Comparative study on the quality control effectiveness of AI-PBRTQC and traditional PBRTQC model in identifying quality risks.

Introduction: We compared the quality control efficiency of artificial intelligence-patient-based real-time quality control (AI-PBRTQC) and traditional PBRTQC in laboratories to create favorable conditions for the broader application of PBRTQC in clinical laboratories. Materials and methods: In the present study, the data of patients with total thyroxine (TT4), anti-Müllerian hormone (AMH), alanine aminotransferase (ALT), total cholesterol (TC), urea, and albumin (ALB) over five months were categorized into two groups: AI-PBRTQC group and traditional PBRTQC group. The Box-Cox transformation method estimated truncation ranges in the conventional PBRTQC group. In contrast, in the AI-PBRTQC group, the PBRTQC software platform intelligently selected the truncation ranges. We developed various validation models by incorporating different weighting factors, denoted as λ. Error detection, false positive rate, false negative rate, average number of the patient sample until error detection, and area under the curve were employed to evaluate the optimal PBRTQC model in this study. This study provides evidence of the effectiveness of AI-PBRTQC in identifying quality risks by analyzing quality risk cases. Results: The optimal parameter setting scheme for PBRTQC is TT4 (78-186), λ = 0.03; AMH (0.02-2.96), λ = 0.02; ALT (10-25), λ = 0.02; TC (2.84-5.87), λ = 0.02; urea (3.5-6.6), λ = 0.02; ALB (43-52), λ = 0.05. Conclusions: The AI-PBRTQC group was more efficient in identifying quality risks than the conventional PBRTQC. AI-PBRTQC can also effectively identify quality risks in a small number of samples. AI-PBRTQC can be used to determine quality risks in both biochemistry and immunology analytes. AI-PBRTQC identifies quality risks such as reagent calibration, onboard time, and brand changes.

A Case Study in Application of the Risk Knowledge Infinity Cycle.

The Risk Knowledge Infinity (RKI) Cycle Framework was featured as part of the ICH-sanctioned training materials supporting the recent issuance of ICH Q9(R1) Quality Risk Management To support ICH Q9(R1) understanding and adoption, this paper presents a case study on the application of the RKI Cycle, based on an underlying out-of-specification investigation. This case study provides a stepwise walk-through of the cycle to illustrate how key concepts within the ICH Q9(R1) revision can be achieved through better connecting quality risk management and knowledge management with a framework such as the RKI Cycle.

Application of Patient-Based Real-Time Quality Control Based on Artificial Intelligence Monitoring Platform in Continuously Quality Risk Monitoring of Down Syndrome Serum Screening.

BACKGROUND: Patient-based real-time quality control (PBRTQC) has gained attention because of its potential to continuously monitor the analytical quality in situations wherein internal quality control (IQC) is less effective. Therefore, we tried to investigate the application of PBRTQC method based on an artificial intelligence monitoring (AI-MA) platform in quality risk monitoring of Down syndrome (DS) serum screening. METHODS: The DS serum screening item determination data and relative IQC data from January 4 to September 7 in 2021 were collected. Then, PBRTQC exponentially weighted moving average (EWMA) and moving average (MA) procedures were built and optimized in the AI-MA platform. The efficiency of the EWMA and MA procedures with intelligent and traditional control rules were compared. Next, the optimal EWMA procedures that contributed to the quality assurance of serum screening were run and generated early warning cases were investigated. RESULTS: Optimal EWMA and MA procedures on the AI-MA platform were built. Comparison results showed the EWMA procedure with intelligent QC rules but not traditional quality rules contained the best efficiency. Based on the AI-MA platform, two early warning cases were generated by using the optimal EWMA procedure, which finally found were caused by instrument failure. Moreover, the EWMA procedure could truly reflect the detection accuracy and quality in situations wherein traditional IQC products were unstable or concentrations were inappropriate. CONCLUSIONS: The EWMA procedure built by the AI-MA platform could be a good complementary control tool for the DS serum screening by truly and timely reflecting the detection quality risks.

Optimization of on-site supervision strategy based on big data of quality risk in drug enterprises / 中国药房

On-site supervision is a risk-based regulatory system that requires the scientific development of supervision plans for quality risks and hidden dangers in pharmaceutical enterprises， the rational allocation of supervision resources based on their risk levels， and the implementation of classified supervision measures. In this study， the quality risk monitoring business support system is set up for pharmaceutical enterprises by establishing the quality risk expert database and quality risk monitoring index system for pharmaceutical enterprises based on the difficulty analysis of on-site drug supervision. Based on this support system， the quality risk classification method， the differentiated spot check strategy and business auxiliary visualization system are established. This support system is used to learn the risk level of pharmaceutical enterprises， so as to innovate supervision methods and optimize monitoring strategies. Taking Jiangxi Province as an example， it is verified that the support system can guide the risk assessment of sample enterprises， can improve the targeting of on-site drug supervision in the process of technical review， scheme editing， on-site implementation and comprehensive evaluation， and can effectively improve the quality and efficiency of supervision.

