Good Manufacturing Practice Guidelines Research Articles

Compliance with good manufacturing practices for medicines in Brazil

Good manufacturing practices (GMP) ensure that products are consistently produced and controlled according to appropriate quality standards. This study aimed to evaluate the GMP compliance of Brazilian medicine manufacturers over the past 3 years. The outcomes, deficiencies, and significance of these were collected from 485 inspections performed between 2015 and 2017. The nonconformities were arranged by sections of the GMP guidelines to demonstrate the main areas of deficiency. During the evaluation period, 61.4 % of inspected companies were classified as GMP ‘satisfactory’; 23.3 % were classified as ‘on hold’; and 15.3 % of inspections concluded that the company did not comply with GMP and resulted in an ‘unsatisfactory’ classification. At least one deficiency was found in 280 inspections (57.7 %). Critical deficiencies were found in 52 (10.7 %) inspections, major deficiencies were observed in 203 (41.9 %) inspections, and minor deficiencies were observed in 251 (51.8 %) inspections. The most common areas of deficiency were qualification and validation, documentation, and premises. The level of GMP compliance increased over the evaluation period. Updates or additional guidelines for the specific issues in which deficiencies are often identified might be useful to improve industry GMP compliance. The public disclosure of inspection outcomes and deficiencies may encourage the industry to comply with GMP and assist regulatory authorities in the maintenance of regulatory transparency. Knowledge of GMP noncompliance patterns and trends may allow the prioritization of inspections on high-risk areas and facilities, with the main goal of protecting the population from substandard medicines.

Perspectives on trace chemical safety and chemophobia: risk communication and risk management.

Safety issues regarding consumer products contaminated with trace amounts of chemicals are of great concern to consumers, with the degree of concern occasionally escalating to the psychological syndrome, chemophobia, i.e., the fear of chemicals. Hazardous substances frequently implicated in safety concerns include heavy metals (arsenic, mercury, cadmium, and lead), volatile organic compounds (VOC) such as benzene and o-toluidine, pesticides, carcinogens, radioactive substances, and endocrine disrupting chemicals (EDC) such as bisphenol A and phthalates. To improve communication of risk to society, members of academia, government, consumer organizations, and industry participated in this workshop to discuss and exchange perspectives on trace chemical safety. From the perspective of academia, integrated risk assessments need to be implemented to encompass various exposure sources and routes. The identification and investigation of new exposure-related biomarkers are also recommended to verify direct causal relationships between specific chemical exposure and effects on human health. As for regulation, governments need to establish and maintain acceptable limits for trace chemicals in products. In addition, harmonized efforts need to be undertaken among government agencies to share regulatory limits and effectively control trace chemicals in consumer products. Manufacturers need to faithfully abide by Good Manufacturing Practice (GMP) guidelines, monitor sources of contamination, and minimize these for consumer safety. To effectively resolve safety issues arising from trace chemicals exposure, collaborative efforts are needed involving academia, government, consumer organizations, and industry. Further, scientific evidence-based risk assessment is a critical approach to effectively manage trace chemical safety issues.

Estudo do perfil de dissolução de cápsulas magistrais de amoxicilina

Pharmacopoeia analysis have limited application to manufactures individual product on pharmacies. The efficacy, safety and credibility of these medicines depend mainly on of Good Manufacturing Practice Guidelines, defined by regulatory Agencies. The dissolution profile provides an indication of drug bioavailability. This is essential requirement to ensure effectiveness therapeutic and avoid microbial resistance in case of antibiotics. In this study, the dissolution profiles were performed for amoxicillin capsules 500 mg obtained from three pharmacies in Belo Horizonte/MG, Brazil. The profiles were compared to the reference drug. All evaluated products attended the criteria for dissolution according Brazilian Pharmacopoeia - 80% (Q) in 90 minutes. However, only one product demonstrated similar profile to the reference product.

