Good Manufacturing Practice Requirements Research Articles

OBSERVATION OF MEDICINES FOR THE TREATMENT OF DIAPER DERMATITIS ON THE PHARMACEUTICAL MARKET OF UKRAINE

Пелюшковий дерматит зустрічається у кожної другої дитини першого року життя. Основними причинами його розвитку вважаються порушення бар’єрної функції шкіри та неправильний догляд за нею. У роботі проаналізовані дані літературних джерел щодо причин виникнення, симптоматики, профілактики та лікування пелюшкового дерматиту, досліджений асортимент лікарських засобів на фармацевтичному ринку України, що використовуються для його лікування.

Regulating phage therapy: The biological master file concept could help to overcome regulatory challenge of personalized medicines.

In a note published in The Lancet in December 1915, Frederic Twort described the discovery of an infectious, filterable agent that causes the glassy transformation and eventual killing of bacteria, now identified as Staphylococcus hyicus [1]. Two years later, Felix d'Herelle independently described an invisible microbe antagonistic to dysentery bacilli in a note to the Comptes Rendus de l'Academie des Sciences [2]. These two reports are the first published descriptions of bacteriophages, a term coined by d'Herelle, who foresaw the therapeutic potential of these newly identified bacteriolytic agents. > The key issue is whether phage therapy medicinal products (PTMPs) require a marketing authorization or not. Yet, phage therapy, despite varying degrees of success during the 20th century, never made it into widespread clinical use owing to the discovery of antibiotics [3]. However, the increasing antibiotic resistance among major pathogens such as Staphylococcus or Mycobacterium has become a critical public health problem—in the European Union (EU) alone, around 25,000 patients die each year from an infection with drug‐resistant bacteria (http://ecdc.europa.eu/en/publications/publications/0909\_ter\_the\_bacterial\_challenge\_time\_to\_react.pdf). Although difficult to estimate, the annual global death toll attributable to antimicrobial resistance might range from the hundreds of thousands to as much as millions in the coming decades (https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations\_1.pdf). In light of this growing health crisis, phage therapy has attracted renewed interest as an alternative to antibiotics [3]. ### Regulatory challenges for phage therapy However, this reemergence raises regulatory concerns. There has been intense discussion on how to classify phage‐based therapeutics within the EU's regulatory framework [4], [5], [6] with some consensus among Members States' regulatory authorities and the European Medicines Agency that these would be regulated as biological medicinal products [7]. Nonetheless, positions still vary because the current medicinal product regulation is not well suited for this unorthodox therapeutic …

PDA Points to Consider: Technical Product Lifecycle Management. Pharmaceutical Quality System Effectiveness for Managing Post-approval Changes.

The International Council for Harmonisation Quality Guideline 10 (ICH Q10) describes the Pharmaceutical Quality System (PQS), indicating it is intended to apply throughout a product9s lifecycle, in conjunction with good manufacturing practice (GMP) requirements, in order to achieve quality in a consistent and reproducible manner. Implementation of an effective PQS is essential for a company to achieve product realization, establish and maintain a state of control, and facilitate continual improvement (1). When changes are made during the commercial life of a product, an effective PQS, product and process understanding, and use of quality risk management should ensure that product quality, patient safety, and adequate supply to patients are maintained; this, according to ICH Q10-Annex 1, should provide companies the opportunity to manage post-approval changes (PAC) with reduced regulatory oversight (1). But what exactly constitutes an effective PQS? And how does it support change management for PACs? This paper intends to answer these questions and guide companies to seize the opportunities outlined in ICH Q10-Annex 1, to manage product and process changes within the PQS, and downgrade the level of regulatory submission required. This is the second of a series of PDA Points to Consider papers on technical product lifecycle management; the first paper focused on the technical product lifecycle management strategy including communication and knowledge exchange between Marketing Authorization Holders and Health Authorities.

Evolution of GMP in Pharmaceutical Industry

This Article gives holistic view of Birth of Good Manufacturing Practices (GMP) in Pharmaceutical Industry. Most of GMP requirements were put in place as responses to tragic incidents to prevent future tragedies. This article exhibit how year after year the laws and regulation were enforced to manufacture the medicines. Though the birth of GMP took place long ago but now the time requires to harmonize the regulatory requirement across the globe. This article is not an all-inclusive history but a representative one.

