Good Manufacturing Practice Compliance Research Articles

Standardized production of hPSC-derived cardiomyocyte aggregates in stirred spinner flasks.

A promising cell-therapy approach for heart failure aims at differentiating human pluripotent stem cells (hPSCs) into functional cardiomyocytes (CMs) in vitro to replace the disease-induced loss of patients' heart muscle cells in vivo. But many challenges remain for the routine clinical application of hPSC-derived CMs (hPSC-CMs), including good manufacturing practice (GMP)-compliant production strategies. This protocol describes the efficient generation of hPSC-CM aggregates in suspension culture, emphasizing process simplicity, robustness and GMP compliance. The strategy promotes clinical translation and other applications that require large numbers of CMs. Using a simple spinner-flask platform, this protocol is applicable to a broad range of users with general experience in handling hPSCs without extensive know-how in biotechnology. hPSCs are expanded in monolayer to generate the required cell numbers for process inoculation in suspension culture, followed by stirring-controlled formation of cell-only aggregates at a 300-ml scale. After 48 h at checkpoint (CP) 0, chemically defined cardiac differentiation is induced by WNT-pathway modulation through use of the glycogen-synthase kinase-3 inhibitor CHIR99021 (WNT agonist), which is replaced 24 h later by the chemical WNT-pathway inhibitor IWP-2. The exact application of the described process parameters is important to ensure process efficiency and robustness. After 10 d of differentiation (CP I), the production of ≥100 × 106 CMs is expected. Moreover, to 'uncouple' cell production from downstream applications, continuous maintenance of CM aggregates for up to 35 d in culture (CP II) is demonstrated without a reduction in CM content, supporting downstream logistics while potentially overcoming the requirement for cryopreservation.

Manufacturing Parameters for the Creation of Clinical-Grade Human-Induced Pluripotent Stem Cell Lines From Umbilical Cord Mesenchymal Stromal Cells.

Induced pluripotent stem cells (iPSCs) are reprogrammed cells with a remarkable capacity for unlimited expansion and differentiation into various cell types. Companies worldwide are actively engaged in developing clinical-grade iPSC lines to address the needs of regenerative medicine, immunotherapies, and precision medicine. However, ensuring the safety and quality of iPSCs is essential, with adherence to Good Manufacturing Practices (GMP) and ethical considerations being paramount. Perinatal cell and tissue banks, such as umbilical cord (UC) blood and tissue banks, are emerging as ideal sources for generating iPSCs due to their unique characteristics and GMP compliance. These banks provide access to immature cells with limited environmental exposure, known family and medical histories of donors, and readily available resources, thereby reducing the time and cost associated with personalized treatment strategies. This study describes the establishment of the first clinical-grade iPSC lines from umbilical cord mesenchymal stromal cells in Brazil. The process involved rigorous quality control measures, safety assessments, and adherence to regulatory standards, resulting in iPSCs with the necessary characteristics for clinical use, including sterility, genomic integrity, and stability. Importantly, the study contributes to the development of a Current Good Manufacturing Practice-compliant iPSC production pipeline in Brazil, using commercially available, chemically defined, and xeno-free products, along with validation by national outsourced laboratories, thereby facilitating the adoption of this technology within the country. The study emphasizes Brazil's contribution to the progress of translational medicine and the promotion of scientific advancements within the field of regenerative and precision medicine.

Good manufacturing practice in low‐ and middle‐income countries: Challenges and solutions for compliance

