USP Dissolution Calibrators: Re-examination and …

1 6 DissolutionTechnologies| FEBRUARY 2005As part of an oral drug product specification, dissolutiontesting is exceptional in that it assesses performancefrom a number of perspectives. This type of testingprovides the formulator a range of indications from thesummative quality of their product manufacturing processesto a surrogate assessment of potential in-vivo performanceduring the product s lifetime. Calibration of Dissolution appa-ratuses is simply a demonstration of suitability for use in thattest and, in concept, is similar to system suitability determina-tions for other analytical procedures. Dissolution perfor-mance is measured by the rate of appearance of the drug insolution and many other variables are at work to produce anobserved Dissolution rate. In the Dissolution test the USPapparatus is merely the operational equipment source of thesample. The use of a standard tablet in Dissolution apparatuscalibration allows verification that the sample produced isrepresentative of what might be considered best providing standard calibrator tablets, the USP acceptsresponsibility for reproducible performance of the calibra-tors and for setting appropriate criteria for calibration.

2 TheUSP Dissolution calibrator program is continually undersurveillance and nurture by the Expert Committee onBiopharmaceutics, USP scientific liaison staff and a richcollection of volunteer stakeholders serving the dissolutiontesting community. The spirit and enthusiasm of this groupwill undoubtedly drive the scientific direction of the cali-brator program in the years of Dissolution Apparatus CalibrationDissolution testing is a powerful and discriminating tech-nique for evaluating the performance similarity of succes-sive lots of primarily solid oral dosage forms. Comparisonsof performance characteristics of a given product or amongvarious products require the test assembly to function in astandard and reproducible fashion. Dissolution failure is aleading cause of product recalls giving an added urgencyfor assurance that these test systems are suitably testing is an umbrella term that takes intoconsideration both the sample preparation and its subse-quent analysis.

3 The analytical procedures used to generatethe finished data reflect the high level of accuracy andprecision associated with modern instrumental , ensuring that the variation seen in the analyzeddrug concentration from multiple Dissolution samplesrepresents some intrinsic difference in the units tested andnot the cumulative effect of small differences in the dissolu-tion test environment presents a formidable challenge tothe test platform. Variation in stirring speed, environmentalvibration, and temperature are examples of perturbationsoccurring during testing that can affect the observed disso-lution rate. Similarly, deviations in the vessel dimensionshave been suggested as sources of variability in results (1).The long standing approach to Dissolution apparatus suit-ability by the USP has been to combine a sufficiently detaileddescription of the compendial testing apparatuses with ademonstration of suitable performance using reference stan-dard materials, the Dissolution calibrators.

4 The process bywhich a test apparatus is determined to meet the compendialdimensional and operational specifications has been termedmechanical calibration, while the use of reference standardtablets is given the designation chemical calibration allows a final and summative confir-mation of the suitable operation of the integrated dissolutionassembly, beyond the evaluation of its separate componentattributes ( , stirring element dimensions, control of rota-tion speed, Dissolution medium volume). It challenges thetest assembly to perform its designed function as a samplepreparation system. We believe that neither mechanical norchemical calibration alone is sufficient to adequately furnish arobust demonstration of system of the purely mechanical approach to calibra-tion recommend that this should not be done until aconcomitant tightening in the dimensional and operationaltolerances given in the Dissolution General Chapter <711>occurs ( , reduce tolerance on rotational speed from 4 %to 2 rpm).

5 However, we believe such suggested reducedtolerances are unfounded. Unless the current toleranceshave been evaluated and found in need of adjustment andthe proposed ideal tolerances are found to reduce the vari-ability in results, no basis for the change is warranted or canbe given. Regardless, any such study of the robustness ofthe Dissolution as a sample preparation procedure willrequire a standard material. It is doubtful that any source ofsuch a standard material other than the USP calibrators willbe found. We therefore recommend that until such a studycan be completed any attempt to set new tolerances iswithout RangesUSP conducts collaborative studies to determine expectedvalues when a new lot of calibrators is tested undercontrolled conditions by qualified laboratories. Typically,between 10 and 40 laboratories from all over the world agreeto participate. For each combination of Apparatus andNote The following represents the opinion of the chair and the staff liaison of the USP Expert Committee on Dissolution Calibrators: Re-examination and Appraisal Tom Foster 1and Will Brown 21 Chair of the USP Expert Committee on Biopharmaceutics2 Corresponding author, USP staff liaison, USP, 12601 Twinbrook Parkway, Rockville, MDemail: FEBRUARY 2005speed, the data is subjected to a nested random effectsmodel statistical method and the variance components frominter-laboratory, intra-laboratory, and inter-tablet sources areestimated.

