Leveraging AI and Machine Learning in Six-Sigma Documentation for Pharmaceutical Quality Assurance.

The pharmaceutical industry must maintain stringent quality assurance standards to ensure product safety and regulatory compliance. A key component of the well-known Six Sigma methodology for process improvement and quality control is precise and comprehensive documentation. However, there are a number of significant issues with traditional documentation procedures, including as slowness, human error, and difficulties with regulatory standards. This review research looks at innovative ways to employ machine learning (ML) and artificial intelligence (AI) to enhance Six Sigma documentation processes in the pharmaceutical sector. AI and ML provide cutting-edge technologies that have the potential to drastically alter documentation processes by automating data entry, collection, and analysis. Natural language processing (NLP) and computer vision technologies have the potential to significantly reduce human error rates and increase the efficacy of documentation processes. By applying machine learning algorithms to support real-time data analysis, predictive analytics, and proactive quality management, pharmaceutical organizations may be able to identify potential quality issues early on and take proactive efforts to address them. Combining AI and ML improves documentation accuracy and reliability while also strengthening compliance with stringent regulatory criteria. The primary barriers and limitations to the current state of Six Sigma documentation in the pharmaceutical industry are identified in this study. It examines the fundamentals of AI and ML with an emphasis on their specific applications in quality assurance and potential benefits for Six Sigma processes. The report includes extensive case studies that highlight notable developments and explain how AI/ML enhanced documentation is used in the real world.

Clarifications on the Intended Use of USP <61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests.

In the execution of its legislated responsibilities, the United States Food and Drug Administration commonly refers to standard test methods detailed in the United States Pharmacopeia (USP). Microbiological test methods (contained in general chapters) are listed in chapters <51> to <80> with details regarded as enforceable where referenced as a test method. USP <61> "Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests" is a globally harmonized chapter that has been successfully employed for the enumeration of microorganisms recoverable from nonsterile finished drug products. The content of USP <61> is not always scientifically principled nor emphatically understood by all pharmaceutical microbiologists. Consequently, misunderstanding and misapplication of USP <61> may result in analyses and assessments of microbiological quality that are flawed or erroneous. In this article, clarification is provided to assist the pharmaceutical microbiologist in the appropriate and intended use of USP <61>, including provision of details not always commonly known or understood.

Analysis of non-mutagenic substances in the context of drug impurity assessment - Few are potent toxicants.

ICH Q3A/B guidelines provide qualification thresholds for impurities or degradation products in new drug substances and products. However, the guidelines note that certain impurities/degradation products may warrant further safety evaluation for being unusually potent or toxic. The purpose of this study was to confirm that especially toxic non-mutagenic compounds are rare and to identify classes of compounds that could warrant lower qualification thresholds. A total of 2815 compounds were evaluated, of which 2213 were assessed as non-mutagenic. For the purpose of this analysis, compounds were considered potent when the point of departure was ≤0.2 mg/kg/day based on the qualification threshold (1 mg/day or 0.02 mg/kg/day for a 50 kg human) in a new drug substance, with an additional 10-fold margin. Only 54 of the entire set (2.4%) would be considered potent based on this conservative potency analysis, confirming that the existing ICH Q3A/B qualification thresholds are appropriate for the majority of impurities. If the Q3A/B threshold, without the additional 10-fold margin is used, 14 compounds (0.6%) are considered "highly potent". Very few non-mutagenic structural classes were identified, including organothiophosphates and derivatives, polychlorinated benzenes and polychlorinated polycyclic aliphatics, that correlate with potential high potency, consistent with prior publications.

Deriving acceptable limits for non-mutagenic impurities in medicinal products - Durational adjustments.

ICH Q3A/B guidelines are not intended for application during the clinical research phase of development and durationally adjusted qualification thresholds are not included. A central tenet of ICH Q3A is that lifetime exposure to 1 mg/day of an unqualified non-mutagenic impurity (NMI) is not a safety concern. An analysis of in vivo toxicology data from 4878 unique chemicals with established NO(A)ELs was conducted to determine whether durationally adjusted qualification limits can be supported. Although not recommended in ICH Q3A/B, a conservative approach was taken by using allometric scaling in the analysis. Following allometric scaling of the 5th percentile of the distribution of NO(A)ELs from available chronic toxicology studies, it was reconfirmed that there is a safety basis for the 1 mg/day qualification threshold in ICH Q3A. Additionally, allometric scaling of the 5th percentile of the distribution of NO(A)ELs from sub-acute and sub-chronic toxicology studies could support acceptable limits of 20 and 5 mg/day for an unqualified NMI for dosing durations of less than or greater than one month, respectively. This analysis supports durationally adjusted NMI qualification thresholds for pharmaceuticals that protect patient safety and contribute to 3Rs efforts for qualifying impurities using new approach methods.

Comparison of permitted daily exposure (PDE) values for active pharmaceutical ingredients (APIs) - Evidence of a robust approach.

Permitted Daily Exposure Limits (PDEs) are set for Active Pharmaceutical Ingredients (APIs) to control cross-contamination when manufacturing medicinal products in shared facilities. With the lack of official PDE lists for pharmaceuticals, PDEs have to be set by each company separately. Although general rules and guidelines for the setting of PDEs exist, inter-company variations in the setting of PDEs occur and are considered acceptable within a certain range. To evaluate the robustness of the PDE approach between different pharmaceutical companies, data on PDE setting of five marketed APIs (amlodipine, hydrochlorothiazide, metformin, morphine, and omeprazole) were collected and compared. Findings show that the variability between PDE values is within acceptable ranges (below 10-fold) for all compounds, with the highest difference for morphine due to different Point of Departures (PODs) and Adjustment Factors (AFs). Factors of PDE variability identified and further discussed are: (1) availability of data, (2) selection of POD, (3) assignment of AFs, (4) route-to-route extrapolation, and (5) expert judgement and differences in company policies. We conclude that the investigated PDE methods and calculations are robust and scientifically defensible. Additionally, we provide further recommendations to harmonize PDE calculation approaches across the pharmaceutical industry.

Emerging Applications and Regulatory Strategies for Advanced Medicines Manufacturing - Towards the Development of a Platform Approach.

The last decade has seen Advanced Medicines Manufacturing (AMM) progress from isolated product developments to the creation of industry-academic centres of excellence, regulatory innovation progressing leading to new standards, and product commercialisation across multiple product formats. This paper examines these developments focusing on successful applications and strategies presented at the 2023 Symposium of the International Consortium for Advanced Medicines Manufacturing (ICAMM). Despite these exemplar applications, there remain significant challenges to the sector-wide adoption of AMM technologies. Drawing on Symposium delegate expert responses to open-ended questions, our coding-based thematic analysis suggest three primary enablers drive successful adoption of AMM technologies at scale, namely: the ability to leverage pre-competitive collaborations to challenge-based problem solving; information and knowledge sharing through centres of excellence; and the development of AMM specific regulatory standards. Further analysis of expert responses identified the emergence of a 'Platform creation' approach to AMM innovation; characterised by: i) New collaboration modes; ii) Exploration of common product-process platforms for new dosage forms and therapy areas; iii) Development of modular equipment assets that enable scale-out, and offer more decentralized or distributed manufacturing models; iv) Standards based on product-process platform archetypes; v) Implementation strategies where platform-thinking and AMM technologies can significantly reduce timelines between discovery, approval and GMP readiness. We provide a definition of the Platform creation concept for AMM and discuss the requirements for its systematic development.

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

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.

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.

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.

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.

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

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.

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.