Decoding the US Pharmacoepia

Sold in 131 countries the USP-NF acts as a reference point to many regulators in countries that lack an official Pharmacopoeia and it will continue to do so as pharmaceutical manufacturing becomes increasingly globalised

The heart of the United States Pharmacoepia (USP) is the council of experts. This performs the core USP activity: setting standards and revising them. The original USP was written in 1820 and have been been trying ever since to get it right.

Bringing in more scientific wisdom

The most widely known product of USP’s work is the publication and continuous updating of the USP and the National Formulary (NF), two volumes that are published together as one book, the USP-NF.

According to the 1938 Federal Food, Drug, and Cosmetic Act, USP standards are enforceable by the Food and Drug Administration (FDA) for drugs manufactured or sold in the United States. The USP-NF is the only official pharmaceutical compendium in the world that is not published by a government agency.

It comprises two main sections: Official Monographs and General Chapters. The monograph is a detailed description of what USP calls a “medical article”. The monographs primarily describe prescription or over the counter products, but some also define dietary supplements, medical devices or other healthcare products. The monograph includes a description, definition, requirements (such as packaging, labeling, and storage), and a specification. The specification consists of the tests, procedures and acceptance criteria for the ingredient or product. If a substance is tested and conforms to the standards in the monograph, it can be identified as that ingredient or product.

The monographs also contain references to standard tests and assays that appear in the General Chapters of the USP (rather than repeating this information in each monograph, which would make the book unwieldy). In addition to the General Tests and Assays, there is another type of General Chapter, numbered above 1000, called the ‘‘General Information’’ chapters.

These provide additional information that is considered interpretative or optional.

The monographs in the National Formulary follow the same model as those in the USP. The difference is that, whereas most drug substances and dosage forms are included in USP, the NF is limited to excipients. If an article is used as both a therapeutic agent and an excipient, it is included in the USP, with a cross-reference from the NF to the USP monograph for the convenience of the user.

Reference standards

In addition to establishing tests, procedures, and acceptance criteria for USP and NF monographs, USP maintains a collection of reference standards.

The reference standards are highly characterised chemical substances used to test drugs and dietary supplements for compliance with USP standards for identity, strength, quality, and purity. These standards are specifically required in many pharmaceutical assays and tests.

Modern chromatography and spectrophotometry, for example, require measurements relative to a reference standard to get accurate and reproducible results.

USP currently maintains more than 1300 pharmaceutical reference standards and has another 500 under development. These samples are donated by industry, and then undergo extensive testing by various groups before being approved by the USP Reference Standards Committee. They are also carefully packaged and controlled for quality before being distributed.

Evolving science and evolving USP

One of the challenges for the USP is weighing the value of older analytical procedure against the sophisticated methods available today.

PAT methods

As part of the process, the USP has been incorporating Process Analytical Technology (PAT) methods into the USP-NF.

Project teams are developing additional chapters on PAT methods, beginning with thermal effusivity, Raman spectroscopy and acoustical procedures as well as chapters on chemometric methods. The new PAT chapters are numbered above 1000, which indicates that they are advisory in nature and not intended to be enforced.

Alternative tests

Readers of the USP-NF will also see another change in some monographs—multiple alternative test for Impurities. There are different routes of synthesis for many drugs and each route usually has different impurity profile. Similar flexibility has been introduced for drug release tests for extended release product.

Generic biologics

Generic Biologics is a hot topic these days and the USP has thrown itself into the fire.

The USP-NF already includes 144 monographs for biological pharmaceuticals. Twenty-eight more proposals have appeared in Pharmaceutical Forum and another 41 are under development.

Essentially the monograph is the start to generic process.

International harmonization

USP is also harmonizing its standards with the two other main Pharmacopoeias, the EP and JP.

Pharmacopeial Discussion Group (PDG) of three main pharmacopoeia have asked International Conference on Harmonization (ICH) to address the issue. Following PDG request, ICH created Q4B Expert working group, “Regulatory Acceptance of Pharmacopeial Interchangeability”. By the spring of 2005, the working group hopes to have a document ready for step 2 of the Step 5 harmonisation process.

Verifying the quality of dietary supplements

With the launch of a Dietary Supplement Verification Programme (DSVP) in 2001, USP is filling an important information gap for consumers.

Through this voluntary programme, the USP inspects supplements to ensure they contain the ingredients listed on the label in stated amounts or strength and meet appropriate impurity limit.

The USP also verifies that the company has followed FDA’s standards for good manufacturing practices. If a product meets all the standards, USP awards its DSVP certification mark which manufacturers can display on the label as a evidence of the products quality. To-date, six manufacturers have joined the programme.

Certification for pharmaceutical compounding

Formed by coalition of eight organizations PCAB (Pharmaceutical Compounding Accreditation Board), the primary purpose is to improve the quality of Pharmaceutical compounding (the preparation of customized medications for individual patients).

USP already publishes standards for compounding in the USP-NF, including monographs for specific compounded formulations and several general chapters on compounding procedures and requirements.

Supporting international public health

Through grants from the United States agency for International development, USP participates in numerous international public health projects.

In Nepal, the Mekong delta region, and Senegal, USP is helping reduce antimicrobial drug resistance and supporting malaria control efforts by ensuring the quality of antimalarial drugs.

In Romania and Moldova, USP is collaborating on training programs for pharmacists and hospital drug committees to improve the selection and rationale for drugs.

An ongoing need

The USP-NF is sold in 131 countries and regulators in countries that lack an official Pharmacopoeia often refer to the USP. That reach will continue to grow as pharmaceutical manufacturing becomes increasingly globalised.

‘‘The World needs safe, effective, good quality medicines and the USP is in the vanguard and making that possible’’.