FAQs: Dissolution Performance Verification Testing (PVT)

PVT PURPOSE AND RS DEVELOPMENT PROCESS

The purpose of the PVT is to provide evidence of instrument and apparatus suitability. USP considers adherence to measurable, dimensional, and operational parameters to be a critical component of dissolution apparatus suitability. However, without a challenge to the apparatus demonstrating the ability to produce dissolution results from a standard material, mechanical calibration alone cannot provide sufficient evidence that the apparatus is performing satisfactorily. The purpose of the PVT is not to diagnose specific problems with the dissolution assembly but to provide confidence that the instrument is functioning properly.

Mechanical calibration is a procedure to verify the fixed parameters for the instrument, e.g., vessel, paddle, basket, etc., and instrument function, e.g., rotation speed, temperature control, etc. Mechanical calibration alone cannot satisfy the Performance Qualification (PQ) component of the dissolution assembly qualification.

The PVT using the USP Dissolution Performance Verification Standard – Prednisone Reference Standard (RS) (catalog #1222818) is a holistic test that demonstrates the operation of the entire assembly setup as it produces dissolution results that can be compared to established acceptance criteria.

Failing the PVT means that the results are different from those obtained by the labs in the collaborative study. Failing results can indicate the faulty operation of the dissolution assembly, deviation from the correct procedure, analyst error and/or other environmental contributions which are difficult to identify.

Approaches to instrument qualification that rely solely on the agreement of mechanical specifications with those described in USP General Chapter <711> Dissolution and other sources assume there is no interaction of these easily quantifiable qualities with those that are more difficult to characterize. The PVT provides a test of the “fitness for purpose” of the entire dissolution system, including the environment in which the equipment is operating. The purpose of the PVT and using the USP Dissolution Performance Verification Standard – Prednisone RS is not to diagnose specific problems with the dissolution instrument but to provide confidence that the instrument is functioning properly.

Refer to the below white paper on dissolution qualification for more details. https://www.usp.org/sites/default/files/usp/document/our-work/chemical-medicines/usp-pvt-dissolution-test.pdf

Although the formula and the process are well controlled, each lot of tablets is unique. Consequently, the PVT limits for the geometric mean (GM) and coefficient of variation (%CV) must be evaluated for each lot. As a global standard, these limits must accommodate reasonable lab-to-lab variability. Establishing the acceptance ranges for the USP Dissolution Performance Verification Standard – Prednisone RS through an international collaborative study captures run-to-run, lab-to-lab, and any remaining residual variability such as vessel-to-vessel, and tablet-to-tablet variability of each lot. USP requires that all participating labs follow a rigorous test protocol. This test protocol relies in large part on the information available in the USP Guideline on Procedures for Mechanical Calibration and Performance Verification Test (Apparatus 1 and Apparatus 2). [Note: This document was formerly referred to as the Dissolution Toolkit.] Various instrument brands and models are used throughout the study to ensure a variety of equipment are accounted for in the determination of ranges for each lot.

Candidate laboratories need to meet USP Quality Assurance qualification requirements. Contact rstech@usp.org if your laboratory is interested in learning more.

ACCEPTANCE CRITERIA 

The ranges for the geometric mean (GM) and the coefficient of variation (%CV) are an integral component of the PVT and are obtained from a multinational collaborative study conducted for each lot of the USP PVT reference standard. Those two statistics, GM and %CV, help the laboratory using the reference standard determine if their results are accurate as defined by ISO 5725-6, Accuracy (Trueness and Precision) of Measurement Methods and Results—Use in Practice of Accuracy Values. Accuracy is comprised of trueness and precision, which are embodied in the GM and %CV, respectively. A discussion of these concepts can be found in an article by Walter Hauck, et al. in Pharmacopeial Forum 33(3), “Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing.”

Historically, PVT collaborative studies have shown that the data are better analyzed in the log scale to improve the normality assumption. The acceptance limits are calculated as the arithmetic mean and standard deviation in the log scale. Therefore, the arithmetic mean and standard deviation are converted into a geometric mean (GM) and the coefficient of variation (%CV), respectively. Then these statistics are converted back to the percent-dissolved scale to make them more easily interpreted. See the 2008 Stimuli Article for further details.

The acceptance ranges for the USP Dissolution Performance Verification Standard – Prednisone RS have been established using 1-Liter vessels. Therefore, the acceptance ranges apply only for dissolution assemblies configured with 1-L vessels.

