Good Manufacturing Practice Research Articles

All-in-one CRISPR/Cas-engineered glucocorticoid-receptor knock-out EBV-gp350-CAR knock-in T cells are potent and resistant to dexamethasone

BackgroundEpstein-Barr virus (EBV) reactivation in immunocompromised patients and post-transplantation is associated with morbidity, mortality and with the onset of a variety of malignant diseases. Adoptive T-cell therapies have emerged as promising therapeutic options, but post-transplant immunosuppression jeopardizes the protective anti-EBV immune surveillance by adoptively transferred T cells.MethodsUsing an all-in-one CRISPR/Cas-mediated approach, we inserted an anti-EBV (gp350) CAR into the T-cell receptor (TRAC) locus and simultaneously knocked-out the glucocorticoid receptor (GR) on a good manufacturing practice (GMP)-compatible platform.ResultsCAR knock-in (CARKI) was confirmed in primary human T cells on genetic and on protein level with a mean efficiency of 41%. With 83%, additional GR knock-out was highly efficient in CARKI cells. On a functional level CARKIGRKO T cells showed target-specific potency in terms of cytokine secretion patterns, proliferative capacity and cytotoxic activity against gp350-expressing target cells. Further, CARKIGRKO T cells were insensitive to dexamethasone treatment and maintained T-cell functionality. In contrast, CARKIGRKO T cells were sensitive to the GR-independent immunosuppressant cyclosporine A (CsA), thereby providing a rescue treatment for patients in case of safety issues.ConclusionsThe study lays the proof-of-concept for virus-free all-in-one GMP-manufacturing of glucocorticoid-resistant CAR T-cell products. Further, the glucocorticoid-resistant gp350-CAR T cells can provide a future therapeutic option for high-risk post-transplant patients with EBV-reactivations or patients with EBV-associated pathologies requiring steroid treatment.

Good Manufacturing Practice Validation and Radiation Dosimetry for the Clinical Application of a Novel α7-nAChR Radioligand: [11C]KIn83

Nicotinic acetylcholine receptor (α7-nAChR) plays a crucial role in cognitive functions like memory and attention. Positron emission tomography (PET) imaging of α7-nAChR is gaining attraction for understanding and monitoring central nervous system disorders, such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia. We developed [11C]KIn83, a novel α7-nAChR radioligand, and evaluated its biological properties. This study focused on two objectives: (1) to validate its Good Manufacturing Practice (GMP)-compliant production, and (2) to assess the dosimetry of [11C]KIn83 using non-human primate (NHP) whole-body PET data. Radiolabeling and drug product delivery of [11C]KIn83 were conducted using an automated synthesis module within a controlled GMP environment. The quality control tests performed adhered to the European Pharmacopoeia guidelines. The production of [11C]KIn83 was validated according to GMP standards, encompassing automated synthesis and quality control measures. For the dosimetry assessment, two female cynomolgus monkeys underwent whole-body PET scans. The radioactivity values injected for [11C]KIn83 were 150 MBq and 155 MBq, respectively, with an estimated radiation dose of 0.0047 mSv/MBq. Our findings pave the way for future clinical studies that investigate the potential of [11C]KIn83 to measure α7-nAChR, aiding our understanding and possibly supporting diagnoses of different cognitive disorders.

Pelatihan Good Farming Practises, dan Good Manufacturing Practises untuk Meningkatkan Daya Saing UKM Abinisa Serang Banten

UKM Abinisa is a leading producer in the duck egg processing industry in Serang, Banten. To maintain competitiveness, SME need to focus on product innovation and implement Good Manufacturing Practices (GMP) and Good Farming Practices (GFP) to ensure product safety. This community service program aimed to provide training related to GMP and GFP. Socialization and training activities were held on the same date in Sujung Village, Tirtayasa Subdistrict, Serang Regency, Banten. The steps of the activity included: a) pre-activity preparation, b) internal coordination, c) implementation, and d) evaluation. The activity began with a visit to a duck farm owned by one of UKM Abinisa's farmer partners. The first training session covered techniques for proper and effective feeding, disease prevention, and maintaining healthy living conditions for ducks. Practical sessions included duck herding or releasing them onto post-harvest rice fields, a method well-suited to the extensive rice fields around Sujung Village. This method is known as the rice-duck integration system. The evaluation results showed a high level of participant satisfaction, with the highest-rated material being Material 1: Duck Farming, scoring 69.57%. Material 3 scored similarly at 65.22%. Material 2: Introduction to GMP received the lowest score, likely because of the complexity and detailed nature of the regulations, which were unfamiliar to all participants.