Good manufacturing practice requirements for the production of tissue vitrification and warming and recovery kits for clinical research.

Products that are manufactured for use in a clinical trial, with the intent of gaining US Food and Drug Administration (FDA) approval for clinical use, must be produced under an FDA approved investigational new drug (IND) application. We describe work done toward generating reliable methodology and materials for preserving ovarian cortical tissue through a vitrification kit and reviving this tissue through a warming and recovery kit. We have described the critical steps, procedures, and environments for manufacturing products with the intent of submitting an IND. The main objective was to establish an easy-to-use kit that would ensure standardized procedures for quality tissue preservation and recovery across the 117 Oncofertility Consortium sites around the globe. These kits were developed by breaking down the components and steps of a research protocol and recombining them in a way that considers component stability and use in a clinical setting. The kits were manufactured utilizing current good manufacturing practice (cGMP) requirements and environment, along with current good laboratory practices (cGLP) techniques. Components of the kit were tested for sterility and endotoxicity, and morphological endpoint release criteria were established. We worked with the intended down-stream users of these kits for development of the kit instructions. Our intention is to test these initial kits, developed and manufactured here, for submission of an IND and to begin clinical testing for preserving the ovarian tissue that may be used for future restoration of fertility and/or hormone function in women who have gonadal dysgenesis from gonadotoxic treatment regimens or disease.

Scientific and regulatory approaches to confirm quality and improve patient perceptions of generic drug products in Japan

The rapidly growing medical expense going with aging population in Japan requires the use of generic products derived from off-patent active pharmaceutical ingredients (APIs) formulations to reduce the financial burden for the national health insurance system, while at the same time avoiding undermining the quality of medical care. This article provides an overview of the regulatory approaches available to confirm the quality of generic products and gain their greater acceptance by patients. Among several approaches taken by the Ministry of Health, Labor, and Welfare (MHLW), designing systems to supply higher quality products, and providing scientific information to patients and healthcare professionals are key elements to promote the voluntary choice of the generic product. The revision of bioequivalence guidelines and the enhancement of good manufacturing practice (GMP) requirements facilitate the rational development and manufacturing control of generic formulations. A program termed Quality Reevaluation of Ethical Drugs was carried out from 1997 to 2012 using dissolution tests to avoid any significant bioINequivalence between originators and generic oral formulations. The evaluation of product quality and the assessment of the literature information by the Expert Committee on Quality of Generic Drug Products have provided a unique science-based and patient-focused approach for the distribution of reliable generic products. Some current and future issues regarding complex generic drugs are also discussed.

Shift toward Mechanical Isolation of Adipose-derived Stromal Vascular Fraction: Review of Upcoming Techniques.

Background:Standard isolation of adipose stromal vascular fraction (SVF) requires the use of collagenase and is considered more than “minimally manipulated” by current good manufacturing practice requirements. Alternatively, nonenzymatic isolation methods have surfaced using physical forces to separate cells from the adipose matrix. The purpose of this study was to review the literature on the use of mechanical isolation protocols and compare the results. The implication for use as a standard procedure in practice is discussed.Methods:A systematic review of the literature was performed on mechanical isolation of SVF with a search of six terms on PubMed and Medline databases. One thousand sixty-six articles were subject to evaluation by predetermined inclusion and exclusion criteria.Results:Two level 2 evidence articles and 7 in vitro studies were selected. SVF was isolated using automated closed systems or by subjecting the lipoaspirate to centrifugation only or by shaking or vortexing followed by centrifugation. Six articles reported isolation in laboratory settings and three inside the operating room. Stromal vascular cells expressed CD34, and CD44, CD73, CD90, and CD105, and differentiated along adipogenic and osteogenic lineages. When compared with enzymatic methods, mechanical isolation required less time but yielded fewer cells. Both case–control studies reported improved volume retention with cell-supplemented fat grafts for breast reconstruction.Conclusions:Mechanical isolation methods are alternatives to circumvent safety issues posed by enzymatic protocols. However, randomized comparative studies with long-term clinical outcomes using mechanically isolated stromal vascular cells are needed to identify their ideal clinical applications.