AbstractApproximately 2 billion people globally have limited access to essential medicines, particularly those living in low‐ and middle‐income countries (LMICs). In addition, there is a higher prevalence of substandard and counterfeit medicines in LMICs, which may cause antimicrobial resistance and therapeutic failure. Good manufacturing practice (GMP) is key to ensuring access to high‐quality, safe and effective medicines, including active pharmaceutical ingredients and excipients used for manufacturing finished dosage forms. Compliance with GMP standards saves resources for both manufacturers (e.g. avoiding expensive product recalls) and governments (e.g. minimising compliance inspections). Concerted collaborations among different countries to harmonise GMP standards and procedures have occurred, and the World Health Organisation (WHO) GMP is commonly used in LMICs. However, barriers to GMP compliance remain apparent, particularly in LMICs. Pharmaceutical manufacturers in LMICs face several barriers such as inadequate resources and infrastructure, inefficient or weak regulation, a shortage of skilled people and limited training opportunities for manufacturing personnel. Although national regulatory authorities (NRAs) have been established in LMICs, most NRAs are not fully independent and are placed within the health department. NRAs in LMICs are not able to fully utilise international and regional reliance mechanisms and collaborations. Therefore, both NRAs and pharmaceutical manufacturers must be adequately supported through resources, infrastructure and capacity‐building opportunities. NRAs must be suitably empowered with assured functional independence. A comprehensive guideline for managing conflicts of interest among pharmaceutical manufacturers, procurement agencies and NRAs is needed. NRAs must liaise with other NRAs, participate in joint GMP inspections and leverage the expertise of regional or international collaborations. Pharmaceutical manufacturers in LMICs can leverage WHO GMP standards to improve GMP compliance and expand their market. However, as these solutions may have cost implications, prioritising key gaps for GMP compliance and optimisation of available resources are essential.

Current Good Manufacturing Practice (cGMP): An Overview for the Analytical Chemist

Good Manufacturing Practice (GMP) is the most significant regulation impacting the pharmaceutical industry and requires substantial investment in resources and time commitments. This paper provides a high-level overview of Current Good Manufacturing Practice (cGMP) regulations and related public quality standards. It discusses GMP compliance requirements and practices, emphasizing those relevant to the analytical chemist in development and quality control.

Compliance and regulatory considerations for the implementation of the multi-attribute-method by mass spectrometry in a quality control laboratory

Multi-attribute methods employing mass spectrometry are applied throughout the biopharmaceutical industry for product and process characterization purposes but are not yet widely accepted as a method for batch release and stability testing under the good manufacturing practice (GMP) regime, due to limited experience and level of comfort with the technical, compliance and regulatory aspects of its implementation at quality control (QC) laboratories. This article is the second part of a two-tiered publication aiming at providing guidance for implementation of the multi-attribute method by peptide mapping liquid chromatography mass spectrometry (MAM) in a QC laboratory. The first part [1] focuses on technical considerations, while this second part provides considerations related to GMP compliance and regulatory aspects. This publication has been prepared by a group of industry experts representing 14 globally acting major biotechnology companies under the umbrella of the European Federation of Pharmaceutical Industries and Associations (EFPIA) Manufacturing & Quality Expert Group (MQEG).

The Importance of Good Manufacturing Practices (GMP) in the Healthcare Industry

In the healthcare industry, maintaining high-quality standards is crucial to ensure the safety and efficacy of medical products. Good Manufacturing Practices (GMP) provide a set of guidelines and regulations that help ensure the consistent production, control, and quality assurance of pharmaceuticals, medical devices, and other healthcare products. This paper explores the significance of GMP in the healthcare industry, highlighting its background, objectives, role in safeguarding patient health and maintaining public trust. It examines the key principles of GMP, its regulatory framework, and its impact on various aspects of the healthcare sector, including drug manufacturing, quality control, product safety, and regulatory compliance. Furthermore, the paper discusses the challenges and future perspectives of GMP implementation, emphasizing the need for ongoing advancements to meet the evolving demands of the industry. To summarize, adherence to GMP standards is crucial for the healthcare industry to produce high-quality, safe, and effective healthcare products. GMP compliance promotes patient safety, regulatory compliance, and innovation in the pharmaceutical industry.

Quality culture and knowledge management in the Japanese pharmaceutical industry - A cross-sectional study and case report.