Ethanol content in traditionally fermented ayurvedic formulations: Compromised Good Manufacturing Practice regulations – compromised health

ABSTRACT Background: A large part of the population of India prefers the traditional medicine (ayurvedic formulations) for primary health care. However, the effective quality control of herbal medicine is still a big challenge. Numerous reports indicate noncompliance with Compromised Good Manufacturing Practice (GMP) guidelines by the manufacturers which may lead to adverse drug reactions or toxic effects. Asava and arishta are the classical herbal dosage forms wherein fermentation occurs during production leading to the generation of ethanol. The presence of ethanol in these preparations may lead to their misuse. The self-generated ethanol is responsible for extraction of active constituents and acts as a self-preservative. As the procedure for preparation for asava and arishta is same, the ethanol content is also expected to be the same irrespective of the manufacturer. Objective: The objective of the present study was to assess and compare the ethanol content of some traditionally fermented ayurvedic formulations available in the market. Method: In this study, 20 formulations from 3 different manufacturers available as over-the-counter products were obtained and their ethanol contents were determined using gas chromatograph with flame ionization detector. Results: Statistically significant differences were noted in the ethanol content of various ayurvedic formulations. A simple, less time-consuming, economic, and validated gas chromatographic method for estimation of ethanol in fermented ayurvedic formulations was also developed successfully in present study. Conclusion: The data generated during study reflected poor compliance of GMP guidelines by the manufacturers and hence the quality is being grossly compromised posing a safety hazard.

Molecular Imaging of Radiolabeled Bispecific T-Cell Engager 89Zr-AMG211 Targeting CEA-Positive Tumors.

Purpose: AMG 211, a bispecific T-cell engager (BiTE) antibody construct, targets carcinoembryonic antigen (CEA) and the CD3 epsilon subunit of the human T-cell receptor. AMG 211 was labeled with zirconium-89 (89Zr) or fluorescent dye to evaluate the tumor-targeting properties.Experimental Design: 89Zr-AMG211 was administered to mice bearing CEA-positive xenograft tumors of LS174T colorectal adenocarcinoma or BT474 breast cancer cells, as well as CEA-negative HL-60 promyelocytic leukemia xenografts. Biodistribution studies with 2- to 10-μg 89Zr-AMG211 supplemented with unlabeled AMG 211 up to 500-μg protein dose were performed. A BiTE that does not bind CEA, 89Zr-Mec14, served as a negative control. 89Zr-AMG211 integrity was determined in tumor lysates ex vivo Intratumoral distribution was studied with IRDye800CW-AMG211. Moreover, 89Zr-AMG211 was manufactured according to Good Manufacturing Practice (GMP) guidelines for clinical trial NCT02760199Results: 89Zr-AMG211 demonstrated dose-dependent tumor uptake at 6 hours. The highest tumor uptake was observed with a 2-μg dose, and the lowest tumor uptake was observed with a 500-μg dose. After 24 hours, higher uptake of 10-μg 89Zr-AMG211 occurred in CEA-positive xenografts, compared with CEA-negative xenografts. Although the blood half-life of 89Zr-AMG211 was approximately 1 hour, tumor retention persisted for at least 24 hours. 89Zr-Mec14 showed no tumor accumulation beyond background level. Ex vivo autoradiography revealed time-dependent disintegration of 89Zr-AMG211. 800CW-AMG211 was specifically localized in CEA-expressing viable tumor tissue. GMP-manufactured 89Zr-AMG211 fulfilled release specifications.Conclusions: 89Zr-AMG211 showed dose-dependent CEA-specific tumor targeting and localization in viable tumor tissue. Our data enabled its use to clinically evaluate AMG 211 in vivo behavior. Clin Cancer Res; 24(20); 4988-96. ©2018 AACR.

