Chemistry , Manufacturing And Controls Research Articles

Drug Substance and Drug Product Impurities, Now what?

An unidentified peak in a drug substance or drug product chromatogram raises many questions. What is the impurity? What is the source of the impurity? How much impurity is there? Can the impurity level be reduced or eliminated? Is the impurity toxic? What do we do now? The answers to these questions are typically provided by scientists in chemistry, manufacturing and controls (CMC) and nonclinical toxicology with the single objective of assuring that unavoidable drug impurities induce no risk or an acceptable level of risk for the intended indication and the stage of development. To help address these issues, the International Council for Harmonisation (ICH) guidelines for impurities in drug substance (Q3A) and drug product (Q3B), and for genotoxic impurities (M7) have been adopted and implemented in the United States, Europe, and many other countries around the world. The guidelines address how impurities in drug substances and drug products should be reported, identified, and/or qualified. This Mini Review offers practical insights regarding drug substance and drug product impurities and next steps for the toxicologist when impurity levels exceed the ICH reporting, identification, and/or qualification thresholds. The information presented is largely derived from the following ICH Harmonised Tripartite Guidelines:Q3A(R2) Impurities in New Drug Substances (October 2006), Q3B(R2) Impurities in New Drug Products (June 2006), and M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (June 2015) and/or the referenced literature. Insights regarding acceptible amounts of residual solvents and the calculation of permitted dialy exposures will be the subject of another review.

A strategy of constructing the technological system for quality control of Chinese medicine based on process control and management

The current situation, bottleneck problems and severe challenges in quality control technology of Chinese Medicine (CM) are briefly described. It is presented to change the phenomenon related to the post-test as the main means and contempt for process control in drug regulation, reverse the situation of neglecting the development of process control and management technology for pharmaceutical manufacture and reconstruct the technological system for quality control of CM products. The regulation and technology system based on process control and management for controlling CM quality should be established to solve weighty realistic problems of CM industry from the root causes, including backwardness of quality control technology, weakness of quality risk control measures, poor reputation of product quality and so on. By this way, the obstacles from poor controllability of CM product quality could be broken. Concentrating on those difficult problems and weak links in the technical field of CM quality control, it is proposed to build CMC (Chemistry, Manufacturing and Controls) regulation for CM products with Chinese characteristics and promote the regulation international recognition as soon as possible. The CMC technical framework, which is clinical efficacy-oriented, manufacturing manner-centered and process control-focused, was designed. To address the clinical characteristics of traditional Chinese medicine (TCM) and the production feature of CM manufacture, it is suggested to establish quality control engineering for CM manufacturing by integrating pharmaceutical analysis, TCM chemistry, TCM pharmacology, pharmaceutical engineering, control engineering, management engineering and other disciplines. Further, a theoretical model of quality control engineering for CM manufacturing and the methodology of digital pharmaceutical engineering are proposed. A technology pathway for promoting CM standard and realizing the strategic goal of CM internationalization is elaborated.

The Jordan Food and Drug Administration: Comparison of its Registration Process with Australia, Canada, Saudi Arabia and Singapore.

ObjectiveThis study outlines the current regulatory review process and good review practices (GRevPs) at the Jordan Food and Drug Administration (JFDA) and compares them with those of regulatory agencies in Australia, Canada, Saudi Arabia and Singapore to gauge how well the JFDA is performing. We identify opportunities for further development of the JFDA as a key global reference agency.MethodsPersonnel within the JFDA completed a questionnaire comprising four sections: organisation, key milestones, review timelines, and GRevPs. The same questionnaire was used concurrently to gather information from Australia’s Therapeutic Goods Administration (TGA), Health Canada, the Saudi Food and Drug Authority (SFDA) and Singapore’s Health Sciences Authority (HSA).ResultsThe JFDA conducts an abridged review for new active substances and requires a certificate of pharmaceutical product (CPP) at the time of submission and 6 months of pharmacovigilance data at the time of the final review as well as full pharmaceutical, chemistry, manufacturing and controls (CMC) and clinical data at the time of submission. A written summary and tabulated data are required for non-clinical data. The four comparator agencies conduct full assessments; the SFDA also requires a CPP, and the JFDA and SFDA both require pricing information at submission. All agencies have established target timelines, and the JFDA, SFDA, TGA and HSA currently exceed those targets. All agencies have also developed GRevPs as well as training and continuous-improvement processes.ConclusionsThe JFDA has achieved significant success in its role as a regulatory agency by setting and implementing clear regulations in line with international guidance. It is recognised as a training centre in the region, with considerable achievements in the development of its activities by simplifying and improving requirements, procedures and actions. It also publishes information regarding guidance, procedures, drug application submissions and registration dates for all new chemical entities on its website. The relationship between the JFDA and the pharmaceutical sector in Jordan has resulted in balanced, practical, internationally compatible regulations and demonstrates a viable model of collaboration. To assist the JFDA in its efforts to become a key global reference agency, it is suggested that the agency explore a risk-stratification approach to the regulatory review; accept CPPs after dossier submission or use alternatives to the CPP; conduct pricing evaluations in parallel with scientific assessments; establish defined target times for review milestones and improve internal tracking systems to monitor these milestones; and make certain information transparent to all stakeholders by publishing a summary basis of approval.

