Current Good Manufacturing Practice Regulations Research Articles

Analytical method development, validation, and out-of-specification investigations for polyethylene glycol

This work was motivated by the United States Pharmacopeia monograph modernization initiative and European directorate for the quality of medicines and healthcare. An out-of-specification (OOS) occurrence prompted OOS investigations for the cGMP (cGMP refers to the Current Good Manufacturing Practice regulations enforced by the FDA) release testing of residual ethylene oxide in polyethylene glycol (PEG) according to the standards detailed within the United States Pharmacopeia/National Formulary (USP-NF) for polyethylene glycol, and the European Pharmacopoeia (Ph. Eur.) for macrogols. During the OOS root cause investigations, we observed a PEG degradant and identified it as methyl formate, which co-elutes with ethylene oxide using the GC (gas chromatography) methods published in current USP-NF and Ph. Eur. for PEGs. To address this, a novel method utilizing static headspace gas chromatography with flame ionization detection (HS-GC-FID) was developed to test various grades of PEGs for the presence of residual ethylene oxide, along with other process related impurities and degradation products. With this new method, ethylene oxide, a known genotoxic impurity and IARC (International Agency for Research on Cancer) Class 1 human carcinogen, can be well resolved from methyl formate, a newly identified and comparatively innocuous degradant derived from PEG. The currently available official compendial methods are unable to separate the specific impurities in PEGs. However, the new GC method presented in this paper has been shown to have a high and unique selectivity, allowing for baseline separations (chromatographic resolutions greater than 1.5) of all related impurities in PEGs, which is a challenging task. Additionally, this method has been found to be stability-indicating based on a forced degradation study. During stress stability study of PEGs involving acid, alkali, heat, light, and oxidation, some other PEG degradants, including formaldehyde, were identified. It is possible that formaldehyde undergoes a disproportionation reaction known as the Cannizzaro reaction, leading to the formation of formic acid and methanol. The formic acid then undergoes an esterification reaction with methanol to produce methyl formate. To the best of our knowledge, this is the first stability-indicating HS-GC-FID method that accomplishes this separation in a single run, and it was successfully validated as per ICH (the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines. Therefore, this method is suitable for the conduct of cGMP batch release and stability testing of PEGs in regulated quality control (QC) laboratories.

Comprehensive multi-attribute method workflow for biotherapeutic characterization and current good manufacturing practices testing.

The multi-attribute method (MAM) is a liquid chromatography-mass spectrometry (LC-MS)-based method that is used to directly characterize and monitor numerous product quality attributes (PQAs) at the amino acid level of a biopharmaceutical product. MAM enables identity testing based on primary sequence verification, detection and quantitation of post-translational modifications and impurities. This ability to simultaneously and directly determine PQAs of therapeutic proteins makes MAM a more informative, streamlined and productive workflow than conventional chromatographic and electrophoretic assays. MAM relies on proteolytic digestion of the sample followed by reversed-phase chromatographic separation and high-resolution LC-MS analysis in two phases. First, a discovery study to determine quality attributes for monitoring is followed by the creation of a targeted library based on high-resolution retention time plus accurate mass analysis. The second aspect of MAM is the monitoring phase based on the target peptide library and new peak detection using differential analysis of the data to determine the presence, absence or change of any species that might affect the activity or stability of the biotherapeutic. The sample preparation process takes between 90 and 120 min, whereas the time spent on instrumental and data analyses might vary from one to several days for different sample sizes, depending on the complexity of the molecule, the number of attributes to be monitored and the information to be detailed in the final report. MAM is developed to be used throughout the product life cycle, from process development through upstream and downstream processes to quality control release or under current good manufacturing practices regulations enforced by regulatory agencies.

