OR WAIT null SECS
Industry, equipment vendors, and regulators are busy refining the precision and reliability of dissolution testing.
Solid dosage formulators rely on dissolution testing to mechanically model the biological conditions of drug release in the body. For quality control, analysts use dissolution studies to ensure product and process consistency. Although the objectives of these two groups are different, both are developing means to improve testing methodologies and ensure results are reliable.
ILLUSTRATION BY M.MCEVOY. IMAGES: ELECTRODES- DON CARSTENS/GETTY IMAGES, WIRE-GEORGE DOYLE/GETTY IMAGES
For the most part, the industry is not in disagreement with the usefulness of current dissolution testers. Roy Hanson, CEO of Hanson Research (Chatsworth, CA), estimates over 80% of dissolution work is conducted using either US Pharmacopeia (USP) Apparatus 1 (basket) or Apparatus 2 (paddle), with the paddle method perhaps being more popular because of its ease in set up. (Apparatus 3 involves the use of biodisks to study extended-release dosage forms designed to release the active pharmaceutical ingredient according to pH; and Appartus 4 is a flow-through cell unit that some analysts believe is more representative of the gastrointestinal tract because it provides a constant flow.)
Nor is there much disagreement regarding the general regulatory guidance of dissolution testing. According to Lucinda Buhse, PhD, Director, Division of Pharmaceutical Analysis, at FDA's Center for Drug Evaluation and Research (CDER), the Pharmacopeia Discussion Group (comprising USP, European Pharmacopeia, and Japanese Pharmacopeia) has harmonized the USP dissolution test general chapter ‹711› (1). Instead, much of the current discussions among regulators, manufacturers, and equipment vendors are centering on making dissolution testing more clinically relevant, implementing the US Food and Drug Administration's quality by design (QbD) principles, and reaching an agreement on equipment calibration and qualification.
Evolution of dissolution equipment
QbD and biorelevance
To bring QbD principles to dissolution testing, FDA and industry are focusing on the development of biorelevant specifications, which requires that dissolution tests also be clinically relevant. "I've seen clinical studies where they have shown differences in drug release due to age, gender, diet, race, whether a patient is in a fed or fasted state, and many other factors that come into play for how a specific individual may assimilate a medicine at a given point in time," says Hanson.
Developing a design space of critical attributes that are related to the dissolution test methodology and linking this space to the level of product quality has become a formidable task (2). Christine M.V. Moore, PhD, acting deputy office director of CDER's Office of New Drug Quality Assessment points out that in the past year, there were several workshops and conference sessions on QbD in biopharmaceutics. "We expect continued dialogue on this subject. Already we are seeing some companies apply QbD approaches to better understand the link between product characteristics and its performance. Additionally, we are seeing some companies use modeling approaches to relate product quality attributes and process parameters with dissolution as a way to facilitate real-time release testing."
Figure 1: Rigorous mechanical calibration has been proposed as a replacement for the need to conduct performance-verification testing. IMAGE COURTESY OF HANSON RESEARCH.
Some scientists are focusing on the characteristics and properties of the particular dissolution media (3, 4). Media containing biosalts, for example, that can imitate the fed and fasted state or of the gastric juices or intestinal fluid are making a lot of progress, according to Vivian Gray, owner of V.A. Gray Consulting (Hokkesin, DE). "Media is a very critical component. There's a good stream of communication and learning going on right now about media and the composition of media," says Gray. FDA recently collaborated with the University of Wisconsin on a workshop that focused on applying QbD in dissolution, including the rationale for choosing dissolution media.
Other work has focused on modifying the dissolution equipment (5). According to Hanson, some university laboratories have developed complex prototypes of equipment that more closely mimic biochemical and biomechanical actions, subjecting the drug through acid pH stage, a peristaltic action, a different pH, and a peristaltic flow that's more like the intestinal tract. "However, it may take a while for a very complex system to give results that are reproducible and not extremely variable," says Hanson. "Honestly, probably what we have right now [in equipment], with some work on the media and the agitation rate and so forth, we can come up with the appropriate relevant test."