Illicit pharmaceutical manufacturing, affecting the quality of drug products, has been frequently reported in Japan. Insufficient good manufacturing practice compliance and lack of quality culture in some pharmaceutical companies have been suggested as the underlying reasons for such cases. We aimed to focus on knowledge management and fostering of quality culture in pharmaceutical companies in Japan to understand their current situation and find a strategy for the availability of high-quality reliable pharmaceutical products. A wide-ranging questionnaire survey was conducted to understand the issues related to knowledge management and fostering of quality culture across pharmaceutical companies in Japan. A published investigation report on an illicit manufacturing case was closely examined by organizing the available facts using the diagram. Based on 395 responses to the questionnaire survey, we found that although pharmaceutical companies understand the importance of knowledge management and quality culture, issues exist in their operational methods. A total of 94% of the respondents agreed that they mentioned ″knowledge management″ as an enabler of the Pharmaceutical Quality System of ICH Q10, and 98% of the respondents accepted that insufficient fostering of quality culture leads to corporate risk. However, the survey revealed that many companies are struggling with this approach. Based on a report on an illicit manufacturing case, we analyzed the direct causes of misconduct and prepared a systematic summary that can be easily comprehended. Comparison of the illicit manufacturing case report with our questionnaire results suggests that many pharmaceutical companies do not regard the misconduct case as a situation that could occur in their company. With the revision of the Pharmaceuticals and Medical Devices Act and good manufacturing practice Ministerial Ordinance, we advocate the need for all employees of pharmaceutical companies to reconsider the priorities of their companies from the patient perspective.

Technical considerations for the implementation of the multi-attribute-method by mass spectrometry in a quality control laboratory

Multi-attribute methods employing mass spectrometry are applied throughout the biopharmaceutical industry for product and process characterization purposes but are not yet widely accepted as a method for batch release and stability testing under good manufacturing practice (GMP) due to limited experience and level of comfort with the technical, compliance and regulatory aspects of its implementation at quality control (QC) laboratories. Here, current literature related to the development and application of the multi-attribute method by peptide mapping liquid chromatography mass spectrometry (MAM) is compiled with the aim of providing guidance for the implementation of MAM in a QC laboratory. This article, focusing on technical considerations, is the first part of a two-tiered publication, whereby the second part will focus on GMP compliance and regulatory aspects. This publication has been prepared by a group of industry experts representing 14 globally acting major biotechnology companies under the umbrella of the European Federation of Pharmaceutical Industries and Associations (EFPIA) Manufacturing & Quality Expert Group (MQEG).

A Nontrivial Analysis of Patient Safety Risk from Parenteral Drug- and Medical Device-Borne Endotoxin.

A thorough and systematic analysis of potential endotoxin-related safety issues from parenteral drugs and devices is important to ensure appropriate current Good Manufacturing Practices, compendial requirements, standards and regulatory guidance. Lately, the US Food and Drug Administration has been expecting pharmaceutical firms to apply an arbitrary safety factor to compendial compliant drug specifications for endotoxin, potentially causing manufacturing challenges, supply issues and additional unwarranted costs. The aim of this study was to evaluate data from three disparate sources over an extended period of time, from 2008 to 2021, to determine if there exists an industry-wide risk to patients from parenteral drugs and devices, thereby evaluating if changes to current Good Manufacturing Practices or compendial requirements are indeed warranted. Food and Drug Administration data from current Good Manufacturing Practices non-compliance observations, product recalls and the FDA Adverse Event Reporting System were used as the three sources of data. Parenteral products were separated into drugs and devices, potential endotoxin-related patient safety issues were characterised in terms of the available non-compliance information, the type and number of product recalls, and the type and number of potential adverse events. Descriptive statistics in Microsoft Excel 2019 and Pivot tables were used for the analysis and presentation of the data. From 2011 to 2021, a total of 188 endotoxin-related current Good Manufacturing Practices compliance observations were recorded, 70% and 30% were associated with laboratory and manufacturing origins, respectively. Finished drug product testing accounted for 56% of these. In contrast, 95% of all endotoxin-related product recalls were associated solely with medical devices. Over the years 2008-2021, approximately 1.4% of all adverse events (23,663,780) were recorded with some reference to pyrexia (fever); however, there are sparse data categorically attributing this to the administration of parenteral drugs or devices or combinations of these possessing high levels of endotoxin. Analysis of data concerning drug- and device-borne endotoxin obtained from FDA data from current Good Manufacturing Practices non-compliance observations, product recalls and the FDA Adverse Event Reporting System demonstrated the absence of industry-wide issues with endotoxin contamination. Based upon these data, changes to current Good Manufacturing Practices and the compendial methodology of setting endotoxin specifications (and hence the compendial methodology of testing for endotoxins) are unwarranted.

