLUSION: This review highlights the need to understand the local population and climate for drug checking to implement a drug checking service successfully. Common themes identified in the literature included considerations related to the choice of technology, the type of venue, and the impact of legality and privacy. We intend to utilize these considerations in future research to help guide discussions with US-based stakeholders.

Considerations for the Terminal Sterilization of Oligonucleotide Drug Products.

A primary function of the parenteral drug product manufacturing process is to ensure sterility of the final product. The two most common methods for sterilizing parenteral drug products are terminal sterilization (TS), whereby the drug product is sterilized in the final container following filling and finish, and membrane sterilization, whereby the product stream is sterilized by membrane filtration and filled into presterilized containers in an aseptic processing environment. Although TS provides greater sterility assurance than membrane sterilization and aseptic processing, not all drug products are amenable to TS processes, which typically involve heat treatment or exposure to ionizing radiation. Oligonucleotides represent an emerging class of therapeutics with great potential for treating a broad range of indications, including previously undruggable targets. Owing to their size, structural complexity, and relative lack of governing regulations, several challenges in drug development are unique to oligonucleotides. This exceptionality justifies a focused assessment of traditional chemistry, manufacturing, and control strategies before their adoption. In this article, we review the current state of sterile oligonucleotide drug product processing, highlight the key aspects to consider when assessing options for product sterilization, and provide recommendations to aid in the successful evaluation and development of TS processes. We also explore current regulatory expectations and provide our interpretation as it pertains to oligonucleotide drug products.

Medicamento para diabetes pode auxiliar no tratamento da leishmaniose cutânea

Baseados em estudos anteriores que investigaram a capacidade de remédios para diabetes regularem a resposta imunológica, pesquisadores da Fiocruz Bahia realizaram um estudo para entender como a pioglitazona, medicamento antidiabético, pode auxiliar no tratamento da leishmaniose cutânea

The default of 1998 and pharmaceutical market. Report I. The chronicle of disaster.

The researchers, in series of articles, analyze significance of the default of 1998 for both pharmaceutical industry and participants of pharmaceutical market. The Report I presents results of investigation of corresponding economic and social aspects of issue. The article presents contradictions in tax and financial policies of then ruling authorities; regulatory drawbacks created by inefficient awareness of economic situation and social specificity of pharmaceutics; means for pharmaceutical companies to survive in these conditions.

Challenges and Opportunities of Implementing Data Fusion in Process Analytical Technology-A Review.

The release of the FDA's guidance on Process Analytical Technology has motivated and supported the pharmaceutical industry to deliver consistent quality medicine by acquiring a deeper understanding of the product performance and process interplay. The technical opportunities to reach this high-level control have considerably evolved since 2004 due to the development of advanced analytical sensors and chemometric tools. However, their transfer to the highly regulated pharmaceutical sector has been limited. To this respect, data fusion strategies have been extensively applied in different sectors, such as food or chemical, to provide a more robust performance of the analytical platforms. This survey evaluates the challenges and opportunities of implementing data fusion within the PAT concept by identifying transfer opportunities from other sectors. Special attention is given to the data types available from pharmaceutical manufacturing and their compatibility with data fusion strategies. Furthermore, the integration into Pharma 4.0 is discussed.

Analysis of genotoxic N-nitrosamines in active pharmaceutical ingredients and market authorized products in low abundance by means of liquid chromatography - tandem mass spectrometry.

In 2018, high levels of the IARC class IIA carcinogen N-nitrosodimethylamine (NDMA) were analytically verified in the active pharmaceutical ingredient (API) valsartan, resulting in extensive regulatory action on angiotensin-II-receptor antagonists and recall of finished drug products by the pharmaceutical industry to ensure patient safety. The root cause of contamination was the unintended reaction of common reagents utilized during drug synthesis. This lead to serious effects on drug quality and immediate regulatory action. Thus, routine analysis of drug product contents are inevitable and necessitate thoroughly performed work up procedures of the product as well as adequate validated analytical methods. The nature of N-nitrosamines (NA), ranging from small, semi-volatile compounds up to highly polar molecules, effort sophisticated requirements in terms of instrumental analysis. Up today, gas as well as liquid chromatographic devices coupled to mass spectrometers are the most widespread systems for analysis. Gas chromatographic - mass spectrometric (GC-MS) systems, obviously superior towards liquid chromatography - mass spectrometry (LC-MS) for detecting small volatile compounds like NDMA, reach their limits for broadly designed studies including polar or acidic NA. In this study, a complementary and highly sensitive approach by means of liquid chromatography - tandem mass spectrometry (LC-MS/MS) is presented, including detection of 13 NA deduced from major classes of secondary amines. Thereby, the fully validated approach was performed in accordance to ICH and European Medicines Agency (EMA) guidelines. Quantitative proof-of-concept measurements with various APIs and market authorized tablets as representative drug formulations conclude applicability for further presumably contaminated substances. The approach employs organic or inorganic extraction steps with solid phase extraction (SPE). The limit of detection for the most prominent NA, NDMA and N-diethylnitrosamine (NDEA), were both 0.025 parts-per-billion (ppb) per matrix, respectively.

