The Essential Guide to Computer System Validation in the Pharmaceutical Industry.

This review aims to provide an essential guide to computer system validation (CSV) in the pharmaceutical industry. CSV is a process for ensuring that computer-based systems produce data and information that meets a set of pre-defined requirements. The pharmaceutical industry relies on data integrity to ensure reliable, accurate, and consistent information throughout the product lifecycle. Nowadays, since CSV plays an important role in the production and the final stages of a product, it is vital to ensure the reliability of the computer system, ensuring that it meets predefined requirements. The life cycle of CSV starts from the planning stage to the modification stage. Validation involves design, installation, operational, and performance qualifications (PQ), starting with a master plan and ending with periodic system reviews. Failure to validate the computer system leads to various regulatory compliances. Validating computer systems offers numerous benefits, including improved quality, reduced validation costs and time, and improved GMP compliance with 21 CFR part 11 regulations. Validating the computer system significantly affects how well, securely, and accurately products are made, ensuring they meet GxP requirements.

Modeling and Analyzing the Availability of Technical Professional Profiles for the Success of Smart Cities Projects in Europe.

The success of developing and implementing Smart Cities (SC) projects depends on a varied set of factors, where the availability of a qualified technical workforce is a critical one. The combination of ICT requirements, like the effectiveness and quality of solutions merging IoT, cloud computing, sensors, and communications with the work from many varied disciplines (e.g., civil engineering, architecture, etc.), mixed with aspects of environmental and business sustainability, makes the management of these projects really challenging. Reports forecast a scarcity of qualified candidates, given this complexity and the growth of activity in SC projects. The European project SMACITE has addressed the requirements of the qualification of an ICT workforce with an analysis of multiples sources of information from the labor market, feedback from involved stakeholders, and the literature. The goal was the development of two occupational ICT profiles as a reference for training and for the availability of candidates for job vacancies. The result is two ICT role profiles for engineers and technicians, mapped with the European skills frameworks ESCO and EN16234. The profiles determined the whole set of requirements, including not only the technical areas and soft skills, but also additional technical areas and sustainability and managerial skills and the analysis of different sources of information. Our work has also determined which existing ESCO occupations are similar to the two reference profiles, so they are better adapted to SC projects. The training activities of SMACITE have also suggested the amount of training expected for a varied sample of candidates who want to be qualified for SC projects.

Risk-Based Qualification of Cellular Starting Material Collection Sites: Tools to Determine Scope of Manufacturer Audits and Reduce Duplicative Efforts.

Cellular and Gene Therapy product (CGT product) manufacturers are required by regulations to qualify sites performing cell collection and processing as part of their manufacturing processes. The use of audits to qualify a site is part of the traditional supplier quality models for drug products. Due to the rapid growth of the CGT industry in recent years, healthcare institutions and manufacturers are finding it difficult to manage the increasing workload and resources needed to support audits when they are applied to the provision of Cellular Starting Material (CSM) collection from patients/subjects for the purpose of manufacturing. To alleviate this audit burden, several manufacturers have applied risk-based approaches to determine the needs and scope of audits. The authors of this commentary recommend that all manufacturers utilize a risk-based assessment program when appropriate and explain the use of tools created to facilitate a risk-based approach to streamline and reduce duplicative audits. This approach and tools, created by The NextGen Industry Working Group (IWG) site certification workstream with representation from pharmaceutical and biotech companies, health care institutions, accrediting organizations, and other stakeholders, is aligned with proposals from other multistakeholder groups, including the ASTCT 80/20 Task Force. The tools aim to streamline the site qualification processes performed by each manufacturer, offering a standardized approach to audits or gap analysis assessments. Offering an abbreviated audit model for sites that have already attained accreditation through agencies such as the AABB (Association for the Advancement of Blood & Biotherapies) and FACT (Foundation for the Accreditation of Cellular Therapy), helping the manufacturer to focus on product-specific requirements rather than re-evaluating systems that have already been audited in great detail by other parties.

Medical examinations of professional and amateur athletes at a sports medicine clinic. Insights from a sports medicine specialist and cardiologist.

