Abstract
The modernization of United States Pharmacopeia (USP) monographs continues to be a priority initiative. The traditional model has been modernization of monographs through submissions by external sponsors. USP continues to welcome submissions by sponsors. However, USP is also using internal monograph modernization supported by its global laboratories to expedite this process. One of the unique features of this model is the development of a more comprehensive and optimized procedure suitable for multiple sources. The new strategy and the different tactics used in improving public quality standards are highlighted in this article.
USP is a scientific nonprofit organization that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, excipients, and dietary supplements that are manufactured, distributed, and consumed worldwide. USP’s drug standards, which are used in many countries, are enforceable in the United States by the Food and Drug Administration (FDA). USP’s mission is to improve global health through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods.
In 2005, USP conducted an initial evaluation of the status of its documentary standards (monographs) published inUnited States Pharmacopeia—National Formulary (USP–NF) and identified approximately 700 outdated monographs in need of revision. In the ensuing years, this list has expanded to over 2600 monographs. The FDA soon recognized that there was an ongoing need to update and modernize the methods contained in these monographs. Thus, in 2010, the Agency established a Monograph Modernization Task Group that interfaced with the USP Monograph Modernization Program to address this need. The goal of the Task Group was to identify USP–NF monographs in need of modernization, and it was especially focused on articles with outdated analytical methodologies that may make the drug or excipient vulnerable to economically motivated adulteration or that have inadequate tests. This FDA initiative was enacted to support a USP Convention Resolution adopted in April 2010 to modernize USP monographs as a major initiative over the next 5 years. Direct participation from the pharmaceutical industry and other interested stakeholders was encouraged to assist USP in providing updated public standards and strengthen FDA and USP efforts to protect public health. Paramount to this effort would be the submission of updated analytical methodologies pertinent to a compendial article as well as data that could be utilized for independent validation.
Although the FDA publicly encouraged all stakeholders to fully support this USP initiative, the number of updated method submissions for monographs was less than expected. Most companies were not yet willing to share with competitors their intellectual properties of patented methods used in the manufacture and evaluation of active pharmaceutical ingredients and drug products.
USP soon realized that in order for the program to be successful, multiple approaches—apart from relying solely on method submissions from pharmaceutical industry sponsors—would have to be implemented to procure updated methods and appropriate validation protocols. The traditional process of monograph revision through pharmaceutical industry sponsors resulted in standards predominantly based on quality specifications obtained from one sponsor. Hence, in addition to sponsored monographs with updated methodologies, USP focused on evaluating alternate sources of samples and monograph procedures from other pharmacopeias. USP develops compendial standards and associated reference standards within its domestic and international facilities and laboratories.
The first steps in this process were deciding on a definition for the term “modernization,” which would be both definitive and meaningful in developing a priority list of documentary standards on which to focus immediate attention. In Figure 1, the monograph modernization scheme describes common processes in the four major sections of monographs: Identification, Assay, Organic Impurities, and Other.
Figure 1. Monograph modernization prioritization scheme.
The most common modernization of assay, identification, and organic impurities tests is the elimination of hazardous solvents and reagents in a procedure. A majority of monographs have assay methods, and replacing non-specific tests (titration, UV-VIS, etc) with stability indicating methods such as high-performance liquid chromatography (HPLC) has been one focus of modernization. In addition, the retention time agreement and UV-visible spectra of the major peak from the assay procedure are utilized for identification tests. Many of the organoleptic tests previously used in identification (eg, flame test, odor test, etc) are replaced with instrumental methods of analysis. For monographs that do not have organic impurities tests, HPLC, gas chromatography (GC), or other suitable chromatographic methods are added. The HPLC organic impurities test replaces the Ordinary Impurities <466> procedural general chapter that is based on thin layer chromatography (TLC). HPLC columns that are no longer commercially available are replaced with alternate columns or newer types of HPLC packings. Also, an organic impurities or assay method that uses GC packed columns is replaced with revised methods using capillary columns. Other test methods or sections in monographs that need updates or additional specific information include system suitability, packaging and storage, etc.