Meeting report: an exploration into the scientific and regulatory aspects of pharmaceutical drug quality in the United States.

INTRODUCTION: The University of Florida College of Pharmacy, Department of Pharmaceutical Outcomes and Policy hosted a seminar 6-7 March 2021, on the quality of pharmaceutical products in the United States. This meeting report summarizes the topics presented at the seminar and highlights the expert opinions offered by the presenters. AREAS COVERED: The seminar, held virtually due to the COVID-19 pandemic, included slide presentations and faculty-moderated panel discussions from experts in the field. These experts from regulatory, academic, and private sectors discussed bioequivalence standards, existing and emerging efforts to promote quality in brand and generic manufacturing, as well as market-based solutions throughout the drug supply chain. EXPERT OPINION: The time spent understanding bioequivalence standards during the seminar felt especially important and relevant in our current pandemic environment, given the present need to have confidence in the science of drug development and to advocate for the safety of pharmaceuticals. Also an important point to emphasize from the seminar, was that every stakeholder along the drug supply chain has a responsibility to do their part to maintain its quality. And those in attendance, many of whom were students of healthcare sciences, were encouraged to be leaders in their fields and develop strategies to advance innovative improvements.

Treatment of patients with neuropathic pain and provision of drug information by clinical pharmacists

Abstract Patient's satisfaction with healthcare services has an influence on pain management, which can be improved by patient education. Therefore, this study was aimed at identifying primary care health service opportunities in the treatment of neuropathic pain and assessing patients' satisfaction with the provision of drug information by clinical pharmacists. This was a cross- sectional, prospective study conducted at a pain unit during March-May 2017. Patients aged >18 years; diagnosed with neuropathic pain; and who used amitriptyline, gabapentin, pregabalin, or duloxetine were included. They were verbally informed about drug treatment by a clinical pharmacist, and their satisfaction was evaluated after 1 month. In all, 90 patients were included. The median duration for which the patients experienced pain until hospital admission was 3.6 years; furthermore, this duration was longer among women (p < 0.05). However, the median time to seeking advice from doctors was 3 months. The patients (15.6%) were less likely to admit pain unit initially and 46.7% had visited different units before being admitted to a pain unit. More than 95% of the patients indicated that they had received information from a pharmacist at a clinic and were satisfied with the provision of information (median duration, 8.5 min). Thus, the involvement of pharmacists in multidisciplinary pain management may help improve health- related outcomes at hospitals and/or in community care settings

Perceptions and Attitudes of Hospital' Prescribers towards Drug Information Sources and Prescribing Practices

Abstract Healthcare professionals use a variety of drug information sources to fulfill their clinical needs and medical practice. The aim of present study was to assess the sources of drug information among hospital' prescribers and evaluate their prescribing behavior in Saudi hospitals. A cross-sectional survey was conducted among randomly selected hospital' prescribers using a self-administered questionnaire. The response rate to the survey was 64.29%, with a ratio of 76.44% male and 23.56% female. The internet 137(60.89%) and textbooks 86(38.22%) were the prevalent sources for drug information used. Up-To-Date 107(47.56%), Medscape 105(46.67%) and FDA 74(32.88%) were the common electronic drug sources used. About 151(67.11%) of hospital' prescribers considered the pharmacist as a reliable drug information source. The most favored drug requests by hospital' prescribers from the pharmacists were drug alternatives 110(48.89%) followed by drug interactions 94(41.78%), side effects 78(34.67%) and indications 60(26.67%). Therapeutic efficacy 168(74.67%) and drug availability 73(32.44%) were the main factors contributed to the selection of drugs. This study shows some differences in hospital prescribers' perceptions of sources of drug information depending upon their background and clinical practice. Therefore, knowing appropriate drug information used by hospital' prescribers is fundamental for drug efficacy and safety in clinical practice.