Inhibition of TGF-β signaling enhances osteogenic potential of iPSC-derived MSCs.

Mesenchymal stem cells (MSCs) represent the most commonly utilized type of stem cell in clinical applications. However, variability in quality and quantity between different tissue sources and donors presents a significant challenge to their use. Induced pluripotent stem cells (iPSCs) are a promising and abundant alternative source of MSCs, offering a potential solution to the limitations of adult MSCs. Nevertheless, a standardized protocol for the differentiation of iPSCs into iPSC-derived mesenchymal stem cells (iMSCs) has yet to be established, as the existing methods vary significantly in terms of complexity, duration, and outcome. Many straightforward methods induce differentiation by culturing iPSCs in MSC media which are supplemented with fetal bovine serum (FBS) or human platelet lysate (hPL), followed by selection of MSC-like cells by passaging. However, in our hands, this approach yielded inconsistent quality of iMSCs, particularly in terms of osteogenic potential and premature senescence. This study examines the impact of the selective TGF-β inhibitor SB431542 on iMSC differentiation, demonstrating that TGF-β inhibition enhances osteogenic potential and reduces premature senescence. Additionally, we present a reliable, xeno-free method for producing high-quality iMSCs that can be adapted for Good Manufacturing Practice (GMP) compliance, thus enhancing the potential for clinical applications.

Nutritional and microbiological quality of smoked sardinella (Sardinella aurita) canned in olive oil

Round sardinella have an important role in food security due to their abundance, low purchase price and nutritional quality. Despite its economic and social importance in Senegal, the sardinella fishery faces a multitude of problems that could compromise the development of the sector, and the food and nutritional security of the people who consume it. The aim of this study was to contribute to the valorization of round sardinella by developing smoked canned sardinella and then improving its availability and creating added value. Fresh round sardinella purchased on the “Yarakh” fish landing ground (Dakar) were used for the cans production. Fresh round sardinellas are decontaminated by removing heads, scales and viscera, then trimmed by opening them in a “wallet” to wash them. The washed sardinellas are then salted brine (5%) before being smoked at 85oC. The smoked sardinellas are then stored in canning jars, before the olive oil is added. The canned sardinella were sterilized at 121oC for 20 min. The physico-chemical and microbiological characteristics of fresh and smoked canned sardinella were assessed. The chemical analysis showed an increase in proteins from 22.4 to 26.7% and lipids from 10.1to 13.1%, respectively, in fresh and canned sardinella. The canned sardinella had higher mineral values than the fresh sardinella, with iron, iodine, potassium and calcium contents of 2.51 mg/100 g, 0.07 mg/kg, 378 mg/100 g and 610 mg/100 g, respectively. For minerals, a significant increase (p<0.05) was noted in the iron content going from 1.78 to 2.51 mg/100 g, in the iodine content from 0.03 to 0.07 mg/kg and the calcium content increase from 382 to 611 mg/100 g. These nutrient values make smoked canned sardinella a potentially beneficial food and could be another way for preventing malnutrition through a dietary approach. The microbiological analyses showed that fresh and canned sardinella have a satisfactory microbiological quality according to the microbiological requirements for fishery and aquaculture products. The quality of the raw material and the use of good manufacturing practice during production can ensure the safety of canned products. The yield of smoked sardinella was 29.3% of fresh sardinella. Hopefully commercialization of smoked canned sardinella can lead to the increased availability of nutritious food in Senegal. Key words: round sardinella, sardinella aurita, canned fish, iron, iodine, calcium, Senegal

