Q&A on USP's Levothyroxine Sodium Standard

Who is USP and what is its role in drug manufacturing and regulation?
The U.S. Pharmacopeia (USP) is a nonprofit scientific organization that has set standards for the quality of medicines and their ingredients since 1820. These standards help ensure the medicines that patients take are of high quality, are pure, are of the appropriate and expected strength, and are consistent from one pill, bottle, shelf, and pharmacy to the next. Once USP develops a drug standard and it becomes "official" (after an extensive process of public review, as described below), it is enforceable by the U.S. Food and Drug Administration (FDA). USP does not approve a drug for sale in the U.S. market, determine a drug's safety or efficacy, or enforce the standards it creates—these are all responsibilities of FDA.

What is the process for revising quality standards and why are such revisions necessary?
USP creates and continuously revises its drug and ingredient standards through a public process that involves the pharmaceutical industry as well as government, scientific researchers, doctors, and other interested parties from around the world. When a change to an existing USP standard is proposed, this proposal undergoes a public comment period where USP solicits any comments on the proposed change(s). This process is designed to allow the broadest possible feedback, helping to ensure the best possible standard. It also provides a forum, for instance, for a drug manufacturer to notify USP of any complications proposed changes might cause in the manufacturing of the affected product or ingredient. After this comment period, a committee of scientific experts considers all feedback and decides upon a final standard. However, if the changes are significant, the revised standard with incorporated changes again is published for a second period of public review. After a final standard is approved, it is still not "official" for an implementation period long enough to allow manufacturers adequate time to comply with the changes (typically at least 6 months).

Revisions to USP standards may be necessary for any number of reasons, including new scientific knowledge, new technologies, or new risks for adulteration that arise. Revisions are always done in the interest of public health. Up-to-date quality standards for medicines are one of the safety nets that helps secure the drug supply for patients.

How, when and why did USP change its standards for levothyroxine sodium?
Levothyroxine sodium is a drug ingredient that is used in finished product medicines; "finished products" are what the patient actually uses. Levothyroxine sodium is one component of the medication liotrix tablets (brand name Thyrolar), which some patients have reportedly had trouble purchasing over the past few months. The USP Levothyroxine Sodium standard has been official since 1960. In 2005, USP began a process to update that standard, and individually invited all manufacturers included in FDA's Orange Book (which lists all approved drug products in the U.S.) to participate in this revision. The revision was intended to update the ingredient's purity method. A purity method is important for ensuring that a medicine or ingredient is free of harmful levels of contaminants - clearly in the best interest of patients. USP presented a revised standard in May 2007 and received only one comment during the public review process, which was addressed. The final standard was published on February 1, 2008 and became official on August 1, 2008. No reports of any problems regarding compliance with this revised standard were communicated to USP by any pharmaceutical manufacturers. USP was made aware of the apparent shortage of Thyrolar when contacted by patients beginning in mid-August 2009-more than one year after the standard became official, more than two years after the revision was proposed, and roughly four years after initiating outreach on its intent to revise.

It appears that this change has resulted in patient difficulty in obtaining Thyrolar-how is USP resolving this situation?
USP is a public health organization, and takes this problem very seriously. The extensive public process by which USP revises its standards was designed to facilitate changes in the interest of public health while balancing the realities of drug manufacturing (and how changes to a USP standard affect a manufacturing process and, potentially, drug availability). This is where a public comment process and implementation timeline are key. However, in this case it appears there may have been a compliance problem that was not brought to USP's attention. Since learning of this situation, USP has reached out both to the affected manufacturer and to FDA. To date, USP has not received a request to revise the standard, which would need to be submitted along with an explanation of the reason for the requested revision. USP is able to revise a standard under an accelerated process when there is an urgent public health concern, and could do so in this case if a change were proposed and justified. It is also important to note that FDA can intervene and suspend its enforcement of a USP standard if public health dictates.

What can patients do in the interim?
Patients who have had trouble obtaining their medication can contact the FDA and report a drug shortage at this link: http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm142398.htm. USP will consider changes to its standard in the interest of patient need on an accelerated timeline if a proposal is made by a manufacturer, FDA, or other credible party and sufficient justification is provided.