Drug recalls due to dissolution failures: What can be done?

Recall is an action taken by a firm to remove a product from the market. Recalls may be conducted on a firm’s own initiative or by FDA, MHRA request/ order. Pharmaceuticals companies such as Sun Pharma, Wockhardt, Dr Reddy’s Laboratories to name a few, have faced such drug recalls from the US FDA recently, as few of their anti-depressant, anti-cancer, anti-diabetes and hypertension drugs did not meet the ‘drug release dissolution specifications’ during the long-term stability studies.

Tablets and capsules taken orally remain one of the most commonly used means of providing treatment. Dissolution tests are commonly conducted to check the time taken for the active ingredient in a dosage form to release into the body and help predict how the drug performs inside the body.

The effectiveness of these drugs relies on the drug dissolving in the fluids of the gastrointestinal tract prior to absorption into the blood stream. The dissolution procedure is an important test both to evaluate safety , predict efficacy and stability with respect to manufacturing and storage conditions. Hence, carrying out dissolution studies on these dosage forms is crucial. Accelerated stability studies are conducted on tablets and capsules by storing them in extreme conditions over an extended period of time to help predict the behavior of medicines over their entire shelf life.

The drugs are marketed prior to the completion of these long-term stability studies with an understanding that the manufacturer will cooperate in recalling the medications if, they don’t meet specifications. Hence, it is important to understand the possible factors that can cause changes and failures in dissolution.

“Dissolution testing is a delicate marriage of man, machine and method, where even if one variable is neglected, it can render your test results useless,” said Amit Marfatia, Managing Director, Electrolab, a leading dissolution equipment manufacturer.

An increase in variability in dissolution testing makes it impossible to describe differences in product quality. Reducing variability in dissolution testing can help identify a batch not meeting specifications before it is marketed and may prevent a recall in the future. Variability in dissolution testing arises primarily from the human conducting the test (Man), the equipment used for the test (Machine), and the method undertaken for the test (Method).

PERFORMANCE OF DISSOLUTION TESTING

Man: An inexperienced or under qualified staff (analyst) may fail to understand the major difficulties occurring during dissolution studies. Regular training of all personnel (analysts and apparatus cleaning staff) may help raise awareness of the sensitivity of the process as a whole. A separate dissolution testing group with trained professionals is an optimal way to handle dissolution method development, routine testing and minimise the variability.

Machine: Variability resulting due to the equipment can be controlled by increasing the number of parameters during the verification process and tightening the tolerances. The pharmacopeial specifications are very broad and many manufacturers provide tighter tolerances to reduce variability within a dissolution test and between multiple dissolution testers.

The United States Pharmacopeia (USP) recommends performance verification testing (PVT) of all dissolution equipment prior to using the equipment. The accepted interval for the PVT is usually once in six months and equipment manufacturers offer third-party verification of the instrument as a service.

Industry experts agree that third-party PVT testing is an excellent risk minimisation tool allowing analysts to focus on their core competency. Experts also believe that it’s more important to implement third-party PVT testing in quality control and quality assurance laboratories. Several research publications have revealed that factors like paddle height, rotation speed, tablet-sticking, level of de-aeration and vessel type attribute to variability and dissolution failure. Vessel type and level of deaeration are reported to be the major causes of variability.

• Vessel geometry: In a study conducted by USP, vessels were shown to be the single largest cause for standard deviation variability (37.7 per cent contribution) (Eaton J., et al., 2007). Vessel related failures are correlated to the use of different vessel types on a single system, deliberate use of poorly manufactured ‘economy’ vessels, misalignment within the system and scratched or dirty vessels. While the majority of vessels available in the market meet USP specifications, but the specifications for vessels are very wide, allowing different manufacturers to create ‘within-specification’ vessels having a wide range of dimensions and geometry. When these vessels with asymmetric geometry are mixed, they often have different inter-vessel hydrodynamics due to the relationship of height, diameter, and hemisphere resulting in variable results. Economy vessels may appear to be of good quality to the naked eye, however, they usually do not have the same level of high quality found in vessels direct from the equipment manufacturers, and will show a wider percentage CV as well. Scratched and dirty vessels can also cause changes in the fluid flow pattern and hence change the dissolution results.

Aditya Saraswat, Director, Analytical, Lupin, mentions “Over the time, dissolution regulations have crept closer and closer to dissolution science, but still there is a significant room for improvement, with regards to vibration and vessel hemisphere.”

• Method: All marketed products have detailed and documented methods for dissolution testing. Most methods have their RRR’s (Robustness, Repeatability and Reproducibility) and variability well documented. However, sometimes as a time/cost saving exercise, some documented steps are not performed or changed without thorough evaluation. The methods are developed after careful consideration of a variety of variables and an omission/change of steps may have an adverse effect on the results of the dissolution test. As mentioned earlier, the level of deaeration of the dissolution medium is a critical method related factor contributing to variability of a dissolution test.
• Deaeration: It is the process which involves removal of air molecules from the dissolution medium. Several research articles have presented the adverse effect of the presence of air molecules in the dissolution media. Bubbles formed on the dosage form may provide a barrier to wetting and reduce the dissolution results, or can cause the dosage form to become buoyant which may change the dispersion characteristics of particles and aggregates.

In the USP study, not effectively deaerating the media was the single largest cause of variability in mean per cent prednisone dissolved (52.3 per cent contribution) (Eaton J., et al., 2007).

Gururaj V, Senior Scientific Manager, Biocon, states “Some laboratories do deaerate the media in part volumes with conventional process, and this can cause significant inter-vessel variability in the level of dissolved air in the media. It would then be important to measure the level of deaeration even with surfactant media, in each of the vessels before starting the dissolution test.”

Experimental studies revealed that, tests that used non-deaerated media experienced significantly higher failure rates than those that used deaeraeted media. Hence, the dissolution medium should be deaerated using a suitable deaeration technique and the level of deaeration should be recorded for each batch of dissolution media.

Multiple recalls of generic medications can sway public perception to believe that generics are not safe, which could reduce the usage of generics and increase the cost of providing healthcare. In addition, drug recalls for India’s high quality manufacturers of pharma products may adversely impact the world view of the safety of Indian-made pharma products and may reduce our pharma exports. Recalls also have an adverse impact on the financial health of the pharma companies costing them millions of dollars in lost revenue and much higher in their brand value. Close attention to multiple factors in manufacturing and quality control of medicines may improve the quality of medications and reduce the frequency of recalls.