Safety and immunogenicity of a plant-produced Pfs25 virus-like particle as a transmission blocking vaccine against malaria: A Phase 1 dose-escalation study in healthy adults

Malaria continues to be one of the world’s most devastating infectious tropical diseases, and alternative strategies to prevent infection and disease spread are urgently needed. These strategies include the development of effective vaccines, such as malaria transmission blocking vaccines (TBV) directed against proteins found on the sexual stages of Plasmodium falciparum parasites present in the mosquito midgut. The Pfs25 protein, which is expressed on the surface of gametes, zygotes and ookinetes, has been a primary target for TBV development. One such vaccine strategy based on Pfs25 is a plant-produced malaria vaccine candidate engineered as a chimeric non-enveloped virus-like particle (VLP) comprising Pfs25 fused to the Alfalfa mosaic virus coat protein. This Pfs25 VLP-FhCMB vaccine candidate has been engineered and manufactured in Nicotiana benthamiana plants at pilot plant scale under current Good Manufacturing Practice guidelines. The safety, reactogenicity and immunogenicity of Pfs25 VLP-FhCMB was assessed in healthy adult volunteers. This Phase 1, dose escalation, first-in-human study was designed primarily to evaluate the safety of the purified plant-derived Pfs25 VLP combined with Alhydrogel® adjuvant. At the doses tested in this Phase 1 study, the vaccine was generally shown to be safe in healthy volunteers, with no incidence of vaccine-related serious adverse events and no evidence of any dose-limiting or dose-related toxicity, demonstrating that the plant-derived Pfs25 VLP-FhCMB vaccine had an acceptable safety and tolerability profile. In addition, although the vaccine did induce Pfs25-specific IgG in vaccinated patients in a dose dependent manner, the transmission reducing activity of the antibodies generated were weak, suggesting the need for an alternative vaccine adjuvant formulation.This study was registered at www.ClinicalTrials.gov under reference identifier NCT02013687.

Quality of medicines: Deficiencies found by Brazilian Health Regulatory Agency (ANVISA) on good manufacturing practices international inspections.

The circulation of poor quality medicines, especially in the developing countries, is a public health concern. Compliance with good manufacturing practices (GMP) is essential to ensure the quality, efficacy, and safety of medicines. This study evaluated the outcomes of the Brazilian Health Regulatory Agency’s (ANVISA) international inspections of two years (2015 and 2016) and compared these to those of other regulatory authorities. The information from 255 inspection reports was analyzed, and the type and extent of deficiencies were collected. In the period evaluated, 62.75% of ANVISA-inspected companies were classified as GMP “satisfactory,” 24.71% were classified as having “on demand” status, and 12.55% of inspections concluded that the company did not comply with Brazilian GMP regulations (“unsatisfactory”). The most common areas of deficiency were documentation (28.63%) and premises (26.27%). The pattern of deficiencies was similar to the findings of other regulatory agencies. However, ANVISA detected a more significant number of non-compliance results than other authorities, which may be caused by differences in classifications adopted by each Agency. Furthermore, manufacturers inspected by ANVISA may follow different standards and practices for products manufactured for the Brazilian market. Disclosure of main GMP deficiencies found can be useful for encouraging the industry to comply with GMP, and additional guidelines in the specific areas where deficiencies are often identified may be useful to industry to improve GMP compliance. Harmonization of GMP guidelines and inspection procedures are the key steps to avoid duplicate work, but regulatory authorities also need to work together to enforce the proper level of GMP compliance by pharmaceutical manufacturers, assuring high quality and safe medicines supply.

Complementary vaccination protocol with dendritic cells pulsed with autologous tumour lysate in patients with resected stage III or IV melanoma: protocol for a phase II randomised trial (ACDC Adjuvant Trial)

IntroductionSurgery is one of the treatments of choice for patients with a single metastasis from melanoma but is rarely curative. Such patients could potentially benefit from consolidation immunotherapy. Vaccination with...

Non Pregnant Human Uterus as Source of Mesenchymal Stem Cells.