Several strategies are used in the internal modernization of USP monographs. Using multiple sources (typically at least 3 sources or more of drug substance or drug products) combines the organic impurities that may be found in different manufacturing processes. Instead of having 2 or more organic impurities procedure in a monograph (ie, a flexible monograph approach), a single organic impurities method is proposed that can be used in more than 1 manufacturing process. This allows the creation of a more comprehensive public standard rather than a standard applicable to a single manufacturing process. Monographs are also modernized based on a family of products with the same active pharmaceutical ingredient. The concept of aligning analytical methods within the same family of monographs or similar class of compounds allows shorter time for method development. Newer types of HPLC columns such as hydrophilic interaction liquid chromatography (HILIC), use of a universal detector for non-UV active impurities like a charged aerosol detector (CAD), and use of mass spectrometry-compatible solvents have been used when applicable. A photodiode array detector is utilized to provide an additional identification test using the UV spectrum of the main peak.
Figure 2 provides a summary of criteria, strategies, and tactics used for monograph modernization. There are several approaches including modernization by individual monographs, family of monographs, individual test, and types of test, but the family monograph concept was shown to be one of the most effective ways to modernize monographs. This also has the benefit of having similar tests within a family of monographs, which provides additional value for users and industry.
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Figure 2. Monograph modernization initiative.
One other significant approach for modernization is the concept of creating a general chapter (GC) with a reference procedure to be used in many monographs. One example impacting the modernization of more than 1000 monographs is development of General Chapter <232> Elemental Impurities-Limits and General Chapter <233>Elemental Impurities-Procedures to replace General Chapter <231>Heavy Metals. These new general chapters include more specific and quantitative instrumental techniques superior to wet chemistry procedures in existing GC<231>. Although these 2 concepts are predominantly used, other approaches such as collaboration with FDA through Cooperative Research and Development Agreements, alternative source monographs, and submission by external sponsors are also used to expedite the monograph modernization process.
The next challenge, as stated above, was to develop a priority list of documentary standards to post on the USP website to stimulate stakeholders’ interest and encourage their assistance and method submissions. It should be taken into consideration that products marketed under the FDA over-the-counter (OTC) monograph system have never been subjected to pre-approval assessment of quality and thus may lag behind the quality standards that are required for drugs marketed under an approved New Drug Application (NDA). Hence, in view of the occurrence of past quality failures attributed to impurity contamination and patient safety, the lack of modernized compendial monographs for these drugs is extremely problematic. It was quite obvious that USP needed to focus its attention on OTC monographs that were vulnerable to economically motivated adulteration, have high sale volumes, and/or have inadequate testing protocols.
Both the FDA and USP have identified acetaminophen drug substance and drug product monographs as documentary standards high on the priority list for modernization. Acetaminophen is considered to be one of the highest-selling drugs regulated under the OTC monograph system, and it is presently marketed in various single-ingredient analgesic and antipyretic products, in addition to being a component in cough and cold combination products. However, several shortcomings have been identified in the testing protocols (or lack of ) for both the drug substance and product monograph. For instance, para-aminophenol (PAP), a nephrotoxin, is a known degradation product of acetaminophen that should be monitored in all acetaminophen-based compendial documentary standards. PAP is also a known process impurity which is also classified as a final intermediate product in some known synthetic processes during acetaminophen production, and is controlled very tightly in recently approved NDAs and abbreviated NDAs. However, only 2 USP compendial monographs had acceptance criteria for this nephrotoxic impurity. Therefore, a concerted effort was made to modernize all USP acetaminophen-based monographs to include comprehensive testing protocols for PAP and other specified, unspecified, and total impurities.