An Overview Of Quality Assurance and Quality Control

This review offers an overview of Quality Assurance (QA) and Quality Control (QC) in the pharmaceutical industry, highlighting their vital roles in ensuring the safety, efficacy, and reliability of products. QA involves preventing defects and ensuring quality throughout a product’s lifecycle, while QC focuses on identifying and correcting defects through testing. Key regulatory frameworks like Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP), and International Council for Harmonisation (ICH) guidelines are discussed, along with Good Warehousing Practices (GWP) for storage integrity. The document covers drug discovery and development, validation processes, and the roles of regulatory authorities such as the FDA, WHO, and MHRA. It concludes by introducing Quality by Design (QbD) and Process Analytical Technology (PAT) as methods for embedding quality from the start.

Data-driven model predictive control for continuous pharmaceutical manufacturing.

Data-driven model predictive control for continuous pharmaceutical manufacturing.

Re-imagining human cell culture media: Challenges, innovations, and future directions.

Re-imagining human cell culture media: Challenges, innovations, and future directions.

Efficient Manufacturing of CAR-T Cells from Whole Blood: A Scalable Approach to Reduce Costs and Enhance Accessibility in Cancer Therapy

Efficient Manufacturing of CAR-T Cells from Whole Blood: A Scalable Approach to Reduce Costs and Enhance Accessibility in Cancer Therapy

Good Manufacturing Practice-grade fibronectin for hollow-fiber bioreactor cell manufacture: a mesenchymal stromal cell case study.

Good Manufacturing Practice-grade fibronectin for hollow-fiber bioreactor cell manufacture: a mesenchymal stromal cell case study.

Excipients in drug delivery systems: A comprehensive review of approved inactive ingredients for human ophthalmic formulations.

Excipients in drug delivery systems: A comprehensive review of approved inactive ingredients for human ophthalmic formulations.

Cell culture expansion media choice affects secretory, protective and immuno-modulatory features of adipose mesenchymal stromal cell-derived secretomes for orthopaedic applications.

Cell culture expansion media choice affects secretory, protective and immuno-modulatory features of adipose mesenchymal stromal cell-derived secretomes for orthopaedic applications.

Advancing regenerative medicine: the Aceman system’s pioneering automation and machine learning in mesenchymal stem cell biofabrication

Mesenchymal stem cells (MSCs) are pivotal in advancing regenerative medicine; however, the large-scale production of MSCs for clinical applications faces significant challenges related to efficiency, cost, and quality assurance. We introduce the Automated Cell Manufacturing System (Aceman), a revolutionary solution that leverages machine learning and robotics integration to optimize MSC production. This innovative system enhances both efficiency and quality in the field of regenerative medicine. With a modular design that adheres to good manufacturing practice standards, Aceman allows for scalable adherent cell cultures. A sophisticated machine learning algorithm has been developed to streamline cell counting and confluence assessment, while the accompanying control software features customization options, robust data management, and real-time monitoring capabilities. Comparative studies reveal that Aceman achieves superior efficiency in analytical and repeatable tasks compared to traditional manual methods. The system's continuous operation minimizes human error, offering substantial long-term benefits. Comprehensive cell biology assays, including Bulk RNA-Seq analysis and flow cytometry, support that the cells produced by Aceman function comparably to those cultivated through conventional techniques. Importantly, Aceman maintains the characteristic immunophenotype of MSCs during automated subcultures, representing a significant advancement in cell production technology. This system lays a solid foundation for future innovations in healthcare biomanufacturing, ultimately enhancing the potential of MSCs in therapeutic applications.

Retina-specific laminin-based generation of photoreceptor progenitors from human pluripotent stem cells under xeno-free and chemically defined conditions.