Stem/progenitor cells for cell therapy and regenerative medicine should ideally be available in large numbers, after having been isolated using minimally invasive or non-invasive methodologies. Also, they should exhibit wide differentiation potential into multiple lineages, as well as capability to be used successfully in autologous or allogeneic transplantation, and all this in accordance with the applicable guidelines of good manufacturing practice. Thus, the identification and characterization of alternative sources of mesenchymal stem cells (MSCs) is of great importance. The human uterus emerges as an interesting source of MSCs. Both endometrial MSCs (eMSCs) and human uterine cervical stem cells (hUCESCs) were easily obtained with minimal morbidity. Both eMSCs and hUCESCs show a high proliferation rate, which allows for the harvesting of high amounts of these cells, both for research studies and potential therapeutic uses. It has been demonstrated that eMSCs have wide capability of differentiation into many cellular lineages, as well as potential therapeutic effects in several pathological processes. Similarly, hUCESCs'secretome (conditioned medium) shows potent antiinflammatory, anti-tumor, anti-bacterial and regenerative properties.

Considering Cell Therapy Product "Good Manufacturing Practice" Status.

The promise of cell therapies is beginning to be recognized internationally. Cell therapy products (CTPs) are different from other drug products because many aim to be curative, and they are less comprehensively characterizable and more variable, sometimes being manufactured one lot at a time. They have complex mechanisms of action that remain incompletely understood. These unique features have led some regulators to take different approaches to cell therapy regulation in the form of special guidance for navigating regulatory frameworks that were originally intended for pharmaceutical drugs. A consideration for CTP developers is where to manufacture them, and under what circumstances. With few regulators developing manufacturing requirements specifically for CTPs, highly harmonized regulatory principles of Good Manufacturing Practice (GMP) for pharmaceuticals and biologics apply. However, what people mean when they say they make “GMP grade” CTPs remains ambiguous, and this confusion is exacerbated because most CTPs in early stage development are processed in whole or in part in academic hospital-based settings instead of industrial facilities. Since GMP guidelines were not originally written with CTPs in mind, the regulatory landscape has been influenced by “multi-level model of practice-driven institutional change” (1). That is to say that, in the absence of prescriptive regulations, the regulated party improvises to meet what they think the regulator expects, and then reorient approaches based on what others can be seen doing. The resulting practices evolve into basic standards of practice that regulators expect the field to follow. This situation compounds confusion about “GMP grade” CTPs because it presents a moving target and creates uncertainty for manufacturing CTPs emerging at the investigational stage of development. To inject some clarity, stating that GMP is a grade of material is overly simplistic. Instead, GMP should be considered a product-specific assertion based on what is known about a product’s relevant characteristics and a system of ensuring its quality and must be determined on a case-by-case, product-specific basis. This assertion can be substantiated, which may or may not include direct or indirect evidence of third party (e.g., regulator) review. Others have identified the need for CTP GMP and noted jurisdictional and study phase differences (2–5). From a review of regulatory documents, here we take a basic look at approaches taken in three full ICH member jurisdictions (Canada, the United States, and the European Union) to briefly summarize in (Table ​(Table1)1) similar but different approaches to assessing GMP throughout clinical trial development, and to suggest potential strategies for cell therapy clinical trial product manufacturers. Table 1 Summary table.

Automated production of [18 F]FTHA according to GMP.

14-(R,S)-[18 F]fluoro-6-thia-heptadecanoic acid is a tracer for fatty acid imaging by positron emission tomography. High demand for this tracer required us to replace semiautomatic synthesis with a fully automated procedure. An automated synthesis device was constructed in-house for multistep nucleophilic 18 F-fluorination and a control system was developed. The synthesis device was combined with a sterile filtration unit and both were qualified. 14-(R,S)-[18 F]fluoro-6-thia-heptadecanoic acid was produced according to good manufacturing practice guidelines set by the European Union. The synthesis includes an initial nucleophilic labelling reaction, deprotection, preparative HPLC separation, purification of the final product, and formulation for injection. The duration and temperature of the reaction and hydrolysis were optimized, and the radiochemical stability of the formulated product was determined. The rotary evaporator used to evaporate the solvent after HPLC purification was replaced with solid phase extraction purification. We also replaced the human serum albumin used in the earlier procedure with a phosphate buffer-ascorbic acid mixture in the final formulation solution. From 2011 to 2016, we performed 219 synthesis procedures, 94% of which were successful. The radiochemical yield of 14-(R,S)-[18 F]fluoro-6-thia-heptadecanoic acid, decay-corrected to the end of bombardment, was 13%±6.3%. The total amount of formulated end product was 1.7±0.8GBq at end of synthesis.

