Stability testing and monitoring is a critical step in the drug development and manufacturing process and something that is applicable to virtually all Food and Drug Administration (FDA) regulated products. The results as derived from a valid stability program plays a key role in the safety of drugs and how pharmaceuticals are produced, packaged, labeled, stored and sold. As a result, stability testing is strictly regulated and reviewed by the FDA. The basic premise of the stability guidelines require that product degradation, or potential degradation, be monitored over time in unique storage conditions to insure that the integrity of the product remains intact and unchanged. A key development of a successful stability storage program is the formal establishment of a product/package shelf life determination.
The FDA has published various guidance documents on the objectives and use of formal stability testing. Many references in any stability related document are made to the International Conference on Harmonization (ICH) which outline, in detail, specific ways to establish, set up, monitor and interpret regulatory compliant stability programs. The following is a link to the stability documents as posted on the ICH web site: http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html . Even with all the current guidance documents and regulatory oversight, there still remains problems and concerns within industry to meet the expectations of the inspectors.
Anyone who is active the arena of stability testing understands the basic storage conditions that are commonly used. For example, according to ICH guidelines, if climatic zones must be met, the common conditions for testing include 21°C / 45% RH; 25°C / 60% RH; 30°C / 35% RH; 30°C / 70% RH whereas numerous conditions are set for long-term, intermediate and accelerated storage to include 25°C / 60% RH; 30°C / 65% RH; 40°C / 75% RH as well as a host of other options inclusive of client directed parameters that are unique to the product under evaluation.
There are a few areas that many clients seemingly overlook in the development of a stability program. This tends to be more common with newer and younger companies that have less experience in bringing products to market. The first pitfall deals with the development of a controlled substance product. Performing a formal stability program on a classified Drug Enforcement Agency (DEA) compound requires a high level of security. The DEA enforces strict guidelines in the research and development arena to insure that controlled substances are always accounted for and traceable. Performing a stability program for a controlled substance requires that the facility housing the study meets all the DEA licensing and security requirements to include a robust monitored alarm system (with motions sensors) and a re-enforced, limit access cage system. Secure cage systems must include a top panel to prevent access through a building’s roof.
The second area routinely overlooked centers on transport stability. This generally refers to the stability of a product/package system as it meanders through the various distribution channels. In many cases, this testing is based upon a freeze / thaw requirement and can become vital when product is moving from different weather zones. A product sitting in the holding center of a plane in Green Bay during February that ends up three days later on the tarmac in Puerto Rico can suffer irreparable damage. Transport stability studies, often overlooked, can prevent this crisis.
The evolution of stability testing guidelines is an ongoing process. In May of 2014 the FDA published the Guidance for Industry ANDAs: Stability Testing of Drug Substances and Products….Questions and Answers. The link to this informative Q&A can be found here: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM366082.pdf
This is a supplement document that “provides answers to questions from the public comments we received on the draft guidance for industry on ANDAs: Stability Testing of Drug Substances and Products (FDA stability guidance) that published in the Federal Register of September 25, 2012. The final guidance for industry of the same title published in the Federal Register of June 20, 2013. Comments received on the draft of this guidance published in the Federal Register of August 27, 2013 have also been incorporated. General issues; drug master files (DMFs); drug product manufacturing and packaging; and stability studies are discussed in this guidance and are intended to clarify the stability testing data recommendations for abbreviated new drug applications (ANDAs).”
While FDAs guidance documents do not establish legally enforceable actions required of manufacturers, the document provided key insights into how the agency would most like to see regulations met. For anyone who is active in the area of stability testing, it is best to take a few moments, on a regular basis, to review. As with any FDA document, it should be noted that the use of the word “should” in Agency guidance means that something is suggested or recommended, but not required.
There are many aspects to a comprehensive stability and storage program and it would take a plethora of articles, guidance documents and text books, all in a state of constant revision, to stay abreast of the topic. The key to stability testing is working with experienced professionals, both in and outside of your organization, that can help guide the program to a successful completion.