The Confusion of Design and Facilities in Good Manufacturing Practice Requirements among Industries in Malaysia

Food manufacturing operations need to fulfil regulatory requirements related to hygiene and Good Manufacturing Practice (GMP) to successfully market their products as safe and high quality products. GMP is a component of the food safety system to ensure the control of public hygiene and environmental conditions of the food production process. This study aims to investigate the confusion over design and facilities elements among food industries through qualitative technique. Design and facilities elements lay a firm foundation for GMP to ensure food hygiene and should be used in conjunction with each specific code of hygiene practice and guidelines.

The Confusion of Design and Facilities in Good Manufacturing Practice Requirements among Industries in Malaysia

Food manufacturing operations need to fulfil regulatory requirements related to hygiene and Good Manufacturing Practice (GMP) to successfully market their products as safe and high quality products. GMP is a component of the food safety system to ensure the control of public hygiene and environmental conditions of the food production process. This study aims to investigate the confusion over design and facilities elements among food industries through qualitative technique. Design and facilities elements lay a firm foundation for GMP to ensure food hygiene and should be used in conjunction with each specific code of hygiene practice and guidelines. © 2016. The Authors. Published for AMER ABRA by e-International Publishing House, Ltd., UK. Peer–review under responsibility of AMER (Association of Malaysian Environment-Behaviour Researchers), ABRA (Association of Behavioural Researchers on Asians) and cE-Bs (Centre for Environment-Behaviour Studies, Faculty of Architecture, Planning & Surveying, Universiti Teknologi MARA, Malaysia.Keywords: food safety; food hygiene; GMP; HACCP

Digital Image Analysis to Assess Quantity and Morphological Quality of Isolated Pancreatic Islets.

Quantity and quality assessment of human pancreatic islets are essential processes to define a safe and potent quality product used for clinical transplantation. The conventional method of manual assessment has been used in the field for longer than two decades. The high degree of variability in product quantity and lack of archival imaging records of the product for verification are two major disadvantages of using the manual method for quantity and quality assessment of human pancreatic islets. Investigators have developed promising new methods for technical improvement. In this study, we briefly review the published methods and highlight the advantages of digital imaging analysis (DIA) when compared to the manual method. The application of DIA reduces measurement variability and increases the precision of islet equivalent (IEQ) determination for batch analysis. It produces images that can be archived for retrospective analysis and validation, and the data can be transmitted electronically for off-site analysis. These features are important for quality pancreatic islet assessment and are consistent with FDA requirements of current good manufacturing practice for clinical islet transplantation.

Specialties of first SMED in pharmaceutical manufacturing

Single Minute Exchange of Die (SMED) is considered as an effective lean management method increasingly used in pharmaceutical manufacturing. By reducing change-over times and costs, the successful implementation of the first SMEDs may bring a significant increase in terms of manufacturing flexibility. The purpose of this study is present the special factors that fundamentally determine SMEDs applied especially in the process of pharmaceutical manufacturing. By focusing on a well defined part of the pharmaceutical manufacturing process, lasting from Weighing and Measuring to the end of Tablet Pressing, the study also aims to highlight the benefits of SMED itself. The findings of the research are based on the practical experiences of four SMEDs implemented in various sections of production. According to the experiences and considering industrial specialties, the implementation of SMED has to harmonise with the requirements of Good Manufacturing Practices (GMP) which are representing the golden quality standards of pharmaceutical manufacturing.

A Platform for the Scalable Derivation of Genetically-Enhanced T and NK Lymphocytes from Naive Human Induced Pluripotent Stem Cells for Cancer Immunotherapy