Optimized Robot Systems for Future Aseptic Personalized Mass Production

For future pharmaceutical personalized mass production, highly flexible aseptic automation solutions are needed such as 6-axis robot systems well known from car manufacturing lines. Up to date, most robots are not suitable for aseptic production due to the lack of hygienic design in regards to cleanability, decontamination and material selection. With one robot manufacturer we designed an aseptic robotic solution right from the initial idea in order to fulfil the required cleanliness level for sterile manufacturing processes described in the Good Manufacturing Practice guidelines (GMP). Finally, the performance of the robot is validated using standardized test scenarios.

A study of knowledge, attitude, and practice on generic drugs among teaching faculties at a tertiary care teaching hospital in South Gujarat, India

Background: The practice of generic medicines prescribing, dispensing, and substitution in developing countries has been controversial among doctors, particularly due to issues on quality, safety, and efficacy. These controversies are as a result of country to country differences in drug policies and laws as well as individualized knowledge and attitudes of healthcare professionals related to generic medicines. Moreover, generic medicines in the past have been criticized for being substandard mainly due to poor adherence with good manufacturing practice guidelines. Aims and Objectives: The aim of this study is to evaluate and compare knowledge, attitude, and practice of generic drugs among teaching faculties in a tertiary care teaching hospital. Materials and Methods: A cross-sectional study was carried out using a questionnaire in a tertiary care teaching hospital in south Gujarat. The questionnaire was designed to assess the knowledge, attitude, and practice about generic drugs. The medical teachers working in the institute during the study period were included. The data were analyzed by MS Excel. Responses were calculated in percentage. Results: Of all participants, 54% were male and majority and 83% were postgraduate degree holders. It was known to 61.8% faculties that generic drug contains the same active substance(s) as the innovator drug, while 63.2% knew that it is used at the same dose(s) to treat the same disease(s) as the innovator drug. Among faculties, 72% believed the fact that generic drug manufacturers need to conduct bioequivalence studies to show equivalence between the generic and innovator drug. Most of the faculties (75%) did not agree that generic drugs are more costly than their innovator counterpart. Among faculties, 59% had not ever switch a patient on innovator drug to available generic drugs. Only 2% were not in favor of supporting generic drug prescribing. Conclusion: Although a good percentage of medical faculties had knowledge about generic medicines, there was gap on knowledge and perception toward generic and brand drugs. Hence, mass awareness programs seemed to be necessary to fill this gap and that would increase the use of generic drugs which ultimately would reduce healthcare expenditure.

Abstract CT033: Phase I study of intraventricular infusions of autologous exvivo expanded NK cells in children with recurrent/refractory malignant posterior fossa tumors of the central nervous system