In 2019, three regulations of the Minister of Health regarding sports medicine examinations in children, adolescents and young athletes came into force. The publication presents in detail the current scope of tests and the frequency of required medical examinations necessary to obtain medical certificates qualify- ing patients to practice sports. The publication also presents the Regulation of the Minister of Health on the required qualifications of doctors authorized to issue medical certificates to athletes. It is very important to properly assess the health of potential and current athletes to ensure their safety while participating in sports competitions. There are diseases that increase the risk of sudden cardiac death which doctors should keep in mind when qualifying athletes for competition. The publication draws attention to the underestimated role of echocardiography and electrocardiographic stress testing.

Challenges and effective tracking down strategies of antibiotic contamination in aquatic ecosystem.

A growing environmental concern revolves around the widespread use of medicines, particularly antibiotics, which adversely impact water quality and various life forms. The unregulated production and utilization of antibiotics not only affect non-targeted organisms but also exert significant evolutionary pressures, leading to the rapid development of antimicrobial resistance (AMR) in bacterial communities. To address this issue, global studies have been conducted to assess the prevalence and quantities of antibiotics in various environmental components including freshwater, ocean, local sewage, and fish. These studies aim to establish effective analytical methods for identifying and measuring antibiotic residues in environmental matrices that might enable authorities to establish norms for the containment and disposal of antibiotics. This article offers a comprehensive overview of methods used to extract antibiotics from environmental matrices exploring purification techniques such as liquid-liquid extraction, solid-phase extraction, green extraction techniques, and concentration methods like lyophilization and rotary evaporation. It further highlights qualitative and quantitative analysis methods, high-performance liquid chromatography, ultra-high-performance liquid chromatography, and liquid chromatography-tandem along with analytical methods such as UV-Vis and tandem mass spectrometry for detecting and measuring antibiotics. Urgency is underscored for proactive strategies to curb antibiotic contamination, safeguarding the integrity of aquatic ecosystems and public health on a global scale.

Non targeted and targeted LC-MS/MS insights into the composition and concentration of atmospheric microplastics and additives: Impacts and regional changes of sandstorms in Shanghai and Hohhot, China.

Increasing dust storms impact ecosystems and human health by resuspending dust and microplastics. Plastic pollution is a major global concern. This study examines the molecular composition and concentration of atmospheric microplastics and additives in Hohhot and Shanghai, China during dust and non-dust days using non-target and target LC-MS/MS analysis with Multiple Reaction Monitoring (MRM) methodology and a self-established plastic monomers database. In Hohhot, 98 microplastics and additives types were identified on dust days (41 unique) and 70 on non-dust days (10 unique), mainly PEG, HTPE, PET, PPG, and Nylon. The types fluctuate ranging from 35 to 65 due to dusty conditions. In Shanghai, 50 types were identified (no unique), with 25 to 30 types consistently present. Hohhot's microplastics concentration during dust days peaked at 3531.59 ng/m3, about three times higher than non-dust days (1669.17 ng/m3) and significantly higher than Shanghai's maximum of 589.85 ng/m3. Overall, microplastic monomers in both cities were mostly compounds with low unsaturation, indicating potential for long-term atmospheric persistence. Highly reactive monomers like HTPE, PEG, thrive on dust days in Hohhot due to insufficient light and strong winds. These conditions reduce photochemical reactivity, accelerate microplastic aging through collisions, and resuspend more microplastics from the soil, resulting in a wider variety of microplastics with different m/z and carbon contents during sandstorms. On non-dust days, microplastics have more concentrated m/z values, indicating that substances with similar chemical properties disperse more under normal conditions. These findings highlight the significant impact of dust storms on microplastics characteristics. SYNOPSIS: This study indicates that dust storms and regional differences can have significant impacts on the diversity and abundance of atmospheric microplastics.

A scoping review of websites for forensic odontology training programs.