The acceptance criteria of the USP Dissolution Performance Verification Standard – Prednisone RS (catalog #1222818) are determined through the statistical analysis of data obtained in a global collaborative study for each individual lot of tablets. In addition, each lot may be obtained from a different manufacturing run of bulk tablets. For these reasons, the acceptance criteria may vary from lot to lot.

No, any intrinsic variability of the tablets is captured by the PVT limits for the geometric mean (GM) as well as the coefficient of variation (%CV). If the limits were simply based on the performance of the tablets in USP labs, they would be tighter. However, the USP PVT is a global standard; therefore, the limits also reflect the lab-to-lab reproducibility based on results from an international collaborative study.

PROCEDURE 

Automated systems are not allowed to be used by participating labs in the collaborative study. This approach is to reduce the contribution of the individual components of the automated system to the variability of the results. For this reason, USP cannot comment on the use of auto-samplers and other automated systems when performing the PVT using the USP Dissolution Performance Verification Standard – Prednisone RS (catalog #1222818). Ensuring that automation does not significantly affect the validity of the dissolution results falls within the responsibility of the individual user. With an automated dissolution system that has been verified to produce equivalent results to those from manually sampled prednisone tablet solutions, the inclusion of the automated system during the PVT should not be a cause for failure.

Click here to view a video of the typical set up for the USP deaeration procedure by vacuum filtration. Click here to open the USP Guideline on Procedures for Mechanical Calibration and Performance Verification Test (Apparatus 1 and Apparatus 2) which includes the written procedure. The preparation of the Dissolution Medium can influence the results of the PVT. Any alternative deaeration procedure should be verified against the USP deaeration procedure.

No, General Chapter <711> Dissolution and the USP Guideline on Procedures for Mechanical Calibration and Performance Verification Test (Apparatus 1 and Apparatus 2) do not require for each individual tablet of the USP Dissolution Performance Verification Standard - Prednisone RS to be weighed.The acceptance ranges for the Prednisone tablets RS have been established using 1-L vessels. Therefore, the acceptance ranges apply only for dissolution assemblies configured with the 1-L vessels.

False 

The design of the PVT allows the use of either a Single-Stage or a Two-Stage testing approach. The choice of Single- or Two-Stage testing is significant. Valid use of this approach to the PVT requires that the laboratory make the choice of Single-Stage testing or Two-Stage testing as a standard procedure. Documentation of that choice will support the validity of the PVT by the individual laboratory.  

In the Single-Stage test, two consecutive runs are to be performed on the dissolution assembly and all data generated are collected. Then the overall geometric mean (GM) and the coefficient of variation (%CV) of the variances of both runs are evaluated and compared with the applicable acceptance limits. Both values have to meet the applicable acceptance criteria to pass the PVT. If either the GM or %CV is not within the respective acceptance range, the PVT failed and the assembly is not suitable.  

In the Two-Stage test, a single set of data (First Stage) is collected from the test assembly and the GM and %CV are compared with the applicable acceptance limits. The acceptance criteria are more stringent for the First Stage than for the Second Stage of the Two-Stage Test. If the GM and the %CV are within the ranges given, the criteria are met and the test is concluded. If either the GM or %CV is not within the respective acceptance range, a second set of data (Second Stage) should be collected. Then the GM and %CV for the combined data are calculated and compared with the respective acceptance ranges for the Second Stage. Both GM and %CV must meet the applicable acceptance criteria to pass the PVT. If either the GM or %CV is not within the respective acceptance range, the PVT failed and the assembly is not suitable.  

In the case of an assembly with 12 or 14 positions, a single run (with all positions tested) is required for the PVT.

Click here to open the USP Guideline on Procedures for Mechanical Calibration and Performance Verification Test (Apparatus 1 and Apparatus 2).

This approach is not acceptable because the acceptance ranges are lot-specific and the results cannot be combined.

Per General Notices Section 7.20 Rounding Rules in the USP-NF Online publication, “numbers should not be rounded until the final calculations for the reportable value have been completed. Intermediate calculations (e.g., slope for linearity) may be rounded for reporting purposes, but the original (not rounded) value should be used for any additional required calculations. Acceptance criteria are fixed numbers and are not rounded.” In particular, the percent dissolved values should be retained to at least three decimal places prior to calculation of the geometric mean (GM) and coefficient of variation (%CV).