Shortages of Prescription Drugs Due to Compliance and Quality Issues in Japan

Several good manufacturing practice (GMP) compliance issues and their associated quality problems that have been revealed since 2020 have led to large-scale recalls and supply suspensions of drug products in Japan. This paper provides an overview of the causes and countermeasures for supply disruptions of low-molecular-weight chemical pharmaceutical agents, focusing on quality-related issues. A recent increase in the use of generic drugs emphasized the importance of strengthening active pharmaceutical ingredient (API) supply chains and ensuring GMP compliance among drug manufacturers. In addition, increasing recalls in the drug products of certain marketing authorization holders due to storage stability problems strongly suggests the need to improve their development process considerably. Other measures to stabilize the supply of pharmaceuticals, including increasing stockpiles of APIs, were also discussed.

Barriers to Treg therapy in Europe: From production to regulation.

There has been an increased interest in cell based therapies for a range of medical conditions in the last decade. This explosion in novel therapeutics research has led to the development of legislation specifically focused on cell and gene based therapies. In Europe, the European medicines agency (EMA) designates any medicines for human use which are based on genes, tissues, or cells as advanced therapy medicinal products or advanced therapy medicinal products (ATMPs). In this article we discuss the hurdles to widespread adoption of ATMPs in Europe, with a focus on regulatory T cells (Tregs). There are numerous barriers which must be overcome before mainstream adoption of Treg therapy becomes a reality. The source of the cells, whether to use autologous or allogenic cells, and the methods through which they are isolated and expanded, must all meet strict good manufacturing practice (GMP) standards to allow use of the products in humans. GMP compliance is costly, with the equipment and reagents providing a significant cost barrier and requiring specialized facilities and personnel. Conforming to the regulations set centrally by the EMA is difficult, and the different interpretations of the regulations across the various member states further complicates the regulatory approval process. The end products then require a complex and robust distribution network to ensure timely delivery of potentially life saving treatments to patients. In a European market whose logistics networks have been hammered by COVID and Brexit, ensuring rapid and reliable delivery systems is a more complex task than ever. In this article we will examine the impact of these barriers on the development and adoption of Tregs in Europe, and potential approaches which could facilitate more widespread use of Tregs, instead of its current concentration in a few very specialized centers.

An assessment of adherence to the WHO-delineated good manufacturing practice by the pharmaceutical companies in Kabul, Afghanistan

BackgroundAfghanistan, a low-income landlocked country, is continuously suffering from domestic war and conflicts; the country struggles to provide quality healthcare services, including affordable medicinal products in the required quantity. Moreover, the quality standards of domestic pharmaceutical companies have not been established yet. One of the internationally recognized guidelines for monitoring manufacturing processes in pharmaceutical companies is Good Manufacturing Practice (GMP), recommended by World Health Organization (WHO). Therefore, this study aimed to assess whether a pharmaceutical company in Kabul, Afghanistan adheres to the GMP standards established by WHO.MethodA descriptive cross-sectional study was conducted to assess the WHO-delineated GMP compliance of 25 pharmaceutical companies in Kabul, Afghanistan. The inspection checklist was developed by Afghanistan's National Medicine and Healthcare Products Regulatory Authority (NMHRA) using the WHO-delineated GMP guidelines. In addition, direct observation, interviews with respective delegates, and documentation reviews were conducted to collect research data.ResultOnly 38.33% (1.14 ± 1.08) of GMP contents were complied. Personnel 66.67% (2 ± 1.15) and materials 58.67% (1.76 ± 1.11) were the most commonly complied components, whereas the product recall 12.98% (0.39 ± 0.85), quality assurance 16.44% (0.49 ± 0.81) and quality control laboratory 28.35% (0.85 ± 1.12) were the least complied ones.ConclusionNone of the GMP components was fully adhered to by the pharmaceutical companies in Kabul, Afghanistan. Quality control and assurance should be implemented immediately, including validation and qualification practices.

A Novel Xeno-Free Method to Isolate Human Endometrial Mesenchymal Stromal Cells (E-MSCs) in Good Manufacturing Practice (GMP) Conditions.