BACKGROUND: Forensic Odontology developed as a discipline in 1898 with the publication of its first textbook; however, 126 years later, a standardised core curriculum for formal training in Forensic Odontology has yet to be decided. This website scoping review aims to provide information on three main distinct categories (and 17 subcategories): Availability, Content, and Quality of Forensic Odontology education globally. The information on formal education programmes was gathered by conducting a web search using 'Google Search' in English, Arabic, Spanish, and French languages between June and July 2022. HIGHLIGHTS: Fifty-six programmes from 18 countries met the inclusion criteria. Of the 14 master's and 42 diploma programmes, only 7.14% provided information on their websites from all the subcategories investigated. The highest numbers of master's and postgraduate diploma programmes were identified in Europe (18 programmes), South America (15), North America (11) and Asia (7). A practical aspect was included by 10 master's and 12 diploma programmes' websites. Research integration in various forms was included by 11 master's and seven diploma programmes. CONCLUSION: Programme providers and applicants must critically consider the quality of the programme being designed or applied to as there are currently no international training standards in Forensic Odontology. This study has developed an 'International Database of Forensic Odontology Programmes' (IDFOP).

Building a healthy nation: A white paper on Olympic sports and the Indian education system.

The Indian education system has produced top-class global corporate leaders in recent decades. The combination of a solid educational foundation, work ethic, adaptability, technical and analytical skills, leadership abilities, networking, entrepreneurial spirit, and cultural values collectively contribute to the success of Indian students and professionals in the corporate world. On the contrary, India's overall performance in Olympic sports has been modest compared to its population and potential. The education system of any country has a significant role in sporting success. To fully harness the potential of sports in schools, addressing these challenges and creating a supportive environment that values and promotes sporting abilities alongside academic excellence is essential. This will require concerted efforts from various stakeholders, including the schooling system, educational institutions, government, sports organizations, corporate sponsors, and the community. This white paper aims to systematically organize the available knowledge and debates around India's sporting performance in the background of mainstream education culture. This paper also addresses the systemic devaluation, exclusion, disfranchisement, and stereotyping of sports and sportspersons in India. One key argument put forward in this paper is to extend absolute equivalence to Olympic sports disciplines (e.g., football) at par with general academic disciplines (e.g., mathematics) in terms of examinations and award of qualifications within the mainstream education system of India. And India must host the Olympics before 2047.

Impact of the endoscopic surgical skill qualification system on the oncological safety of laparoscopic gastrectomy for gastric cancer: A single-center retrospective cohort study.

BACKGROUND: This study aimed to investigate the laparoscopic gastrectomy (LG) performance of non-Endoscopic Surgical Skill Qualification System (ESSQS)-qualified surgeons under the ESSQS-qualified surgeon guidance and compare oncological outcomes of gastric cancer to LG performed by the ESSQS-qualified surgeons. METHODS: This study enrolled 1,030 patients diagnosed with both clinical and pathological stage ≤ III gastric cancer and undergoing LG from January 2009 to June 2019. ESSQS-qualified surgeons served as the operator or the instructive assistant in all LG procedures involving them. A propensity score-matched analysis was used to retrospectively compare the long-term outcomes between the ESSQS-qualified and non-ESSQS-qualified surgeons. RESULTS: Each group included 315 pairs after propensity score matching. The 3-year recurrence-free survival rates were 84.4% and 81.7% in the non-ESSQS and ESSQS groups, respectively. The difference was 2.7% (95% confidence interval: - 3.20%-8.44%, P < 0.001), and the non-ESSQS group statistically demonstrated noninferiority as the lower 95% confidence limit was greater than the prespecified margin of -10%, indicating the achieved primary endpoint. No significant differences in 5-year recurrence-free survival (non-ESSQS: 78.5% vs. ESSQS: 77.4%, P = 0.627) and 5-year overall survival (non-ESSQS: 80.9% vs. ESSQS: 79.3%, P = 0.475) were found between the two groups. The oncological outcomes stratified according to the presence of pathological stage I, II, and III disease did not significantly differ between the two groups. CONCLUSIONS: LG performed by non-ESSQS-qualified surgeons achieved comparable oncological outcomes to the ESSQS-qualified surgeons, as long as ESSQS-qualified surgeons provided intraoperative instructions, in a high-volume center.

[The impact of public organizations on development of professional qualification of medical workers].

