Tablets & Capsules

TC0716

Issue link: https://www.e-digitaleditions.com/i/701238

Contents of this Issue

Navigation

Page 61 of 65

48 July 2016 Tablets & Capsules After years of discussion, analysis of elemental impurities is switching from a wet chemical technique to an instru- mental technique. The new approach is more than a simple change in tech- nique. It establishes risk-based limits. The United States Pharmacopeia's (USP's) general chapters <232> and <233> provide options and guidance about how to comply. You may be thinking, "Why can't I just submit a sample to the labora- tory to determine the concentration of elemental impurities observed in micrograms per gram (µg/g) and let the quality assurance (QA) people- calculate whether the acceptance cri- teria are met?" That's a good ques- tion. The answer: To comply with the new chapters, analytical chemists must set up the experiment at concen- trations dependent on the permissible daily exposure (PDE) based on the route of administration and daily dose. The QA unit could also choose to test each component added to a drug product and sum the individual ele- mental impurities or it could simply test the finished product. A third option is available if the drug product's total daily dose doesn't exceed 10 grams. The FDA's September 2015 "Guidance for Industry: Q3D Ele- mental Impurities" provides examples of how to apply each option. The USP lists the PDEs of the 15 elements in question, and those can vary significantly by element and by route of exposure. The PDE for chromium in an oral dose, for exam- ple, can be 11,000 µg per day, while the PDE for eight of the elements when administered by inhalation can be just 1 µg per day. For many ele- ments, the PDE decreases by about an order of magnitude from oral to par- enteral and another order of magni- tude from parenteral to inhalation. As an example, let's determine how much lead is allowable in a tablet taken four times a day. Per the general chapter, the PDE for lead in oral dosage forms is 5 µg per day. To deter- mine the allowable amount of lead per tablet, we divide the PDE by the num- ber of doses per day. In this example, the result is 1.25 µg of lead per tablet. Continuing with the lead example, let's assume you're testing an excipient in the finished product. If the total weight of the tablet is 1,000 milligrams (mg) and the weight of the excipient under test is 200 mg, then it accounts for 20 percent of the tablet's weight. To calculate the total allowable amount of lead in the excipient, you multiply the total lead in the tablet by 20 percent. The result is 0.25 µg of lead in 200 mg of excipient, or 1.25 µg/g. Note that the approach in the sec- ond example assumes an equal contri- bution of elemental impurity from each raw material. While the USP allows you to simply sum the contribu- tion of each component when deter- mining the disposition of a finished product, lab personnel use the equal contribution calculation to validate their analytical method. In fact, method validation is required for each raw material or fin- ished product to be tested. The USP <233> provides guidance on how to perform the method validation for ele- mental impurities and lists acceptance criteria for accuracy, precision, and specificity. The accuracy challenge for a quan- titative method consists of testing trip- licate samples spiked at two concen- tration levels. Let's choose concent- rations of 50 and 150 percent of the calculated limit. Continuing with the lead example in the finished product, this would equate to 0.6 and 1.9 µg/g of finished product. The average recovery must be between 70 and 150 percent of the theoretical concentra- tion. To demonstrate precision, the relative standard deviation (RSD) of six preparations from a single sample spiked at an appropriate level (i.e., 150 percent) must not be more than 20 percent. The precision experiment is repeated on a different day or by a dif- ferent analyst, and the RSD for those results—when combined with the first experiment—must not be more than 25 percent. If you decide to outsource elemen- tal impurity testing, provide the fol- lowing information to the lab: 1) route of administration (oral, parenteral, or inhalation). 2) maximum dose per day, and 3) for excipients, the percentage in the finished product. T&C Timothy Klock is the director of drug discovery and development at Microbac Laboratories, 101 Bellevue Road, Suite 301 Pittsburgh, PA 15229. Tel. 252 237 4175. Website: www.microbac.com. b a c k p a g e Options for conducting elemental impurities testing USP <233> offers guidance on performing method validation for testing elemental impurities and lists acceptance criteria.

Articles in this issue

Links on this page

Archives of this issue

view archives of Tablets & Capsules - TC0716