BETHESDA, MD 19 September 2012—Work is under way to scientifically define the term functional score and use it to designate only tablets that reliably split into equal portions, FDA and the United States Pharmacopeia (USP) recently said.
Guidance, standard. Although many tablets have an indentation that facilitates breakage into portions, FDA has admitted that no standards or regulatory requirements specifically address tablet scoring.
Russell Wesdyk, with the FDA Center for Drug Evaluation and Research, said the agency wants to help health care practitioners determine whether a product should be split.
The work under way at FDA will result in guidance to drug companies, Wesdyk said.
A company whose potential drug product meets the criteria outlined in the guidance document, he said, could then state in the labeling that the product has a functional score. Then, a health care practitioner would be able to look at the labeling and know that the product had been evaluated against FDA’s criteria, Wesdyk said August 9 at a public meeting of agency advisers.
The work under way at USP, said Anthony DeStefano, one of the standards-setting organization’s senior vice presidents, will result in a "general chapter" on functional scoring in The United States Pharmacopeia and The National Formulary. If the planned chapter is assigned a number less than 1000, DeStefano said, then FDA can declare an approved drug product misbranded or adulterated if it does not satisfy the standards.
As of August 9, he said, the chapter does not have a number. He said USP plans to publish its draft of the chapter in the first half of 2013.
Wesdyk did not say when FDA expects to finalize and release its guidance document.
A draft of the document was distributed in November 2011. FDA gave the public 90 days in which to submit comments.
Hints at content. The labeling for two drug products, both approved by FDA in October 2011, include the term functional score or the term functionally scored.
Both products’ instructions on dosage note the possible need to split the tablets in half to achieve the desired dose.
According to FDA’s chemistry review of the new drug application for the iron chelator Ferriprox, ApoPharma Inc. adequately addressed divisibility of the tablets, uniformity of the blend of ingredients, and stability of the split tablets.
There is only one strength of Ferriprox: 500 mg. The labeling recommends the weight-based dosage of 25–33 mg/kg and tells prescribers to round the dose to the nearest 250 mg, or half tablet.
FDA’s chemistry review of Edgemont Pharmaceuticals LLC’s new drug application for 60-mg fluoxetine tablets stated that the split tablets "complied well" with the USP requirements for uniformity of mass for whole tablets. Also, the split tablets released fluoxetine hydrochloride at a rate proportionately similar to that of the whole tablets.
Enforcement actions. FDA’s draft guidance says the agency considers tablet splitting to be a manufacturing operation. Therefore, FDA requires companies that split tablets to register with the agency and comply with its current good manufacturing practice (CGMP) regulations.
The draft guidance also states that split tablets are new drugs unless the drug product’s labeling says the tablets may need to be split. New drugs, by law, must have an FDA-approved new drug application before a company ships them out of state.
Shamrock Medical Solutions Group LLC in 2010 recalled 78,852 split tablets that had been distributed in Massachusetts, New York, Ohio, Pennsylvania, and Wisconsin. According to FDA documents, the company did not have the agency’s approval to manufacture and distribute the split tablets.
FDA had inspected the company’s repackaging and relabeling facility in Massachusetts several times in 2009. The next year, the agency informed the company its facility violated CGMP regulations for finished pharmaceuticals.
The company, FDA said, had no data showing that the split tablets met the specifications in the labeling. Neither had the company established tests and specifications for assay, content uniformity, and tablet friability. FDA had expressed particular concern about tablets that had active ingredients with narrow therapeutic ranges and required monitoring of patients’ blood concentrations.
Pharmacists are viewed differently from companies, however. In the draft guidance, FDA states the agency "generally would not object to tablet splitting if it is performed by a pharmacist pursuant to a valid prescription for an individually identified patient."
Discussions at FDA. The agency said last year that its reviewers of drug applications had previously not been concerned about tablet scores other than to ensure consistency between a generic product and its brand-name predecessor.
Concern about tablet scores changed in response to FDA’s Drug Safety Oversight Board.
In October 2009, the oversight board discussed how insurance companies and physicians were increasingly recommending that patients split tablets to adjust the dose or save money. According to the public summary of the meeting, board members talked about situations in which it is safe to split tablets and patient-specific considerations that would make the situations unsafe. The board discussed tablet splitting again in November 2010.
FDA’s Wesdyk said the topic of tablet scoring and splitting can "lead to extreme views."
He said members of the public have told FDA it should mandate that a scored 40-mg tablet, once split in half, meet all the requirements applicable to an individual 20-mg tablet. And FDA has also been told that for some scored drug products, from a clinical point of view, a little variation in the amount of drug a patient takes from day to day doesn’t really matter.
What FDA is trying to do, he said, is "find the middle ground" between these views.
One of FDA’s proposed criteria for the designation functional score, for example, would address the stability of split tablets when stored for 90 days.
ASHP since 2005 has "opposed mandatory tablet splitting for cost containment in ambulatory care."
The Society shared its four-part policy, which encourages further research by USP and FDA on the effect of tablet splitting on product quality, with USP.