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D'Souza S.,University of Kentucky | D'Souza S.,Sunovion Pharmaceuticals | Faraj J.A.,University of Kentucky | Faraj J.A.,Fresenius Kabi United States | And 3 more authors.
AAPS PharmSciTech | Year: 2014

Accelerated in vitro release testing methodology has been developed as an indicator of product performance to be used as a discriminatory quality control (QC) technique for the release of clinical and commercial batches of biodegradable microspheres. While product performance of biodegradable microspheres can be verified by in vivo and/or in vitro experiments, such evaluation can be particularly challenging because of slow polymer degradation, resulting in extended study times, labor, and expense. Three batches of Leuprolide poly(lactic-co-glycolic acid) (PLGA) microspheres having varying morphology (process variants having different particle size and specific surface area) were manufactured by the solvent extraction/evaporation technique. Tests involving in vitro release, polymer degradation and hydration of the microspheres were performed on the three batches at 55°C. In vitro peptide release at 55°C was analyzed using a previously derived modification of the Weibull function termed the modified Weibull equation (MWE). Experimental observations and data analysis confirm excellent reproducibility studies within and between batches of the microsphere formulations demonstrating the predictability of the accelerated experiments at 55°C. The accelerated test method was also successfully able to distinguish the in vitro product performance between the three batches having varying morphology (process variants), indicating that it is a suitable QC tool to discriminate product or process variants in clinical or commercial batches of microspheres. Additionally, data analysis utilized the MWE to further quantify the differences obtained from the accelerated in vitro product performance test between process variants, thereby enhancing the discriminatory power of the accelerated methodology at 55°C. © 2014 American Association of Pharmaceutical Scientists. Source


D'Souza S.,Sunovion Pharmaceuticals | Faraj J.A.,Fresenius Kabi United States | Giovagnoli S.,University of Perugia | Deluca P.P.,University of Kentucky
International Journal of Biomaterials | Year: 2014

In this study, four PLGA microsphere formulations of Olanzapine were characterized on the basis of their in vitro behavior at 37°C, using a dialysis based method, with the goal of obtaining an IVIVC. In vivo profiles were determined by deconvolution (Nelson-Wagner method) and using fractional AUC. The in vitro and in vivo release profiles exhibited the same rank order of drug release. Further, in vivo profiles obtained with both approaches were nearly superimposable, suggesting that fractional AUC could be used as an alternative to the Nelson-Wagner method. A comparison of drug release profiles for the four formulations revealed that the in vitro profile lagged slightly behind in vivo release, but the results were not statistically significant (P < 0.0001). Using the four formulations that exhibited different release rates, a Level A IVIVC was established using the deconvolution and fractional AUC approaches. A nearly 1: 1 correlation (R 2 > 0.96) between in vitro release and in vivo measurements confirmed the excellent relationship between in vitro drug release and the amount of drug absorbed in vivo. The results of this study suggest that proper selection of an in vitro method will greatly aid in establishing a Level A IVIVC for long acting injectables. © 2014 Susan D'Souza et al. Source


Szajek A.Y.,Pharmacopeia | Chess E.,Baxter Healthcare Corporation | Johansen K.,Sjolundsparken | Gratzl G.,Boehringer Ingelheim | And 15 more authors.
Nature Biotechnology | Year: 2016

The contamination of the widely used lifesaving anticoagulant drug heparin in 2007 has drawn renewed attention to the challenges that are associated with the characterization, quality control and standardization of complex biological medicines from natural sources. Heparin is a linear, highly sulfated polysaccharide consisting of alternating glucosamine and uronic acid monosaccharide residues. Heparin has been used successfully as an injectable antithrombotic medicine since the 1930s, and its isolation from animal sources (primarily porcine intestine) as well as its manufacturing processes have not changed substantially since its introduction. The 2007 heparin contamination crisis resulted in several deaths in the United States and hundreds of adverse reactions worldwide, revealing the vulnerability of a complex global supply chain to sophisticated adulteration. This Perspective discusses how the US Food and Drug Administration (FDA), the United States Pharmacopeial Convention (USP) and international stakeholders collaborated to redefine quality expectations for heparin, thus making an important natural product better controlled and less susceptible to economically motivated adulteration. © 2016 Nature America, Inc. Source


