As pharmaceutical products have evolved over the decades, so have processes for their manufacture and analytical techniques
for understanding their composition. For every medicine taken by a patient, it is important for a drug maker to be able to
identify impurities of any significance that can result from its manufacturing process and to take measures to control for
unwanted impurities, especially because they may affect the safety and efficacy of a product.
An impurity is a substance occurring in a finished drug product that plays no functional role and is not an inherent component
of the pure form of the intentionally used ingredients. It can be the result of a manufacturing process, can be added intentionally
as a catalyst during drug synthesis, or can be a byproduct of degradation that emerges during the lifecycle of a drug.
Beginning in the 1990s, the International Conference on Harmonization (ICH) began the development of guidelines relating to
impurities in pharmaceuticals. ICH guidelines provide a framework for regulatory filings for new drugs. This body of work
on impurities led to what is now well-recognized as the ICH Q3 series, which includes guidelines (allowable levels) for organic
and inorganic impurities as well as residual solvents. In developing its own standards for impurities, the US Pharmacopeial
Convention (USP) has worked to harmonize with ICH, where feasible, while maintaining its goals of modernizing and creating
standards that reflect current-day practices in industry that help to ensure drug quality.
A nonprofit scientific organization, USP develops standards for the identity, strength, quality, and purity of medicines and
their ingredients. In addition, USP's standards include those for specific impurities associated with drug substances and
drug products. Documentary standards in USP's compendia—United States Pharmacopeia and the National Formulary (USP–NF)—are published as individual monographs and general chapters as well as General Notices.
With regard to organic impurities, USP established in recent years standards for residual solvents in drug products, drug
substances, and excipients. In addition, USP has initiated a review of other general chapters relevant to organic impurities
overall and has developed revised standards for elemental impurities. In 2013, USP will host a workshop on yet another group
of impurities—residual host-cell proteins and DNA in biotechnology products.
Organic impurities
Organic impurities cover a wide spectrum of compounds that have varying structures, behavior, and characteristics. They can
result from process manufacturing, storage conditions, or even degradation. Some may be volatile and may be very liable to
change as a result of exposure to heat, light, or other external factors.
A USP Expert Panel has been charged with making recommendations on revisions to General Chapter <1086> Impurities in Drugs Substances and Drug Products, General Chapter <466>—Ordinary Impurities and General Notices 5.60. Composition of the advisory Expert Panel includes representatives from pharmaceutical and over-the-counter (OTC) product
manufacturers and their trade groups (i.e., the Consumer Healthcare Products Association, Pharmaceutical Research and Manufacturers
of America, and others), members of USP's Expert Committees on Physical Analysis, Small Molecules and Toxicology, and liaisons
from FDA.
General Chapter <1086> includes some key definitions associated with impurities that are aligned with those established by
ICH, other pharmacopoeias and current FDA guidance. General Chapter <466> applies a relatively simple, yet old, method—thin-layer
chromatography (TLC)—for impurity detection. Although TLC enables a user to compare a test article against a known standard
and confirm the presence of that article in a sample, it is limited in its ability to distinguish between APIs, excipients,
or impurities and to accurately quantify impurities within a given sample.
The Expert Panel's review will take into account organic impurities associated with hundreds of monographs appearing in the
USP–NF, which include OTC drugs and various dosage forms associated with a single OTC. As part of its work, the Expert Panel is
assessing the feasibility of categorizing different types of organic impurities (e.g., heterocyclic compounds) and, based
on those categorizations, will explore relevant methods for detection and measurement that may be applied to multiple monographs
within a single group.