Figure 2: A bathless unit incorporates heating jackets for each vessel and a control system that communicates the temperature of each unit. IMAGE IS COURTESY OF DISTEK
Another notable debate right now that will affect manufacturers, analysts, and regulatory agencies deals with the calibration of dissolution equipment. An industry accepted recommendation is to calibrate the equipment every six months, and for many years, the industry practice was to conduct both a simple mechanical test and a chemical test. The mechanical calibration test evaluated parameters such as centering, temperature, and rotation speed. The chemical calibration test (i.e., now called a performance verification test) used USP calibration tablets (now performance-verification standards).
However, recently there has been a push from industry, regulatory agencies, and other collaborative groups to eliminate the chemical calibration portion of the testing. Some believe it is sufficient to forego the performance test and run a rigorous mechanical check of the instrument. One of the suggested is the accepted standard ASTM E2503-07, "Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus). Mechanical calibration would involve system evaluation of various points through the dissolution instrument with appropriate measurement tools and documenting all set-up parameters (e.g., centering of the vessel, the straightness of the shaft of the paddle, and the proper depth position).
One reason in favor of only requiring mechanical calibration is that it is a routine that is faster than running performance tests. Performance tests are run with a group of six samples (sometimes extra if the method calls for a control or blank). Testing takes at least a couple of hours, says Hanson, and it may be expensive to devote a piece of equipment and an analyst for a long period of time, instead of having the analyst do something more productive. Sometimes, if there is variation in the test results, tests take an even longer period of time to complete.
FDA is not opposed to the idea. The agency has released a draft guidance related to the mechanical calibration of Apparatus 1 and 2, which says a firm can use an "appropriately rigorous method" of mechanical calibration (6). One example of a rigorous method is CDER's "Mechanical Qualification of Dissolution Apparatus 1 and 2" procedure that is used by its Division of Pharmaceutical Analysis (DPA, St. Louis, MO) to set up, calibrate, and maintain its dissolution units. DPA procedures suggest reviewing vessel, paddle, and basket dimensions. In addition, the calibration portion of this document includes measurements of the following: shaft wobble, paddle and basket shaft verticality, basket wobble, vessel centering and verticality, basket and paddle depth, and rotational speed.
According to the FDA draft guidance, the use of USP calibration tablets can lead to variability in the dissolution measurement system. Specifically, the document states, "The newer USP [prednisone] 10-mg tablet tends to give lower dissolution results with the paddle method and higher results with the basket method over time." Moreover, other studies have been conducted on the variabililty of USP prednisone reference standard tablets (7). The variability in the USP calibrator tablets led the agency to develop the guidance for mechanical calibration.
In addition, according to Buhse, the draft guidance would "meet or exceed" the criteria for mechanical calibration proposed in USP General Chapter ‹711›. "The dissolution test general chapter is part of the ICH Q4B (Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions) work plan, but a final annex describing how this chapter can be used as interchangeable in the ICH regions is still pending publication of final versions of the chapter by the pharmacopeia," says Buhse.
Other groups also have stated their opinion, including the International Pharmaceutical Federation (FIP), which published a white paper titled "FIP Position Paper on Qualification of Paddle and Basket Dissolution Appartus." "The phrase that caught my attention," says Hanson, "says 'any strict requirement on the use of a specific performance verification test tablet is not recommended at this time.'"
But decisions on the "correct" physical specifications for the equipment are still under discussion. Gray points to the vessels, for example. "It is well known, within the past five years, that vessels can be malformed. They can be made improperly or differently so that a different vessel can have hydrodynamic forces that affect the dissolution." One of the efforts USP has been involved is to make the vessel dimensions more uniform by developing specifications of the dimensions. "This is a big effort that would affect dissolution equipment providers, so you can't go fast with something like this," says Gray. FDA also has a task force looking into the effects of vibration of the equipment, how it may introduce variability, and how it might be corrected. "The demands are up for better methods and people are really paying attention to it," says Gray. "In this way we will understand more about what is going on with dissolution tests and how we can improve it and understand it."