Chemistry, manufacturing and control (CMC) and clinical trial technical support for influenza vaccine manufacturers

With the support of the Biomedical Advanced Research and Development Authority (BARDA) of the US Department of Health and Human Services, PATH has contributed to the World Health Organization’s (WHO’s) Global Action Plan for Influenza Vaccines (GAP) by providing technical and clinical assistance to several developing country vaccine manufacturers (DCVMs). GAP builds regionally based independent and sustainable influenza vaccine production capacity to mitigate the overall global shortage of influenza vaccines. The program also ensures adequate influenza vaccine manufacturing capacity in the event of an influenza pandemic.Since 2009, PATH has worked closely with two DCVMs in Vietnam: the Institute of Vaccines and Medical Biologicals (IVAC) and VABIOTECH. Beginning in 2013, PATH also began working with Torlak Institute in Serbia; Instituto Butantan in Brazil; Serum Institute of India Private Ltd. in India; and Changchun BCHT Biotechnology Co. (BCHT) in China.The DCVMs supported under the GAP program all had existing influenza vaccine manufacturing capability and required technical support from PATH to improve vaccine yield, process efficiency, and product formulation. PATH has provided customized technical support for the manufacturing process to each DCVM based on their respective requirements.Additionally, PATH, working with BARDA and WHO, supported several DCVMs in the clinical development of influenza vaccine candidates progressing toward national licensure or WHO prequalification. As a result of the activities outlined in this review, several companies were able to make excellent progress in developing state-of-the-art manufacturing processes and completing early phase clinical trials. Licensure trials are currently ongoing or planned for several DCVMs.

32. Towards a Phase I Clinical Trial for Cystinosis

Cystinosis is an autosomal recessive lysosomal storage disorder characterized by the accumulation of cystine in the lysosomes leading to cystine crystals formation. The gene involved, CTNS, encodes a lysosomal cystine transporter, cystinosin. Cystinosis leads to a renal Fanconi's syndrome before the age of one characterized by polyuria and nutrients loss, and to multi-organ degeneration especially the eyes and kidneys. The cysteamine treatment allows the exit of cystine out of the lysosomes but only delays the evolution of the disease. We showed that transplantation of wild-type Hematopoietic Stem and Progenitor Cells (HSPCs) in a lethally irradiated Ctns−/− mouse leads to cystine content decrease in every tissues tested and kidney, eye and thyroid function and structure improvement in treated mice compared to mock-treated mice. An autologous HSPCs gene therapy approach has then been developed with Ctns−/− HSPCs gene-modified ex vivo to express a functional CTNS cDNA using the lentiviral vector pCCL-CTNS. Tissue cystine decrease and kidney function rescue were observed with this strategy. The toxicology and pharmacology studies required by the FDA are in progress with a targeted Vector Copy Number (VCN) included between 1 and 3. The in vitro studies, Colony Forming Unit assay and In Vitro Immortalization assay, have been completed using peripheral blood CD34+ cells from five healthy donors and four cystinosis patients. The in vivo studies are in progress: Ctns−/− HSPCs are isolated and transduced with pCCL-CTNS and transplanted into primary Ctns−/− mice and 6-months later their bone marrow cells are transplanted into secondary Ctns−/− recipients. Primary and secondary mice are carefully monitored and comprehensive histological, biochemical, molecular and clinical analyses are performed at 6 months post-transplant. So far, seven primary and one secondary Ctns−/− mice transplanted with pCCL-CTNS-transduced Ctns−/− HSPCs have reached the 6 month post-transplantation time point. The primary mice had a mean VCN of 1.713 and the secondary 2.04. Clinical evaluations, histopathology and Vector Integration Site (VIS) analyses revealed no adverse event so far suggesting a good safety profile of our product. Moreover, cystine content was significantly decreased in all tissues tested. Analysis of the remaining primary and secondary recipient mice is in progress and these data will be included in an Investigational New Drug (IND) for a phase 1 clinical trial for autologous transplantation of pCCL-CTNS-modified CD34+ HSPCs in patients with nephropathic cystinosis, For the design and conduct of the future clinical trial, the Cystinosis Stem Cell and Gene Therapy Consortium was recently created and is composed of experts in cystinosis, bone marrow transplant and gene therapy. The clinical grade pCCL-CTNS virus preparation is about to be produced at the Gene Therapy Resources Program (GTRP), Clinical Grade Lentivirus Vector Core directed by Dr. Kenneth Cornetta who prepared the Good Manufactory Practice-comparable (GMPc) virus used for the pharmacology/toxicology studies. We are currently preparing the documents necessary for the IND such as the clinical protocol, the toxicology/pharmacology report, the Chemistry, Manufacturing and Controls (CMC) report, etc. This clinical trial will represent the first stem cell and gene therapy treatment strategy for cystinosis.