The cyclic regeneration of human endometrium is guaranteed by the proliferative capacity of endometrial mesenchymal stromal cells (E-MSCs). Due to this, the autologous infusion of E-MSCs has been proposed to support endometrial growth in a wide range of gynecological diseases. We aimed to compare two different endometrial sampling methods, surgical curettage and vacuum aspiration biopsy random assay (VABRA), and to validate a novel xeno-free method to culture human E-MSCs. Six E-MSCs cell samples were isolated after mechanical tissue homogenization and cultured using human platelet lysate. E-MSCs were characterized for the colony formation capacity, proliferative potential, and multilineage differentiation. The expression of mesenchymal and stemness markers were tested by FACS analysis and real-time PCR, respectively. Chromosomal alterations were evaluated by karyotype analysis, whereas tumorigenic capacity and invasiveness were tested by soft agar assay. Both endometrial sampling techniques allowed efficient isolation and expansion of E-MSCs using a xeno-free method, preserving their mesenchymal and stemness phenotype, proliferative potential, and limited multi-lineage differentiation ability during the culture. No chromosomal alterations and invasive/tumorigenic capacity were observed. Herein, we report the first evidence of efficient E-MSCs isolation and culture in Good Manufacturing Practice compliance conditions, suggesting VABRA endometrial sampling as alternative to surgical curettage.

Automating the final cell therapy bioprocess step for robust CMC/GMP compliance Cell & Gene Therapy Insights 2021; 8(1), 61–74

Until recently, Tracy Moore worked with the Medicines and Healthcare products Regulatory Agency (MHRA) as an Expert Good Manufacturing Practice (GMP) Inspector, specializing in sterile products and data integrity. In the following article and interview, she draws on this experience to highlight:Regulatory considerations and requirements for GMP compliance when manufacturing advanced therapy medicinal products (ATMPs) How to identify specific gaps in compliance that may occurCommon areas of weakness found upon inspectionThe potential benefits and pitfalls of open versus closed processes

Pharmacokinetics of a 503B outsourcing facility-produced theophylline in dogs.

Theophylline is an important drug for treatment of canine chronic bronchitis and bradyarrhythmias, but new products require validation since pharmacokinetics in dogs can vary by formulation. A new, 503B outsourcing facility-produced theophylline product (OFT) is available for veterinary use. Outsourcing facilities have many advantages over traditional compounding sources including current good manufacturing practice compliance. The purpose of this study was to establish the pharmacokinetics of OFT in dogs. Eight healthy dogs received 11 mg/kg intravenous aminophylline and 10 mg/kg oral OFT followed by serial blood sampling in a two-way, randomized, crossover design with 7-day washout. Plasma theophylline concentrations were quantified by liquid chromatography-mass spectrometry. Bioavailability, maximum concentration, time to maximum concentration, half-life and area under the curve were: 97 ± 10%, 7.13 ± 0.71 μg/mL, 10.50 ± 2.07 h, 9.20 ± 2.87 h, and 141 ± 37.6 μg*h/mL, respectively. Steady-state predictions supported twice daily dosing of the OFT, but specific dosage recommendations are hindered by lack of a canine-specific therapeutic range for plasma theophylline concentration. These findings suggest that the OFT is well absorbed and can likely be dosed twice daily in dogs, but future pharmacodynamic and clinical studies are needed to establish a definitive therapeutic range for theophylline in this species.

Evaluation of GMP Compliance on Cosmetics: Case Study on Cosmetic Industries in Indonesia

The cosmetic industry has been designated as one of the priority sectors, as stated in the Master Plan of National Industry Development 2015-2035. The priority development programs in the cosmetic sector are mastering technology and building international standard manufacturing capabilities. The cosmetic industry's ability to comply with international standards, including good manufacturing practices (GMP), is mandatory, mainly since the ASEAN Harmonized Cosmetics Regulatory Scheme was fully implemented. It has been almost 14 years since the scheme's implementation, and the Indonesian FDA has enforced all stipulations within the scheme framework. This study aims to evaluate the policy impact of GMP compliance on cosmetic industries in Indonesia through a cost-benefit analysis. A qualitative descriptive method is conducted to identify the benefits and the costs of GMP compliance and determine the importance or significance of the benefits and costs components. The result findings showed the more significant cost components include maintenance of building and facilities, quality control, maintenance of equipment, and sanitation and hygiene. In comparison, the weight scores of the benefit components do not differ much, with the benefit of increased product sales being perceived to be the most important.

COVID-19 vaccines and treatments: When speed is necessary and not enough.

COVID-19 vaccines and treatments: When speed is necessary and not enough.

