MEETING DISSOLUTION REQUIREMENTS PROBLEMS OF VARIABLE CONTROL IN DISSOLUTION TESTING

The dissolution profile data from the pivotal clinical batches and primary (registration) stability batches should be used for the setting of the dissolution acceptance criteria of your product (ie, specification-sampling time point and specification value).

1. MEETING DISSOLUTION REQUIREMENTS, PROBLEMS OF VARIABLE CONTROL IN DISSOLUTION TESTING PRESENTED BY-MUKESH KR BHAGAT DEPARTMENT OF PHARMACEUTICS 2 ND SEM M.PHARM ABMRCP, Bangalore

2. MEETING DISSOLUTION REQUIREMENTS According to the Code of Federal Regulations (CFR), a drug product application should include the following specifications necessary to ensure the I dentity, Strength, Quality , P urity, Potency, Bioavailability of the drug product, including , and acceptance criteria relating to, dissolution rate in the case of solid dosage forms .

3. Dissolution acceptance criteria For the selection of the dissolution acceptance criteria, the following points should be considered: 1.The dissolution profile data from the pivotal clinical batches and primary (registration) stability batches should be used for the setting of the dissolution acceptance criteria of your product ( ie , specification-sampling time point and specification value). A significant trend in the change in dissolution profile during stability should be justified with dissolution profile comparisons and in vivo data in those instances where the similarity testing fails

4. 2. Specifications should be established based on average in vitro dissolution data for each lot under study, equivalent to USP Stage 2 testing (n = 12 ). 3. For immediate-release formulations, the last time point should be the time point where at least 80% of drug has been released. If the maximum amount released is less than 80%, the last time point should be the time when the plateau of the release profile has been reached. Percent release of less than 80% should be justified with data ( eg , sink conditions information)

5. 4. For extended-release formulations, a minimum of three time points is recommended to set the specifications. These time points should cover the early, middle, and late stages of the release profile. The last time point should be the time point where at least 80% of drug has been released. If the maximum amount released is less than 80%, the last time point should be the time when the plateau of the release profile has been reached . 5. The dissolution acceptance criterion should be set in a way to ensure consistent performance from lot to lot, and this criterion should not allow the release of any lots with dissolution profiles outside those that were studied clinically.

6. The term Q means the amount of drug dissolved within a given time period established in the drug product specification table and is expressed as a percentage of label content. For example, a value of Q = 80% at 30 minutes means that the mean percent dissolved of 12 units individually tested is at least 80% at the selected time point of 30 minutes. when implementing dissolution as a quality control tool for batch release and stability analysis, the testing should follow the recommendations listed in the USP method <711> for immediate-release dosage forms and <724> for modified-release dosage forms.

7. For example, for Stage 1, which considers the testing of 6 units, each unit must meet the criterion of not less than 85% at 30 minutes for a drug product whose acceptance criterion was set to Q = 80% at 30 minutes . Testing should continue through the three stages (S1, S2, S3) unless the results conform at either Stage 1 or Stage 2 (Table 15-9)

8. The USP-NF monographs may have multiple dissolution tests for generic drug products that are approved by the FDA as therapeutic equivalents. Although both the brand and approved generic drug products are bioequivalent, their in vitro dissolution profiles may be different . Ideally, both methods should have very similar discriminating ability; however, this can only be determined when an IVIVR or an IVIVC has been established for the drug products rending the method not only discriminating but also predictive of in vivo performance.

9. PROBLEMS OF VARIABLE CONTROL IN DISSOLUTION TESTING The source of deviation from accurate results in dissolution test can be broadly classified into following categories: A. Equipment Related Factors B. Process Related Factors C. Drug Substance Properties Related Factors D. Drug Product Properties Related Factors E. Miscellaneous Factors

10. A. Equipment Related Factors Dissolution equipment is a machine. The initial quality of the device and its subsequent care and maintenance will influence both operational reliability and product dissolution rate results. A discussion of the dissolution equipment is important as the dissolution rate is generated by the stirring mechanism interacting with the dosage form in the media. The environment in which it operates will affect performance, and it needs to be running properly at all times Some of the parameters associated 1. Dissolution Test Vessel 2. Paddle/ Basket Shaft 3. Vibrations 4. Use of Filters 5. Calibration of Dissolution Vessel