Parameter for Process Validation of Sevelamer Hydrochloride Film Coated Tablet

Validation is a tool of quality assurance which provides confirmation of the quality in equipment system, manufacturing process, software and testing methods. Validation of the individual step of manufacturing processes is called the process validation. The concept of validation was first proposed by two Food and Drug Administration(FDA) officials, Ted Byers and Bud Loftus, in the mid-1970s in order to improve the quality of pharmaceuticals Assurance of product quality is derived from careful attention to number of factors including selection of quality parts and materials, adequate product and process design, control of the process, and in process and end product testing. Process Validation has now become a part of Current Good Manufacturing Practices Regulations (cGMP), it is mandatory for manufacturer to go through Process Validation much more rigorously than earlier. Coating process proven as validated from the weight build up data of tablets as validation data provided for after 50%coating, 75% coating and 100% coating and found in accordance with process validation protocol. Finished product result was evidence of Weight gain while the inspection activity as this material is in very high hygroscopic in nature. However results found within specified limit

Gene Transduction of Natural Killer Cells for Clinical Application.

Autologous T cells expressing chimeric antigen receptor (CAR) have produced a spectacular response in hematological malignancies. This success of cellular therapy has inspired the exploration of the therapeutic potential of other immune cell types. In this regard, natural killer (NK) cells hold great potential as they can identify tumor cells by mechanisms that are different from those used by T cells and have a high cytotoxic capacity. Their capacity to recognize tumors and killing potency can be further enhanced by genetic modification. Our laboratory has developed a clinically adaptable method to manufacture genetically modified NK cells using retroviral vectors in compliance with current good manufacturing practice regulations. Here, we describe relevant technical procedures, including isolation of peripheral blood mononucleated cells from a leukapheresis product, T-cell depletion, stimulation and transduction of NK cells, and preparation of transduced NK cells for infusion.

Enhanced brain delivery and therapeutic activity of trastuzumab after blood-brain barrier opening by NEO100 in mouse models of brain-metastatic breast cancer.

The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity. An in vitro BBB, consisting of human astrocytes and brain endothelial cells, was used to determine trastuzumab penetration in the presence or absence of NEO100. For in vivo studies, we administered intravenous (IV) trastuzumab or the trastuzumab-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Roche), to mouse models harboring intracranial HER2+ breast cancer, with or without BBB opening via IA NEO100. Brain and tumor tissues were examined for the presence of trastuzumab and infiltration of immune cells. Therapeutic impact was evaluated based on overall survival. NEO100 greatly increased trastuzumab penetration across an in vitro BBB. In vivo, IA NEO100-mediated BBB opening resulted in brain tumor-selective accumulation of trastuzumab, without detectable presence in normal brain tissue, along with increased presence of immune cell populations. IV delivery of trastuzumab or T-DM1 achieved significantly greater overall survival of tumor-bearing mice when combined with IA NEO100. IA NEO100 facilitates brain tumor entry of trastuzumab and T-DM1 and significantly enhances their therapeutic efficacy, along with increased antibody-dependent immune cell recruitment.

Cell Banking of HEK293T cell line for clinical-grade lentiviral particles manufacturing

BackgroundCell banks are widely used to preserve cell properties as well as to record and control the use of cell lines in biomedical research. The generation of cell banks for the manufacturing of Advanced Therapy Medicinal Products, such as cell and gene therapy products, must comply with current Good Manufacturing Practice regulations. The quality of the cell lines used as starting materials in viral-vector manufacturing processes must be also assessed.MethodsThree batches of a Master Cell Bank and a Working Cell Bank of the HEK293T cell line were manufactured under current Good Manufacturing Practices regulations. Quality control tests were performed according to product specifications. Process validation includes the training of manufacturing personnel by performing simulation tests, and the continuous measurement of environmental parameters such as air particles and microorganisms. Cell number and viability of cryopreserved cells were periodically measured in order to define the stability of these cellular products.ResultsAll batches of HEK293T Master and Working Cell Banks met the acceptance criteria of their specifications showing the robustness and homogeneity of the processes. In addition, both Master and Working Cell Banks maintained the defined cell viability and concentration over a 37 month-period after cryopreservation.ConclusionsManufacturing cell banks under Good Manufacturing Practice regulations for their use as raw materials or final cellular products is feasible. HEK293T cell banks were used to manufacture clinical-grade lentiviral particles for Chimeric Antigen Receptor T-cell based clinical trials.

