A good partner will be able to offer sophisticated equipment, turnkey programs, and moreUnless your product is made and used within the same day, stability testing is required to demonstrate how long the product can be stored safely before it starts to degrade. It’s the science behind the expiration date.
In general, companies perform stability testing to look for evidence of degradation and the formation of impurities and to ensure that the active ingredients are still within specification. Tablets, oral medications, injectables, and topicals all need to demonstrate stability. Every formulation of the drug product must be tested, and each drug product is subject to a variety of tests.
Companies define the requirements for stability testing in each product’s regulatory submission. International Committee on Harmonization (ICH) guidelines recommend that all testing be performed at approximately the same time. This means that at every stability interval, samples must be pulled from storage and tested within a few days of the target date.
Fortunately, even stability programs that are run in house can be outsourced, so it is never too late to turn your stability testing over to a qualified partner.
Key ConsiderationsIn addition to maintaining a more consistent workflow in the lab, managers may choose to outsource stability testing to minimize the risk of transporting samples. Temperature excursions may occur while the samples are in transit from the stability storage facility to the lab for testing and then back into storage. These changes have the potential to affect the test results and, therefore, the projected expiration date of the product.
Contract labs with on-site stability storage eliminate this risk and reduce the time samples are outside their stability chambers. It is these same stability chambers that offer the most compelling reason for outsourcing: Purchasing, qualifying, and maintaining stability chambers can be an expensive proposition.
Both reach-in and walk-in versions of stability chambers must be continuously monitored for temperature and humidity, and there must be mechanisms in place to regulate the temperature and humidity so that each chamber operates within specified limits. These requirements make stability chambers costly to install and maintain.
Contract providers will have chambers and backup chambers on an uninterrupted power supply, with backup generators and 24/7 monitoring systems that feature alarms and backup alarms to notify personnel in the event of a temperature or humidity excursion. They will also have the staff and resources to ensure the chambers are serviced, inspected, calibrated, and qualified regularly and to maintain the significant paperwork involved in keeping the chambers consistent with current good manufacturing practices (cGMP) and ICH guidelines.
In addition, by offering a suite of chambers, contract testing providers can help companies meet regulatory requirements for distribution into countries with different climate conditions.
The ICH has established four zones for stability testing, each with different specifications, limits, and time points. Zone I conditions are for products that will be distributed in the United States, Canada, the United Kingdom, and Northern Europe. Zone II includes countries on the Mediterranean such as Portugal and Greece and more tropical parts of Japan. Zone III conditions are hot and dry, for places such as Iran, Iraq, and the Sudan. Zone IV conditions are hot and humid, about 40°C and 75% humidity, simulating the rain forests of Brazil and many countries in Southeast Asia.
Get Started with a Method Transfer
Even though your facility may follow GMPs, some early-stage stability methods are not formalized for outside use. Only validated methods should be utilized for stability testing. However, for some early stage programs the robustness of the method may not have been fully understood.
For example, Celsis received a method to be used for stability testing of a pharmaceutical product. While following the written transfer protocol, Celsis found that its results did not match those of the customer’s lab. The customer’s lab manager reviewed the instructions provided and confirmed that these were the same steps. But when the Celsis analyst talked directly with the company’s technician, the analyst learned that the tech had mixed the sample for longer than had been indicated in the provided method.
Small details like this must be determined prior to the execution of a stability program. Otherwise, your early data—and months or years of internal testing—may not be useful, and expiration dates may be affected.
Method transfer can be as simple as having the contract lab run your protocol to demonstrate that the test can be executed accurately and precisely. Some contract labs can also help you write a formal protocol if you do not have one. In either case, method transfer can be an important step to ensure that you can trust the accuracy of the results generated.
Extreme TestingSome products may require non-standard storage at conditions for which a manufacturer may not have qualified chambers. Contract labs are not always limited by the standard or zone conditions, however. Ask if the provider has variable chambers capable of being qualified at non-standard conditions.
For example, a Celsis International client asked that a product be tested under extremely humid conditions. Celsis was able to create and qualify a difficult-to-maintain chamber condition of 40˚C and 90% humidity for this project.