Photoreceptor cell replacement therapy for retinal degenerative diseases is a promising approach. Presently, most protocols aimed at generating clinically safe and functional cells for retinal diseases face challenges such as low efficiency, poor reproducibility, and time-consuming and complex procedures. These could be due to the dependency on animal-derived components in cell culture media and substrates that support the cell differentiation process. Such conditions are poorly defined chemically, which could affect the robustness of the method and hinder clinical translation of cell therapy in retinal diseases. Here, we describe a simple protocol that is xenogen free and chemically defined to differentiate human embryonic stem cells to photoreceptor progenitors. Human recombinant extracellular matrix laminin 523 and 521 isoforms were used to mimic the inter-photoreceptor matrix niche environment to promote the retinal cell differentiation process. This was also accomplished by the unique combination of two cell differentiation media that recapitulates the retinal development signaling processes. In comparison to other protocols, our protocol does not require any mechanical dissection, which can be technically subjective and tedious. Our directed differentiation method generates photoreceptor progenitors that express ~17% cone-rod homeobox (CRX) transcript based on single-cell transcriptomic analyses by day 32. These day 32 photoreceptor progenitors can be cryopreserved and still maintain high cell viability after thawing for cell transplantation. This protocol can be easily reproduced and performed by researchers with basic cell culture experience, which is particularly important for retinal research progress and clinical cell manufacturing in a Good Manufacturing Practice facility.

Gap Analysis CPOB 2018 Terhadap Rancangan Revisi CPOB 2024 Aneks 1 Pembuatan Produk Steril Aspek Peralatan, Sarana Penunjang, dan Personalia

The pharmaceutical industry operates under a strict regulatory framework to ensure that the products produced are safe, of high quality, and effective. These regulations are continuously updated to keep up with advancements in science, technological developments, and global demands for higher quality standards. The pharmaceutical industry also faces the challenge of global regulatory harmonization, such as standards set by WHO and PIC/S. These regulations are designed to ensure drug quality from development to distribution. Changes in Good Manufacturing Practices (GMP) regulations are crucial for improving pharmaceutical production quality in Indonesia. This study aims to conduct a gap analysis between the 2018 GMP and the draft 2024 GMP Annex 1, particularly in terms of equipment, supporting facilities, and personnel. The method used is a comparative analysis by comparing the provisions of the 2018 GMP with the draft 2024 GMP. The gap analysis results between the 2018 GMP and the draft 2024 GMP Annex 1 in terms of equipment, supporting facilities, personnel, and sterile product completion indicate significant changes in the adopted standards. The proposed 2024 GMP revision introduces substantial improvements in sterile product manufacturing standards. As part of efforts to enhance global competitiveness, the Indonesian pharmaceutical industry must continue to adapt to dynamic technological and regulatory changes. By implementing various strategies—including substantial investments in modern equipment, adjustments to supporting facilities, and capacity building for personnel—the Indonesian pharmaceutical industry can meet global standards while ensuring the availability of safe, high-quality, and effective sterile products for the public.

Evaluation of cannabidiol-based products in Brazil: how can current regulations influence their labeling quality?

There is concern about the quality of cannabis-based products used in Brazil, mainly cannabidiol (CBD). This study aimed to evaluate the quality of labeling on CBD products marketed in Brazil authorized by two regulations – N660/2022 on imported products and N327/2019 on products with temporary trade permits – and whether there were differences between them concerning four domains: prescription, good manufacturing practices (GMP), laboratory tests, and safety of use. Determined labeling quality was based on a score of 45 criteria divided per domain and weights from 1 to 3 (according to the relevance for users' and prescribers' safety) built by public information provided by product manufacturers/representatives on websites and e-mail consultations. The quality score was classified as very satisfactory, satisfactory, or not very satisfactory, represented in median and interquartile range. Between the N327 and N660 products, the quality scores were compared using the Mann–Whitney U-test. All tests considered two-tailed hypotheses and a significance level of 5%. After applying the inclusion criteria, from 148 products selected, 105 were evaluated. Most of the evaluated CBD products were classified as satisfactory (47), followed by not very satisfactory (39) and very satisfactory (19). The N327 products presented information that was more accessible than the N660 products. Similarly, there was a significant difference between the two groups concerning the domains of prescription and safety of use; products in the N327 showed better results than those in the N660. This study contributes to the urgent debate on the quality of labeling and the risks of CBD widely marketed in Brazil.