Compendial Methods: Suitability Verification, Challenges and Recommendations for Proteins

Compendial testing methods are not required to be fully validated, but their suitability for testing should be verified under actual conditions of use. This requirement is established in 21 CFR 211.194(a)(2) of the current Good Manufacturing Practice regulations in the United States. ANVISA (Agência Nacional de Vigilância Sanitária) also requires that compendial analytical methods shall have their suitability demonstrated for the intended use by a partial validation study. Suitability verifications or partial validation can be divided into two major categories: visual and instrumental methods. For visual methods, the color and opalescence of interferences should be checked. If the color or clarity/opalescence of the sample is outside of the range of the Pharmacopeia standards/reference solutions, the validity of the test results should be evaluated. Specificity is usually waived because the methods are not specific to products, and accuracy/precision can be addressed by comparing results from analyst to analyst. For instrument methods, specificity can also be waived for certain assays. Accuracy is addressed by implementation of instrument calibration and/or method control. Precision is required either in suitability verification or when testing the samples. Here, we present approaches for suitability verification and the scientific rationale supporting compendial methods: visible particulates, subvisible particles, pH, osmolality, color and clarity/opalescence. Current challenges and recommendations are also discussed specifically for the analysis of protein products.

Regulatory Challenges of Sterile Formulation Development As Per USFDA Prospectives

For the sterile product development FDA has taken many initiatives for the safety and efficacious products. Recently, many works have been done for the improvement in drug development. Quality by Design (QBD) Product and manufacturing process development, as well as safe use and product design, are among the elements of enhanced technical involvement. In this review, we discussed an overview of regulatory challenges to improve the quality aspects for sterile drugs. FDA has regulated current good manufacturing practice (CGMP) regulations for the manufacture of large volume parenterals. The studies can then be prolonged to multiple ingredients to assure compatibility with the API and each of the excipients. The compatibility of the drug product should provide appropriate information about the drug product. It should deals with the quality of drug product and route of administration for the intended use. Microbiological review conducted in 1970–1971 for the manufacture of sterile drug was one of FDA's responses to the nosocomial bacteremias, Recently the new drug microbiology review function has been re-examining its role in non-sterile dosage forms in order to Know about recalls and adverse event for oral and topical drug products. For the Active pharmaceutical ingredient justifying the quality source is generally time-consuming effort whether the product is manufacturein-house, as with an Non chemical entity, or sourced externally, as with a generic API.5

Evaluation of microcystin contamination in blue-green algal dietary supplements using a protein phosphatase inhibition-based test kit

The cyanobacterium Aphanizomenon flos-aquae (AFA), from Upper-Klamath Lake, Oregon, are used to produce blue-green algal (BGA) dietary supplements. The periodic co-occurrence of hepatotoxin-producing contaminant species prompted the Oregon Health Division to establish a limit of 1 μg/g microcystin (MC) for products sold in Oregon in 1997. At the federal level, the current good manufacturing practice (CGMP) regulations for dietary supplements require manufacturers establish a specification, and test, for limits on contaminants that may adulterate finished products. Despite this, several previous international surveys reported MC in BGA supplements in excess of 1 μg/g. The objectives of this study were (1) identify a reliable, easy to use test kit for the detection of MC in dried BGA materials and (2) use this kit to assess the occurrence of MC contamination in AFA-BGA dietary supplements in the U.S. A commercial protein phosphatase inhibition assay (PPIA), based on the enzyme PP2A, was found to have acceptable relative enzyme inhibition and accuracy for the majority of MC variants tested, including those most commonly identified in commercial samples, making the kit fit for purpose. Using the PPIA kit, 51% (26 of 51) distinct AFA-BGA products had MC ≥0.25 μg/g (the detection limit of the kit), 10 products had MC concentrations between 0.5 and 1.0 μg/g, and 4 products exceeded the limit (1.1–2.8 μg/g). LC-MS/MS confirmed PPIA results ≥0.5 μg/g and determined that MC-LA and MC-LR were the main congeners present. PPIA is a reliable method for the detection of MC contamination in dried BGA dietary supplements produced in the U.S. While the majority of AFA-BGA products contained ≥0.25 μg/g MC, most were at or below 1.0 μg/g, suggesting that manufacturers have adopted this level as a specification in these products; however, variability in recommended serving sizes prevented further analysis of consumer exposure based on the concentrations of MC contamination found.