Can Continuous Manufacturing of Topical Semisolids by Hot Melt Extrusion Soon Be a Reality?

For more than five decades, pharmaceutical manufacturers have been relying heavily on batch manufacturing that is a sequential, multistep, laborious, and time-consuming process. However, late advances in manufacturing technologies have prompted manufacturers to consider continuous manufacturing (CM) is a feasible manufacturing process that encompasses fewer steps and is less tedious and quick. Global regulatory agencies are taking a proactive role to facilitate pharmaceutical industries to adopt CM that assures product quality by employing robust manufacturing technologies encountering fewer interruptions, thereby substantially reducing product failures and recalls. However, adopting innovative CM is known to pose technical and regulatory challenges. Hot melt extrusion (HME) is one such state-of-the-art enabling technology that facilitates CM of diverse pharmaceutical dosage forms, including topical semisolids. Efforts have been made to continuously manufacture semisolids by HME integrating the principles of Quality by Design (QbD) and Quality Risk Management (QRM) and deploying Process Analytical Technologies (PAT) tools. Attempts have been made to systematically elucidate the effect of critical material attributes (CMA) and critical process parameters (CPP) on product critical quality attributes (CQA) and Quality Target Product Profiles (QTPP) deploying PAT tools. The article critically reviews the feasibility of one of the enabling technologies such as HME in CM of topical semisolids. The review highlights the benefits of the CM process and challenges ahead to implement the technology to topical semisolids. Once the CM of semisolids adopting melt extrusion integrated with PAT tools becomes a reality, the process can be extended to manufacture sterile semisolids that usually involve more critical processing steps.

[Quality control strategy of traditional Chinese medicine based on pharmaceutical product lifecycle management].

Quality control is pivotal in the research and development of traditional Chinese medicine, whose connotation is not limi-ted to the qualitative or quantitative detection of an indicator component, but extends to the establishment of a whole process quality control system from the perspective of pharmaceutical product lifecycle management. This study discussed the quality control strategy of Chinese medicine based on the concept of pharmaceutical product lifecycle management, and proposed the following suggestions:(1) to focus on the "holistic view" and "phased" characteristics of quality control and strengthen the establishment of quality control strategy based on top-level design;(2) to strengthen the research on quality control of Chinese medicine based on quality risk management, focus on the correlations of quality control indicators with the safety and effectiveness of traditional Chinese medicine, and establish a quality evaluation system consistent with the characteristics of traditional Chinese medicine;(3) to consider the characteristics of different registration classifications in the establishment of quality control strategy;(4) to highlight the quality correlation research, strengthen the quality transfer research, ensure the quality traceability, and establish a sound quality management system;(5) to strengthen the quality research on marketed drugs to achieve dynamic quality improvement.

Quality control strategy of traditional Chinese medicine based on pharmaceutical product lifecycle management / 中国中药杂志

Quality control is pivotal in the research and development of traditional Chinese medicine, whose connotation is not limi-ted to the qualitative or quantitative detection of an indicator component, but extends to the establishment of a whole process quality control system from the perspective of pharmaceutical product lifecycle management. This study discussed the quality control strategy of Chinese medicine based on the concept of pharmaceutical product lifecycle management, and proposed the following suggestions:(1) to focus on the "holistic view" and "phased" characteristics of quality control and strengthen the establishment of quality control strategy based on top-level design;(2) to strengthen the research on quality control of Chinese medicine based on quality risk management, focus on the correlations of quality control indicators with the safety and effectiveness of traditional Chinese medicine, and establish a quality evaluation system consistent with the characteristics of traditional Chinese medicine;(3) to consider the characteristics of different registration classifications in the establishment of quality control strategy;(4) to highlight the quality correlation research, strengthen the quality transfer research, ensure the quality traceability, and establish a sound quality management system;(5) to strengthen the quality research on marketed drugs to achieve dynamic quality improvement.

Isotopically Modified Bioassay Bridges the Bioavailability and Toxicity Risk Assessment of Metals in Bedded Sediments.

