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The October 2015 FDA/PQRI Conference on Advancing Product Quality provided a forum for the exchange of ideas focused on drug product quality between regulatory agencies, the pharmaceutical industry, and academia. Key topics of the 2015 conference were (i) emerging regulatory initiatives; (ii) regulatory submission, assessment, and inspection; (iii) product and process development; and (iv) manufacturing, risk management, and quality assurance. Key discussion points and recommendations for each track and session have been captured. With powerful advancements in product quality encompassing regulatory, industrial, and technological elements, an era of rapidly improving pharmaceutical quality is underway. At the conference, one theme prevailed through all sessions: regulators, industry, and academia are aligned in their desire for drug product quality on behalf of the ultimate stakeholder–the patient. 3D three dimensional, ANDA abbreviated new drug application, API active pharmaceutical ingredient, ASTM American society for testing and materials, BCS biopharmaceutics classification system, BLA biological license application, CGMP current good manufacturing practice, CMA critical material attribute, CMC chemistry manufacturing and controls, CPP critical process parameters, CQA critical quality attribute, CU content uniformity, DLS dynamic light scattering, DOE design of experiment, EMA European Medicines Agency, EWG Expert Working Group, FDA Food and Drug Administration, GDUFA generic drug user fee amendments, HCl Hydrogen Chloride, ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, IND investigational new drug, IQA integrated quality assessment, IR immediate release, IR information request, ISPE International Society for Pharmaceutical Engineering, MIT Massachusetts Institute of Technology, NDA new drug application, NIPP new inspection protocols project, NIR near-infrared spectroscopy, OPQ office of pharmaceutical quality, PAI pre-approval inspection, PAT process analytical technology, PDUFA prescription drug user fee act, PHS public health service, PQRI Product Quality Research Institute, PQS pharmaceutical quality system, QbD quality by design, QMS quality management system, QRM quality risk management, QTPP quality target product profile, RPM revolutions per minute, RTRT real time release testing, SUPAC scale-up and post-approval changes, UDU uniformity of dosage units, USP U.S. Pharmacopeial Convention.

On September 16 and 17, 2014, the Food and Drug Administration (FDA) and Product Quality Research Institute (PQRI) inaugurated their Conference on Evolving Product Quality. The Conference is conceived as an annual forum in which scientists from regulatory agencies, industry, and academia may exchange viewpoints and work together to advance pharmaceutical quality. This Conference Summary Report highlights key topics of this conference, including (1) risk-based approaches to pharmaceutical development, manufacturing, regulatory assessment, and post-approval changes; (2) FDA-proposed quality metrics for products, facilities, and quality management systems; (3) performance-based quality assessment and clinically relevant specifications; (4) recent developments and implementation of continuous manufacturing processes, question-based review, and European Medicines Agency (EMA)-FDA pilot for Quality-by-Design (QbD) applications; and (5) breakthrough therapies, biosimilars, and international harmonization, focusing on ICH M7 and Q3D guidelines. The second FDA/PQRI conference on advancing product quality is planned for October 5–7, 2015.

The apoptosis-linked gene product, ALG-2, is a member of the family of intracellular Ca(2+)-binding proteins and a part of the apoptotic machinery controlled by T-cell receptor (TCR), Fas, and glucocorticoid signals. To explore the physiologic function of ALG-2 in T-cell development and function, we generated mice harboring a null mutation in the alg-2 gene. The alg-2 null mutant mice were viable and fertile and showed neither gross developmental abnormality nor immune dysfunction. Analyses of apoptotic responses of ALG-2-deficient T cells demonstrated that ALG-2 deficiency failed to block apoptosis induced by TCR, Fas, or dexamethasone signals. These findings indicate that ALG-2 is physiologically dispensable for apoptotic responses induced by the above signaling pathways and suggest that other functionally redundant proteins might exist in mammalian cells.

Sphingosine kinase catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a novel lipid mediator with both intra- and extracellular functions. Based on sequence identity to murine sphingosine kinase (mSPHK1a), we cloned and characterized the first human sphingosine kinase (hSPHK1). The open reading frame of hSPHK1 encodes a 384 amino acid protein with 85% identity and 92% similarity to mSPHK1a at the amino acid level. Similar to mSPHK1a, when HEK293 cells were transfected with hSPHK1, there were marked increases in sphingosine kinase activity resulting in elevated SPP levels. hSPHK1 also specifically phosphorylated D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol. Northern analysis revealed that hSPHK1 was widely expressed with highest levels in adult liver, kidney, heart and skeletal muscle. Thus, hSPHK1 belongs to a highly conserved unique lipid kinase family that regulates diverse biological functions.

Programmed cell death is a process required for the normal development of an organism. One of the best understood apoptotic pathways occurs in T lymphocytes and is mediated by Fas/Fas ligand (FasL) interaction. During studies of apoptosis induced by T cell-receptor engagement, we identified ALG-4F , a truncated transcript that prevents T cell-receptor-induced FasL upregulation and cell death. Overexpression of full-length ALG-4 induced transcription of FasL and, consequently, apoptosis. These results indicate that ALG-4 is necessary and sufficient for FasL expression. Fas/FasL interaction initiates cell death in many other systems, and its dysregulation is a mechanism by which several pathologic conditions arise. Understanding the molecular mechanisms of FasL regulation could be very useful in elucidating how these diseases develop and in identifying potential therapeutic targets.

ALG-3, a truncated mouse homologue of the chromosome 1 familial Alzheimer's disease gene PS2, rescues T hybridoma 3DO cells from T-cell receptor-induced apoptosis by inhibiting Fas ligand induction and Fas signaling. Here we show that ALG-3 transfected 3DO cells express a COOH-terminal PS2 polypeptide. Overexpression of PS2 in ALG-3 transfected 3DO cells reconstitutes sensitivity to receptor-induced cell death, suggesting that the artificial PS2 polypeptide functions as a dominant negative mutant of PS2. ALG-3 and antisense PS2 protect PC12 cells from glutamate-induced apoptosis but not from death induced by hydrogen peroxide or the free radical MPP+. Thus, the PS2 gene is required for some forms of cell death in diverse cell types, and its function is opposed by ALG-3.

Two apoptosis-linked genes, named ALG-2 and ALG-3, were identified by means of a functional selection strategy. ALG-2 codes for a Ca(2+)-binding protein required for T cell receptor-, Fas-, and glucocorticoid-induced cell death. ALG-3, a partial complementary DNA that is homologous to the familial Alzheimer's disease gene STM2, rescues a T cell hybridoma from T cell receptor- and Fas-induced apoptosis. These findings suggest that ALG-2 may mediate Ca(2+)-regulated signals along the death pathway and that cell death may play a role in Alzheimer's disease.