Post-marketing sampling and testing programs for licensed medicinal products: a narrative review

Abstract The globalization of the pharmaceutical market has enabled access to a considerable number of new medicinal products. Consequently, the circulation of substandard medicinal products has also increased. To minimize this problem, post-marketing quality sampling and testing programs are performed to monitor and confirm that the medicinal products available in the market meet appropriate quality requirements. In this review, the post-approval sampling and testing procedures of six regulatory authorities were compared with the goal of strengthening these market surveillance systems. Similarities were observed between the procedures adopted by different regulatory authorities. However, the agencies were not always transparent about the results of these monitoring procedures. A probable mismatch between the registration procedures and the quality requirements listed in official compendiums was observed, which resulted in dissonance and contradiction between the specifications approved by the regulatory authorities and those required in the pharmacopeias. Therefore, strengthening harmonization projects related to these activities can help minimize such difficulties.

Practical aspect of dimer adduct formation in small-molecule drug analysis with LC-MS/MS.

Aim: Since the MS/MS based detection of small-molecule drugs with poor or even no ion fragmentation is a challenge in bioanalysis, alternative MS/MS detection strategies were in focus of this study and applied in the field of forensic toxicology. Material & methods: Analyte quantification with liquid chromatography-tandem mass spectrometry of problematic drugs was studied by the application of dimer adduct formation and valproic acid (VPA) was used as a model drug. VPA adduct ions could be identified during infusion experiments and the VPA dimer adduct ion was optimized for the detection. Conclusion: Dimer adduct ion formation can be used as an effective way of VPA quantification in human serum. Further, the parallel detection of dimer adduct ions with other adduct ion types can be stated as advantage in LC-MS/MS analysis of problematic drugs.

ICH Q10 Pharmaceutical Quality System Guidance: Understanding Its Impact on Pharmaceutical Quality.

The International Council for Harmonization (ICH) "Q10 Pharmaceutical Quality Systems" (ICH Q10) guidance was introduced to address the growing gap between current good manufacturing practices and pharmaceutical manufacturing quality systems. This study evaluated the impact of the ICH Q10 guidance on the PQS of pharmaceutical manufacturers. Data were obtained from the enabler questionnaire from pharmaceutical manufacturers surveyed by the St. Gallen OPEX Benchmarking Program. These results represent the degree of implementation for enabler-focused questions based on a 5-point Likert scale self-assessment. Data analysis included a comparison of means and medians before and after the release of the ICH Q10 guidance and annual changes. There was a statistically significant difference for enabler implementation as a whole (p value < 0.0000), before and after the release of ICH Q10. Furthermore, statistically significant differences were observed for four of the five enabler categories (p values <0.05). In particular, the EMS enabler category showed a decrease in mean enabler score, suggesting the Management Responsibilities ICH Q10 PQS element was not effectively described or implemented. These results indicate that the release of ICH Q10 had a positive impact on the PQSs of pharmaceutical manufacturers. This was driven primarily by the changes observed in the TQM and JIT enabler categories and complimented by the TPM and BE categories. This would suggest that the Management Review, Change Management System, and Process Performance and Product Quality Monitoring System ICH Q10 PQS elements were all effectively described and implemented.

Cost-Effectiveness Analysis of Branded Drugs With Market Demand and Insurance.

OBJECTIVES: Cost-effectiveness analysis of branded pharmaceuticals presumes that both cost (or price) and marginal effectiveness levels are exogenous. This assumption underlies most judgments of the cost-effectiveness of specific drugs. In this study, we show the theoretical implications of letting both factors be endogenous by modeling pharmaceutical price setting with and without health insurance, along with patient response to the prices that depend on marginal effectiveness. We then explore the implications of these models for cost-effectiveness ratios. METHODS: We used simple textbook models of patient demand and pricing behavior of drug firms to predict market equilibria in the drug and insurance markets and to generate calculations of the cost-effectiveness ratios in those settings. RESULTS: We found that ratios in market settings can be much different from those calculated in cost-effectiveness studies based on exogenous prices and treatment of all patients at risk rather than those who would demand treatment in a market setting. We also found that there may be considerable similarity in these market cost-effectiveness ratios across different products because drug firms with market power set profit-maximizing prices. CONCLUSIONS: We found that market cost-effectiveness ratios will always indicate an excess of benefits over cost. Insurance will lead to less favorable ratios than without insurance, but when insurers bargain with drug firms, rather than taking their prices as given, cost-effectiveness ratios will be more favorable.

Understanding Quality Paradigm Shifts in the Evolving Pharmaceutical Landscape: Perspectives from the USP Quality Advisory Group.

