Differences in Stability Testing for CDER & CDRH
When submitting pharmaceutical products to the FDA for approval, testing must be performed to ensure they are effective and ultimately safe for public use. Stability testing helps ensure international regulation requirements are met and includes downstream analytical testing and stability storage stages. These tests measure the quality of a product after exposure to environmental factors such as light, heat, and humidity. Any product changes recorded, whether microbiological, chemical, or physical, are then assessed for impact on the overall product integrity. The results of those assessments are used to recommend storage conditions and calculate the shelf-life of the product in different regions of the world.
The International Conference on Harmonisation (ICH) has used temperature and relative humidity to divide the world into five climatic zones which are as follows:
Zone I: Temperate
Zone II: Mediterranean/subtropical
Zone III: Hot/dry
Zone IV: Hot/humid
Zone IVb: Hot/higher humidity – the most recent addition to cover Association of Southeast Asian Nations (ASEAN) conditions
Long-term stability studies replicate these zones to simulate a product’s reaction to exposure in each relevant climate. The zones used for testing are determined by the production, storage, shipping, and distribution locations. Once testing is completed, the results are sent with the application to the FDA for approval. All pharmaceutical products, whether drugs or medical devices, must meet stability testing standards before they can be distributed to the public. These regulations are determined by two FDA organizations, the Center for Drug Evaluation and Research (CDER) and Center for Devices and Radiological Health (CDRH).
CDER and CDRH
Within the FDA, two organizations are responsible for determining and enforcing regulations for pharmaceutical products. The Center for Drug Evaluation and Research (CDER) was created to handle submissions for drug applications, and the Center for Devices and Radiological Health governs regulations for medical devices. At one time, the two organizations operated independently of one another which resulted in duplicate submissions for combination devices and drugs that are designed to work together. Now, the organizations are required to work as a single entity, each governing their respective specialty and working together for combination products that fall under both categories.
For many products, it can be easy to determine which organizational regulations apply. However, for those that could fall under either organization’s authority, there are specific sets of criteria that define the applicable regulations. In most cases, it is imperative to review the Intercenter Agreement of these agencies.
For example, a drug delivery system device involves both the device and the drug it was designed to deliver. In this case, the CDER would act as the primary agency if the device will be distributed prefilled, because the device’s intended use is entirely dependent on the drug for which it was designed. This would include products such as prefilled syringes and transdermal patches. In situations where the drug delivery system device will be distributed independently, the CDRH would take the lead on regulating the device while the CDER would handle the drug intended for delivery. Devices created to produce or process a drug, such as oxygen concentrators, also fall under CDER jurisdiction. If a device is created with a drug component, of which the sole purpose is to aid in the device’s function, the CDRH will take the lead. An example of this would be a dental device that includes an application of fluoride.
There are many possible combinations of medical devices and drugs being developed to be used together and the FDA offers a complete guide to help determine which organizational regulations will be applied. Drug and medical device regulations share some similarities, but also have some pronounced differences. This article will focus on the regulations for applications within the United States, Japan, and the three regions of the European Union as these are the areas covered by the CDER and the CDRH.
CDER Stability Testing Regulations
When submitting an application to the FDA for a drug products, there are very specific standards that must be met concerning stability testing. According to section 211.166 of the Code of Federal Regulations:
(a) “There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include:
- Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability;
- Storage conditions for samples retained for testing;
- Reliable, meaningful, and specific test methods;
- Testing of the drug product in the same container-closure system as that in which the drug product is marketed;
- Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted.
(b) An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained. Accelerated studies, combined with basic stability information on the components, drug products, and container-closure system, may be used to support tentative expiration dates provided full shelf life studies are used to project a tentative expiration date that is beyond a date supported by actual shelf life studies, there must be stability studies conducted, including drug product testing at appropriate intervals, until the tentative expiration date is verified or the appropriate expiration date determined.
(c) For homeopathic drug products, the requirements of this section are as follows:
- There shall be a written assessment of stability based at least on testing or examination of the drug product for compatibility of the ingredients, and based on marketing experience with the drug product to indicate there is no degradation of the product for the normal or expected period of use.
- Evaluation of stability shall be based on the same container-closure system in which the drug product is being marketed.
(d) Allergenic extracts that are labeled “No U.S. Standard of Potency” are exempt from the requirements of this section.”
The CDER expects a thorough series of stability tests, on multiple batches, under specific conditions, to ensure that approved products can safely be made available to the public with clear expiration dates and storage recommendations. The methods for conducting these tests are established and proven to be reliable and effective. Considering that drugs are generally developed to interact with the human body in some way, whether ingested, administered intravenously, or applied topically, this accuracy of this information can have a direct impact on the health of consumers who use these drug products. Degradation of drugs can impact their efficacy resulting in reduced potency, so every drug application is required to include evidence and results of stability testing.
CDRH Stability Testing Regulations
The medical device applications reviewed by the CDRH must adhere to a different set of standards. Just like drug products, medical devices must be go through stability testing to ensure they will perform their intended function when needed. However, not all devices require a shelf life. For example, tongue depressors are considered medical devices but are exempt from the need for a shelf life because the likelihood that they would degrade with use is small and degradation is unlikely to cause serious consequences. For other devices that are intended for life-saving procedures, such as pacemakers, a shelf life must be calculated with a failure rate near zero.
Stability regulations for medical devices are less established and originate from the definition of stability by the United States Pharmacopoeia (USP) which is:
“The extent to which a product retains, within specified limits, and throughout its period of storage and use, i.e., its shelf life, the same properties and characteristics that it possessed at the time of manufacture.”
