Tablet Splitting: A New Focus for Regulators

PTE: Tablet splitting and scoring have not typically been regulated by FDA and other regulatory agencies? Why is there growing focus in this area now?

FDA: CDER’s Drug Safety Oversight Board considered the practice of tablet splitting at its October 2009 and November 2010 meetings. During these meetings, they discussed how insurance companies and doctors in the US are increasingly recommending that patients split tablets, either to adjust the patients’ dose or as a cost-saving measure. Although there are no standards or regulatory requirements that specifically address the scoring of tablets, the Agency recognises the need for consistent scoring between a generic product and its reference-listed drug (RLD).

Consistent scoring ensures that the patient can adjust the dose by splitting the tablet in the same manner as the RLD. This enables the patients to switch between products made by different manufacturers without encountering problems related to dose.

PTE: For what medicines is tablet splitting of particular concern? How does patient compliance factor in?

The FDA has proposed several measures:

• The dosage amount meant to be achieved after splitting the tablet should not be below the minimum therapeutic dose indicated on the approved labeling.
• The split tablet should be safe to handle and not pose risk of unintended drug exposure.Modified-release products, for which the control of drug release can be compromised by tablet splitting, should not have a scoring feature.
• The split tablet, when stored in pharmacy dispensing containers (no seal/no desiccant), should demonstrate adequate stability for a period of 90 days at 25 º C, plus or minus 2 º C/60% RH, plus or minus 5 percent RH.
• The split tablet portions should meet the same finished-product testing requirements as for a whole-tablet product with equivalent strength.
• To ensure the product will function as designed in the hands of patients, the assessment should be undertaken on both tablets that are split nonmechanically (by hand) and tablets that are split mechanically (with a tablet splitter).

What response has FDA received to its draft guidance for tablet scoring? What important issues have been raised? What areas will FDA be developing further?

FDA: Comments to the docket were generally supportive of the need for and contents of the guidance. An Advisory Committee meeting was also helpful both in terms of the support provided and some suggestions for clarification.

How is FDA working with USP and EP in the area of uniformity of dosage units and related testing?

FDA: Tablet splitting also is addressed in pharmacopeial standards. The European Pharmacopeia (EP) currently applies accuracy of subdivision standards for scored tablets, and has at various times also included standards for content uniformity, weight variation, and loss of mass. Meanwhile, the United States Pharmacopeia (USP) published a Stimuli article in 2009 proposing criteria for loss of mass and accuracy of subdivision for split tablets.