Traditional medicine regulation status and challenges in Malawi and Nigeria

BackgroundThe World Health Organization encourages governments to develop legal frameworks for the regulation of traditional medicines to ensure safety, quality, and efficacy. There is inadequate published research on the traditional medicine legislative tools and Good manufacturing practices compliance by manufacturers in many countries in Sub-Saharan Africa. The study assessed the traditional medicine regulatory status and challenges in Malawi and Nigeria.MethodsA descriptive cross-sectional study was done using a structured questionnaire and a checklist of regulatory requirements to collect data from officers, manufacturing facilities, and herbal medicinal products. Twenty-three officers from the Medicines Regulatory Authorities and Ministries of Health from Malawi and Nigeria were interviewed. Thirty-one small-scale manufacturers, sixty-six herbal medicinal products from Malawi, and twenty-eight herbal medicinal products from Nigeria, that were used by people living with HIV and AIDS, were evaluated.ResultsThe Pharmacy and Medicines Regulatory Authority scored 7.7% in Malawi while the National Agency for Food and Drug Administration and Control in Nigeria, scored 77.0% on the 13-item regulatory checklist of regulatory requirements. The Ministry of Health, Malawi scored 28.6% while Nigeria scored 71.4% on the 7-item checklist of regulatory requirements. Both countries have no regulations on traditional medicine practice, and traditional medicine has not been integrated into the healthcare system. Most Malawian manufacturers showed poor compliance, with deficiencies observed in personnel hygiene (58.6%), cleaning production equipment (69.0%), storage rooms (72.4%), and documentation on standard operating procedures for cleaning equipment and premises (93.1%). Labelling non-compliance was observed in Malawi and Nigeria, respectively, for the list of active ingredient names (45.5% vs. 93.0%, p < 0.001), quantities of active ingredients (12.1% vs. 53.6%, p < 0.001), side effects (9.1% vs. 57.1%, p < 0.001), and storage conditions (15.2% vs. 67.9%, p < 0.001).ConclusionMalawi lacks a strong regulatory framework for herbal medicines, with poor compliance to current Good Manufacturing Practices standards in manufacturing and labelling, posing serious public health risks. Urgent action is needed to establish comprehensive regulations, including guidelines for registering herbal medicines used by people living with HIV and AIDS. While Nigeria has a more developed regulatory framework, enforcement remains a challenge. Strengthening inspections and ensuring adherence to safety and quality standards for herbal products is critical to safeguarding public health and building consumer confidence in both countries’ traditional medicine industries.

Case Study: Visual Inspection of Topical Ophthalmic Formulations Packaged in Opaque and Semi-Transparent Containers: Working towards alignment with USP Visible Inspection of Injections.

Topical ophthalmic solutions, suspensions, and emulsions are typically packaged in opaque or semi-transparent plastic dropper bottles. This packaging provides resistance to breakage and controlled drop size needed in ophthalmic container systems. Recent changes to general chapter USP<771> Ophthalmic Products - Quality Tests have impacted the particulate and foreign matter testing requirements for ophthalmic products dosed via topical application. The USP<771> chapter instructs that topical products undergo visual inspection for particulate matter as described in general chapter USP<790> Visible Particulates in Injections Visual inspection for particulates in the filled unit is not feasible due to lack of package transparency and therefore alternative test strategies are needed to evaluate the acceptability of the batch. Aspects of this visual inspection approach include: a statistically based sampling plan for the batch, a destructive testing process and acceptance limits based on manufacturing process capability supported with benchmark testing of competitor products to confirm manufacturing performance. Overall, the visual inspection program should include: historical trending; process monitoring; and upstream lifecycle controls for facilities, raw materials, components, and product contact equipment to meet current regulatory expectations and good manufacturing practices.

