There has been a lot of discussion about the need to retain up to five times the amount of test and reference drug product to perform release testing as reserve samples for products used in in vivo or in vitro bioavailability (BA) or bioequivalence (BE) testing for NDA or ANDAs products.  The requirements were at times very expensive for certain products like metered dose inhalers, some topical products, and raised other questions about control of products narcotics or other controlled substances or chemotherapeutic agents.

Industry has spoken, and the FDA has listened.  Much of the original regulations were developed in response to the generic drug scandal and the shenanigans that occurred with fraudulent BE testing.  The quintessential example of this fraud occurred when the firm Bolar was seeking approval of a generic version of Dyazide Capsules, a medication to control blood pressure.  Apparently, it was a difficult product to copy and BE tests never seemed to pan out.  So, to overcome this problem, Bolar simply took their empty capsule shells, filled it with the powder from the Dyazide Capsule brand and then essentially tested the product against itself and it then passed!  This was uncovered during the widespread generic drug scandal investigations of the late 1980s.  Regulations eventually were proposed and adopted that required retention of BA/BE test and reference samples so that the FDA could examine the fingerprint of the product to make certain that this fraudulent practice was less likely to occur, and that the FDA would have the means to forensically evaluate both the brand and generic test product used in the studies to support approval of the applications.

The regulations “[S]pecifically, 21 CFR 320.38 and 320.63 require the applicant (or its CRO) to retain reserve samples of the test article and reference standard used in conducting any in vivo BA and in vivo or in vitro BE study that support the approval of its application or supplemental application.”  And they specifically state that the quantity to be retained be five times the number of samples necessary to complete full release testing.  The Agency cannot make changes to regulations via guidance documents and would need to go through the long and tedious comment and rule-making process.  However, FDA can decide, based on reasonable circumstances, to exercise enforcement discretion in dealing with the existing regulation or policies where such polices have become overly burdensome.  And that is what this immediately effective Compliance Policy Guide (CPG) (here) does.

The Agency explained in the CPG that based on new, and improved analytical methods, it is no longer necessary to place a burden on applicants to set aside the number of reserve samples called for by the regulations.  Based on FDA’s evaluation, it will only be necessary to reserve 30 units of both the test and reference products that contain a single dose and 3 units of both the test and reference product if it contains multiple doses.  Now you are thinking, does that mean thee bottles of 100 tablets because that contains multiple doses in the bottle or 30 tablets?  The answer, according to the two tables that appear in the Compliance Policy Guide (CPG) that outline the requirements for retention for different dosage forms, is just 30 tablets of each test and reference product.

Please review the CPG and if a dosage form that you are developing does not appear in one of the two tables (which by the way are fairly comprehensive) the Agency suggests you submit a controlled correspondence asking for a waiver for the need to retain five times the quantity of test and reference product to be retained for samples used in in vivo/in vitro BA/BE testing.  This is going to be a game changer for industry and in many instances (e.g., MDIs) a significant cost saving for drug product development.  In addition, studies that may not have been possible because of the lack of availability of sufficient quantities of the same lot of the reference product to meet the regulatory retention policy, may now proceed.