If nothing but the stirring elements are changed when switching from Apparatus 1 to Apparatus 2, then the PVT for Apparatus 1 is still considered to be successful even after the PVT fails for Apparatus 2. In this case, the dissolution assembly can be used for Apparatus 1 but not for Apparatus 2. The cause of failure for Apparatus 2 should be investigated and any necessary adjustments should be made prior to repeating the PVT. If the cause is the paddle stirring elements and no other changes are made, the PVT must be repeated for Apparatus 2 only. If any changes are made other than the replacement of the paddle stirring elements, the PVT must be repeated for both Apparatus 1 and Apparatus 2.

The use of an inside divider was removed because the metal tool can scratch the inside of the dissolution vessels.

The use of a spirit level was removed because the vessel verticality and shaft verticality are difficult to measure with this type of level.

In order for the dissolution bath to meet the requirements of General Chapter <711> Dissolution, basket clips must be present even if the dissolution bath also uses O-rings to secure the basket. The clips are not only cosmetic; their removal can result in a change in the hydrodynamics in the dissolution vessel. 

This approach is not acceptable because the acceptance ranges are lot-specific, and the results cannot be combined.

TECHNICAL DATA SHEETS 

As with all USP Reference Standards, the USP Certificates for current & previous lots can be viewed in the online USP Store by using the search bar to navigate to the product page. This product page in the USP Store can also be accessed by clicking on the catalog number of the RS in the USP Catalog.

No, the Dissolution Toolkit (Version 2.0) was specifically for performing the PVT using the USP Prednisone Tablets RS (catalog #1559505). Moreover, it has been replaced with the USP Guideline on Procedures for Mechanical Calibration and Performance Verification Test (Apparatus 1 and Apparatus 2). Refer to FAQ #22 for more information.

The Dissolution Toolkit has been replaced with the USP Guideline on Procedures for Mechanical Calibration and Performance Verification Test (Apparatus 1 and Apparatus 2). Please refer to the footer of the document to make certain that you are using the appropriate Guidelines document. Click here to open the Guidelines document for use with the USP Dissolution Performance Verification Standard – Prednisone RS (catalog #1222818) which describes techniques enhanced beyond those provided in General Chapter <711> Dissolution and the RS’s USP Certificate.

STORAGE & HANDLING 

Store the USP Dissolution Performance Verification Standard – Prednisone RS at controlled room temperature.  General Chapter <659> Packaging and Storage Requirements in the USP-NF Online publication defines Controlled Room Temperature as “the temperature maintained thermostatically that encompasses the usual and customary working environment of 20°–25° (68°–77° F).” Refer to <659> for the complete definition which includes available information on excursions.

USP does not recommend the storage of a partially used blister strip. Each blister strip is packaged in an aluminum sachet. The sachet serves as a barrier to protect the tablets from moisture. As moisture can impact the dissolution results in the Performance Verification Test (PVT), remaining tablets from an opened sachet should not be saved for later use.

USP Dissolution Performance Verification Standard - Prednisone RS tablets should be pushed through the aluminum foil of the blister strip. Upon opening the aluminum sachet, tablets should be promptly removed and used for the Performance Verification Test (PVT) to prevent any impact from environmental conditions and maintain a controlled experiment. Efforts should be made to minimize the time between removal of the tablets from the blister strip and the start of the PVT procedure.

USP Dissolution Performance Verification Standard - Prednisone RS tablets are more resistant to surface damage than the USP Prednisone Tablets RS (catalog #1559505). Due to the changes in the size and formulation of the USP Dissolution Performance Verification Standard - Prednisone RS, the tablets require a significantly higher tablet breaking force compared to the USP Prednisone Tablets RS. We have not observed any issues with crushing or scratching the tablet surface when using metal forceps to handle the USP Dissolution Performance Verification Standard - Prednisone RS tablets in our lab.

Please refer to the following video for additional information on USP Dissolution Performance Verification Standard - Prednisone RS packaging and handling: https://www.youtube.com/watch?v=ou_qjeXXsVg

EXPIRATION DATING 

USP Reference Standards (RS) do not carry expiration dates in the traditional sense. A Valid Use Date (i.e., the period of validity) is assigned to each lot and is stated on the lot’s USP Certificate. It can also be viewed on the product page in the online USP Store and in the online USP Catalog. The lot should not be used after its assigned Valid Use Date.

