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Advanced Drug Delivery Reviews (v.59, #1)
Pharmaceutical impurities: Analytical, toxicological and regulatory perspectives
by Arup K. Basak Theme Editor; Andre S. Raw Theme Editor; Lawrence X. Yu Theme Editor (pp. 1-2).
Assuring quality of drugs by monitoring impurities by Satinder (Sut) Ahuja (pp. 3-11).
To assure the quality of drugs, impurities must be monitored carefully. It is important to understand what constitutes an impurity and to identify potential sources of such impurities. Selective analytical methods need to be developed to monitor them. It is generally desirable to profile impurities to provide a yardstick for comparative purposes. New impurities may be observed as changes are made in the synthesis, formulation, or production procedures, albeit for improving them. At times it is necessary to isolate and characterize an impurity when hyphenated methods do not yield the structure or when confirmation is necessary with an authentic material. Availability of an authentic material can also allow toxicological studies and provide a standard for routine monitoring of the drug product.
Keywords: Characterization; Chiral impurity; Degradation product; Drug product; Drug substance; Isolation; Profiling; Selective analytical methodologies; Terbutaline
Strategies for the investigation and control of process-related impurities in drug substances by Mark D. Argentine; Paul K. Owens; Bernard A. Olsen (pp. 12-28).
The understanding, identification, quantification and control of impurities in drug substances are essential as new molecular entities are evaluated in clinical development. As chemical processes used to produce drug substances mature from the early phases of development through registration, a concomitant maturing of process-related impurity understanding and control is required. This paper outlines strategies available to pharmaceutical scientists to aid in that understanding. Methodology aspects for impurity investigations are discussed along with an emphasis on understanding the origin and fate of impurities to guide decisions on process controls and specifications. Orthogonal analytical approaches for impurity investigations to provide a complete understanding of a drug substance impurity profile and to aid chemical process development are described. Special considerations necessary for stereochemical impurity investigations are also discussed. Considerations for control of toxic impurities include sensitive and selective analytical methodology and determination of the process capability for removing the impurity. A case study is given where routine analytical testing for a toxic impurity was not required because a high impurity rejection efficiency of the synthetic process was demonstrated. Quality assessment of starting materials from multiple sources and the impact of starting material impurities on the impurity profile of the drug substance are discussed with illustrative examples. Knowledge gained from these investigations provides a sound basis for setting specifications for impurities in key starting materials.
Keywords: Process impurities; Related substances; Drug substance; Active pharmaceutical ingredient; Chiral; Orthogonal; Genotoxic impurity; Starting material; Formaldehyde; Sulfonate ester
The role of degradant profiling in active pharmaceutical ingredients and drug products by Karen M. Alsante; Akemi Ando; Roland Brown; Janice Ensing; Todd D. Hatajik; Wei Kong; Yoshiko Tsuda (pp. 29-37).
Forced degradation studies are used to facilitate the development of analytical methodology, to gain a better understanding of active pharmaceutical ingredient (API) and drug product (DP) stability, and to provide information about degradation pathways and degradation products. In order to fulfill development and regulatory needs, this publication provides a roadmap for when and how to perform studies, helpful tools in designing rugged scientific studies, and guidance on how to record and communicate results.
Keywords: Forced degradation; Oxidation; Acid/base hydrolysis; Thermal; Humidity; Stability-indicating; CAMEO
Toxicological overview of impurities in pharmaceutical products by David Jacobson-Kram; Timothy McGovern (pp. 38-42).
While the use of pharmaceuticals is always a balance of risks and benefits, the same is not true for impurities in pharmaceuticals; impurities convey only risk. A number of international guidelines and regional guidances instruct drug developers and regulatory agencies on how to evaluate and control impurities in drug substances and drug products. While impurities should always be reduced to the lowest levels that are reasonably practical, it is acknowledged that impurities cannot be reduced to zero and specifications for impurities need to be established. This chapter discusses practical and theoretical methods for qualification of different classes of impurities.
Keywords: Toxicology; Pharmaceutical impurities; European Medicines Agency (EMEA); Genotoxic impurities
Progress in QSAR toxicity screening of pharmaceutical impurities and other FDA regulated products by Naomi L. Kruhlak; Joseph F. Contrera; R. Daniel Benz; Edwin J. Matthews (pp. 43-55).
Active ingredients in pharmaceutical products undergo extensive testing to ensure their safety before being made available to the American public. A consideration during the regulatory review process is the safety of pharmaceutical contaminants and degradents which may be present in the drug product at low levels. Several published guidances are available that outline the criteria for further testing of these impurities to assess their toxic potential, where further testing is in the form of a battery of toxicology assays and the identification of known structural alerts. However, recent advances in the development of computational methods have made available additional resources for safety assessment such as structure similarity searching and quantitative structure–activity relationship (QSAR) models. These methods offer a rapid and cost-effective first-pass screening capability to assess toxicity when conventional toxicology data are limited or lacking, with the potential to identify compounds that would be appropriate for further testing. This article discusses some of the considerations when using computational toxicology methods for regulatory decision support and gives examples of how the technology is currently being applied at the US Food and Drug Administration.
Keywords: Genotoxicity; Carcinogenicity; In silico screening; Predictive toxicology; Drug development; OECD principles
Impurities in generic pharmaceutical development by John Kovaleski; Bela Kraut; Annette Mattiuz; Michael Giangiulio; Geoffrey Brobst; Wayne Cagno; Prakash Kulkarni; Taylor Rauch (pp. 56-63).
The current practice of characterization and control of impurities in pharmaceuticals is reviewed with emphasis on issues specific to the generic industry. Case studies are discussed to demonstrate that generic pharmaceuticals are therapeutically equivalent to the branded product, even though the color, size, shape, and excipients utilized may not be identical.
Keywords: Degradation; Formulation; Characterization; Specification; Stability; Pre-formulation
Pharmaceutical impurities: Regulatory perspective for Abbreviated New Drug Applications by Arup K. Basak; Andre S. Raw; Ali H. Al Hakim; Scott Furness; Nashed I. Samaan; Devinder S. Gill; Hasmukh B. Patel; Roslyn F. Powers; Lawrence Yu (pp. 64-72).
Impurities in drug substances and drug products have been important regulatory issues in the Office of Generic Drugs by having significant impact on the approvability of Abbreviated New Drug Application (ANDAs). This review begins with a discussion of ANDAs and its similarity/differences with NDAs, highlighting the importance of control of pharmaceutical impurities in generic drug product development and regulatory assessment. An overview of the FDA draft guidance documents “ANDAs: Impurities in Drug Substances” and “ANDAs: Impurities in Drug Products” are provided. This introduces the identification and qualification procedures for ANDAs and approaches to the establishment of acceptance criteria for both drug substance and drug product. Case studies included in this review illustrate the proposed pathway for determination of impurities and their acceptance criteria, based upon the general principles of these guidances.
Keywords: Impurity; Drug substance; Drug product; Abbreviated New Drug Applications (ANDAs)