11. Dissolution Test Vessel: Dissolution testing is an attempt to create a perfectly controlled space, with a hydrodynamically consistent environment. “Ideally the upper portion of each vessel would be perfectly cylindrical, and its bottom would be a perfect hemisphere. They are made one at time by manually blowing a molten mass of glass into a molds . As a result, the vessels are not uniform with respect to weight, height, cylindrical shape, hemispherical curvature, and inner diameter. The inside surface of each should be inspected for abnormalities.” Some have concluded that a major source of dissolution result variability appears to be the geometric parameters of the dissolution vessel and stirring mechanism. A precision vessel (Takao, Japan) was manufactured by a new glass processing technology and displayed an almost ideal inner shape consisting of a cylinder and hemisphere. In contrast, two conventional vessels, vessel A (manufacturer A, Japan) and vessel B (manufacturer B, USA), exhibited distortion and unevenness in various places. The vessel bottoms in particular deviated from the ideal hemispherical shape, and curvature among vessels differed widely. The inside of the cylinder of these two manufacturers' vessels also deviated from the ideal circular shape.

12. The dissolution results of USP Prednisone Calibrator tablets were compared for the precision vessel and vessel A. For vessel A, however, test results varied widely between vessels used and between positions in the dissolution tester. In addition, the mean values of prednisone dissolution percentages obtained from six positions differed significantly (p < 0.05) among vessels. These results suggest that the shape of a glass vessel is critical to obtaining unvarying and reproducible dissolution test results . 2. Paddle/ Basket Shaft: Close inspection of USP apparatus I & II before use can help identify sources of error. In both cases, shafts must be straight and true. The paddles are sometimes partially coated with Teflon. This coating can peel and partially shed from paddle, causing flow disturbance of hydrodynamics within the vessel. Paddles can rust and become nicked and dented; this can adversely affect dissolution hydrodynamics and be a source of contamination .

13. Two types of basket shafts are commercially available to the analyst. One type has an O-ring inset in the disk at the end of the shaft with the basket fitting around the O-ring. The other has three clips attached to the disk at the end of the shaft . The basket is attached by fitting between the clips and the disk. There was no difference between the two basket shaft types for the three development products. The difference showed a higher dissolution rate using the clipped basket shaft design. The clipped basket shaft is the official USP design; however there are some drawbacks to this design. The clips protrude and disturb the fluid flow in the vessel. 3. Vibrations : Vibration is a complicated concept that can result in the addition of energy to a system. The addition of energy from an external source can alter the results of a dissolution evaluation. Such an alteration is an unacceptable source of error that must be minimized. As far as USP is concerned it has been noted that there is brief mention of vibrations requirements consisting of statement that "No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smoothly rotating stirring element " .

14. 4. Use of Filters: Most current dissolution procedures require samples to be withdrawn from the vessel, the exception being when the concentration is determined in situ with fiber optics. No matter whether the sample is withdrawn manually or automatically, effective filters are necessary to prepare the sample for analysis; otherwise, undissolved material from the medium could influence the results. All of the filter materials available on the market for dissolution testing may not be equally suitable for this task. For example, it is important that filter materials should have little or no tendency to adsorb the drug, since adsorption to the filter will result in out-of-specification results. 5. Calibration of Dissolution Apparatus: The process by which a test apparatus is determined to meet the compendial (dimensional and operational) specifications has been termed mechanical calibration, while the use of reference standard tablets is given the designation chemical calibration. Chemical calibration allows a final and summative confirmation of the suitable operation of the integrated dissolution assembly, beyond the evaluation of its separate component attributes (e.g., stirring element dimensions, control of rotation speed, dissolution medium volume).

15. B. Process Related Factors The dissolution test should not be considered as absolute analytical procedure. It is always comparative, whether as a bioequivalence test assessing different formulations, as a stability test comparing stored products with the original one, or as a quality control test comparing different batches against previously established limits. As a comparative test procedure, the consistency and reproducibly of both the analytical equipment itself and the techniques used are essential . Various factors associated with dissolution test procedure that may lead to errors: 1. Use of water as dissolution media 2. Sample introduction 3. Single point Vs multiple point sampling 4. De- airation of media 5. Controlled release dosage forms Use of Water as Dissolution Media: Many compendial dissolution tests specify water as the dissolution medium. When dissolution procedures were first being added to themonographs , the default "First Case" was usually specified. This consisted of 900 mL of water as dissolution medium with USP Apparatus 1 (Basket Method) at 100 rpm, or later, USP Apparatus 2 (Paddle Method) at 50 rpm. Products not meeting the "First Case" tolerance specification of NLT 75% "Q" in 45 minutes using this method was asked to submit data for a new procedure.