The application of bioavailability-based risk assessment for the management of contaminated sediments requires new techniques to rapidly and accurately determine metal bioavailability. Here, we designed a multimetal isotopically modified bioassay to directly measure the bioavailability of different metals by tracing the change in their isotopic composition within organisms following sediment exposure. With a 24 h sediment exposure, the bioassay sensed significant bioavailability of nickel and lead within the sediment and determined that cadmium and copper exhibited low bioavailable concentrations and risk profiles. We further tested whether the metal bioavailability sensed by this new bioassay would predict the toxicity risk of metals by examining the relationship between metal bioavailability and metal toxicity to chironomid larvae emergence. A strong dose-toxicity relationship between nickel bioavailability (nickel assimilation rate) and toxicity (22 days emergence ratio) indicated exposure to bioavailable nickel in the sediment induced toxic effects to the chironomids. Overall, our study demonstrated that the isotopically modified bioassay successfully determined metal bioavailability in sediments within a relatively short period of exposure. Because of its speed of measurement, it may be used at the initial screening stage to rapidly diagnose the bioavailable contamination status of a site.

Risk Assessment for a Twin-Screw Granulation Process Using a Supervised Physics-Constrained Auto-encoder and Support Vector Machine Framework.

Quality risk management is an important task when it pertains to the pharmaceutical industry, as this is directly related to product performance. With the ICH Q9 guidelines, several regulatory bodies have encouraged the pharmaceutical industry to implement risk management plans using scientific and systemic approaches such as quality-by-design to asses product quality. However, the implementation of such methods has been challenging as assessment of risks requires accurate quantitative models to predict changes in quality when variations occur. This study describes a framework that quantitatively assesses risk for a twin screw wet granulation process. This framework consists of a physics-constrained autoencoder system, whose outputs are constrained using physics-based boundary conditions. The latent variables obtained from the auto-encoder are used in a support vector machine-based classifier to understand the granule growth behavior occurring within the system. This framework is able to predict the process outcomes with 86% accuracy and classify the granule growth regimes with a true positive rate of 0.73. Based on the classification the risk associated with the process can be estimated.

Interventions Risk Evaluation and Management in Aseptic Manufacturing.

Interventions performed by personnel during an aseptic process can be a key source of microbiological contamination of sterile biopharmaceutical products, irrespective of the type of manufacturing system used. Understanding the relative risk of this source of contamination provides valuable information to help make decisions for the design, qualification, validation, operation, monitoring, and evaluation of the aseptic process. These decisions can be used to improve the aseptic process and provide assurance of the sterility of the products. To achieve these goals, an assessment of the contamination risk is needed. This risk assessment should be objective, accurate, and useful. This article presents an Intervention Risk Evaluation Model (IREM) philosophy and an objective, accurate, and useful method for intervention risk determination. The IREM uses a key word approach to identify, obtain, measure, and evaluate intervention risk factors. This article presents a general discussion of the method with the help of a case study to illustrate the development of the model, whereas subsequent parts would focus on application of this model with practical examples. This not only attempts to create objectivity of the entire process, but it develops awareness of the associated risks among shop floor operators, which can lead to a reduction of the overall risk level of the process and an improvement in the sterility assurance level.

The Identification of Quality Risk Factors for Non-biological Complex Drugs and Epilepsy Drugs Using Statistical Analysis of Formulation-Based Recalls in the USA.

Pharmaceutical companies use the quality by design (QbD) approach to build high-quality drug products. A thorough understanding of risk factors is required to successfully employ QbD. In order to better understand risk factors that potentially impact drug product quality and inform future QbD approaches, we hypothesized root causes of drug product recalls based on publicly available data and a retroactive analysis of drug products recalled by the United States Food and Drug Administration (USFDA) from 2012 to 2018. We focused on two categories of drug products that pose unique regulatory challenges and an increased risk of shortage that could hinder the adequate supply of quality medicine to the patient. Knowing the significant risk factors from previous drug product recalls can help inform QbD and avoid future recalls. Quality recall reasons were studied individually to find risk factors associated with each recall category. Logistical regression statistical tests were done in R using a significance level of 0.05 to find correlations between a recalled product and its manufacturing information such as excipients and manufacturing steps. The results showed significant positive and negative correlations, such as products containing magnesium stearate are more likely to be recalled for impurities and degradation. This information could be used in the future to inform the design and manufacturing of drug products, ensuring consumers receive high-quality products with a low risk of recall.

A Proposal of a Combined Convergence Regulatory Strategy Applied to Post-approval Changes by Latin American Countries, Reducing Workload and Allowing Continuous Improvement to Guarantee the Quality, Safety, and Efficacy of Medicines.