Due to the wide variety of medical devices developed and their equally varying functions, it would be difficult to establish a concrete set of stability rules to govern them all. Instead, the five criteria set by section <1191> of the USP for drug product stability standards are used as a starting point. The criteria are:
(4) therapeutic, and
When working through these criteria, they must be applied to all the individual components that make up the device. The FDA has developed an outline for medical device stability that breaks down each criterion into applicable considerations.
1.1 Degradation: Do any active ingredients or components of the device degrade over time in a manner which adversely affects device safety or performance?
1.2 Interactions: Do ingredients or components interact to alter the device? Does the device have interactions among the various components that cause degradation of the ability to perform the intended function?
1.3 Device and Packaging Interaction: Is there an interaction between the device and package that has undesirable effects?
1.4 Radioactive Decay: Does the device contain radioactive material with a relatively short half-life? Do the radioactive decay by-products alter the safety or effectiveness of the device either by themselves or through further interaction?
1.5 Manufacturing: Do any of the manufacturing processes alter the chemistry of raw materials, components, or finished device in a manner which adversely affects device safety or performance?
2.1 Physical Characteristics: Does the device have physical characteristics that vary with time; e.g., appearance, viscosity, elasticity, tensile strength, burst strength, or electrical resistance? In some cases, a significant change in appearance may cause concern to the user even though the performance of the device is not affected.
2.2 Manufacturing Process: Do the different steps in the manufacture of the device affect the physical characteristics of the individual components or the finished device in a manner which adversely affects device safety or performance?
2.3 Storage Conditions: Do the storage conditions, e.g., temperature, humidity, light, etc., have an effect on the device in a manner which adversely affects device safety or performance?
3.1 Sterility: Do sterile devices remain sterile? Maintenance of sterility is primarily determined by the examination of package and seal integrity.
3.2 Environmental Control: Is an environmental control program needed during manufacturing or storage to monitor and adjust the microbial load in or on the device and packaging below an established tolerance level to prevent adverse degradation of the product?
3.3 Antimicrobial Effectiveness: Does the device lose the ability to perform the intended antimicrobial function?
3.4 Integrity: Do the device’s barrier characteristics change?
3.5 Preservative Effectiveness: If the device uses a preservative system, how long does the preservative system retain effectiveness within tolerance levels?
- Therapeutic: Does the ability of the device to perform the intended therapeutic or diagnostic function change under storage or use conditions?
- Toxicological: Do device degradation by-products form during storage or use that produce an adverse toxic affect?
- Biocompatibility: Does the biocompatibility of the product change adversely during storage or use?” (Shelf Life of Medical Devices, April 1991)
The variables that need to be considered when calculating the shelf life of a medical device are numerous and manufacturers will be unable to control them all. However, it is important to consider each to minimize their impact on performance. When writing the procedures for medical device shelf life calculations, there are several things that must be included such as storage conditions, the device’s intended use, components used for manufacturing the device, method of manufacture, packaging, and transportation conditions. Because many of the variables involve raw materials and manufacture methods, shelf life considerations should be part of the planning and development stage of the device before production begins. For this reason, medical devices are often assigned a target shelf life that is set to cover estimated times for production, storage, distribution, and use. Once the target shelf life is established, all raw materials, manufacturing methods, and packaging options are compared to identify potential stability issues.
Medical devices adhere to the same section in the Code of Federal Regulations that was listed above for drug products. The CDRH does not offer a comprehensive policy that governs all medical devices, but there are guidance documents available for specific subjects such as sterility of Premarket Notification (510 (k)) submissions, contact lenses, in vitro diagnostic devices, and medical gloves.
How They Compare
When preparing to submit an application to the FDA for a pharmaceutical product, there are differences in the regulations that govern stability testing for drugs and medical devices. Although both adhere to the regulations laid out in section 211.166 of the Code of Federal Regulations, the application of those regulations can be very different.
Drug applications must follow a strict set of guidelines when conducting stability tests and submitting results. All FDA-approved drugs shall be tested according to established proven and validated analytical methods, in all applicable environmental variables, and the results must be used to determine an expiration date and recommended storage conditions. The procedures for a written stability testing program are clearly defined by the CDER and the tests must simulate environmental conditions for the relevant climatic zones established by the ICH.
Medical device applications can be a bit more complex depending on the type of device being submitted. First, it is necessary to determine whether the device qualifies for a designated shelf life. If a shelf life is necessary, all components must be considered, along with potential variables in manufacturing, packaging, shipping, storage, and raw materials used. The CDRH relies heavily on the guidelines already established by the CDER with the exception of some common devices with specified regulations and instructions for submission. Without specific published regulations, the written stability testing programs for medical devices must consider all variables that are determined to be reasonably applicable using the FDA’s published stability outline.
The differences between stability testing regulations defined by the CDER and the CDRH make it important, especially when developing a combination product, to review the Intercenter Agreement between both organizations that clearly outlines which guidelines will apply. The biggest difference between stability testing for drugs versus medical devices is the establishment of a shelf life for each product. The expiration dates for drugs are set after the drug has been created and stability testing has begun so it can be calculated using the results. Medical devices are often assigned a target expiration date, so stability considerations must be factored in while the product is still in the research and development stage. In either case, writing stability testing programs that follow all guidelines and regulations is required to obtain FDA approval for a pharmaceutical product and allow the public life-saving access.
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