Challenges to the Dissolution Test Including Equipment Calibration

The dissolution test has been under scrutiny in several areas: the quality-by-design initiative has called for the end to dissolution testing along with all end-product testing (1–3); there is a push for more clinically relevant specifications (4); the potential flaws in the hydrodynamic fluid flow patterns from the vessel and paddle interaction are being examined closely (5–8); and the use of the calibrator tablets has been questioned (9).

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The US Food and Drug Administration's quality-by-design and process analytical technology (PAT) initiatives urge manufacturers to know their drugs and drug products much more thoroughly than is the present practice. Nothing is more disheartening than a significant change in the dissolution results on stability of a Phase III product or on a release batch of a commercial product—especially when no assignable cause is forthcoming. The increased knowledge expected from PAT may prevent these "surprises," and that would be a welcome change. The dissolution test is sensitive to a nearly infinite number of parameters, from characterizations of the drug to formulation changes to, most importantly, manufacturing parameters. The dissolution test's ability to show changes in so many parameters is its power and its frustration. The power of the test outweighs the frustration for one simple reason: the dissolution test is the only test that has some degree of relevance to the drug's therapeutic effect in vivo.

Eliminating dissolution as an end-product test would be problematic from several angles. Can you be sure in-process testing has detected all of the many sources of potential change in the final product? How do you measure the stability of the finished product unless you test it at release and then over its shelf life? What is the value of eliminating a proven indicator of stability?

The push for more clinically relevant dissolution specifications and methods is laudable, and in this effort, the method-development stage is particularly critical. Many a naïve manager has viewed the dissolution test as simple—until a problem occurs. Only then does the manager discover that the staff is too inexperienced to understand the test's nuances or sources of error (10). A separate dissolution-testing group is the optimal way to handle both dissolution-method development and routine testing. A group enables better training, accumulation of direct product experience, and useful collaboration. In addition, a separate laboratory devoted to dissolution testing will better avoid equipment problems stemming from vibration and other related issues.

Finding the appropriate method and specifications, especially with the typical low drug solubility, takes time and resources. Cutting corners at this stage is very risky. The robustness and variability of the method should be examined thoroughly. Guidance on method development is available in the literature (11, 12), FDA guidances (13–15), a new proposed informational general chapter from the US Pharmacopeia: ‹1092› The Dissolution Procedure: Development and Validation (16), the American Association of Professional Scientists In Vitro Release and Dissolution Testing Focus Group, books (17, 18), and Web sites that offer chat rooms, bulletin boards, or interactive questions and answers (19–21).

Variability should be examined early in method development. High variability is problematic, making trend analyses and F2 (similarity factor) calculations difficult. It is vital to isolate and understand the sources of variability. Observe the physical dissolution process for any anomalous stirring. The test should show gentle homogenous mixing. Note the hydrodynamic flow of the fluid and look for any coning (i.e., a concentrated gathering of excipients and drug under the paddle), tablet-sticking, air bubbles, or off-center placement of the dosage form, and examine the dissolution rate to see if a correlation exists. If so, the method developers should make every effort to minimize this anomalous behavior. At the method-development stage, all aspects of the mechanical or physical dissolution test that can affect the results should be illuminated and minimized, so that if a dissolution test failure occurs later on, the failure can, with confidence, be attributed to some change in the dosage form.

When the time comes to set specifications, the sponsor and FDA must collaborate to make the specifications appropriate. The specification must describe a very fine line, preventing bioinequivalent batches from passing, while not being so tight as to fail good (meaning fully effective in vivo) batches that may vary slightly. In some instances, a specification is borderline: over time, the product goes more and more to stage 2 retesting. Although batches may initially pass after retesting, this scenario may produce later failures and recalls. Again, special care should be taken to understand critical parameters and, in particular, the stability behavior of the product.

In later phases of the product's life, method development and validation should include robustness of the method and examining the aspects of the test (as opposed to the product) that may influence the dissolution rate results. Typical parameters such as temperature changes, changes in media concentration, basket attachment type, paddle height, changes in media pH, and many other aspects should be altered within small tolerance ranges to see if the dissolution rate is sensitive to them. Other factors—such as the presence of air bubbles or dosage form position in the bottom of the vessel—should be examined. This process helps in understanding where the method is robust and where it may be overly sensitive. Developers can expand test-method instructions or modify the test itself. The importance of the method development and validation stage cannot be overemphasized. It assists in knowing and characterizing the product well and even predicting the in vivo behavior when an in vivo–in vitro correlation is developed (22). Problems with variability, poor mixing, or fluid flow can usually be overcome with appropriate change in apparatus type, speed of rotation, sinkers, or even media choice.

A discussion of the dissolution equipment is important: the dissolution rate is generated by the stirring mechanism interacting with the dosage form in the media. But always be aware that the dissolution equipment is a machine. The initial quality of the device and its subsequent care and maintenance will affect both operational reliability and product dissolution rate results. Almost any industrial process will produce a lemon occasionally, and any machine will wear out over time. The environment in which it operates will affect performance, and it must be running properly at all times. Current practice requires calibrator-tablet tests every six months to assess the performance of the dissolution equipment.