A modernized monograph for acetaminophen became official less than 2 years ago and is a great example of a documentary standard that was subjected to a series of necessary and scientifically sound revisions in an effort to meet the pharmaceutical industry expectations of state-of-the-art methodologies required for improved public quality standards. First of all, the definition of the article was revised to be consistent with the customary range afforded to HPLC assays of bulk active ingredients. The identification section of the article was also revised by replacing the TLC test with a retention time comparison test based on HPLC. This section was further modernized by the deletion of the ultraviolet absorption test that was deemed non-specific and offered no substantial benefits because the monograph already possessed 2 orthogonal identification tests. The tests for Melting range or Temperature and Chloride, Sulfate and Sulfite were deleted because the identity, quality, and purity of the drug substance had already been adequately established by the proposed impurity tests. The ultraviolet spectrometric procedure for Limit of Free p-Aminophenol was replaced with a more specific chromatographic limit test. This proposed liquid chromatographic procedure was based on analysis performed with a state-of-the-art column and was evaluated and endorsed by 6 independent laboratories as part of an external 12-member USP Acetaminophen Expert Panel formed to oversee the modernization of the acetaminophen drug substance and drug product monographs.
With regard to monitoring the levels of PAP in the acetaminophen API, it should be stressed that the corresponding acetaminophen drug product monographs are in the process of being modernized to monitor this impurity by using the general chapter approach. This approach refers to the development of a new General Chapter <227>4-Aminophenol in Acetaminophen-Containing Drug Products which focuses on a liquid chromatographic procedure to quantify the degradant by using a standard addition methodology.
Furthermore, additional modernization to this article involved the replacement of the TLC test for Limit of p-Chloroacetanilide with an HPLC procedure for Organic Impurities. This proposed test has the added advantage of being able to monitor the aforementioned impurity as well as all other specified and unspecified impurities. The test for Readily Carbonizable Substances was also removed because it is nonspecific and adds no value to ensuring the quality of the drug substance, while the UV spectrophotometric procedure in the Assay was replaced by a more specific validated HPLC procedure. Finally, the Water Determination test was replaced with a test for Loss on Drying to harmonize with the European Pharmacopoeia. The latter revision serves to emphasize that harmonization of methods among the pharmacopoeias is important. The revisions to the acetaminophen drug substance monograph captured above are representative of modifications associated with a modernized monograph and represent the type of expected revisions that will become prevalent in modernizing outdated documentary standards in the USP-NF.
In conclusion, it should emphasized that USP, with the support and assistance from both the FDA and the pharmaceutical industry, has made a tremendous impact on addressing and correcting the issues associated with outdated methodologies in documentary standards in the compendium. For some time, the pharmaceutical industry has expressed its concerns about monograph methods and procedures that do not reflect current practices in industry. The modernization of the acetaminophen drug substance and drug product monographs are a prime example of USP, FDA, and industry collaborating and working together to enhance global health through the improvement of public quality standards.
Author Biographies
Leonel M. Santos, PhD is currently Director—Chemical Medicines Department at the United States Pharmacopeia and was previously a Senior Scientific Liaison to Small Molecules Expert Committee 1. He is a member of the American Chemical Society and the American Association of Pharmaceutical Scientists. Currently, Leonel is a board member of the Eastern Analytical Symposium.
Behnam Davani, PhD, is the Director—Chemical Medicines Department at the United States Pharmacopeia. He leads a group of US and international-based scientific liaisons responsible for the development and modernization of monographs for small molecule pharmaceuticals. He also supports the USP Expert Committee and Expert Panel.
Clydewyn M. Anthony, PhD, is currently a Senior Scientific Liaison with the Chemical Medicines Department at the United States Pharmacopeia and is responsible for the modernization of Documentary Standards. He earned his PhD in Analytical Chemistry from The Pennsylvania State University and a BS in Chemistry from Hunter College of the City University of New York.
Jon E. Clark, MS, is Vice President of the Chemical Medicines Department at the United States Pharmacopeia. Prior to that, he amassed 12 years of experience in the global pharmaceutical industry and over 20 years of experience with the US Food & Drug Administration (FDA). Mr. Clark holds an MS in Chemistry from Rutgers University and a BS in Chemistry from the University of Michigan.