Abstract Scientific background/rationale: The prognosis of recurrent/refractory medulloblastoma (MB), ependymoma (EP) and atypical teratoid/rhabdoid neoplasms (AT/RT), which constitutes the majority of malignant posterior fossa tumors (MPFT) in children, remain dismal with no defined effective therapy. Current treatment strategies have significant toxicities and thus profiling newer trials with clinical efficacy and minimal side-effects are imperative. Advantages of direct infusion of natural killer (NK) cells into the ventricles could enhance therapeutic efficacy by maximally concentrating them in the central nervous system (CNS) near the tumor area, bypassing the blood brain barrier and alleviating toxicity as seen with systemic chemotherapy. We have shown the efficacy of activated and propagated NK cells to lyse and kill the MPFT in vitro and tumor explants in mice models. Also, in a first-time human in vivo pilot study, we demonstrated the feasibility of infusions of biologic agents into the fourth ventricle. Infusing biologic agents through catheters placed in the lateral ventricles are well established in neurooncology. The current ongoing study is the first-in-human, loco-regional infusion of NK cells directly into the brain evaluating safety with intent to avoid the significant side-effects of systemic therapy. This novel trial will hopefully be able to provide therapeutic efficacy and a significant increase in the survival of these children. The current format of this trial incorporates changes including different dose, schedule, routes of intraventricular infusions of NK cells from the previously presented version of the trial, and thus submitted. Correlative studies: Cerebrospinal fluid (CSF) drawn during infusions of NK cells will be evaluated for the immunophenotype, function, persistence of NK cells and influx or presence of any other immune cells and correlating with tumor response. Methods: This trial (NCT02271711-recruiting) will proceed with infusions of NK cells directly into the lateral or fourth ventricles, after placement of a catheter at that location. Recurrent or refractory MB, AT/RT and EP involving the brain and/or spine at original diagnosis or relapse with histological verification will be eligible. Three to six evaluable patients may be entered at a dose level in this study for determination of maximum tolerated dose (MTD). A minimum of nine patients and a maximum of twenty-four patients will be enrolled. After autologous expanded NK cell product have been manufactured as per good manufacturing practice (GMP) guidelines and released, patients will receive three cycles of NK cell infusions over 12 weeks. Each cycle consists of one infusion per week for three weeks followed by a rest week (week 4). Dosing is based on recipient body surface area (BSA), and three dose levels will be evaluated. Currently, the trial is in the second cohort, with no dose limiting toxicity (DLT) noted with the previous dose level. 35% of the minimal accrual has been met. Also as a secondary aim, we will evaluate the antitumor activity of the NK cell infusions within the confines of a phase I study Citation Format: Soumen Khatua, Vidya Gopalakrishnan, Laurence Cooper, Dean Lee, David I. Sandberg, Michael Rytting, Jason J. Johnson, Leena Ketonen, Diane Liu, Judy Moyes, Wafik Zaky. Phase I study of intraventricular infusions of autologous exvivo expanded NK cells in children with recurrent/refractory malignant posterior fossa tumors of the central nervous system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT033. doi:10.1158/1538-7445.AM2017-CT033

Efficacy of Humanized Mesenchymal Stem Cell Cultures for Bone Tissue Engineering: A Systematic Review with a Focus on Platelet Derivatives.

Fetal bovine serum (FBS) is the most commonly used supplement for ex vivo expansion of human mesenchymal stem cells (hMSCs) for bone tissue engineering applications. However, from a clinical standpoint, it is important to substitute animal-derived products according to current good manufacturing practice (cGMP) guidelines. Humanized alternatives to FBS include three categories of products: human serum (HS), human platelet derivatives (HPDs)-including platelet lysate (PL) or platelet releasate (PR), produced by freeze/thawing or chemical activation of platelet concentrates, respectively, and chemically defined media (serum-free) (CDM). In this systematic literature review, the in vitro and in vivo osteogenic potential of hMSCs expanded in humanized (HS-, HPD-, or CDM-supplemented) media versus hMSCs expanded in FBS-supplemented media, was compared. In addition, PL and PR were compared in terms of their growth factor (GF)/cytokine-content and cell-culture efficacy. When using either 10-20% autologous or pooled HS, 3-10% pooled HPDs or CDM supplemented with GFs, in comparison with 10-20% FBS, a majority of studies reported similar or superior in vitro proliferation and osteogenic differentiation, and in vivo bone formation in ectopic or orthotopic rodent models. Moreover, a trend for higher GF content was observed in PL versus PR, although evidence for cell culture efficacy is limited. In summary, humanized supplements seem at least equally effective as FBS for hMSC expansion and osteogenic differentiation. Although pooled HPDs appear to be the most favorable supplement for large-scale hMSC expansion, further efforts are needed to standardize the preparation and composition of these products in compliance with cGMP standards.

