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Dissolution is the chemical process by which a given solute dissociates into solvent, thereby forming a solution of some description. In the pharmaceutical industry, dissolution testing is used to predict in-vivo drug release behavior based on in-vitro tests. This can help determine the extent to which a compound integrates into its surroundings – which, in the case of pharmaceutical compounds, will likely represent human tissues – as well as gauge the speed with which it does so. These measurements are critical for assessing a compound’s bioavailability and establishing dosing, while ensuring therapeutic goals are achieved, and managing possible safety risks.
Dissolution is the chemical process by which a given solute dissociates into solvent, thereby forming a solution of some description. In the pharmaceutical industry, dissolution testing is used to predict in-vivo drug release behavior based on in-vitro tests. This can help determine the extent to which a compound integrates into its surroundings – which, in the case of pharmaceutical compounds, will likely represent human tissues – as well as gauge the speed with which it does so. These measurements are critical for assessing a compound’s bioavailability and establishing dosing, while ensuring therapeutic goals are achieved, and managing possible safety risks.
The correlation between dissolution rate and total body absorption of pharmaceutical compounds is generally thought to have been made in the 1960s, and in the following decade, dissolution tests had become a mandatory quality control tool for pharmaceutical labs. By the late 1990s, the FDA had issued additional guidances and direction regarding more specific requirements for labs. Today, dissolution testing is usually accomplished via mechanical calibration and quantification (“mechanical qualification,” MQ), or by performance verification testing (PVT) paired with mechanical qualification.
These different approaches to dissolution testing each come with their own challenges and benefits, which will be discussed in this paper, along with guidance on industry best practices for each approach.
The process of dissolution testing requires accuracy and precision, because these measures are what ultimately determine reliability of data. As a result, the process has become highly standardized, with guidance and oversight provided by entities ranging from the FDA (including cGMP) and USP in the United States to the ICH and ASTM globally. This oversight not only details specifics of the test process – for example, the USP has standardized the dissolution apparatus to include four parts: the basket, paddle, reciprocating cylinder, and flow-through cell – but also PVT for the tools themselves.
PVT, as a procedure, is intended to help determine the suitability and integrity of results from any apparatus used in drug dissolution testing. The results can then be compared to those of other labs on a global scale, ensuring the consistency that is set forth in pharmacopoeias and by the ICH. This focus on integrity of data collection aligns heavily with the recent industry shifts toward more robust audit trails and can prove challenging for labs.
In regard to general industry direction, most regulatory agencies have issued guidance that indicates labs need only to conduct qualification activities that involve mechanical calibration and quantification. This extends to installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ).
Not all labs adhere to this recommendation, however, and some have elected to use a combination of PVT and mechanical calibration. This style of testing is typically done on an annual basis, with additional mechanical quantification done every six months. Although more involved, this approach can help labs maintain a high degree of data integrity, which helps with everything from audit trails to new drug applications.
Mechanical qualification and PVT each have their benefits and drawbacks. Assuming the use of proper tools, MQ is much simpler and less time-consuming than PVT. While MQ can be completed in only a few hours, PVT can take days. This is due to PVT being a holistic test, which is beneficial in the sense that it can concurrently demonstrate variation in a number of parameters at once. PVT, unlike MQ, can also take into account “hidden” issues such as those in the testing environment. While this feature is helpful in providing a comprehensive approach to testing, it also makes the testing process longer and more complex.
The increased complexity of PVT must take into account USP standards and tablets, and requires assessors to undergo special training and certification. This is expensive for employers and time-consuming for employees, who then go on to spend additional hours overseeing the longer-duration PVT tests versus MQ. Due to the complexity of PVT, failure is very common amongst first-time analyzers, and unfortunately the failures can be hard to pinpoint or explain.
Unacceptable results can stem from any number of contributors, from improper assembly and operation of the dissolution apparatus to outright procedural deviations. Due to the vast amount of data obtained during PVT, analysis of failure may then lead to long investigations. For this reason, industry experts point out that it is often helpful to have the oversight of those with a strong background in dissolution testing and PVT when making a first attempt.