It is the responsibility of the user to ascertain that a particular lot of a USP RS has official status either as a "Current Lot" or as a "Previous Lot" within the Valid Use Date. The USP Catalog and the online USP Store are updated daily. USP recommends referring to one of these sources prior to using any USP RS to make sure the lot is valid for use. USP cannot support the use of any USP RS lot after its assigned Valid Use Date.

View USP's policy statement on Expiration Dating of USP Reference Standards.

The assigned Valid Use Date is assigned based on statistical analysis of dissolution performance data obtained over a period of time for the specified lot. The dissolution performance is monitored prior to and throughout its valid use period.

The Valid Use Date was extended beyond the date of the replacement of the USP Prednisone Tablets RS with the USP Dissolution Performance Verification Standard – Prednisone RS in General Chapter <711> in order to allow customers the ability to purchase USP Prednisone Tablets RS in early 2023. USP has received feedback from customers that they are not able to purchase any product lot with a Valid Use Date or expiration date within 3 months of the order date. To enable companies the ability to purchase the USP Prednisone Tablets RS in early 2023 to perform the PVT, the Valid Use Date was set to 31-July-2023. Having a Valid Use Date in April 2023 would have prevented companies from being able to qualify their instruments. As the USP Prednisone Tablets RS has no associated USP compendial use as of 01-May-2023, any use after this date would be considered non-compendial and the responsibility of the user.

TRANSITIONING FROM USP PREDNISONE TABLETS RS TO USP DISSOLUTION PERFORMANCE VERIFICATION STANDARD – PREDNISONE RS

The release of the USP Dissolution Performance Verification Standard – Prednisone RS is a part of USP's commitment to continuous enhancement of our products and services. The introduction of this reference standard and the associated revisions to General Chapter <711> Dissolution that became official on 01-May-2023 was based on discussions with and feedback from various USP stakeholders. The revisions were posted for public comment in Pharmacopeial Forum (PF) 48(6) from 01-Nov-2022 to 31-Jan-2023.

No, there were no additional revisions that became official on 01-May-2023.

Based on the internal USP studies that have been performed, the USP Dissolution Performance Verification Standard – Prednisone RS is considered more sensitive to operational and mechanical variables of instrument setup, less sensitive to media degassing, and more reproducible. The packaging configuration has also been changed. Each blister pack of 6 tablets is packaged in an aluminum sachet to provide additional protection against moisture. The tablets are also a different shape. USP Prednisone Tablets RS is a Bi-convex tablets while the USP Dissolution Performance Verification Standard – Prednisone RS is a modified ball shape. An individual tablet of the USP Dissolution Performance Verification Standard – Prednisone RS also has a higher mass in comparison (350 mg versus 222 mg).

Only those results obtained by the method and/or procedure given in the USP–NF are conclusive. As of 01-May-2023 (official date), only those results obtained using the USP Dissolution Performance Verification Standard – Prednisone RS (catalog #1222818) will provide conclusive results to meet the requirements of General Chapter <711>.

The General Chapter <711> Dissolution revision does not require customers to reevaluate an instrument that passed the PVT prior to the official date. General Chapter <711> indicates that the apparatus suitability test must be performed “periodically” (without a requirement of a definitive time-period). USP recommends six-month intervals in the USP Guideline on Procedures for Mechanical Calibration and Performance Verification Test (Apparatus 1 and Apparatus 2).

Additional Information 

USP has a number of informational tools available to users, including but not limited to a product factsheet, webpage, videos, webinars, and white paper(s). Visit the links below to access these tools and find more information on the USP Performance Verification Test (PVT) and the USP Dissolution Performance Verification Standard – Prednisone RS:
https://go.usp.org/dpvs-prednisone
https://www.usp.org/small-molecules/pvt
https://www.usp.org/small-molecules/dissolution
https://www.usp.org/resources/compendial-tools
https://apps.usp.org/app/USPNF/pvtCalculationTool/

Contact Details 

Please contact Reference Standard Technical Services (RStech@usp.org) with any additional questions about the USP Dissolution Performance Verification Standard – Prednisone RS and its use in the PVT. [RS FAQ’s: https://www.usp.org/frequently-asked-questions/reference-standards]

Please contact Margareth Marques (mrm@usp.org), Senior Principal Documentary Standard Scientist responsible for General Chapter <711>, with any additional questions about the General Chapter and the PVT procedure. [General Chapter <711> FAQ’s: https://www.usp.org/frequently-asked-questions/dissolution]