In recent years, post-approval changes (PACs) for medicinal products have increased faster than the national regulatory agencies can attend to without causing any negative impact. This study presents a proposal for regulatory management based on our analysis of the data available from the national regulatory agencies of Latin America on the total post-approval changes evaluated, and the time spent in the process. A retrospective search on the official websites of competent national regulatory authorities (NRAs) of 14 Latin American countries (México, Guatemala, Nicaragua, Honduras, El Salvador, Panamá, Costa Rica, Venezuela, Colombia, Ecuador, Peru, Argentina, Chile and Brazil) was conducted to collect data on post-approval changes in the last 4-6 years, up to January 2021. The NRAs considered were Brazil, México, Colombia, and Costa Rica. Our analysis was focused on the post-approval changes that required approval before implementation, those that were submitted, and those that were submitted and approved for small molecules, biologics, and biotechnological products. The results indicated differences in the regulatory processes and procedures applied by the different agencies. We also found that the implementation of the PACs was directly impacted by limited resources, which puts the medication supply for chronic treatments at risk resulting in serious consequences for patients. For local decision-making, Latin American NRAs should implement regulatory pathways already made by regulatory agencies included in the World Health Organization Listed Authorities on PAC approval to optimize their resources and to ensure the continuity of medicine supply for their patients.

Quality by design (QbD) in the formulation and optimization of liquid crystalline nanoparticles (LCNPs): A risk based industrial approach.

The intersection of lipid-based nanoparticles and lyotropic liquid crystals has provided a novel type of nanocarrier system known as 'lipid-based lyotropic liquid crystals' or 'liquid crystalline nanoparticles' (LCNPs). The unique advantages and immense popularity of LCNPs can be exploited in a better way if the formulation of LCNPs is done using the approach of quality by design (QbD). QbD is a systematic method that can be utilized in formulation development. When QbD is applied to LCNPs formulation, it will proffer many unique advantages, such as better product and process understanding, the flexibility of process within the design space, implementation of more effective and efficient control strategies, easy transfer from bench to bedside, and more robust product. In this work, the application of QbD in the formulation of LCNPs has been explored. The elements of QbD, viz. quality target product profile, critical quality attributes, critical material attributes, critical process parameters, quality risk management, design of experiments, and control strategy for the development of LCNPs have been explained in-depth with case studies. The present work will help the reader to understand the nitty-gritties in the application of QbD in the formulation of LCNPs, and provide a base for QbD-driven formulation of LCNPs with a regulatory perspective.

A Systematic Review Assessing Clinical Utility of Curcumin with a Focus on Cancer Prevention.

SCOPE: There is extensive pre-clinical evidence for utility of curcuminoids across many diseases with a particular focus on cancer prevention, yet there remains a paucity of clinical evidence for its approved use. To assess current knowledge on the broader potential for clinical efficacy of curcumin and in particular, in cancer prevention strategies, this study undertook a systematic review determining the number and quality of randomized controlled trials (RCTs) undertaken across any pathology. METHODS AND RESULTS: Search strategies for RCTs using a quantifiable amount of curcuminoids, are applied across Medline (Medical Literature Analysis and Retrieval System Online), Embase (Excerpta Medica dataBASE), Cochrane and clinicaltrials.gov. There are 314 curcuminoid-based RCTs, with 100 of these revealing significant within- and between-group changes relating to the primary outcome. Twenty three studies are conducted in a setting where there is an increased risk of cancer. Fifteen of these meet all prescribed quality criteria, and 10 reveal positive outcomes. CONCLUSIONS: A substantial number of studies reveal positive outcomes following curcumin use. However, despite the vast array of preclinical data, there are relatively few RCTs conducted in the prevention setting. Future approaches to trials must deliver improved robustness and credibility of curcumin-related research to facilitate approvals for use in clinical settings.

Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs.

Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation is increasingly used as a tool in drug product development, not only in support of clinical pharmacology applications (e.g., drug-drug interaction, dose selection) but also from quality perspective, enhancing drug product understanding. This report provides a summary of the status and the application of PBPK absorption modeling and simulation in new drug application (NDA) submissions to the U.S. Food and Drug Administration to support drug product quality (e.g., clinically relevant dissolution specifications, active pharmaceutical ingredient (API) particle size distribution specifications). During the 10 years from 2008 to 2018, a total of 24 NDA submissions included the use of PBPK absorption modeling and simulations for biopharmaceutics-related assessment. In these submissions, PBPK absorption modeling and simulation served as an impactful tool in establishing the relationship of critical quality attributes (CQAs) including formulation variables, specifically in vitro dissolution, to the in vivo performance. This article also summarizes common practices in PBPK approaches and proposes future directions for the use of PBPK absorption modeling and simulation in drug product quality assessment.Graphical abstract.