The professional development of personnel is one of highest priority task of development of both medicine as science and health system as mechanism protecting health of citizens. The public organizations are professional communities of medical specialists specializing in particular sectors of medicine that actively participate in implementation of educational measures and other initiatives targeted to support opportunities for professional growth and improving competence level of participants of these communities. The article considers examples of such initiatives as exemplified by foreign and Russian public organizations of pulmonologists and dentists.

Development of a Cell-Based Reporter Potency Assay for Live Virus Vaccines.

The rapid development of potency assays is critical in the development of life-saving vaccines. The traditional plaque assay or fifty percent tissue culture infectious dose (TCID50) assay used to measure the potency of live virus vaccines is time consuming, labor intensive, low throughput and with high variability. Described here is the development and qualification of a cell-based reporter potency assay for two vaccines for respiratory viral infection, one based on the recombinant vesicular stomatitis virus (rVSV) backbone, termed Vaccine 1 in this paper, and the other based on the measles virus vector, termed Vaccine 2. The reporter potency assay used a Vero E6 cell line engineered to constitutively express NanuLuc® luciferase, termed the VeroE6-NLuc or JM-1 cell line. Infection of JM-1 cells by a live virus, such as rVSV or measles virus, causes a cytopathic effect (CPE) and release of NanuLuc® from the cytoplasm into the supernatant, the amount of which reflects the intensity of the viral infection. The relative potency was calculated by comparison to a reference standard using parallel line analysis (PLA) in a log-log linear model. The reporter assay demonstrated good linearity, accuracy, and precision, and is therefore suitable for a vaccine potency assay. Further evaluation of the Vaccine 1 reporter assay demonstrated the robustness to a range of deliberate variation of the selected assay parameters and correlation with the plaque assay. In conclusion, we have demonstrated that the reporter assay using the JM-1 cell line could be used as a potency assay to support the manufacturing and release of multiple live virus vaccines.

Research on the Influence of HMFI and PWHT Treatments on the Properties and Stress States of MAG-Welded S690QL Steel Joints.

The aim of this study was to analyze the effect of the HFMI (high-frequency mechanical impact) treatment of each weld bead on the properties of a butt joint with a ceramic backing welded by robotic method 135 (MAG-metal active gas welding method) and to determine the effect of HMFI on the stress level. This analysis was based on a comparison of three butt joints made of a S690QL plate, in the as-welded condition, with the HFMI of each bead and with the heat treatment carried out with PWHT stress relief annealing. The high-frequency (90 Hz) peening of each weld bead was linked with a stress reduction in the weld via the implementation of compressive stresses into the joint. The HFMI pneumatic hammer was used for this. The correctness of treatment was achieved when 100% of the surface of each bead including the face was treated. As part of the post-welding tests, basic tests were carried out based on the standards for the qualification of welding technology, and as a supplementary test, a stress state analysis using the Barkhausen effect was carried out. The tests carried out showed that the use of high-frequency peening after each pass did not affect the negative results of all the required tests when qualifying the welding technology of S690QL sheet metal compared to the test plates in the as-welded condition and after heat treatment-stress relief annealing. Inter-pass peening of the welded face and HAZ (heat-affected zone) resulted in a reduction in post-weld residual stresses at a distance of 12 mm from the joint axis compared to the stress measurement result for the sample in the as-welded condition. This allowed for a positive assessment of peening in the context of reducing the notch, which is the concentration of tensile stresses in the area of the fusion line and HAZ. The tests carried out showed that the peening process does not reduce the strength properties of welded joints, and the results obtained allow the technology to be qualified based on applicable standards.

Predictor Selection for Case Complexity Based on Routine Data for Needs-Based and Competence-Based Staff Planning.

Due to nursing staff shortage and growing nursing care demand, resource allocation and optimal task distribution have become primary concerns of nursing management. Grade mix analysis based on nursing interventions and nurse qualifications from routine patient documentation can support this. Case complexity is a key linking factor of nursing interventions, workload, and grade mix. This study determined case complexity predictors based on one year of routine patient documentation (n = 3,373 cases) from a Swiss hospital and predicted the patient clinical complexity level via weighted cumulative logistic regression models. Significant predictors were sex, age, pre-admission residence, admission type, self- care index, pneumonia risk, and number of nursing interventions. The models' accuracy is limited yet appropriate for applications such as needs- and competence- based staff-planning. After calibration via in-hospital data it could support nursing management in these tasks. The next step is now to test the model in a clinical setting.

