USP provides Reference Standards (Abbreviated by RS symbol) for drug substances. In practical terms their purpose is to provide a goal post or reference against which purity (quality) of drug substances, and then drug products, be established. An RS comes with its own purity certificate, established independently by different analytical tests. These RS compounds are used extensively for qualification, development and then validation of analytical methods such as chromatographic or spectrophotometric. In addition, for cost/expense savings, often these standards are used as primary standards for developing in house secondary standards.
As stated above, these standards are used for various purposes utilizing numerous analytical techniques, such as HPLC, TLC, GC, GC/MS, and other much more involved analytical techniques. However, they are not described as performance evaluation standards or faults/deficiencies detectors of the apparatuses, such that these standards are to be used to indicate deviation/variations in diameters of the glass capillary or HPLC columns, flow rate of mobile phase (gas or solvent) through columns, temperatures of oven or enclosures of columns, or the training/expertise of the analysts. It is usually understood that if the apparatuses are operating under their expected physical and operational specifications in the hands of experienced and trained analysts, then their output using RS would be exactly as described in the certificate of analyses. If not, then necessary corrective measures are to be taken, which may or may not be relevant to the technique itself. For example, purity or composition of the mobile phase, instability of electric current may cause out of spec results or performance of apparatus. This does not mean that the RS will become a performance evaluation procedure for solvent purity or stability of electric current or related circuit boards.
With this background, if one sees the current practices of Performance Evaluation Test or Tablets (PVT) which are also marketed by the USP as Dissolution RS Tablets, these tablets do not appear to meet the requirement of a reference standard. The reasons are: (1) Dissolution RS Tablets release values are not independently determined. The values are set, using the apparatuses which are then assessed by the use of these tablets. (2) The RS tablets have different values for different apparatus (e.g. Basket and Paddle). PVT must have the same values for all commonly referred apparatuses, Basket, Paddle, Reciprocating, Flow-through, and any other apparatus or technique suggested in the future. This is similar to the current practices for other RS standards, which are expected to provide the same results (purity) whether tested by UV, TLC, HPLC, GC and others. (3) These PV Tablets do not have desired outcome characteristics. As the dissolution testers are used to establish potential drug release quality/characteristics of products in humans, therefore, the RS tablets should have known release characteristics in humans independently determined e.g. based on pharmacokinetic studies. (4) Similarly, the RS Tablets should also be from an approved product for human use and within its shelf life duration.
It is hoped that the suggestion will help in developing improved RS Tablets and will alleviate the difficulties one faces in using current Performance Evaluation Tablets.
In the absences of appropriate RS tablets, one may evaluate and establish operational parameters of the apparatus based on relative dissolution testing. In this case, one may analyze two products of know release characteristics in humans of the same API product such as IR and ER. Both products should provide differential drug release characteristics within their recommended (prescription) dosage intervals. Based on such testing, the operational parameters of the apparatuses are set (fixed), which would be used for testing the test product. The product(s) used to establish or determine the operating parameters for the apparatuses would become the RS Tablets.