Differentiation of Crataegus spp. guided by nuclear magnetic resonance spectrometry with chemometric analyses

For compliance with US Current Good Manufacturing Practice regulations for dietary supplements, manufacturers must provide identity of source plant material. Despite the popularity of hawthorn as a dietary supplement, relatively little is known about the comparative phytochemistry of different hawthorn species, and in particular North American hawthorns. The combination of NMR spectrometry with chemometric analyses offers an innovative approach to differentiating hawthorn species and exploring the phytochemistry. Two European and two North American species, harvested from a farm trial in late summer 2008, were analyzed by standard 1D 1H and J-resolved (JRES) experiments. The data were preprocessed and modelled by principal component analysis (PCA). A supervised model was then generated by partial least squares-discriminant analysis (PLS-DA) for classification and evaluated by cross validation. Supervised random forests models were constructed from the dataset to explore the potential of machine learning for identification of unique patterns across species. 1D 1H NMR data yielded increased differentiation over the JRES data. The random forests results correlated with PLS-DA results and outperformed PLS-DA in classification accuracy. In all of these analyses differentiation of the Crataegus spp. was best achieved by focusing on the NMR spectral region that contains signals unique to plant phenolic compounds. Identification of potentially significant metabolites for differentiation between species was approached using univariate techniques including significance analysis of microarrays and Kruskall-Wallis tests.

FDA warns Mylan about alleged violations at Indian facility

Generic drug maker Mylan has received a warning from FDA about alleged failure to control drug quality, significant violations of manufacturing standards, and data integrity lapses at a facility in India. The facility produces antiretroviral therapies used to treat HIV infection. In an April 3 letter, the agency says its investigator, who inspected the Nashik factory in India’s western state of Maharashtra, allegedly found significant violations of current Good Manufacturing Practice regulations for finished pharmaceuticals. “Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture,” the letter says. The agency adds that failure to correct these violations may result in FDA refusing admission into the U.S. of items produced at the plant. In 2015, FDA expressed concerns over quality controls at three Mylan factories in Bengaluru, in south India.

A practical and pyrogen-free preparation of 11C-L-methionine in a good manufacturing practice-compliant approach

Aims: 11C-L-methionine, an amino acid tracer used to delineate certain tumor tissues, has proven to be a prevailing nonfluorodeoxyglucose positron emission tomography (PET) radiopharmaceutical. We intended to prepare 11C-L-methionine by following modified synthetic strategies at a rebuilt working area to meet the PET drug current good manufacturing practice (cGMP) and Pharmaceutical Inspection Co-operation Scheme (PIC/S) regulations. Furthermore, we overcame the problem of pyrogen cross-contamination using a cleaner and more efficient program. Material and Methods: The task of upgrading air filtration equipment was integrated with the set of Web-Based Building Automation system (WebCTRL®). 11C-L-methionine synthesis was carried out in accordance with redesigned methods to meet the requirements of PET drug cGMP. The product quality was tested by a series of quality control tests and was found to be satisfactory. Depyrogenation was carried out by three different methods with different flow rates and flushing durations. The results were examined through limulus amebocyte lysate clotting test. Results: The level of air cleanliness in each section meets the PIC/S GMP standards after the reconstructions. Moreover, after delicate modifications, the radiochemical yield of 11C-L-methionine was 36.20% ± 3.59% (based on 11C-CH3I, n = 7), which is about 10% higher than the average former yield. Besides, the used depyrogenation methods could wipe the bioburden off within 8 h. Conclusions: The modifications done not only offer a good production environment but also protect the products from contamination. The modified approaches in both 11C-L-methionine production and depyrogenation resulted in prominent progress in stability and efficiency as well.