Historically, calibrator tablets were developed because representatives from FDA, USP, and the Pharmaceutical Manufacturers of America (PhRMA) all agreed that vibration (internal and external) was affecting the dissolution results (23). In the late 1970s, the calibrator tablets were put in place and required in ‹711› USP General Chapter on Dissolution.

Today, we still cannot assess vibrational effects except by calibrator tablet tests. A PhRMA study (24) assessing the value of the calibrator tablets, concluded that "some type of calibrator tablets should be maintained until enhanced mechanical calibration is further defined (e.g., establishing a definitive vibration tolerance)." Equipment manufacturers have diligently designed testers that have less and less internal vibration. Even well-designed equipment that is used for years for 1, 8, or even 24 hours per day will eventually show signs of wear, however. In addition, the external environment can subject the equipment to vibration from heavy foot traffic, nearby construction, or nearby equipment, to name just a few sources. We must also acknowledge that not all equipment on the global market is designed solidly. With no mechanical means to test vibration other than calibrator tablets, eliminating them from the equipment performance assessment raises great concern. It is well documented that vibration affects the dissolution results (25–29); in some cases, vibration biases the results high, giving a false passing result. The consequences of false passing results should be of great regulatory concern.

Vessel asymmetry also is detectable by calibrator tablets. The glass dissolution vessel is not made from a mold but from a combination of individual hemispheres shaped from standard tubing (30). The irregularities in the vessel shape can cause a change in the fluid flow and change the dissolution results. FDA laboratory scientists pointed out this situation in a 1982 publication (31). Since then, other publications and practical laboratory experience have substantiated the finding (32). At this time, no available mechanical means of detecting flaws in the vessel design exists, although there may be some devices on the horizon. Until then, the calibrator tablets are the only appropriate tool for detecting this problem.

Some recent articles suggest that new apparatus for dissolution testing may give less variability and more homogenous mixing, and might even produce better correlations with in vivo performance of the product (33, 34). New technology has added to the utility of the dissolution test. Fiber optics have increased the automation of on-line testing. Premixed media also increase test efficiency. With novel dosage forms, the other official apparatus (3, 4, and 7) are becoming more suitable as are their modifications. Some performance tests for unique dosage forms may not use the official equipment at all; this is fitting and should not be resisted if the advantages are truly apparent. For immediate-release and extended-release dosage forms, however, Apparatus 1 and 2 can often provide appropriate methods with special care and study during the method-development stage. Approximately 700 compendial tests use the present apparatus for very large numbers of product brands. And, new products are constantly being approved with dissolution methods using Apparatus 1 or 2. The investment of resources and scientific data backing these apparatus is indisputable. Newly designed equipment must go through the same rigorous qualification and will be sensitive to the same parameters that affect the present equipment. Industry will resist a move away from the equipment it already owns. And the regulatory agencies have many times discouraged, from the podium, the proliferation of new equipment types.

Though these arguments may appear to support the status quo, this is not the case. A more thorough understanding of active pharmaceutical ingredients and finished drug products in the early development stages would undoubtedly benefit the industry. More careful training and analyst experience are of paramount importance to minimize sources of variability and maximize sensitivity to critical parameters during the method development stage. New equipment that significantly adds to generation of a proper in vitro release test is a worthy endeavor. Until appropriate mechanical means to detect vibration and vessel asymmetry are created, calibrator tablets are our best tools, though a search for better ways to characterize the equipment should continue.

Note

The American Association of Pharmaceutical Scientists' In Vitro Release and Dissolution Testing Focus Group will sponsor a workshop May 1–3, 2006, in Arlington, Virginia.

Vivian A. Gray is the president of V.A. Gray Consulting, Inc, Hockessin, DE. vagray@rcn.com.

References

1. J. Woodcock, "The Concept of Pharmaceutical Quality," Am. Pharm. Rev.7 (6), 10–15 (2004).

2. A.S. Hussain, "Quality by Design: Next Steps to Realize Opportunities," paper presented to the US Food and Drug Administration Advisory Committee for Pharmaceutical Science: Manufacturing Science Subcommittee, Sept. 17, 2003.

3. A.S. Hussain, "Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, a Look into the Future," paper presented at the USP Annual Scientific Meeting: The Science of Quality, Iselin, NJ, Sept. 26–30, 2004.

4. H. Zhang and L. Xu, "Dissolution Testing for Solid Oral Drug Products: Theoretical Considerations," Am. Pharm. Rev.7 (5), 26–31 (2004).

5. P.J. Missel, L.E. Stevens, and J.W. Mauger, "Reexamination of Convective Diffusion–Drug Dissolution in a Laminar Flow Channel: Accurate Prediction of Dissolution Rate," Dissolution Technol. 10, 6–15 (2003).