Investigational New Drug applications: a 1-year pilot study on rates and reasons for clinical hold

BackgroundThe Food and Drug Administration (FDA)'s Center for Drug Evaluation and Research (CDER) receives about 1500 initial Investigational New Drug applications (INDs) per year. In the first 30 days after...

Regulation of cell‐based medicinal products

The regulation of cell‐based medicinal products in the EU is governed by legislation for medicinal products in general plus dedicated regulations for advanced therapy medicinal products (ATMPs). In addition, the procurement and use of the tissues and cells used to manufacture these products are regulated by additional legislation. This presentation will focus on how a regulatory strategy for bringing a cell‐based ATMP under development into clinical trials and ultimately to marketing authorisation should be formulated around all relevant legislation and the guidelines used to implement it. A regulatory strategy should address the quality, safety and efficacy aspects of a medicinal product intended for human use, through defined strategies around CMC (chemistry, manufacturing and controls), nonclinical studies and clinical trials. In addition, regulatory routes to clinical trials and market authorisation that are appropriate to the ATMP under development should also be considered from an early stage, for example including orphan designation, paediatric investigation plans and accelerated approval schemes. Building a regulatory and product development strategy around these elements for a cell‐based ATMP will be outlined.

Nanomedicine drug development: a scientific symposium entitled "Charting a roadmap to commercialization".

The use of nanotechnology in medicine holds great promise for revolutionizing a variety of therapies. The past decade witnessed dramatic advancements in scientific research in nanomedicines, although significant challenges still exist in nanomedicine design, characterization, development, and manufacturing. In March 2013, a two-day symposium "Nanomedicines: Charting a Roadmap to Commercialization," sponsored and organized by the Nanomedicines Alliance, was held to facilitate better understanding of the current science and investigative approaches and to identify and discuss challenges and knowledge gaps in nanomedicine development programs. The symposium provided a forum for constructive dialogue among key stakeholders in five distinct areas: nanomedicine design, preclinical pharmacology, toxicology, CMC (chemistry, manufacturing, and control), and clinical development. In this meeting synopsis, we highlight key points from plenary presentations and focus on discussions and recommendations from breakout sessions of the symposium.

An Update from the United States National Heart, Lung, and Blood Institute‐funded Production Assistance for Cellular Therapies (PACT) Program: A Decade of Cell Therapy

Recognizing the challenges faced by researchers and clinicians working in the field of cellular therapy, the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, established the Production Assistance for Cellular Therapies (PACT) program in 2003 and expanded it in 2010. The PACT program provides both clinical product manufacturing support that furthers the mission of NHLBI in the areas of cardiac, lung, and blood diseases and broad support of translational development across all disease areas to serve the entire cell therapy community. The program also provides access to expertise in project management, regulatory affairs, and quality assurance and control. Education initiatives include webinars, cell processing facility-hosted workshops, national workshops, and active participation and leadership within the cell therapy community through collaboration with other cell therapy organizations and academia. So far, over 650 PACT-manufactured cell therapy products have been administered in 32 clinical trials for a range of illnesses and diseases such as acute myocardial infarction, sickle cell disease, and graft-versus-host disease.