Dietary supplements quality analysis tools from the United States Pharmacopeia.

The United States Food and Drug Administration (FDA) issued the dietary supplement (DS) current good manufacturing practice (GMP) regulations in compliance with the mandate from the Dietary Supplements Health and Education Act (DSHEA), with the intention of protecting public health by ensuring the quality of DS. The GMP regulations require manufacturers to establish their own quality specifications for identity, purity, strength, composition, and absence of contaminants. Numerous FDA‐conducted GMP inspections found that the private specifications set by these manufacturers are often insufficient to ensure adequate quality of dietary ingredients and DS. Wider use of the public standards developed by the United States Pharmacopeial Convention (USP), in conjunction with GMP compliance, can help ensure quality and consistency of DS as they do for medicines. Public health protection could be enhanced by strengthening the GMP provisions to require conformance with relevant United States Pharmacopeia–National Formulary (USP–NF) standards, or in the absence of USP standards, other public compendial standards. Another serious concern is the presence of synthetic drugs and drug analogues in products marketed as DS. Use of the new USP General Chapter Adulteration of Dietary Supplements with Drugs and Drug Analogs <2251> may reduce the exposure of consumers to dangerous drugs disguised as DS. © 2016 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.

Staphylococcus aureus Outbreak Investigation of an Illinois Bakery

AbstractOver 100 individuals were sickened after ingesting an assortment of desserts linked to four staphylococcal food poisoning outbreaks leading investigators to products manufactured by an Illinois bakery. The investigative team identified substantial deviations from the current Good Manufacturing Practice Regulations, 21 CFR Part 110, during multiple visits to the bakery. A total of 299 environmental swabs and 16 raw ingredients were collected for bacteriological analysis. Staphylococcus aureus isolates recovered from these samples were evaluated using either serological or polymerase chain reaction methods for the identification of staphylococcal enterotoxins SEA‐SEE, SEG‐SEI, SE‐like SElJ‐SElU or their respective genes, and for Panton–Valentine leukocidin cytotoxin. A raw ingredient and 16% of the environmental samples revealed the presence of enterotoxigenic S. aureus capable of producing diverse combinations of toxins. Antimicrobial susceptibility testing found that all S. aureus isolates were resistant to one or more agent(s). Pulsed field gel electrophoresis characterization of the isolates identified six pattern types.Practical ApplicationsThis Staphylococcus aureus outbreak investigation revealed the prevalence and diversity of antimicrobial‐resistant strains of S. aureus carrying both classical staphylococcal enterotoxins (SEs) and genes for nonclassical SE and SE‐like enterotoxins found in the environment of an Illinois bakery. In this occurrence, nonclassical SE and SE‐like enterotoxin serotypes were coupled with classical SEs, and therefore detectable by commercially available kits. This outbreak investigation demonstrated the abundance of the nonclassical SE and SE‐like enterotoxin serotypes in the environment and the anticipated need for new screening method requirements.