[Application of traditional Chinese medicine(TCM) traceability system based on TCM quality characteristics and HACCP system].

It is crucial to establish a complete set of traditional Chinese medicine(TCM) quality traceability management process system, in order to stabilize the pricing order of TCM market and reconstruct the transmission path of TCM quality signals. In this study, we reviewed the mature experience of food and drug supervision at home and abroad, analyzed the quality characteristics of TCM, and put forward that the quality control of TCM products can learn from the hazard analysis and critical control point(HACCP) system in food safety quality control. This study points out that the HACCP system provides not only technical guidance for the traceability management of TCM, but also ideas for improving the quality of TCM products and the safety risk control of TCM. The application of the HACCP system in TCM quality control can help establish an international dialogue platform for TCM and help realize the modernization and internationalization of TCM industry.

[French Health Authority certification visit in a radiotherapy department]. / Conduite d'une visite de certification par la Haute Autorité de santé dans un service de radiothérapie.

The French Higher Health Authority's (Haute Autorité de santé [HAS]) certification process is an important issue for a health care facility and in particular for a radiotherapy department. It is based on a quality-risk management methodology driven by the commitment and involvement of professionals. The radiotherapy department of the university hospital in Brest (France) has been engaged for many years in a demanding quality-risk management policy implementation, subjected to regular inspections by the French Nuclear Safety Authority (Autorité de sûreté nucléaire [ASN]). This implementation is driven by a strong commitment from department managers, who are determined to maintaining an efficient level for care quality and safety.

Toolkit for ICH E6 (R2) Quality Risk Management for Small to Medium Size Companies.

One of the most significant revisions to the ICH E6 GCP Guideline in the last 20 years was issued in November 2016, adopted by the EMA in December 2016 and by the FDA as a Guidance Document in March 2018. The new section on Quality Management requires the implementation of a systematic approach for managing risks throughout the course of a clinical study. The addendum also emphasizes appropriate sponsor oversight. Currently available risk management solutions are fairly elaborate, having been developed for and adopted mainly by larger companies. Small to medium size companies find these solutions too complex and not easily adaptable. In this paper, we present a simple but robust toolkit for clinical study risk management for small to medium sized organizations in order to facilitate compliance. The toolkit consists of customizable templates for the following: Clinical Risk Management SOP; Clinical Risk Management Plan; Vendor Oversight SOP; Vendor Oversight Plan; and Clinical Risk Log. The tools were prepared by the DIA GCP-QA Community members and presented at the 2018 DIA Annual Meeting in Boston.

Quality Risk Management and Quality by Design for the Development of Diclofenac Sodium Intra-articular Gelatin Microspheres.

The aim of the present study was to evaluate the development of an intra-articular nonsteroidal anti-inflammatory drug gelatin microsphere formulation based on quality risk management and quality by design approaches. Specifically, after setting the quality target product profile and the critical quality attributes, risk assessment was performed by constructing Ishikawa fishbone diagrams based on preliminary hazard analysis. A Plackett-Burman screening experimental design was applied in order to identify the factors (previously classified by risk assessment analysis as having high risk of failure) having a statistically significant impact on the formation of gelatin microspheres. Particle size, polydispersity index, and drug loading were used as responses, while diclofenac sodium was selected as a model drug. All drug-loaded gelatin microspheres were prepared by emulsion-crosslinking process. Screening results showed that gelatin type, surfactant type and quantity, oil phase type, emulsification speed, and glutaraldehyde's concentration had a statistically significant impact on microsphere's final and intermediate critical quality attributes. A design space was then constructed based on central composite design overlaying contour plots, while verification experiments for the optimum suggested formulation (derived from a set control strategy) showed good agreement between the predicted and the experimentally observed results. In addition, the physicochemical characterization of the optimum formulation showed the formation of significant molecular interactions between the drug and the gelatin matrix, leading to the complete amorphization of diclofenac within the microsphere structure, while dissolution release experiments showed a biphasic release profile which extended the drug's release for up to 30 days, governed by a Fickian diffusion release mechanism.

Managing Excipient Supplier Name and Address Changes in the Pharmaceutical Quality System.

It is important to identify, assess, and address current barriers to implementation of post-approval changes that are intended to ensure continued (uninterrupted) operations and drive innovation and continual improvement in a maximally efficient, agile, and flexible pharmaceutical manufacturing sector. Leveraging the International Conference for Harmonisation Quality Guideline Q10 provides regulatory relief when it comes to addressing changes related to excipients, specifically excipient supplier's name and address changes, which will ensure a sustainable, reliable global supply and the availability of high quality product to patients through the entire commercial lifecycle of a product without extensive regulatory oversight.