Recent changes in the pharmaceutical industry have led to significant paradigm shifts in the pharmaceutical quality environment. Globalization of the pharmaceutical industry, increasingly rapid development of novel therapies, and adoption of new manufacturing techniques have presented numerous challenges for the established regulatory framework and quality environment and are impacting the approaches utilized to ensure the quality of pharmaceutical products. Regulators, industry, and standards-setting organizations have begun to recognize the need to rely more on integrated risk-based approaches and to create more nimble and flexible standards to complement these efforts. They also increasingly have recognized that quality needs to be built into systems and processes throughout the lifecycle of the product. Moreover, the recent COVID-19 crisis has emphasized the need to adopt practices that better promote global supply chain resilience. In this paper, the USP Quality Advisory Group explores the various paradigm shifts currently impacting pharmaceutical quality and the approaches that are being taken to adapt to this new environment. Broad adoption of the Analytical Procedure Lifecycle approach, improved data management, and utilization of digital technologies are identified as potential solutions that can help meet the challenges of these quality paradigm shifts. Further discussion and collaboration among stakeholders are needed to pursue these and other solutions that can ensure a continued focus on quality while facilitating pharmaceutical innovation and development.

A Review of the Main Considerations for Formulation Development in Preclinical Toxicology Studies.

The main considerations for the development of a formulation for preclinical safety assessment testing are explored. Intravenous, inhalation, oral and dermal dosing are given focus and although different dose routes do present their own individual challenges there are common themes that emerge. In each case it is necessary to maximise exposure to achieve high doses to satisfy regulatory requirements for safety assessment testing. This often involves producing formulations that are at the limits of solubility and maximum volumes possible for administration to different test species by the chosen route. It is concluded that for all routes it is important to thoroughly explore the stability of the test item in the proposed formulation matrix well ahead of dosing any animals, giving careful consideration to which excipients are used and what their underlying toxicity profile may be for the relevant preclinical species. In addition, determining the maximum achievable concentrations and weighing that against the maximum volumes that can be given by the chosen route in all the test species at an early stage will also give a read on whether it would be theoretically possible to achieve suitably high enough doses to support clinical work. Not doing so can cause delays in the development programme and may have ethical repercussions.

Current Trends of Practices in Nonclinical Toxicology: An Industry Survey.

The growth in drug development over the past years reflects significant advancements in basic sciences and a greater understanding of molecular pathways of disease. Benchmarking industry practices has been important to enable a critical reflection on the path to evolve pharmaceutical testing, and the outcome of past industry surveys has had some impact on best practices in testing. A survey was provided to members of SPS, ACT, and STP. The survey consisted of 37 questions and was provided to 2550 participants with a response rate of 24%. Most respondents (∼75%) came from the US and Europe. The survey encompassed multiple topics encountered in nonclinical testing of pharmaceuticals. The most frequent target indications were oncology (69%), inflammation (55%), neurology/psychiatry/pain (46%), cardiovascular (44%), and metabolic diseases (39%). The most frequent drug-induced toxicology issues confronted were hepatic, hematopoietic, and gastrointestinal. Toxicological effects that impacted the no observed adverse effect level (NOAEL) were most frequently based on histopathology findings. The survey comprised topics encountered in the use of biomarkers in nonclinical safety assessment, most commonly those used to assess inflammation, cardiac/vascular, renal, and hepatic toxicity as well as common practices related to the assessment of endocrine effects, carcinogenicity, genotoxicity, juvenile and male-mediated developmental and female reproductive toxicity. The survey explored the impact of regulatory meetings on program design, application of the 3 Rs, and reasons for program delays. Overall, the survey results provide a broad perspective of current practices based on the experience of the scientific community engaged in nonclinical safety assessment.

Evaluation of portable devices for medicine quality screening: Lessons learnt, recommendations for implementation, and future priorities.

Céline Caillet and co-authors discuss a Collection on use of portable devices for the evaluation of medicine quality and legitimacy.

Considerations for Updates to ICH Q1 and Q5C Stability Guidelines: Embracing Current Technology and Risk Assessment Strategies.

In consideration of the recent ICH Quality Discussion Group (QDG) recommended revision to the ICH series of stability guidelines, the IQ Consortium (International Consortium for Innovation and Quality in Pharmaceutical Development) Science- and Risk-based Stability Working Group conducted a comprehensive review of ICH Q1A, Q1B, Q1C, Q1D, Q1E, and Q5C to identify areas where the guidelines could be clarified, updated, and amended to reflect the potential knowledge gained from current risk-based predictive stability tools and to consider other science- and risk-based stability strategies in accordance with ICH Q8-12. The recommendations propose a holistic approach to stability understanding, utilizing historical data, prior knowledge, modeling, and a risk assessment process to expand the concept of what could be included (or would be acceptable) in the core stability data package, including type and amount of stability evidence, assignment of retest period and shelf-life for a new product, and assessment of the impact of post-approval changes.