▪Human induced pluripotent stem cell (hiPSC) technology enables the generation of a potentially unlimited source of therapeutically viable hematopoietic cells for the treatment of numerous hematological and non-hematological malignancies, and represents a highly promising approach for overcoming many of the challenges and limitations of patient-derived cancer immunotherapies. To advance the promise of hiPSC technology as an "off-the-shelf" source of hematopoietic cellular therapeutics, it is essential to be able to efficiently and reproducibly generate not only hematopoietic stem cells (HSCs) but also immune effector populations, including the diverse subsets of T and NK lymphoid cells, through a robust and scalable process. The in vitro derivation of HSCs and lymphocytes is complicated by the existence of at least two temporally and spatially distinct waves of blood cell formation during embryonic development: primitive and definitive. Primitive hematopoiesis initiates in the extraembryonic yolk sac and generates a transient and restricted hematopoietic repertoire consisting mainly of primitive erythroid and myeloid cells. Nascent HSCs only emerge later during the definitive wave from a specialized endothelial progenitor within the arterial vasculature termed hemogenic endothelium (HE). HE undergoes an endothelial-to-hematopoietic transition to give rise to HSCs, which then ultimately migrate to the bone marrow where they sustain multi-lineage hematopoiesis, including T and NK lymphoid cells, throughout adult life. Therefore the generation of HSCs and the formation of lymphoid effector cells from hiPSCs is dependent upon our ability to accurately recapitulate the intricate stages of early embryonic hematopoietic development towards the definitive program.While a limited number of studies have described the directed differentiation of hiPSCs to definitive HE in vitro, a major hurdle in utilizing hiPSCs for therapeutic purposes has been the requirement to initially co-culture such cells with murine-derived stromal cells in the presence of ill-defined serum-containing media in order to maintain pluripotency and induce differentiation. In addition, these protocols have employed an intermediate strategy consisting of embryoid body (EB) formation, which is difficult to scale and hindered by lack of reproducibility. We have previously demonstrated that our proprietary platform for robust and rapid derivation of clonal hiPSC lines, which utilizes small molecule reprograming and single cell selection strategies, generates cells with properties indicative of the naïve, or ground state of pluripotency. In addition to maintaining a homogeneous population of hiPSCs, our platform enables the genetic engineering of such pluripotent cells, at a single cell level, in both nuclease-dependent and -independent strategies.Here we describe a novel method for the generation of definitive HE from naïve hiPSCs in a scalable manner, void of an EB intermediate, under serum/feeder-free conditions. This platform represents a well-defined, small molecule-driven, staged protocol that can readily be translated to meet current good manufacturing practice (cGMP) requirements for the development of "off-the-shelf" hematopoietic cell-based immunotherapies. The derived HE population is definitive in nature as determine by Notch dependency and exhibits multi-lineage potential, as demonstrated through the formation of both T and NK lymphoid cells. HE generated by this protocol can be successfully cryopreserved and banked, serving as a highly-stable feedstock for subsequent derivation of various cell types for therapeutic use, including for T and NK cell-based immunotherapies. We have demonstrated that our proprietary, clinically-adaptable method for the large-scale production of definitive HE can efficiently give rise to a variety of lymphoid cell subsets. These derived lymphocytes, including NK cells, have been extensively characterized in vitro and in vivo, and we have demonstrated functionality through cytokine release and cellular cytotoxicity. Furthermore, through genetic modifications at the single cell hiPSC stage, tumor antigen-targeting and inducible caspase-mediated safety systems have been introduced into safe harbor loci to improve the specificity and safety profiles of hiPSC-derived T and NK cells for cancer immunotherapy applications. DisclosuresClarke:Fate Therapeutics Inc: Employment. Abujarour:Fate Therapeutics Inc: Employment. Robinson:Fate Therapeutics Inc: Employment. Huang:Fate Therapeutics Inc: Employment. Shoemaker:Fate Therapeutics Inc: Employment. Valamehr:Fate Therapeutics Inc: Employment.

Performance assessment of registration, sales and the regulatory management system of in vitro diagnostic veterinary medical reagents in Korea

In this study, we investigated and analyzed the registration, sales and regulatory management system of in vitro diagnostic veterinary medical reagents (IVDVMRs) in Korea. The registration of IVDVMRs has gradually increased since 2000, and total of 233 products from 58 companies were registered from 1975 to 2014. The market size of IVDVMRs is estimated to be approximately 12 billion Won per year from 2011 to 2013: the export sales and proportion was estimated to be 36.8% as 4.4 billion Won in 2013. Of these products, the ranking of the sales were canine heartworm, bovine tuberculosis, swine fever, porcine reproductive and respiratory syndrome, canine distemper+adenovirus+parvovirus disease, foot and mouth disease, etc. In vitro diagnostic human medical reagents were diverted biological medicine from the medical devices by the revision of the Pharmaceutical Affairs Law Enforcement Regulations in 2014 in Korea. In contrast, in vitro diagnostic devices for animal were still managed as medical devices and biological medicines, respectively. The diagnostic reagents for infectious diseases have neither classification nor grade systems. Good manufacturing practices (GMP) requirements on IVDVMRs were also exempted from the current system. This study suggested that the registration of the IVDVMRs has increased since 2005, and regulations of these devices should be improved for the effective operating system.