Despite all the work on defining mechanical specifications, the industry doesn't appear to be ready to eliminate chemical calibration altogether. A dissolution testing group from PhRMA, developed an enhanced mechanical calibration and conducted a collaborative study, says Gray. This study showed the performance verification test tablets still had some value because there are some aspects about the equipment that can't be picked up accurately through a mechanical method. According to Gray, a lot of studies have shown that current performance verification standards are very sensitive to the attributes of the equipment that can't be picked up mechanically. "That doesn't mean that someday it won't all be picked up mechanically, but at the moment we are not there yet."
Hanson agrees, "In reality, laboratories are mostly still using the performance verification tablets because they aren't confident that the mechanical calibration will pick up any problems with their equipment. And the bottom line is the onus is on their shoulders." Chemical calibration captures some of the what-ifs, he says, such as analyst error, spectrophotometers set up incorrectly, dirty flow cells, and so forth. "However, as mechanical calibration improves, my sense is that industry is going to move away from chemical calibrator tablets and move toward rigorous mechanical calibration."
An alternative option to the chemical calibration method that has been suggested is to give companies the choice to develop and use an in-house standard for performance verification. Currently USP has provides prednisone tablets for chemical calibration. The tables come with a certificate that indicates the range of results that should be obtained if a test is performed in a certain way with these tablets. An in-house tablet to use in performance-verification studies that would replace the commercially available performance tablets would have to have prove that it is as sensitive to problems with the equipment (e.g., vibration, centering, vessel asymmetry). The in-house standard also would have a method developed around it, which is not easy to do. "There may some Big Pharma companies that have done it, but I don't see it as an easy option for contract laboratories and smaller companies," says Gray. "It would definitely be work to come up with an in-house standard and my question would be, why devote those resources when you have a proven performance-verification standard already available?"
Dissolution equipment has changed significantly since the 1970s (see sidebar, "Evolution of dissolution equipment"). Equipment vendors continue to incorporate automated systems in their dissolution instruments, especially in the collection and sampling, which are controlled by user interface systems on the units. Sophisticated equipment configurations are connected to a computer with dissolution software running the tests. "I think as time goes by you are going to see that more. You can archive all of your methods, cross reference, and download into your instruments," says Hanson. "You'll never be able to cut out analysts, but you will definitely be able to make their lives easier."
Those who engineer dissolution equipment are also working on extending drug-release analysis to other dosage forms such as skin permeation products, ointments, creams, stents, patches, and implants, including those with microchips (8). But does this really qualify as dissolution? "If you take the strict definition of dissolution in USP, maybe not," says Hanson. "But if you consider the general definition of dissolution to be testing the release rate of a pharmaceutical dosage delivery vehicle, then that maybe something we see on the horizon."
1. USP 28–NF 23, General Chapter ‹711› "Dissolution," 2412–2414.
2. C. Sinko, "Quality by Design and Dissolution," presented at the Advisory Committee for the Pharmaceutical Science, Oct. 25, 2005, available at http://22.214.171.124/search?q=cache:f_JEWzBgEaEJ:www.fda.gov/ohrms/dockets/AC/05/slides/2005-4187S1_05_Sinko.ppt+dissolution+qbd&cd=3&hl=en&ct=clnk&gl=us, accessed Sep. 1, 2009.
3. E. Jantratid and J. Dressman, "Biorelevant Dissolution Media Simulating the Proximal Human Gastrointestinal Tract: An Update," Dissol. Technol. 21–25 (Aug. 2009).
4. H. Jogia, T. Mehta, and M. Patel, "Evaluation of Dissolution Media Containing a Novel Synthetic Surfactant by In Vivo Testing of BCS Class II Drugs," Dissol. Technol. 14-19 (Aug. 2009).
5. W. Qingxi, N. Fotakl, and Yun Mao, "Biorelevant Dissolution: Methodology and Application in Drug Development," Dissol. Technol. 27–30 (Aug. 2009).
6. FDA, Draft Guidance for Industry: The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2, Current Good Manufacturing Practice (Rockville, MD), Oct. 2007.
7. W.W. Hauck et al. "Variability of USP Lot P Prednisone Reference Standard Tablets," Pharm. Technol.32 (7) 24–33 (2008).
8. FIP workshop, "In Vitro Release of Special Dosage Forms," Oct.20-21, London, England, http://www.fip.org/www/index.php?page=ps_sig_invitro, accessed Oct. 2, 2009.