16. 2. Sample Introduction: Sample introduction can be tricky and unfortunately at times, not easy to perform reproducibly. Products can have a dissolution rate that is “position dependent”. For example, if the tablet is offcenter , the dissolution rate is high due to shear forces or if it is in the centre, coning may occur and dissolution rate will go down. Film coated tablets can be sticky and pose problems related to tablet position in the vessel. Suspensions can be introduced in a variety of ways. Some examples are to manually use syringes or pipettes, pour from beaker, or automate delivery using calibrated pipettes. Each method has its own set of limitations. Mixing of the sample will generate air bubbles; therefore, the mixing time of suspension samples must be strictly uniform to reduce biased results. 3. Single Point Vs Multiple Point Sampling : A seemingly robust and discriminating method can present unexpected results based on the number of sampling time points and sample withdrawals. A s in a “profile” experiment (typically used in the R&D or stability testing environments) versus a single-pull (typically used in the QC environment), resulted in different dissolution rates. It is believed that this discrepancy is a result of a greater disturbance of the fluid hydrodynamics in the dissolution vessel caused by the additional insertions and residence of the sampling probe in the vessel during multi-point sampling. This may be due to hydrodynamic effects that can potentially influence in vitro dissolution results. Additional examples in the literature suggest that the hydrodynamic conditions, drug release pattern, or mechanical forces of an in vitro dissolution are crucial to the drug release rate.

17. 4. Deaeration of Media: The level of dissolved gases is related to the presence of bubbles. Bubbles are common and will cause problems in non- deaerated medium. I t is stated that bubbles can interfere with dissolution test results and should be avoided. Dissolved air can slow down dissolution by creating a barrier; either adhering to tablet surface or to basket screens or particles can cling to bubbles on the glass surface of the vessel or shafts. 5. Controlled Release Dosage Forms The current trend is to evaluate each and every sustained or controlled release dosage form on individual basis. The formulation scientists and regulatory authorities face an enormous challenge of generalising the test conditions for dissolution testing because most individual drug candidates for sustained or controlled release dosage forms and their delivery design possess diverse physicochemical and pharmacokinetic properties requiring specific considerations. The difficulties are also in simulating in vivo conditions in in vitro . Since most sustained or controlled release preparations are designed for prolonged release and therapeutic effect, variabilities in in vivo conditions (such as presence and nature of food in the gastrointestinal tract, time of the day the dosage form is administered) which can substantially affect the release profile of the drug are bound to happen.

18. 6. Automation : While automation of dissolution sampling is very convenient and labor saving , errors often occur with these devices because the analysts tend to overlook problem area. Sample lines are often a source of error for a number of reasons: unequal lengths, crimping, wear beyond limits, disconnection, carry-over, mix-ups or crossing and inadequate cleaning. Pumping tubes may wear out through normal use or repeated organic solvent rinsing and may necessitate replacement . C. Drug Substance Properties Related Factors Knowledge of drug properties like solubility of drug, effect of pH change, crystalline structure is important. One could anticipate precipitation of the drug as the pH changes in solution, or if release from the dosage form leads to supersaturation of the test media e.g. preparation of a standard solution may is an important step. It is customary to use a small amount of alcohol to dissolve the standard completely . A history of the typical absorptivity range of the standard can be very useful to determine if the standard has been prepared properly.

19. D. Drug Product Properties Related Factors Dissolution profile may help in identifying trends and effects of formulation changes. When the results are highly variable, it indicates that the method is not robust. Two major casual factors influence variability: Mechanical and Formulation. Mechanical causes can arise from the dissolution conditions chosen. An apparatus or speed change may change the results. The formulation can have poor content uniformity, additionally, reactions and/ or degradation may be occurring in situ . The film coating may cause sticking to the vessel walls. Upon aging, capsule shells are known for the pellicle formation and tablets may become harder or softer, depending upon the excipients and drug interaction with moisture, which in turn may affect the dissolution and disintegration rate .

20. E . Miscellaneous Factors Personal Errors: Anomalous dissolution usually involves some of following observations: floating chunks of tablets, spinning, coning, mounding, gumming, swelling, capping, off- center position, sticking, particles adhering to apparatus or vessel walls, sacs, swollen/rubbery mass. A well trained analyst can pinpoint many of such problems. Along with good documentation, familiarity with the dissolution behavior of the product is essential in quickly identifying changes in stability or changes associated with a modification of the formulation . 2. Cleaning: The analyst should take special care to examine this aspect when validating the method. In many laboratories, where different products are tested on the same equipment, this is a critical issue that, if inadequately monitored, may be a cause of inspection failures.

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