Kahkashan Zaidi, PhD,* is a senior scientist in the Department of Standards Development; at the US Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, tel. 301.816.8269, kxz@usp.org

Kahkashan Zaidi, PhD

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—

)—are published as individual monographs and general chapters as well as 

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 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

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 

, 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.  

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 

 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 

Regarding elemental impurities, USP has developed two relevant general chapters—<232> 

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 

provision, expected to be proposed in January 2013 in 

 and become official May 1, 2014. For updated information about the current status of USP's standards on elemental impurities, see 

is senior scientific liaison, all with the US Pharmacopeial Convention (USP). 

Articles

USP's focus in 2013 involves standards relating to organic impurities, measurement of residual DNA and host-cell proteins in biotechnology products, and elemental impurities.

Standards-Setting Activities on Impurities

 oxygen, carbon dioxide, helium, nitrogen, nitrous oxide, medical air, and combinations of these) are drugs regulated by section 201(g) of the Federal  Food, Drug, and Cosmetic Act. The United States Pharmacopeia (USP) sets standards for all medical gases, including those that address quality, strength, purity, packaging, labeling, and identification. The proper handling of medical gases has been called into question during the past several years because of incidents resulting in patient harm and even death that have been documented by the US Food and Drug Administration, by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), and by USP through its Medication Errors Reporting Program. In most cases, the deaths and injuries occurred to patients who were thought to be receiving medical-grade oxygen but instead were receiving a different gas (

 nitrogen or argon) that had been mistakenly connected to the oxygen supply system. 

In April 2001, FDA issued a Public Health Advisory addressing the reports from hospitals and nursing homes concerning deaths and injuries to patients resulting from medical gas errors (1). In the advisory, FDA pointed out that incorrect gases were administered to patients who should have received oxygen. The advisory also described recurring errors caused by a lack of training of personnel who connected gas to the systems and who failed to carefully examine the labels on the gas containers. In response, FDA made several recommendations to help prevent future errors: 					

In hospitals and other patient-care facilities, medical-grade products should be stored separately from industrial-grade products.

All personnel who handle medical gases should be trained to recognize various types of medical gas labels and should be trained to examine labels carefully.

Personnel should understand how containers are connected to oxygen supply systems and be instructed about the serious consequences of changing or forcing connections.

Facilities should emphasize repeatedly that the fittings on medical gas containers should not be changed under any circumstances.

Once a cryogenic container is connected to an oxygen supply system and before the product is introduced into an air-supply system, a knowledgeable person should ensure that the correct container has been connected properly.

In 2001, the USP Medication Errors Reporting Program received a report from a community hospital indicating that mislabeled gas cylinders were delivered to the hospital. According to the report, four yellow air tanks with air tank fittings (valves) were delivered from the supplier and were mislabeled as nitrogen. An alert respiratory therapist recognized the distinctive air-tank fittings and alerted the appropriate personnel, thus preventing these mislabeled products from reaching patients. As a result of this error and others reported to FDA, USP posted an article on its Web site alerting practitioners about the possibility of medical gas mix-ups and cited the FDA Public Health Advisory (2). 

Taking into account the seriousness of the situation, USP and FDA staff met to discuss the errors and establish what USP could do to prevent further medical gas errors. Part of USP's public health mission is to assure consumers that prescription and many nonprescription medications and related items used in the medical field are of high quality, that ingredients and strength of these products are consistent, and that these items are properly labeled and stored. After the meeting with FDA, USP staff published an article, "Proposed Standards for Medical Gases: A Public Health Initiative," in 

, USP's bimonthly journal of standards development and compendial revision (3). The article elicited numerous public comments and recommendations for USP, FDA, and JCAHO regarding the safe use of medical devices. They included: 					

 monographs on medical gases to require specific colors for medical gas containers and connections (see next bullet point also). Harmonizing this requirement with United States and Canadian medical gas suppliers was considered favorably. (For more information, see the Compressed Gas Association's Web site, 

www.cganet.com/FDA_materials/Medgasmixup.asp

Requiring specific colors for hookups, perhaps by means of plastic tabs or rings, on hospital or nursing home walls where medical gas connections are made. This action may involve coordination with JCAHO and the American Society of Healthcare Engineers.