Long-term experiences in cryopreservation of mobilized peripheral blood stem cells using a closed-bag system: a technology with potential for broader application.

In several European countries, preparation of cellular products with open manufacturing systems as used for cryopreservation of peripheral blood stem cells (PBSCs) needs to be performed in a clean-room facility. However, this form of manufacturing is highly expensive and laborious. Thus, safe techniques providing improved efficacy regarding time and material, which are in accordance with legal requirements are highly desirable. We have developed, validated, and applied a simple method for cryopreservation of PBSCs within a functionally closed-bag system using the closed cryo freeze prep set. This process fulfills good manufacturing practice requirements and allows for the cryopreservation of PBSCs without a clean-room facility. In addition to cryopreservation of PBSCs, we have recently successfully modified our system for processing, portioning, and cryopreservation of allogeneic donor lymphocytes. Since 2010, cryopreservation of PBSCs using a closed-bag system has been performed in our facility on a routine basis and 210 patients and healthy donors have been included in this analysis. No significant reduction in viability of CD34+ cells and no process-related contamination were observed. Outcome of hematopoietic stem cell transplantation regarding time of engraftment and infectious complications is comparable to products manufactured in conventional clean-room facilities. Our data confirm that cryopreservation of PBSCs within a functionally closed-bag system is safe, effective, and economical. Furthermore, the system has the potential to be extended to other manufacturing processes of cellular products.

Efficient and Scalable Expansion of Human Pluripotent Stem Cells Under Clinically Compliant Settings: A View in 2013

Human pluripotent stem cells (hPSCs) hold great promise for revolutionizing regenerative medicine for their potential applications in disease modeling, drug discovery, and cellular therapy. Many their applications require robust and scalable expansion of hPSCs, even under settings compliant to good clinical practices. Rapid evolution of media and substrates provided safer and more defined culture conditions for long-term expansion of undifferentiated hPSCs in either adhesion or suspension. With well-designed automatic systems or fully controlled bioreactors, production of a clinically relevant quantity of hPSCs could be achieved in the near future. The goal is to find a scalable, xeno-free, chemically defined, and economic culture system for clinical-grade expansion of hPSCs that complies the requirements of current good manufacturing practices. This review provides an updated overview of the current development and challenges on the way to accomplish this goal, including discussions on basic principles for bioprocess design, serum-free media, extracellular matric or synthesized substrate, microcarrier- or cell aggregate-based suspension culture, and scalability and practicality of equipment.

Stimulating surface molecules, Th1-polarizing cytokines, proven trafficking—a new protocol for the generation of clinical-grade dendritic cells

Dendritic cells (DC) have been vigorously investigated as an immunological basis for therapeutic vaccination against cancer and infections, even among patients after allogeneic stem cell transplantation. Effective induction of cell-mediated immunity strongly depends on the ability of DC to (i) migrate to the draining lymphoid organs mediated by chemokine receptors, (ii) prime T cells through high expression of costimulatory molecules and major histocompatibility complexes and (iii) secret Th1-polarizing cytokines such as Interleukin-12 (IL-12). However, there is no protocol to generate fully matured and functional DC according to methodical requirements of current good manufacturing practice (CGMP) guidelines. We established a protocol conforming to CGMP standards that permits the generation of fully matured and functional DC on the basis of cell culture in adherence bags with the use of serum-free media with a maturation cocktail, containing tumor necrosis factor-alpha/Interferon-alpha/polyinosinic:polycytidylic acid. Our DC superiorly display three critical features for an effective induction of cell-mediated immunity without evidence of exhaustion, along with its ability to prime infectious or tumor-specific T cells in a short-term cell culture. Our newly developed protocol offers an attractive method to produce fully matured Th1-polarizing DC with proven migratory and stimulatory capacity for any clinical application according to CGMP standards.