Morrison A.,Microbiology and Components RD andI Group | Mcmillan L.,Microbiology and Components RD andI Group | Radwanski K.,Fresenius Kabi United States | Blatchford O.,Health Protection Scotland | And 2 more authors.
Vox Sanguinis | Year: 2014

Background and Objectives: Recently, a glucose- and bicarbonate-containing additive solution termed PAS 5 demonstrated acceptable 7-day platelet storage after >95% plasma replacement with PAS on the day of collection (Day 0). In this study, we examined platelet storage in >95% PAS 5 after manual washing of Day 1 apheresis platelets in plasma collected using either the Amicus or Trima plateletpheresis devices. Material and Methods: Triple platelet donations in plasma were obtained from Amicus (n = 10) and Trima (n = 10) plateletpheresis devices and stored overnight before being centrifuged and manually processed into three units with the following storage media: 100% plasma, >95% PAS 5 or 65% PAS 5/35% plasma. Platelet units were sampled on Days 1, 5 and 7 of storage using a range of tests recommended by the UK guidelines. Results: The majority of in vitro assay results for platelets in PAS 5 were similar to results in paired 100% plasma platelets (controls). The pH of PAS 5 stored platelet units was above the UK recommended guidelines of 7·4 by Day 5. PAS 5 platelets were no more activated than controls as evidenced by comparable soluble P-selectin levels and CD62p and CD42b expression. PAS 5 platelets also exhibited adhesion and aggregation profiles higher than (Day 1) or comparable to (Days 5 and 7) controls as measured by Impact R. Conclusion: The 7-day in vitro storage parameters investigated were comparable between >95% PAS 5 and 100% plasma platelets derived from both Amicus and Trima plateletpheresis devices, with the exception that lactose dehydrogenase release rate and pH were significantly higher in PAS 5 units. © 2014 International Society of Blood Transfusion. Source


Tabor E.,Fresenius Kabi United States
Therapeutic Innovation and Regulatory Science | Year: 2015

Many drugs approved by the US Food and Drug Administration (FDA) for use in adults lack adequate data on safety and efficacy in pediatric patients, a potential source of unintended harm to pediatric patients. Through a series of laws, regulations, and guidance documents, the US Congress and FDA have created a program both to encourage and mandate clinical studies in pediatric patients to develop evidence-based dosing, safety, and efficacy information. A "Pediatric Study Plan" (PSP) is required for every new drug. FDA provides incentives for the voluntary conduct of clinical trials in pediatric patients, including opportunities for added marketing exclusivity and for obtaining a "priority review voucher." FDA also mandates that clinical studies for new drugs be conducted in each pediatric age group (newborns, infants, children, and adolescents), except in circumstances where a waiver or a deferral of studies can be justified. Sometimes this mandate can be met by extrapolation from studies in adults, or from patients in one pediatric age group to another, for evidence of efficacy. However, separate studies of safety and dosing are usually required for each pediatric age group. The package insert for each new drug now must address the use in pediatric patients. In addition, the FDA website displays all changes in drug labeling related to pediatric patients (excerpted from the labels for easy access), summaries of all pediatric studies that have led to labeling changes, links to FDA medical reviews of pediatric studies, summaries of all pediatric safety issues presented to the FDA Pediatric Advisory Committee (with links to the meeting materials and transcripts), and details of deferred pediatric studies with their timelines and progress. These measures reflect the increasing attention by FDA and the medical community to the importance of clinical studies in pediatric patients. © The Author(s) 2015. Source

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