Revising the names of medical gases to include the term 

 "Medical Oxygen USP," "Medical Air USP"). This task would be the responsibility of the USP Nomenclature Expert Committee and would result in changes to monograph titles in 

 and, therefore, a change in the labels. In addition, there would be revisions to the relevant section in 

 monographs by inserting information in the Packaging and Storage section to preclude errors.

 medical gases monographs to bring the specifications (

 tests, procedures, and acceptance criteria) more in line with modern industry practices. (The monographs currently are under review.)

Adding information about color coding to an existing general chapter or creating a new general chapter.

Adding information to General Chapter ‹661› Containers about the characteristics of cryogenic vessels for medical gases and the labeling requirements for application to all medical gases.

Since these recommendations were proposed, USP has initiated several monograph revisions, including:  

 (4) (July–Aug. 2002), a revision to the identification test in the medical gases monographs proposed replacing the rudimentary test requiring a burning wood splint, sometimes in conjunction with a floating balloon, with a more specific gas chromatography test. This proposed new gas chromatographic procedure was not adopted at that time. 

 (2) (Mar.–April 2004), the use of a gas chromatographic identification test with USP reference standards rather than the certified standards was proposed. In this way, the retention time could be matched for identification.

USP also organized several meetings with the Compressed Gas Association and FDA to move the revision process forward and to determine what improvements have been initiated to address the patient safety issues acknowledged by all parties.  

In 2003 FDA released a draft guidance on current good manufacturing practices requirements for medical gases (4). An attachment in this guidance cites in detail the adverse events resulting from medical gas errors. This guidance also identifies several associated CGMP violations, including: 					

inadequate training of medical gas filling and delivery personnel;

 monographs for medical gases appeared in 

 (4) (July–Aug. 2005) and include changes to the packaging and labeling sections of the monographs. Specific modifications include standardizing the colors and couplings of containers as recommended in the FDA draft guidance.  

USP standards are enforceable by FDA and have been recognized by other regulatory agencies around the world. They play an important role in labeling, packaging, storage, and finished product testing. 

 monographs, if they are consistently observed and applied, can help reduce medical gas errors. However, adoption of the revisions proposed in 2005 regarding helium, nitrous oxide, nitrogen, and nitrogen 97% was postponed after USP received industry inquiries. As a result of the postponement, USP formed an 

 advisory panel on medical gases that convened its first meeting on Aug. 9, 2005 at USP headquarters. Attendees included members of the Aerosols Expert Committee, representatives of the Compressed Gas Association, and other medical gas industry representatives. Although they were unable to attend, FDA representatives were invited to participate in these discussions. Issues related to the revised medical gases monographs included identification, assay, and color-coding of containers and connections. Industry representatives also were very interested in discussing and debating issues regarding the need for updated medical gases monographs and in working to further improve the safety of medical gases. 

USP will continue to work with the medical gases industry to ensure that all revisions of USP standards for medical gases are in line with industry practices and advances in technology. The USP advisory panel will continue to enlist the expertise of the medical gases industry, FDA, and practitioners to provide for the safe use of these products in our healthcare institutions and in-home care. 

 is a senior scientist in the Department of Standards Development; 

 is vice-chairman of the Aerosols Expert Committee; and 

 is the director of Patient Safety at the US Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, tel. 301.816.8269, 

Guidance for Hospitals, Nursing Homes, and Other Health Care Facilities—Public Health Alert

2. United States Pharmacopeia, "USP Practitioners' Reporting News. Medical Gas Errors," 

www.usp.org/patientSafety/newsletters/practitionerReportingNews/prn882001-06-19.html

3. S. Becker and G. Bormel, "Proposed Standards for Medical Gases: A Public Health Initiative," 

Guidance for Industry. Current Good Manufacturing Practice for Medical Gases,

USP monographs, if they are consistently observed and applied, can help reduce medical gas errors.