Community interpreting in Germany: results of a nationwide cross-sectional study among interpreters.

BACKGROUND: Community interpreters (CIPs) play a crucial role in various community services, including healthcare, when service providers and users do not share a common language. However, there is a lack of evidence-based data on this population globally. This explorative cross-sectional study aims to gain a better understanding of CIPs and their work in Germany. METHODS: A nationwide online survey was conducted among CIPs in Germany to collect data on their qualification background, working conditions, mental health, interpreting-related psychosocial distress and sociodemographics. Participants were recruited through interpreting pools, training institutions and migrant organizations. Data were analyzed descriptively, dependent t-test, multiple logistic and hierarchical stepwise regression analyses were performed to predict participation in interpreting-specific training, interpreting competence and interpreting-related psychosocial distress. RESULTS: Across all 16 federal states, N = 873 responses were used for analysis. Most participants are female (74%), born abroad (77%) and have a high level of education (69%). The vast majority interpret occasionally in their leisure time (44%) and are self-employed/freelance (51%). 34% interpret solely or additional on a voluntary basis (unpaid). The median hours of interpreting per month are 10 h, 75% do not exceed 30 h. On average interpreters work in four different settings. 69% attended any kind of interpreting training with a median of 25 h in total. Interpreting in more settings emerged as an associated factor with participation in training. Of those who have never attended any training, 69% consider themselves as rather/very competent in interpreting. Interpreting more frequently, having less severe anxiety symptoms, getting higher and more often paid and being less satisfied with the payment is associated with self-reported interpreting competence. In total, 36% reported moderate or severe psychosocial distress regarding interpreting. Higher general psychosocial distress and depressive symptoms, higher interpreting frequency and lower payment satisfaction were found to be associated with higher distress regarding interpreting. Additionally, factors such as precarious work conditions, lack of recognition and discrimination (e.g. racism and sexism) were reported as distressing. CONCLUSION: This study provides a first comprehensive evidence-based national database on CIPs in Germany. The findings can be valuable for the development of qualifications, guidelines, policies and the process of professionalizing the field of CIPs.

How to Accelerate Early Stage of Malaria Vaccine Development by Optimizing Functional Assays.

While two Plasmodium falciparum circumsporozoite protein-based pre-erythrocytic vaccines (PEV), RTS,S and R21, have been approved by the WHO, no blood-stage vaccine (BSV) or transmission-blocking vaccine (TBV) has reached a phase 3 trial. One of the major obstacles that slows down malaria vaccine development is the shortage (or lack) of in vitro assays or animal models by which investigators can reasonably select the best vaccine formulation (e.g., antigen, adjuvant, or platform) and/or immunization strategy (e.g., interval of inoculation or route of immunization) before a human phase 2 trial. In the case of PEV, RTS,S and R21 have set a benchmark, and a new vaccine can be compared with (one of) the approved PEV directly in preclinical or early clinical studies. However, such an approach cannot be utilized for BSV or TBV development at this moment. The focus of this review is in vitro assays or in vivo models that can be used for P. falciparum BSV or TBV development, and I discuss important considerations during assay selection, standardization, qualification, validation, and interpretation of the assay results. Establishment of a robust assay/model with proper interpretation of the results is the one of key elements to accelerate future vaccine development.

O perfil dos egressos de um mestrado profissional: uma contribuição para o entendimento da relação formação-trabalho no SUS / Profile of graduates of a Professional Master's Degree: a contribution to understanding the training-work relationship in the SUS

