A top ten US pharmaceutical company was developing packaging for a new drug formulation. There were 3 prototypes being considered. USP 661 Containers Performance Testing was conducted, and all three packages were designated Class A. The packages were filled with the new drug and sent off for stability study. After months of stability testing, two of the three packaging systems failed. Time and money were wasted because one important test was not performed.
Keep reading to discover what went wrong so you can avoid making the same mistakes and increase your probability of stability testing success.
Package design starts with determination of the physical and chemical properties of the product it will contain, and its relevant protection and marketing requirements. According to FDA regulations, pharmaceutical packaging must:
Provide protection against light, moisture, oxygen, and temperature changes
Not react with the product
Not introduce odor/taste to the product
Be approved by the FDA
Comply with tamper-resistance requirements
The United States Pharmacopeia (USP) currently offers more than 3,500 reference standards legally recognized in the US and more than 140 countries. The USP also works with the World Health Organization to provide international biological standards and chemical reference materials for antibiotics, biologics and chemotherapeutics.
USP 661 and 671 is a test method for the water vapor transmission rate (WVTR) of a drug package based on the gravimetric method of observing the weight loss of a package, bottle or blister at 23°C and 75% RH test conditions. The gravimetric method has poor sensitivity that fails to provide adequate limits-of-detection for packaging that uses high barrier materials. Consequently, these test results may be less than accurate. Packages with differing transmission rates may all pass the USP test without distinction because gravimetric test is not sensitive enough to determine small permeability difference. Differences in barrier permeability at levels below those measurement may affect the final drug stability, but this can take years to be detected, like the case described at the beginning of this article.
Example of a USP test.
USP testing is not always sufficient enough to detect issues within the packaging system; testing with high sensitivity barrier testing instruments can often provide you the added data some USP tests miss.
Pharmaceutical shelf life/expiration dates reflect the time in which the drug is expected to work safely and effectively. The "shelf life" of a pharmaceutical product is determined using a "Stability test". Drug shelf life varies but usually 24, 36, or up to 60 months.
The FDA requires that all drugs undergo stability testing. In the stability study, a specified number of packaged drugs under constant temperature and humidity and periodically tested for various indicators: Potency, Physical Characteristics, and Purity (3P’s). Many attributes of the 3P’s are directly affected by water vapor and oxygen transmission rates.
To attain desired shelf life for manufactured drugs, not only the stability of the drug itself, but also the drug packaging and storage are important factors. Any defects in the packaging materials may adversely affect drug quality. Commonly used storage or environmental test conditions for drug stability test are as the follows:
Long-term stability storage: Products are stored at 25°C ± 2°C, 60% RH +/- 5% RH for up to 60 months. Tests for drug stability specifications are conducted at designated time points (e.g., 0, 3, 6, 9, 12, 18, 24, 36 months).
Accelerated stability storage: Packaged drugs are stored for up to 6 months at 40°C ± 2°C, 75% RH ± 5% RH. This method is called ‘accelerated’ because the product’s exposure to high temperature/humidity over a short time speeds up the product’s degradation. Typical sampling periods are 0, 3 and 6 months.
Intermediate stability storage: Packaged drugs are typically stored at 30°C ± 2°C, 65% RH ± 5% RH, which is a slightly sever condition than that of a long-term test if a significant change in stability is identified during an accelerated stability test but is not as intensive as an accelerated test program. There should be an intermediate point in time with each acceleration point until 6 months. Some intermediate studies allow the product to be stored less than 12 months.
Since drug stability testing is a lengthy process, many pharmaceutical packaging engineers choose to test with instrumental method such as ASTM F-1249 prior to conducting stability testing to ensure that appropriate packaging materials are chosen from the start. Here is a list of common WVTR test conditions with moisture permeability instrumental tester:
25°C ± 2°C, 60% RH ± 5% RH
30°C ± 2°C, 65% RH ± 5% RH
40°C ± 2°C, 75% RH ± 5% RH
Test conditions listed above for WVTR with the instrument are consistent with the stability test storage conditions required by the FDA.
Returning to the matter of the failed stability test at the beginning of this article - After the failure of the stability test, the pharmaceutical manufacturer sent three packaging systems to the MOCON Permeation Test Lab for WVTR testing on the instrument that equipped with modulated IR sensor (conforms to ASTM F1249). Transmission rate measurements accurately demonstrated barrier differences among these three types of packages. These details are not able to be reported by the gravimetric method due to its limited sensitivity. The drug Project Manager instantly realized the mistake of not having tested the transmission rates of the packages earlier with instrumental test method. The company had to start over with a new package design. This not only wasted valuable time and money but also possibly delayed the product release. The company has since implemented early barrier assessment with instrumental method for newly designed drug packages in additional to the USP test required by FDA.
The development of new drugs itself is a very time-consuming process. It can be very costly to have something go wrong in the final packaging system. If you do not choose the right packaging materials before your stability study, you would have to redo the long test stability testing. Conduct instrumental WVTR testing in addition to FDA required USP test, is the key to win success of drug stability study. Why prolong the discovery of inadequate packaging?
Throughout the pharmaceutical industry there are new trends and new products. For example, the drugs delivery systems, which is a combination of drug and medical device. To choose the correct package, considerations should be taken from both the drug packaging and medical device packaging. Likewise, nutraceuticals that is a combination of medicine and foods, which is related to both pharmaceutical packaging and food packaging. For these new trends, how to properly protect products starts with choosing the right packaging materials and sometimes going beyond standard test method. This poses new topics for the packaging industry and a new change to existing test standards and regulations.
Georgia Gu is Applications Specialist at AMETEK MOCON. You may contact her at email@example.com or visit her contributor page.
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