Questions and Answers May 2019
William Brown and Margareth Marques
The following questions have been submitted by readers of Dissolution Technologies. Margareth Marques, Ph. D. and Will Brown, United States Phamacopeia, authored responses to each of the questions.
*Note: These are opinions and interpretations of the authors, and are not necessarily the official viewpoints of the USP
Email for correspondence: email@example.com
Q Can you advise us on the interchangeability of USP apparatus 1, 2, and 3. We would like to develop dissolution tests using apparatus 3 (reciprocating cylinder) and later transfer those methods to apparatus 1 (basket) or 2 (paddle). Any comments?
A USP apparatus 1, 2, and 3 are not interchangeable. They have different design and operating conditions. The dissolution method is designed, in most cases, to be discriminative for the critical quality attributes of the product. Once you have defined the conditions within the method, changes in those conditions are allowed only with appropriate justification. The new conditions still need to be discriminative of unacceptable product.
Q I would like to know if there is any equivalence between USP apparatus 1, 2, and 3. We are developing a product containing venetoclax and the FDA dissolution methods database lists USP apparatus 3. We do not have this equipment in our lab.
A There is no reason to assume equivalence between USP apparatus 1 (basket), 2 (paddle), and 3 (reciprocating cylinder). Venetoclax is a poorly soluble drug, BCS 4. Consequently, dissolution procedures may be formulation-dependent. You will need to develop a dissolution test that is discriminative for the critical quality attributes of your formulation. It is likely that bioequivalence will be determined with in vivo data for this drug substance.
Q If a particular USP monograph has a dissolution test but no disintegration test, is a disintegration test necessary?
A No. In most cases, dissolution results incorporate effects of disintegration. The test stated in the monograph should be sufficient. The only dosage forms that require both dissolution and disintegration tests are orally disintegrating tablets and chewable tablets. See the FDA guidances http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070578.pdf and https://www.fda.gov/downloads/Drugs/Guidances/UCM507098.pdf.
Q In what cases is a dissolution test required or considered to provide useful development data for pediatric oral suspension formulations? The pediatric oral suspension is in the early development stage, and we have already developed an immediate-release tablet for the same drug substance. Is there any value in comparing dissolution data of the tablet with those for the suspension?
A The dissolution test is required for all suspensions, regardless of route of administration and the targeted patients. See the proposal for a new USP general chapter, <1711> Oral Solid Dosage Forms - Dissolution Testing, published in Pharmacopeial Forum 44(5), available free of charge at www.usppf.com. Suspensions and tablets are very different dosage forms. Any comparison of dissolution data obtained with these dosage forms are useful only as supplemental information.
Q The USP monograph for tamsulosin hydrochloride capsules has 10 different dissolution tests. Probably one of them is for the innovator product and the other nine tests are for the generic products. Does this imply that all these products have demonstrated bioequivalence?
A Not necessarily. To see which products are bioequivalent to the Reference Listed Drug(s) (RLD) you need to look at the FDA Orange Book, available free of charge at https://www.accessdata.fda.gov/scripts/Cder/ob/index.cfm. There are some products with more than one RLD. Those RLDs have not been shown to be bioequivalent among themselves. Some other examples of Orange Book listings are nifedipine extended-release tablets and levothyroxine tablets.
Q During paddle dissolution testing for one of our modified-release products, we noticed that the tablets were not dropped at the center of the dissolution vessels. Some of the tablets were stuck on the edges of the vessel hemisphere and remained at this position during the test. Can we proceed with the dissolution testing with the tablets at off-centered position or should we force the tablets to move to the center of the vessel?
A You should evaluate the effect of off-center dissolution for this product. If the results for the offcenter and centered samples differ significantly, one solution is to use a sinker. Many sinker designs and sizes are available. Select the design and size that are most appropriate for your product.
Q What performance verification procedure should be used with an automated sampling displacement pumping system versus automated sampling with peristaltic pump? USP states that “if automated equipment is used for sampling or the apparatus is otherwise modified, verification that the modified apparatus will produce results equivalent to those obtained with the standard apparatus described in this general chapter is necessary.” Does the performance verification need to be done with USP Prednisone Tablets RS? Can a finished product be used? How can we determine that both sampling procedures are equivalent?
A The automated sampling system should be validated using the dissolution samples that will be tested. Adsorption and other interference to the results will be dependent on the drug being tested, the formulation components, and the dissolution medium. The performance qualification for the dissolution test assembly needs to be done through the use of the USP performance verification test (PVT). Typically, that PVT testing is performed with manual sample introduction, manual sample withdrawal, and with any attachments removed from the dissolution vessels.
Q Is there a minimum amount of vessels for dissolution testing with USP apparatus 1 and 2? Can only dissolution test equipment with six vessels be used?
A The USP general chapter <711> Dissolution describes the equipment and procedure for only one vessel. This procedure should be repeated for each one of the vessels in the equipment being used. It is up to the user to decide on the configuration of their dissolution equipment; however, for routine analysis, all acceptance tables require a minimum of six results.
Q In which document is the precise performance verification test (PVT) described, including recommended mechanical calibration steps and acceptance criteria for tests?
A The basket and paddle apparatus (1 and 2, respectively) dimensional and operational descriptions can be found under the Apparatus section of the chapter, <711> Dissolution. At the end of that section is the Apparatus Suitability section, which includes the use of the USP Prednisone Tablets RS in the PVT for the basket and paddle. USP reference standards come with documentation that, in the case of PVT standard, speaks to the experimental details. The certificate can be found at https://static.usp.org/pdf/EN/referenceStandards/certificates/1559505-R072M0.pdf