RESUMO Este artigo apresenta perfil dos egressos, efeitos da formação e trajetória profissional dos concluintes do Curso de Mestrado Profissional em Saúde Pública, do Instituto Aggeu Magalhães, parte de pesquisa avaliativa em desenvolvimento. Dos 99 egressos convidados que concluíram seus cursos entre 2013-2020, 54 responderam a um questionário aplicado por meio do software Lime Survey. O estudo descritivo e transversal utilizou frequência absoluta e relativa e cruzamento de variáveis na análise, cujo instrumento constou dos temas: identificação do egresso e do programa/curso; atividade profissional antes e ao término do curso e expectativas; condição empregatícia atual e efeitos da formação; avaliação da trajetória formativa. Entre os respondentes, a maioria é do sexo feminino, com idade entre 31-40 anos, enfermeiros de formação, autodeclarados pretos ou pardos, não ser pessoa com deficiência, predominantemente residentes em Pernambuco e não ingressaram mediante cota. Como efeito na vida profissional, encontrou-se que o curso aumentou o prestígio/reconhecimento dos colegas, qualificou para atividades que já exerciam e para atividades diferentes, e trouxe ganhos de remuneração, proporcionando mudanças na vida pessoal e profissional. Os resultados estão em conformidade com achados científicos desse mesmo contexto, e a ferramenta desenvolvida pela Fiocruz permitiu conhecer a relação entre formação e trabalho.

ABSTRACT This article presents the profile of graduates, the effects of training, and the professional trajectory of the Professional Master's Course in Public Health graduates at the Aggeu Magalhaes Institute. Of the 99 invited graduates who completed the program between 2013-2020, 54 responded to a questionnaire applied through the Lime Survey software. The descriptive and cross-sectional study used absolute and relative frequency cross-tabulation variables in the analysis, with the instrument covering the following themes: identification of the graduate and program/course; professional activity before and at the end of the program and expectations; current employment status and formation effects; evaluation of the formative trajectory. Among the respondents, most are female, aged between 31-40 years, trained as nurses, self-declared as black or brown-skinned, not having a disability, predominantly residing in Pernambuco, and did not enter through a quota system. As an effect on their professional life, it was found that the program increased prestige/recognition among colleagues, qualified them for activities they were already performing and also different activities, and brought salary increases leading to changes in personal and professional lives. The results are consistent with scientific findings in the same context, and the tool developed by FIOCRUZ made it possible to understand the relationship between education and work.

Critical View on the Qualification of Electronic Tongues Regarding Their Performance in the Development of Peroral Drug Formulations with Bitter Ingredients.

In this review, we aim to highlight the advantages, challenges, and limitations of electronic tongues (e-tongues) in pharmaceutical drug development. The authors, therefore, critically evaluated the performance of e-tongues regarding their qualification to assess peroral formulations containing bitter active pharmaceutical ingredients. A literature search using the keywords 'electronic', 'tongue', 'bitter', and 'drug' in a Web of Science search was therefore initially conducted. Reviewing the publications of the past decade, and further literature where necessary, allowed the authors to discuss whether and how e-tongues perform as expected and whether they have the potential to become a standard tool in drug development. Specifically highlighted are the expectations an e-tongue should meet. Further, a brief insight into the technologies of the utilized e-tongues is given. Reliable protocols were found that enable (i) the qualified performance of e-tongue instruments from an analytical perspective, (ii) proper taste-masking assessments, and (iii) under certain circumstances, the evaluation of bitterness.

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.

New limits proposed for the management of non-mutagenic impurities.

Multiple international guidelines exist that describe both quality and safety considerations for the control of the broad spectrum of impurities inherent to drug substance and product manufacturing processes. However, regarding non-mutagenic impurities (NMI) the most relevant ICH Q3A/B guidelines are not applicable during early phases of drug development leading to confusion about acceptable limits at this stage. Thus, there is need for more flexible approaches that ensure that patient safety remains paramount, while taking into consideration the limited duration of exposure. An EFPIA survey, which collected quantitative data from different types of studies applied to qualify impurities in accordance with ICH Q3A, shows that no toxicities could be attributed to any of the 467 impurities at any tested level in vivo. This data combined with earlier published toxicological datasets encompassing drug substances and intermediates, food related substances and chemicals provide convincing evidence that for NMIs, the application of a generic 5 mg/day limit for an exposure duration <6 months, and a 1 mg/day generic limit for life-long exposure, provides sufficient margins to ensure patient safety. Hence, application of these absolute limits to trigger qualification studies (instead of the relative limits described in Q3A/B), is considered warranted. This approach will prevent conduct of unnecessary dedicated impurity qualification studies and the resulting use of animals.