6. J. Kukura, J.L. Baxter, and F.J. Muzzio, "Shear Distribution and Variability in the USP Apparatus 2 Under Turbulent Conditions," Int. J. Pharm. 2004, 279, 9–17.

7. A.M. Healy et al., "Sensitivity of Dissolution Rate to Location in the Paddle Dissolution Apparatus," J. Pharm. Pharmacol. 54 (3), 441–444 (2002).

8. T. Mirza et al.,"Evaluation of Dissolution Hydrodynamics in the USP, Peak and Flat-Bottom Vessels using Different Solubility Drugs," Dissolution Technol. 12, 11–16 (2005).

9. L. Buhse, "Measuring and Managing Method Variability," paper presented to the FDA Advisory Committee for Pharmaceutical Science: Manufacturing Science Subcommittee, Oct. 25, 2005.

10. V. Gray, "Identifying Sources of Error in Calibration and Sample Testing," Am. Pharm. Rev. 5 (2), 8–13 (2002).

11. B.R. Rohrs, "Dissolution Method Development for Poorly Soluble Compounds," Dissolution Technol. 8, 6–12 (2001).

12. C.K. Brown et al.,"Dissolution Testing of Poorly Soluble Compounds," Pharm. Technol. 28, 56–43 (2004).

13. Dissolution Testing of Immediate Release Solid Oral Dosage Forms. Guidance for Industry (FDA, Center for Drug Evaluation and Research [CDER],Washington, DC, 1997).

14. Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations. Guidance for Industry (FDA, CDER, Washington, DC, 1997).

15. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on Biopharmaceutics Classification System. Guidance for Industry (FDA, CDER, Washington, DC, 2000).

16. USP Informational General Chapter ‹1092› "The Dissolution Procedure: Development and Validation," Pharm. Forum , 31, 1463–1475 (2005).

17. R. Hanson and V. Gray, Handbook of Dissolution Testing, 3 (Dissolution Technologies, Hockessin, DE, 2004).

18. J. Dressman and J. Krämer, Pharmaceutical Dissolution Testing (Taylor and Francis, Boca Raton, FL, 2005).

19. Dissolution Discussion Group, www.dissolution.com, accessed Jan. 16, 2006.

20. Dissolution Technologies, www.dissolutiontech.com, accessed Jan. 16, 2006.

21. Dissolution Solutions, www.dissolutionsolutions.net, accessed Jan. 16, 2006.

22. R.S. Uppoor, "Regulatory Considerations for In Vitro–In Vivo Correlations," Am. Pharm. Rev. 8 (5), 42–45 (2005).

23. A.C. Sarapu, A.R. Lewis, and M.F. Grostic, "Analysis of PMA Collaborative Studies of Dissolution Test Calibrators," Pharm. Forum, 6, 172–176 (1980).

24. PhRMA Dissolution Calibration Subcommittee. "Dissolution Calibration: Recommendations for Reduced Chemical Testing and Enhanced Mechanical Calibration," Pharm. Forum, 26, 1149–1166 (2000).

25. W. Beyer and D. Smith, "Unexpected Variable in the USP/NF Rotating Basket Dissolution Rate Test," J. Pharm. Sci. 60, 2350–2351 (1971).

26. W. Hanson, "Solving the Puzzle of Random Variables in Dissolution Testing," Pharm. Technol. 1, 30–41 (1977).

27. C.C. Collins, "Vibration: What Is it and How Might it Effect Dissolution Testing," Dissolution Technol. 5, 16–18 (1988).

28. K. Thakker et al., "Fine Tuning of the Dissolution Apparatus," Pharm. Forum, 6, 177–185 (1980).

29. B. Crist and D. Spisak, "Evaluation of Induced Variance of Physical Parameters on the Calibrated USP Dissolution Apparatus 1 and 2," Dissolution Technol. 12, 28–34 (2005).

30. P. Scott, "Geometric Irregularities Common to the Dissolution Vessel," Dissolution Technol. 12, 18–21 (2005).

31. D.C. Cox et al., "Systematic Error Associated with Apparatus 2 of the USP Dissolution Test II: Effects of Deviations in Vessel Curvature From that of a Sphere," J. Pharm. Sci. 71, 395–399 (1982).

32. M. Tanaka, H. Fujiwara, and M. Fujiwara, "Effect of the Irregular Inner Shape of a Glass Vessel on Prednisone Dissolution Results," Dissolution Technol. 12, 15–19 (2005).

33. J.L. Baxter, J. Kukura, and F.J. Muzzio, "Hydrodynamics-Induced Variability in the USP Apparatus 2 Dissolution Test," Int. J. Pharmaceutics, 292, 17–28 (2005).

34. S. A. Qureshi, "A New Crescent-Shaped Spindle for Drug Dissolution Testing—but Why a New Spindle?" Dissolution Technol. 11, 13–18, (2004).