Molecular Biotheranostic Approaches of Cancers Using LAT Kit Probes

Purpose: Positron emission tomography (PET) and single photon emission computed tomography (SPECT) tracers have been applied to pharmacokinetic, pharmacodynamic, dose-finding, and proof-of-concept studies. PET/SPECT tracers could non-invasively assess treatment endpoints for diseases which used to rely on biopsies and histopathological assays. 18F-Fluorodeoxyglucose (FDG) is a gold standard for PET to detect unsuspected distant metastases in cancers. However, 18F-FDG has difficulties in distinguishing between inflammation/infection related masses versus cancer recurrence. Also, tumors with low glycolysis show poor FDG uptake, which leads to the high rate of false-negative results. Recent studies indicate that radiolabeled tyrosine derivatives using L-type amino acid transporters (LAT) can differentiate cancer from inflammation. Methods: We have synthesized 99mTc- and 68Ga-labeled chelator-based tyrosine analogs and their potential uses as kit probes for molecular radiotheranostic of tumors were evaluated. Results: The active ingredient in the kit is considered a drug substance, which allows standardization for chemistry, manufacturing and control (CMC). CMC is a crucial element in the centralized Investigational New Drugs (IND) process, and can be readily solved with kit probes. Conclusion: The use of PET and SPECT tracers has also helped to control and monitor dosage for increased safety and effectiveness, which have high impact on economy. Keywords: LAT, technetium-99m, gallium-68, fluorine-18, iodine-131

Compliance Issues in Manufacturing of Drugs

AbstractThe therapeutic process relies on the assumption that the prescription written by the clinician is what is dispensed to the patient. In this article, we review the many factors involved in the manufacture of pharmaceutical products so that they consistently meet quality standards as approved by regulatory agencies. Industry and government agencies have developed procedures and laws to assure quality in Chemistry, Manufacturing and Controls (CMC) for pharmaceuticals, addressing conditions that may be harmful to patient health. This includes procedures for receipt of materials, production, packaging, labeling, quality control, release, storage and distribution, known as current Good Manufacturing Practice. Special control considerations for ophthalmic products include foreign particulate matter control, preservative effectiveness tests, sterility and leaching of chemicals from the packaging into the product. We also describe the “form, fill and seal” manufacture process as used in unit-dose, non-preserved ophthalmic products; product expiration dates; stages of drug development; and financial considerations for pharmaceutical companies.

Organization and Responsibilities of the Chemistry, Manufacturing, and Controls Function within Regulatory Affairs: A Survey of 17 Companies

To facilitate management of the technical and regulatory Chemistry Manufacturing and Controls (CMC) issues within core dossiers, companies have turned to a range of organizational structures and procedures to manage the input most effectively. The objectives of this survey were to identify how companies have organized to provide regulatory strategy for the CMC sections of dossiers and to assess how, on a global basis, CMC documentation is created and reviewed. Seventeen of the top 30 United States- and European-based pharmaceutical companies participated in the survey.

Regulatory aspects of modifications to innovator bronchodilator metered dose inhalers and development of generic substitutes.

Regulatory requirements for modifications to an approved innovator metered dose inhaler (pressurized MDI; USP nomenclature: inhalation aerosol) and for development of a new generic product are discussed. Although many of the requirements apply generally to MDI's, they are discussed with specific reference to albuterol. Changes to the container and closure system may impact on the dosimetry of the redesigned product, as well as upon toxicologic and chemistry, manufacturing and controls (CMC) concerns. Changes to the formulation, including the use of alternate propellants, may raise issues requiring both clinical and in vivo performance evaluation. In view of the level of interest of a number of firms in approval requirements for generic Albuterol Inhalation Aerosol products, the article discusses in considerable detail the CMC and bioequivalence requirements for a generic product. Similarities in the CMC requirements for innovator and generic products are evident. Three comparative in vivo bioequivalence tests, particle size distribution, spray pattern and plume geometry, and unit spray content, established by the Division of Bioequivalence are discussed. Similarities and differences in the in vivo requirements for innovator and generic products are evident. Differences are the result of U.S. statute, which requires safety and efficacy testing for a product approved under a new drug application (NDA), but documentation of bioequivalence for a product approved under an abbreviated new drug application (ANDA). The advantages and disadvantages of three pharmacodynamic study designs which have potential usefulness for documentation of in vivo bioequivalence are discussed.