Standards-Setting Activities on Impurities

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.

Residual DNA and host-cell proteins

Although traditional small-molecule drugs are made through chemical synthetic routes, many biologic and biotechnology products are made using recombinant technologies in host cells designed to produce a genetically engineered therapeutic protein. These recombinant products are often transcribed from human DNA sequences that are placed into host cells such as mouse cell lines, yeast cells, or Escherichia coli. After the cells produce the proteins, they are purified and characterized. Manufacturers of these protein products must be able to demonstrate that their final products contain very low levels of host-cell DNA and proteins because there could be a risk of tumorigenicity or immunogenicity, respectively, from these materials when given to the patient. Currently, USP is developing a chapter on residual DNA, and at least two material reference standards will be available to support the chapter. USP also is developing a general information chapter containing best practices for critical reagent development and characterization as well as development, validation, and use of host-cell protein measurement procedures.

In June 2013, USP will cohost a workshop with the BioPharmaceutical Emerging Best Practices Association (BEBPA) focused on the measurement of residual DNA and host-cell proteins in biotechnology products. The meeting will feature current industry practices and provide perspectives from the regulatory community. For a workshop description and registration information, see http://uspgo.to/host-cell-protein.

Elemental impurities

Regarding elemental impurities, USP has developed two relevant general chapters—<232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures. General Chapter <232> specifies limits for selected elemental impurities, including limits for mercury, cadmium, arsenic, and lead—toxic elements commonly found in the environment. In General Chapter <233>, procedures for identifying impurities using inductively couple plasma technology are described. In addition, General Chapter <233> provides validation criteria should a manufacturer choose to use procedures other than the one described in the new general chapters. As is the case with residual solvents, the elemental impurities chapters will be applied to articles recognized in USP–NF by means of a General Notices provision, expected to be proposed in January 2013 in Pharmaceutical Forum and become official May 1, 2014. For updated information about the current status of USP's standards on elemental impurities, see http://uspgo.to/elemental-impurities.

Maura Kibbey, PhD, is senior scientific liaison, Antonio Hernandez-Cardoso, MSc, is senior scientific liaison, and Kahkashan Zaidi, PhD, is senior scientific liaison, all with the US Pharmacopeial Convention (USP).