INTRODUCTION
Impurities are critical quality attributes of drug substances and drug products because they have the potential to affect the safety and efficacy of the product. This general information chapter provides guidance on the control of impurities in drug substances (API process impurities and degradation products) and drug products (degradation products). Definitions of key terms used in this chapter can be found in Appendix 1: Glossary.
This chapter is relevant for drug substances and drug products described in the USP–NF. This chapter addresses impurities arising during the manufacturing process and/or storage of the drug substance. Also the chapter covers those impurities in drug products classified as degradation products of the drug substance or reaction products of the drug substance with an excipient and/or immediate container–closure system (collectively referred to as “degradation products”).
This chapter does not cover veterinary products, biological/biotechnological products, peptides, oligonucleotides, fermentation products and semisynthetic products derived from them, polymorphic forms, radiopharmaceuticals, herbal products, or crude products of animal or plant origin. In addition, inorganic/elemental impurities, residual solvents, impurities in excipients, and leachables from the container–closure system are out of the scope of this chapter.
The regulatory and compendial standards for the control of impurities continue to evolve due to advancements in analytical science, technology, and toxicology. Therefore, communications about impurities and degradation products in drug substances and drug products can be improved by including in this Pharmacopeia the definitions for terms and the contexts in which these terms are used (see Appendix 1: Glossary). For additional information about impurities, see General Notices, 5.60. Impurities and Foreign Substances. Some other general chapters added over the years have also addressed topics of purity or impurity as these have come into focus or as analytical methodology has become available. Analytical aspects are enlarged upon in Validation of Compendial Procedures 〈1225〉.
Purity or impurity measurements for drug products present a challenge to Pharmacopeial standards setting. Resolution of the active ingredient(s) from the excipients necessary for the formulation presents the same qualitative issue. Thus, many monographs for Pharmacopeial preparations feature chromatographic assays. Where more significant impurities are known, some monographs set forth specific tests for these impurities. In general, however, this Pharmacopeia does not repeat impurity tests in the monographs of drug products where these tests appear in the monographs of drug substances and where these impurities are not expected to increase during manufacturing and/or storage. It is presumed that adequate retention specimens are in storage for the exact batch of drug substances used in any specific lot of a drug product. Whenever analysis of a drug product raises a question of the quality attributes of a drug substance used, subsequent analysis of retention specimens is necessary.
DRUG SUBSTANCE
In general, impurities in drug substances can be classified into the following categories:
Organic impurities
Inorganic impurities
Residual solvents
Organic impurities can arise during the manufacturing process and/or storage of the drug substance. They can be identified or unidentified, volatile or nonvolatile, and include the following:
Starting materials
Byproducts (e.g., geometric and stereoisomers)
Intermediates
Degradation products
Reagents and ligands
Inorganic impurities can result from the manufacturing process. They are normally known and identified and include the following:
Reagents and catalysts
Elemental impurities
Inorganic salts
Other materials (e.g., filter aids)
Elemental impurities include catalysts and environmental contaminants that may be present in drug substances. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment and the container–closure system). When elemental impurities are known to be present, have been added, or have the potential for introduction, assessment of the drug substance in the context of its use in the finished product is required (see Elemental Impurities—Limits 〈232〉).
Residual solvents are organic liquids used as vehicles in the synthesis of a drug substance. Because these are generally of known toxicity, the selection of appropriate controls is easily accomplished (see Residual Solvents 〈467〉).
Concepts for setting impurity limits in drug substances are based on quality and safety concerns. As such, limits for organic and inorganic impurities and residual solvents should be established according to the applicable guidances. Elemental impurity limits for a drug substance may be required depending on the outcome of the risk assessment for the finished prod
uct. The basic tenet for setting limits is that levels of impurities in a drug substance must be controlled throughout its development to ensure its safety and quality for use in a drug product.
Documented evidence that the analytical procedure used to evaluate impurities is validated and suitable for the detection and quantitation of impurities should be established.
Source from USP and Please refer to USP for details:
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