Trans-Resveratrol in Nutraceuticals: Issues in Retail Quality and Effectiveness

Fourteen brands of resveratrol-containing nutraceuticals were evaluated in order to verify their actual resveratrol content and to control if their health-promoting properties are related to manufacturing quality. Products included pure resveratrol capsules or multi-ingredient formulations with standardized amounts of resveratrol and other phytochemicals. Samples were analyzed for total trans-resveratrol, flavonoids, procyanidin, polyphenol content and the results were compared with the content declared on-label. Only five out of 14 brands had near label values, compliant with Good Manufacturing Practices (GMP) requirements (95–105% content of active constituent), four products were slightly out of this range (83–111%) and three were in the 8–64% range. Two samples were below the limit of detection. The greater the difference between actual and labeled resveratrol content, the lower was the antioxidant and antiproliferative activity strength. Dietary supplements containing pure trans-resveratrol exhibited a greater induction of differentiation towards human leukemic K562 cells when compared to multicomponent products. Great differences currently exist among resveratrol food supplements commercially available and GMP-grade quality should not be taken for granted. On the other side, dosages suggested by most “pure”, “high-dosage” supplements may allow a supplementation level adequate to obtain some of the purported health benefits.

Human Platelet Lysate Gel Provides a Novel Three Dimensional-Matrix for Enhanced Culture Expansion of Mesenchymal Stromal Cells

Cell culture in regenerative medicine needs to facilitate efficient expansion according to good manufacturing practice requirements. Human platelet lysate (HPL) can be used as a substitute for fetal calf serum without the risk of xenogeneic immune reactions or transmission of bovine pathogens. Heparin needs to be added as anticoagulant before addition of HPL to culture medium; otherwise, HPL-medium forms a gel within 1 h. Here, we demonstrated that such HPL-gels provide a suitable 3D-matrix for cell culture that-apart from heparin-consists of the same components as the over-layered culture medium. Mesenchymal stromal cells (MSCs) grew in several layers at the interface between HPL-gel and HPL-medium without contact with any artificial biomaterials. Notably, proliferation of MSCs was much higher on HPL-gel compared with tissue culture plastic. Further, the frequency of initial fibroblastoid colony forming units (CFU-f) increased on HPL-gel. The viscous consistency of HPL-gel enabled passaging with a convenient harvesting and reseeding procedure by pipetting cells together with their HPL-matrix-this method does not require washing steps and can easily be automated. The immunophenotype and in vitro differentiation potential toward adipogenic, osteogenic, and chondrogenic lineage were not affected by culture-isolation on HPL-gel. Taken together, HPL-gel has many advantages over conventional plastic surfaces: it facilitates enhanced CFU-f outgrowth, increased proliferation rates, higher cell densities, and nonenzymatic passaging procedures for culture expansion of MSCs.

Derivation and propagation of human embryonic stem cell lines from frozen embryos in an animal product–free environment

The protocols described here are comprehensive instructions for deriving human embryonic stem (hES) cell lines in xeno-free conditions from cryopreserved embryos. Details are included for propagation, cryopreservation and characterization. Initial derivation is on feeder cells and is followed by adaptation to a feeder-free environment; competent technicians can perform these simplified methods easily. From derivation to cryopreservation of fully characterized initial stocks takes 3-4 months. These protocols served as the basis for standard operating procedures (SOPs), with both operational and technical components, that we set to meet good manufacturing practice (GMP) and UK regulatory body requirements for derivation of clinical-grade cells. As such, these SOPs are currently used in our current GMP compliant facility to derive hES cell lines ab initio, in an animal product-free environment; these lines are suitable for research and potentially for clinical use in cell therapy. So far, we have derived eight clinical-grade lines, which will be freely available to the scientific community after submission/accession to the UK Stem Cell Bank.

Quality risk management for prepared sterile products in hospital pharmacy

BackgroundA hospital pharmacy (HP) prepares compounded sterile preparations (CSPs) following the current good manufacturing practice (cGMP) requirements. A quality risk management (QRM) is needed for the assessment, control, communication and...