MQ, for all of its relative simplicity, does not come entirely without challenges and drawbacks. For starters, it relies on stringent specifications that may not be supported by older equipment – even if this same equipment was able to pass PVT testing. A reliance on the tools being used is a common theme with MQ, as it can be prohibitively challenging to measure specifications without adequate tools, and measuring devices must be calibrated to an especially precise degree. MQ also does not take vibration into account, which, as discussed above, can lead to a greater degree of inter-test variability. This variability may lend itself to misleading conclusions, false trends, and the need for additional testing.
Beyond being prone to variability, the tools used in MQ to characterize dissolution are universally recognized as being expensive; part of this reason is their necessary complexity. There are many factors that influence drug distribution in the human body, and in order to capture these via in-vitro testing, the dissolution apparatus must be equally complex. Factors that can influence results include everything from mechanical measurement parameters (wobble, rotation speed, temperature, vibration) to human involvement (e.g., technique).
This expense is recognized more in the case of mechanical qualification testing than PVT, as MQ relies heavily on tools. Luckily, there are some options to help labs avoid this expense and maintain a high standard of data integrity, as detailed below.
There are a number of recognized best practices when it comes to enhanced mechanical calibration of dissolution apparatuses.
First, to ensure consistency, it is recommended that labs only use paddles, baskets, and vessels that have been issued a certificate of conformity. While this should be enough to qualify integrity, assessors are nonetheless also encouraged to demonstrate redundancy and check materials for damage prior to using them for calibration. Further, it is typically advised to not mix paddles, baskets, or vessels across different rounds of testing.
Next, it is recommended that maintenance is performed using a defined schedule, which has been identified as acceptable via thorough risk analysis. To this end, the lab environment itself is also of great significance when it comes to ensuring consistency of calibration testing; it is recommended that changes are not made to the testing environment without first completing an impact analysis. Should changes be necessary – whether it involves repairing tools, relocating equipment, or something else – experts suggest performing mechanical qualification afterwards.
As far as technique, it is particularly important to control sources of vibration, including shakers, mixers, vacuum pumps, fume hoods, and heater pumps. Vibration has recently been recognized as a strong contributor to variances in dissolution; therefore it must be consistently abated or conducted in an identical manner with each test if the goal is producing reliable results.
Finally, as mentioned earlier, it is important to conduct verification activities on a regular basis. This will allow issues to be identified earlier, and hopefully limit the impact they have on lab functions.
In regard to managing the expense of MQ versus technicality of PVT, some labs find it helpful to outsource certain aspects of their dissolution testing. This option can be particularly valuable in the case of MQ, as maintaining the software and tools for this process might prove overwhelmingly costly for labs.
Third-party vendors, being more siloed in terms of contribution to the dissolution testing process, are more likely to have the latest equipment (e.g., wireless tools to avoid environmental interference, which increases the stability of results) and place great value on its accuracy – indeed, they are hired for the specific purpose of ensuring that their clients meet the parameters set forth by the FDA, USP, cGMP, and ASTM.
Vendors can also help clients determine which requirements need to be met, and whether they may need to lean more heavily toward satisfying those from certain agencies than others (e.g. USP vs. non-USP). In addition, their highly-trained service engineers may be more privy to emerging industry practices and standards, given their work with numerous clients, which can help a lab alleviate any potential blind spots.
The best approach to dissolution testing ultimately needs to be decided on a lab-by-lab basis, taking into account factors such as cost of tools and whether staff have the bandwidth for additional training. However, whether a lab decides to go forward with mechanical qualification alone or a combination of PVT and qualification activities, it is always in their interest to adhere to best practices and industry standards. Having a foundational understanding of the differences between the processes, as well as associated benefits and drawbacks, can help lab management determine the right approach for their group and avoid common pain points associated with dissolution testing.
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