6 The ranges are determined as an interval aroundthe mean of the data by adding or subtracting the product ofa standard deviation term (incorporating the several sourcesof variance) and a constant representing the probabilitydesired. Typically, a small fraction of the submitted resultswill fall outside of the ranges , individual data values obtained in a calibrationtest must fall within the range determined as describedabove. Acceptable results may fall anywhere within therange. The statistical methods used incorporate severalsources of error in estimating the range of acceptable sources of variation of results, inter-tablet intrinsicperformance variability and intra-laboratory variability, are ofinterest. The intrinsic performance from tablet to tabletwithin a production lot of calibrator tablets presents anunderlying source of variability in results. An argument hasbeen raised that the variability in intrinsic performance of theUSP calibrator tablets is so great that it exceeds the variabilityof performance of modern test Dissolution variability of results, which includes tabletperformance, is a significant source contribution to themagnitude of the calibrator ranges.

7 Clearly, a standard refer-ence material used to estimate the performance of a dissolu-tion test assembly must exhibit an intrinsic performancewith exceedingly low variability across the lot in variability of inter-laboratory values brings an effect ofsimilar magnitude to the width of the calibrator the effect of inter-laboratory variability in theranges without restricting the precision allowed in data fromall vessels in one assembly reduces the value of chemical cali-bration. A lack of precision in calibration results is an indi-cator of problems in the operation of the assembly andshould be used in the system suitability USP InitiativesSalicylic Acid non-disintegrating calibrator tablet has suffered image problems over its history. Fused and chippedtablets may be found in bottles from the current lot. Tocorrect this problem, USP staff has worked with a contractmanufacturer to blister pack individual tablets insucceeding lots of tablets and thereby eliminate the occur-rence of fused tablets.

8 We anticipate that improved manu-facturing and packaging procedures will dramaticallyreduce the number of flawed tablets Salicylic acid calibrator tablets have also been criticizedfor alleged insensitivity to perturbational variables relatedto Apparatuses 1 and 2. Evaluation of studies examiningthese criticisms has currently not warranted a recommenda-tion to remove the salicylic acid calibrator . Further study isnecessary and this is under consideration. Initial stages ofthe evaluation of the calibrator for its use in the calibrationof Apparatus 4, the flow-through cell, are underway by focus of the USP Project Team on Dissolution Calibratorshas been the concept of developing an ideal calibrator . Thecurrent reference standard for a disintegrating calibrator isthe 10-mg prednisone tablet. This tablet represents a modi-fication of the NCDA #2 tablets (see sidebar for discussion ofcalibrator tablet terminology) that have been shown to besensitive to several operational variables by the Division ofPharmaceutical Analysis of the FDA (2, 3, 4, 5, 6).

9 The ProjectTeam has recommended that USP attempt to reproduce a50-mg prednisone tablet that was distributed by USP as itsdisintegrating calibrator until 1999. In an effort to determineif NCDA #2, the current 10-mg USP reference standard, orthe reproduced 50-mg prednisone tablet, is of value as anapproximately ideal calibrator , the USP has committed toproduce a demonstration batch for each of the three prod-ucts and subject them to an abbreviated study of theresponse to perturbational variables for Apparatus 1 and 2in a head-to-head challenge. The variables under study willbe vessel symmetry, vibration, stirring element displace-ment (height), and wobble. The study is currently in theplanning calibrator and Side By Side USP Dissolution test implies the concomitant systemsuitability demonstration. Results of Dissolution testing mustbe obtained on a suitable apparatus. We encourage consider-ation of the following: in common with other analytical tech-niques such as HPLC, system suitability could be performedwith a minimal number of additional samples required, withvery little interruption of the workflow.

10 Same-day or near-daycalibration would increase the confidence in results andreduce the risk that quantities of data might be obtained onunsuitable apparatuses. In contrast, current Dissolution appa-ratus calibration interrupts the workflow from a test assembly,requiring a different medium and volume, and often adifferent apparatus speed for each of two separate calibratortablets. Most will agree that as currently designed, the calibra-tion cannot be performed with the implied frequency, hencethe present six-month interval between current calibration design requires two separateconditions per apparatus. We believe that the ideal cali-brator deployed side by side could give adequate controlwith only one test condition per apparatus. Ideally, theinvestment of time required should be reduced to the pointwhere it could be performed, if not daily, then at least morefrequently than current calibration | FEBRUARY 2005 Along with the time spent in calibration, the laboratoryrisks a failing result.