Review of red yeast rice content and current Food and Drug Administration oversight

Red yeast rice (RYR) is a commonly used dietary supplement for the management of dyslipidemia. In 2007, the Food and Drug Administration (FDA) issued a consumer warning to avoid RYR products because they may contain unauthorized drug (lovastatin) and also implemented Current Good Manufacturing Practices (CGMP) requiring that proper controls be in place by dietary supplement companies to ensure products are manufactured and processed in a consistent manner and produce high-quality products that are not adulterated with impurities or contaminants and are accurately labeled. To assess the FDA oversight of companies manufacturing RYR products and review the labeled content of available RYR products. The FDA was audited through the Freedom of Information Act, we requested answers to a series of questions concerning their oversight of companies manufacturing RYR products. The labeled content of each RYR product listed in the Natural Medicines Comprehensive Database (NMCD) was tabulated and summarized. Statin-related product warnings and if product certification and verification by an independent laboratory had been performed were documented. The FDA had no information on the number of RYR manufacturers and their compliance with CGMP regulations. A total of 101 products containing RYR were reviewed. No product could be confirmed as passing any independent laboratory verification testing. Nearly one-half (42.6%) of the RYR product labels contained statin-related warnings (ie, potential for muscle pain or weakness, etc). Currently, the FDA is not regulating manufacturers of RYR products and as a result, many of these products may contain monacolin K and toxins such as citrinin.

Islet isolation from adult designated pathogen‐free pigs: use of the newer bovine nervous tissue–free enzymes and a revised donor selection strategy would improve the islet graft function

In clinical trials using adult porcine islet products, islets should be isolated from the designated pathogen-free (DPF) pigs under the current good manufacturing practice (GMP) regulations. Our previous studies suggested that male DPF pigs are better donors than retired breeder pigs and histomorphometrical parameters of donor pancreas predict the porcine islet quality. We aimed to investigate whether the use of the newer bovine nervous tissue-free enzymes and a revised donor selection strategy could improve the islet graft function in the context of islet isolation with DPF pigs. Using 30 DPF pigs within a closed herd, we compared the islet yield of porcine islets isolated with Liberase PI (n = 11, as a historical control group), Liberase MTF C/T, which is a GMP-grade enzyme (n = 12), and CIzyme collagenase MA/BP protease (n = 7). We analyzed the relationship between the diabetes reversal rate of recipient NOD/SCID mice (n = 75) and histomorphometric parameters of each donor pancreas as well as donor characteristics. Proportion of islets larger than 200 μm from the biopsied donor pancreas (P = 0.006) better predicted islet yield than age (P = 0.760) or body weight (P = 0.371) of donor. The proportion of islets larger than 200 μm from the biopsied donor pancreas was not related to the sex of the donor miniature pig (P = 0.358). The islet yield obtained with the three enzymes did not differ, even after stratification of the donor with the histomorphometric parameters of the biopsied donor pancreas and the sex of donor. The use of the newer bovine nervous tissue-free enzymes (P < 0.001), a higher proportion of large islets in donor pancreas (P = 0.006), and a male sex of the donor (P = 0.025) were independent predictors of earlier diabetes reversal. Use of the newer bovine nervous tissue-free enzymes including a GMP-grade enzyme resulted in better islet quality than that of islet isolated using Liberase PI. To obtain high-quality islet from DPF pigs, the donor should be male pig and histomorphometrical parameters from donor pancreas should be considered.

ACCF/AHA 2011 Health Policy Statement on Therapeutic Interchange and Substitution

Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1291 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1291 1. Purpose of This Document . . . . . . . . . . . . . . .1291 2. Document Development Process . . . . . . . . . .1291 3. Definitions, Terminology, and Regulations . . .1292 1. Terminology . . . . . . . . . . . . . . . . . . . .1292 2. Generics . . . . . . . . . . . . . . . . . . . . . . . .1293 3. Bioequivalence . . . . . . . . . . . . . . . . . .1293 4. Biologics and Biosimilars. . . . . . . . . . .1294 2. Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . .1295 3. Federal Regulations and State Laws . . . . . . . . . . .1296 4. Therapeutic Approaches . . . . . . . . . . . . . . . . . . . . .1296 1. Therapeutic Interchange . . . . . . . . . . . . . . . . .1296 2. Therapeutic Substitution . . . . . . . . . . . . . . . . .1297 3. Generic Substitution . . . . . . . . . . . …