Other examples of non-standard stability testing conducted to meet client needs include an environment with humidity below 20%—an extremely dry chamber—and a number of studies that cycled samples from minus 20°C to 40°C in 12 hours and back down to minus 20°C over the next 12 hours, repeating this up-and-down cycle every 12 hours for five days or more.
Some providers, including Celsis, also offer a special chamber for photostability storage. Photostability testing is required to demonstrate that the final packaging configuration is suitable for protecting a photo-liable product from photodegradation. Photostability can also be used during method validation to determine photodegradants during forced degradation studies.
Throughout the supply chain, there are containers on trucks or ships reaching very high temperatures during the summer months or freezing during a cold winter. Not all warehouses are climate controlled. And consider the large animal veterinarian who must keep all types of medications in his or her vehicle throughout the year.
Freeze/thaw and shipping studies are separate studies that can help evaluate overall stability. If your samples are found to degrade faster in higher temperatures, for example, a shipping study will identify the conditions at which the product can be shipped safely.
Even before a product is manufactured, a company may run a number of accelerated stability programs on formulation batches to evaluate the product’s feasibility. By using higher temperatures and higher humidities than expected, these accelerated programs are designed to predict the shelf life of a product prior to demonstrating it in real time.
Testing SupportBeyond its standard and specialized storage conditions, a good outsourcing lab will be able to offer a full range of chemistry and microbiological testing options. In addition to the assay, dissolution, and impurities, other common tests include pH, color, sterility, endotoxin, and preservative efficacy testing (PET).
Some multiple-dose containers of sterile products, such as IVs, have a resealable fabric. One aspect of stability testing for these types of products involves repeatedly opening the container and removing a dose to ensure that the correct number of doses is in the container, that the container seals up, and that the re-entry does not introduce contaminants.
Similarly, PET is required for multiple-use containers. PET ensures that over the life of the product the preservative will still be present and the bioactivity of the preservative will be maintained within specification.
What to ExpectWhen selecting a contract lab for your stability storage and testing program, choose one that is licensed with the U.S. Food and Drug Administration (FDA) and, as the FDA recommends, schedule an on-site audit, or at least make certain that third parties regularly review the lab’s facilities and systems.
Look for a comprehensive stability chamber qualification, calibration, and preventive maintenance program; qualified personnel running the program; and current, thorough SOPs, based on cGMP and ICH protocol, that govern every aspect of the program.
Discuss the lab’s process for maintaining files for studies. Is the system paper-based or electronic? What backups are in place? Ask what you can expect for reporting.
You should expect to receive a summary report at each time point. In some cases this will include a brief history of the testing along with a table showing the full results to date. At the end of the study, a full and final report should be issued.
Finally, you don’t want to be the lab’s first or only stability customer. It’s important that the partner you select can accurately anticipate and meet the testing requirements and volume your stability program entails. For example, Celsis has more than 30 years’ experience conducting stability studies, with 50 to 100 stability programs conducted simultaneously.
Contract labs invest hundreds of thousands of dollars in stability storage chambers, testing equipment, and qualification and maintenance of equipment. More money is spent on staffing, so they have the resources to jump in and do all the required testing within the proscribed time frame—be it every three months for a new product or three lots a year for a released product.
Best of all, the right contract lab will offer a turnkey program that means you won’t have to worry about the varying workload, temperature changes, chamber qualification, and reporting. When your program has been reliably transferred to the right outsourcing partner, the word stability will bring on of a feeling of calm.
Ryan Williams is manager of chemical sciences for Celsis in St. Louis, Mo. Sean Gavor is supervisor and metrology/stability coordinator for Celsis in Edison, N.J.
- Microbac Laboratories, Inc. Pharmaceutical stability studies. Microbac website. 2005. Available at: www.microbac.com/technical_articles/news_detail.php?news_ID=10. Accessed June 2, 2011.
- Rignall A. Physical stability testing during the product development lifecycle. Pharmaceutical Outsourcing website. 2011. Available at: http://pharmoutsourcing.com/ViewArticle.aspx?ContentID=161. Accessed June 2, 2011.
- Barron MD. Outsourcing stability testing: a tool for resource and risk management. Paper presented at: AAPS Workshop—Pharmaceutical Stability Testing to Support Global Markets; September 2007; Bethesda, Md. Available at: www.aapspharmaceutica.com/meetings/files/100/MichaelBarron.pdf. Accessed June 2, 2011.