REGULATIONS AND STANDARDS OF THE COSMETIC COTTAGE INDUSTRY IN KENYA: A SUMMATIVE OVERVIEW

The cosmetic industry, a major player in the global economy, encompasses a diverse range of products manufactured and distributed by large-scale and small-scale producers. The cosmetic cottage industry, characterized by small-scale production at affordable rates, is gaining prominence, particularly in countries like Japan, the US, and Germany. In Kenya, the cosmetic cottage industry is on the rise, with a ready multibillion market worth and poised to contribute significantly to entrepreneurship opportunities in the country. Though there are stringent regulations for mass-produced cosmetic products globally, the same cannot be said for the cottage industry. This study presents a summative overview of the regulations and standards of the Kenya cosmetic cottage industry. A literature review was conducted on the regulatory framework and standards of the cosmetic cottage industry. The standards and regulations set forth by the Kenya Bureau of Standards (KEBS) and the Pharmacy and Poisons Board (PPB) were examined. It outlines standards for raw materials, manufacturing processes, and finished cosmetic products, covering aspects like good manufacturing practices, ingredient specifications, and adherence to global standards. The study found that ensuring the safety and quality of cosmetic cottage products is hampered by the complexity that comes with their categorization. Moreover, the regulatory framework for the cottage industry in Kenya is scanty and relies majorly on regulations set for commercial cosmetic products. The study highlights a gap in the adherence to quality standards and regulations within the cottage industry, compared to commercial counterparts. Further, the study reveals challenges in monitoring and enforcing these regulations. Collaboration between KEBS and PPB is thus paramount to ensure effective oversight and consumer education to safeguard against substandard products. Thus, enhanced surveillance, consumer awareness, and regulatory enforcement are essential for ensuring the safety of cosmetic products from the cottage industry in Kenya.

Exploring the Therapeutic Potential of Mitragynine and Corynoxeine: Kratom-Derived Indole and Oxindole Alkaloids for Pain Management.

The search for effective pain management solutions remains a critical challenge, especially amidst growing concerns over the use of conventional opioids. In the US, opioid-related mortality rates have surged to as many as 80 deaths per 100,000 people in some states, with an estimated economic burden of USD 1.5 trillion annually-exceeding the gross domestic product (GDP) of most US industrial sectors. A remarkable breakthrough lies in the discovery that indole and oxindole alkaloids, produced by several genera within the plant Tribe Naucleeae, act on opioid receptors without activating the beta-arrestin-2 pathway, the primary driver of respiratory depression and overdose deaths. This systematic review explores the pharmacological properties, mechanisms of action, dosing considerations, interactions, and long-term effects of mitragynine and corynoxeine, alkaloids from the Southeast Asian plant Mitragyna speciosa (kratom) and others in the Tribe Naucleeae. Mitragynine, a partial opioid receptor agonist, and corynoxeine, known for its anti-inflammatory and neuroprotective effects, demonstrate significant therapeutic potential for managing diverse pain types-including neuropathic, inflammatory, nociceptive, visceral, and central pain syndromes-with a focus on cancer pain. Unlike traditional opioids, these compounds do not recruit beta-arrestin-2, avoiding key adverse effects such as respiratory depression, severe constipation, and rapid tolerance development. Their distinct pharmacological profiles make them innovative candidates for safer, non-lethal pain relief. However, challenges persist, including the unregulated nature of kratom products, inconsistencies in potency due to crude extract variability, potential for misuse, and adverse drug interactions. Addressing these issues requires establishing standardized quality control protocols, such as Good Manufacturing Practices (GMP), to ensure consistent potency and purity. Clear labeling requirements with dosage guidelines and warnings should be mandated to ensure safe use and prevent misuse. Furthermore, the implementation of regulatory oversight to monitor product quality and enforce compliance is essential. This review emphasizes the urgency of focused research to optimize dosing regimens, characterize the pharmacodynamic profiles of these alkaloids, and evaluate long-term safety. By addressing these gaps, the mitragynine- and corynoxeine-related drug classes can transition from promising plant-derived molecules to validated pharmacotherapeutic agents, potentially revolutionizing the field of pain management.