BackgroundAccording to ICh Q1A (R2), “The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.”1 In the case of biologics, ICh Q5C states, “The evaluation of stability may necessitate complex analytical methodologies. Assays for biological activity, where applicable, should be part of the pivotal stability studies. Appropriate physicochemical, biochemical, and immunochemical methods for the analysis of the molecular entity and the quantitative detection of degradation products should also be part of the stability program whenever purity and molecular characteristics of the product permit use of these methodologies.”2
ICh provides specific guidance for biologics for several reasons. When compared to typical small molecule products, proteins exhibit greater instability, are more sensitive to the environment, and require more complex analytical methodologies to fully characterize them. Some of the most common types of instability are shown in Table 1.
Points to Consider
The laboratory should also have the ability to troubleshoot method and/or product issues and perform investigations of out-of-specification/out-of-trend results. This is especially important during early phase stability studies, where unexpected degradation products and/or contaminants may arise that require further characterization. Thus, additional, specialized techniques such as accurate mass (mass spectrometry), micro-flow imaging (MFI), light scattering, nonroutine lC detection (RI, CAD, and ElSD), and microbial identification may be necessary.
In conjunction with the capabilities, it is imperative that the laboratory have adequate capacity. Stability studies have the potential to produce many samples that need to be tested in a relatively short time frame. Therefore, redundancy of specialized equipment and trained staff must be considered.
According to ICh Q5C, the stability protocol should include all necessary information that demonstrates the stability of the biological product throughout the proposed expiration dating period. Therefore, clear, well-written stability protocols are another vital aspect of these programs, and the potential outsourcing partner should be adept and experienced in drafting these protocols. All of this must be captured in the protocol. Key elements of a stability protocol are listed in Table 3.
- The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Stabilty Testing of New Drug Substances and Products Q1A(R2). February 6, 2003. Available at: http://www.ich.org/fi leadmin/ Public_Web_Site/ICH_Products/Guidelines/Quality/ Q1A_R2/Step4/Q1A_R2__Guideline.pdf. Accessed August 27, 2014.
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Quality of Biotechnological Products: Stability Testing of Biotechnological/ Biological Products Q5C. November 30, 1995