NIR Spectroscopy of Actaea racemosa L.rhizome - En Route to Fast and Low-Cost Quality Assessment.

Rhizomes of Actaea racemosa L. (formerly Cimicifuga racemosa) gained increasing interest as a plant-derived drug due to its hormone-like activity and the absence of estrogenic activity. According to the Current Good Manufacturing Practices guidelines and pharmacopeial standards, quality assessment of herbal starting materials includes tests on identity and substitution, as well as quantification of secondary metabolites, usually by HPTLC and LC methods. To reduce the laboratory effort, we investigated near-infrared spectroscopy for rapid species authentication and quantification of metabolites of interest.Near-infrared spectroscopy analysis is carried out directly on the milled raw plant material. Spectra were correlated with reference data of polyphenols and triterpene glycosides determined by LC/diode array detection and LC/evaporative light scattering detection, respectively. Quantification models were built and validated by cross-validation procedures. Clone plants, derived by vegetative propagation, and plants of a collection from different geographical origins cultivated in Berlin were analysed together with mixed batches from wild harvests purchased at wholesalers.Generally, good to excellent correlations were found for the overall content of polyphenols with coefficients of determination of R2 > 0.93. For individual polyphenols such as fukinolic acid, only models containing clone plants succeeded (R2 > 0.92). For the total content of triterpene glycosides, results were generally worse in comparison to polyphenols and were observed only for the mixed batches (R2 = 0.93).Next to quantitative analysis, near-infrared spectroscopy was proven as a rapid alternative to other, more laborious methods for species authentication. Near-infrared spectroscopy was able to distinguish different Actaea spp. such as the North American Actaea cordifolia and the Asian Actaea cimicifuga, Actaea dahurica, Actaea heracleifolia, and Actaea simplex.

Legislation on the preparation of medicinal products in European pharmacies and the Council of Europe Resolution

IntroductionThe rights of patients should be sufficiently protected even when an appropriate authorised medicine does not exist or is unavailable on the market. The Resolution, which was adopted by the...

BPOG Response to Annex 2.

This paper is an interpretive response to Annex 2 of Eudralex—Volume 4; the European Union (EU) guidelines for good manufacturing practice (GMP) of medicinal products for human and veterinary use ([1][1]). It was written collaboratively, by a team of experts in closed system processing, from 26

Evaluation of GMP-compliant culture media for invitro expansion of humanbone marrow mesenchymal stromal cells.

Mesenchymal stromal cells (MSCs) from human bone marrow serve as a resource for cell-based therapies in regenerative medicine. Clinical applications require standardized protocols according to good manufacturing practice (GMP) guidelines. Donor variability as well as the intrinsic heterogeneity of MSC populations must be taken into consideration. The composition of the culture medium is a key factor in successful MSC expansion. The aim of this study was to comparatively assess the efficiency of xeno-free human platelet lysate (HPL)-based cell expansion with two commercially available media-StemPro MSC SFM CTS (for human exvivo tissue and cell culture processing applications) and MSCGM (non-GMP-compliant, for research only)-in an academic setting as the first optimization step toward GMP-compliant manufacturing. We report the feasibility of MSC expansion up to the yielded cell number with all three media. MSCs exhibited the typical fibroblastoid morphology, with distinct differences in cell size depending on the medium. The differentiation capacity and characteristic immunophenotype were confirmed for all MSC populations. Proliferation was highest using StemPro MSC SFM CTS, whereas HPL medium was more cost-effective and its composition could be adjusted individually according to the respective needs. In summary, we present a comprehensive evaluation of GMP-compatible culture media for MSC expansion. Both StemPro and HPL medium proved to be suitable for clinical application and allowed sufficient cell proliferation. Specific differences were observed and should be considered according to the intended use. This study provides a detailed cost analysis and tools that may be helpful for the establishment of GMP-compliant MSC expansion.

Allogenic banking of dental pulp stem cells for innovative therapeutics.

Medical research in regenerative medicine and cell-based therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells (DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products (ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen (HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues (dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice (GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat.