Questions and Answers May 2020
Margareth R. Marques, Ph.D. and Mark Liddell, Ph.D.
The following questions have been submitted by readers of Dissolution Technologies. Margareth R. Marques, Ph.D., and Mark Liddell, Ph.D., United States Pharmacopeia (USP), 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: firstname.lastname@example.org
Q The USP general chapter <711> Dissolution has a section entitled “For Dosage Forms Containing or Coated with Gelatin” that describes how to prepare several dissolution media containing enzymes for different pH ranges. When was this text added to USP? Do you have any history of this procedure that you can share?
A The revision to the USP general chapter <711> Dissolution concerning the use of enzymes in the dissolution medium to be used when there is evidence of cross-linking in the gelatin capsules or gelatin coating was published in Pharmacopeial Forum 40(6), available free of charge at www.usppf.com. The USP general chapter <711> is partially harmonized with the European and Japanese Pharmacopoeias. This revision became official in USP 39 as national text (only for the USA) because this procedure was not accepted by the European Pharmacopoeia nor the Japanese Pharmacopoeia. Additional information can be found in the paper “Use of enzymes in the dissolution testing of gelatin capsules and gelatin coated tablets - Revisions to Dissolution <711> and Disintegration and Dissolution of Dietary Supplements <2040>” available at DT201411_A01.pdf.
Q Which is the correct form to write the dissolution specification for not less than (NLT) 85% according to the USP general chapter <711> Dissolution, NLT 80% (Q) or NLT Q+5% (Q = 80%)?
A If the acceptance criteria for this particular product is NLT 85% (Q), for batch release purposes the results are going to be evaluated using the Acceptance Table 1 in the USP general chapter <711> Dissolution. This table has three stages, and the product does not meet the acceptance criteria if it fails the three stages. At stage 1 (S1), the acceptance criterion is going to be Q + 5%. Using the acceptance criterion included in your question, the acceptance criterion at S1 will be NLT 85% of the product label claim plus 5%. The acceptance criteria in the dissolution procedure remains NLT 85% (Q).
Q Should dissolution vessels, baskets, and disks dimensions be checked during the initial qualification only or should they be also checked periodically?
A The dimensions and appearance of dissolution vessels, baskets, and disks are checked upon receiving to see if they conform to the specifications. Their aspects/ appearances should be checked periodically to see if they are become damaged, deformed, or scratched.
Q Our formulation is complex. It presents a coning at the bottom of the vessel even at 250 rpm and has very bad repeatability. We tried to use the peak vessel and got much better results with lower variability. As peak vessels are not compendial, which parameters should we pay attention to?
A As peak vessels are not standardized, you need to well characterize the ones you are using (angle and height of the peak, etc.) and include this information in the final version of the dissolution procedure.
Q When running the dissolution test with gelatin capsules presenting evidence of cross-linking, should the paddles/basket be raised or stopped during the addition of the dissolution medium containing enzymes? Should the time needed to add the medium containing the enzyme be included in the total dissolution time?
A When there is evidence or presence of cross-linking in the gelatin during the dissolution test of gelatin capsules or gelatin-coated tablets, you should stop the test and run the test again with the dissolution medium containing the enzyme with new units (not previously tested). Follow the procedures as stated in the USP general chapter <711> Dissolution: transfer the medium to the vessels, wait for the temperature to equilibrate, introduce the new units, and run the test for the time stated in the method.
Q Is USP going to develop a similar section to the section entitled “For Dosage Forms Containing or Coated with Gelatin” in <711> Dissolution for hypromellose capsules?
A Hypromellose capsules do not present cross-linking. Look at the USP general chapter <1094> Capsules - Dissolution Testing and Related Quality Attributes, section 6.1.2 Chemistry of other polymers, where it is stated that hypromellose capsules do not show cross-linking. Keep in mind that hypromellose capsules take a longer time to open when compared with gelatin capsules.
Q We are developing a dissolution test for a transdermal tape. We are using the apparatus disk to hold the transdermal patch, 125 mesh, which we believe is the one mentioned in the European Pharmacopoeia (EP) under 2.9.4 Dissolution Test for Transdermal Patches. USP general chapter <724> Drug release, under Apparatus 5, refers to a 90-mm, 17-mesh screen. Is the screen described in USP equivalent to the one in EP? Also, is the information in <724> harmonized with EP?
A The USP general chapter <724> Drug Release is not harmonized with EP. If it were, this information would be at the very beginning of the chapter. This screen is used only to keep the transdermal system flat. According to <724>, using the screen is not mandatory; other means to keep the transdermal system (TDS) flat, such as doublesided tape, membrane, etc., can be used. You need to evaluate which one works best with your product. Keep in mind that, when using double-sided tape or membrane, you need to demonstrate noninterference with the quantitative step.
Q Are there any documents stating the timepoints in a dissolution profile?
A No, because it depends on the product behavior and how the information is going to be evaluated. There are some recommendations, but it is up to you to decide after taking into consideration if it is an immediate-release or modified-release dosage form. The general rule is to measure until plateau is reached or when the dissolution rate remains almost constant. Another recommendation is, during product development, to run the dissolution profile for the same time as the treatment. If a fiber optic probe is available, more points can be collected, allowing a better understanding of drug release.
Q If only online sampling is going to be used in the routine for the dissolution tests, should the performance verification test (PVT) with the USP Prednisone Tablets RS be also done with online sampling?
A The PVT procedure was developed and validated only for manual sampling. It is up to your lab to demonstrate the suitability of the PVT for online sampling.
Q We have a dissolution equipment in our lab that has eight vessels. We did the PVT for the eight vessels and input the data in the calculation tool available in the USP website (pvtCalculationTool), and the PVT failed. When we took six good results from the eight results and input the data in the calculation tool, the test passed. Is it allowed to perform such evaluations of the PVT results?
A Although it is common to perform the PVT with all eight vessels and then, after passing the PVT criteria, use only six vessels for routine testing, caution needs to taken when using your approach. According to the test interpretation instructions included in the certificate that accompanies the USP Prednisone Tablets RS, step 1 for both the single-stage and two-stage tests instructs “for each position in the assembly, test one USP Prednisone Tablets RS, and record the percent dissolved at the sampling time point specified.” Hence, the test instructions require that all positions of the test apparatus are included in the mean and variance calculations. If two positions are failing, the user should investigate those positions and make the necessary adjustments for the whole system to meet the test criteria.