Regulatory Comparative Quality Systems of India and USA and its Significance in Pharmaceutical Industry Facilities

The intentions of the current study are to compare the regulatory requirements of USFDA and CDSCO-Schedule M in GMP with significance to the pharmaceutical industry to speed up the criteria for enforcement to facilitate the regulatory approval of specified pharmaceutical products in the United States and India. The literature search is done using different resources, such as regulatory authority websites, pharmaceutical review articles, journals and public domains. To discuss the numerous dilemmas, root causes and challenges confront by pharmaceutical companies and to suggest remedial and pro-active measures to GMP issues and all pharmaceutical manufacturers are required to develop and enforce effective quality control systems in order to ensure quality. Whereas the regulated markets like the United States have well-established guidance compared to emerging markets like India on good manufacturing practice compliance, to assess the effectiveness of this quality management systems, inspections are carried out on manufacturing units. The primary objective of the analysis is to differentiate between the type of application or license that causes the inspection and the outcome of the inspection and to also provide enough details identified by the authority during the evaluation.

Good Manufacturing Practice for Medicinal Products in Bulgaria: an Analysis of Regulatory Inspection Findings.

The manufacture of medicinal products for human use in the European Economic Area is governed by European Directives and Regulations stipulating the relevant principles and guidelines of Good Manufacturing Practice, describing the minimum standard to be fulfilled in the production processes. To present analysis of the deficiencies reported following Good Manufacturing Practice inspections in Bulgaria in two consecutive years (2016, 2017) and to compare them with results from similar inspections reported by other EU member states. A retrospective study was carried out by reviewing the complete Good Manufacturing Practice inspection reports of all manufacturers conducted by the Bulgarian Drug Agency in 2016 and 2017, according to relevant requirements and applicable local legislation. The items reviewed were scope of inspection, type of companies, classification of deficiencies – ‘critical’, ‘major’ and ‘other significant deficiencies’, their nature and reference to EU Good Manufacturing Practice. The analyzed data included 55 inspections, revealing 460 various deficiencies, of which 2 were critical and 102 – major. Twenty inspections were performed in 2016 vs. 35 inspections in 2017. The pattern of deficiencies was similar to the findings of other EU regulatory agencies, showing that equivalent requirements were applied. Our analysis showed that Bulgarian Drug Agency inspectors rarely raised deficiencies related to Computer Systems, Qualification/Validation, Personnel and Qualification of Suppliers unlike other EU regulators agents. Our analysis of Good Manufacturing Practice inspection findings in 2016 and 2017 showed that the Bulgarian Drug Agency demonstrated its ability to detect non-compliances and take necessary regulatory actions. Quality related issues constitute the main reasons for non-compliances with the requirements.

Determination of Select Nonvolatile Ginger Constituents in Dietary Ingredients and Finished Dosage Forms, First Action 2018.04.

A consensus industrial reference was necessary to be established for meeting the U.S. Food and Drug Administration's current Good Manufacturing Practice Compliance for the manufacture and quality control of dietary ingredients and supplements that contain ginger rhizome, dry extract, and/or purified nonvolatile ginger constituents. An analytical method has been developed, validated, and previously published for identifying and quantifying 6-,8- and 10-gingerols, 6-, 8- and 10-shogaols, 6-paradol, and zingerone. HPLC with UV-Vis detector was used for the determination of nonvolatile ginger constituents by following AOAC Guidelines for Single-Laboratory Validation. Sample was accurately weighed and diluted with acidified water and methanol mixture. The sample solution was then sonicated and filtered through a PTFE filter and analyzed under a linear gradient scheme instrument condition. A reverse-phase superficially porous particle C18 column and an absorption wavelength of 230 nm were used for analyte separation and determination. The method was demonstrated to be selective, linear (R2 > 0.999), specific, accurate (91.1-103.2% spike recovery rate), and precise (RSDr < 5%, RSDR < 8%) and therefore met all AOAC Standard Method Performance Requirements (2017.012) criteria. With a relatively short run time (12 min) and optimized extraction solvent system, the method has been validated to simultaneously determine nonvolatile ginger constituents in a variety of dietary ingredients and dietary supplements matrices including dry extract, powder, tablet, capsule, liquid capsule, softgel capsule, and oleoresin.