Chapter 3: Pig islet product manufacturing and release testing

This chapter provides recommendations on pig islet product manufacturing and release testing to scientific and corporate programs interested in future clinical studies using xenogeneic porcine pancreatic islet cell products for the treatment of type 1 diabetes.To facilitate control of manufacturing as well as reproducibility and consistency of product lots, the manufacturing process, and the manufacturing facility must be in compliance with current Good Manufacturing Practices regulations. Data must be provided to demonstrate that islet products can be consistently prepared that would meet basic lot release requirements. To facilitate product safety: (i) materials used in the manufacturing process, including the pig pancreas, must be free of adventitious agents; (ii) islets must be manufactured using aseptic processing; and (iii) final product must undergo tests for sterility, mycoplasma (if cultured) and endotoxin. Safety specifications for pig islet product release include a negative Gram stain and an endotoxin content of <5.0 EU/kg recipient body weight. Product post-release assessments must include sterility cultures on the final product. Because results for sterility are available only retrospectively, a plan of action must be in place for patient notification and treatment in case the sterility culture results are positive for contamination. Product characterization information must address important aspects of lot release testing such as identity/purity (cell composition), quantity [islet equivalents (IE), cell number] and potency (insulin secretory capacity, oxygen consumption rate corrected for DNA or transplant bioassay in immunoincompetent diabetic mice). This information is also critical to demonstrate manufacturing control and product consistency across multiple islet preparations (lots). Providing islet products containing an islet mass sufficient to restore euglycemia in trial participants (>or=10 000 IE/kg) requires pooling of islets from multiple donor pancreata (two to four from adult donors and seven to 10 from neonatal donors). Demonstration of product consistency across products from individual pancreata would warrant release testing to be performed on a sample of the pooled product. As product development and clinical trials advance, the increasingly more detailed specifications of potency assays on adult porcine islet products are expected to be predictive of post-transplant glycemic control. The immaturity of fetal and neonatal porcine islet tissue precludes the use of in vitro insulin secretion as a potency test as part of lot release testing; another measure of potency appropriate to fetal and neonatal cells will need to be developed for product release testing and evaluation of aliquots of these products in mouse transplant bioassays should be performed to provide meaningful post-release information.

Current challenges for FDA‐regulated bioanalytical laboratories for human (BA/BE) studies. Part I: defining the appropriate compliance standards – application of the principles of FDA GLP and FDA GMP to bioanalytical laboratories

AbstractThis article is the first of a three‐part series that deals with current compliance issues/challenges for bioanalytical laboratories performing analysis for bioavailability/bioequivalence studies. Part 1 of this series provides the application of key elements from the Food and Drug Administration Good Laboratory Practices and the current Good Manufacturing Practices regulations as the framework for the implementation of sound quality systems in a bioanalytical laboratory to be in compliance with current regulatory expectations. Copyright © 2007 John Wiley &amp; Sons, Ltd.

CGMP violations may be the basis for QUI TAM lawsuits in the United States

AbstractPharmaceutical manufacturers continue to battle with the Food and Drug Administration (FDA) over compliance with current Good Manufacturing Practice regulations (cGMP), which outline the requirements that drug manufacturers must follow for the manufacture, processing, packing, and holding of a drug. Pharmaceutical manufacturers have already been the target of successful Federal False Claims Act (FCA) prosecutions, mostly due to pricing and kickback issues raised in qui tam lawsuits. Qui tam lawsuits are brought under the FCA by private citizens who sue on behalf of the United States (US). In exchange for their efforts, the US law provides that the private citizen is entitled, generally, to 15 to 30 % of the recovery generated by the qui tam lawsuit.Kenneth J. Nolan, a top qui tam attorney says that in the last several years, total payouts by manufacturers to settle qui tam lawsuits have amounted to over USD 2.0 billion. Copyright © 2004 John Wiley &amp; Sons, Ltd.