This article was originally published in American Pharmaceutical Review on November 26, 2014
As the pipeline of biologics continues to grow, biopharmaceutical organizations are outsourcing an increasing number of stability studies. Careful consideration must be given when choosing a partner for these programs due to their inherent complexity. Several key points to consider, including capability, capacity, protocol development, and project management, are discussed here.
According 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.
In addition, biological activity is highly dependent on interactions (both non-covalent and covalent), and biologics are particularly sensitive to environmental factors, such as temperature, light, oxidation, shear, and ionic content. Therefore, strict storage, packaging, handling, and transport conditions are usually necessary.
Points to Consider
Validated, robust, stability-indicating methods are critical to a successful stability program. As noted above, these studies require quite a wide variety of testing and expertise. A typical biologics stability study may require many of the assays listed in Table 2. Some products, such as antibody drug conjugates (ADCs), increase the complexity immensely as the monoclonal antibody is considered an intermediate that also needs to be studied. There is a regulatory expectation that key characteristics linked to critical quality attributes (CQAs) are measured with orthogonal methods, so multiple methods may be used to measure purity or other aspects.
Therefore, the laboratory must have the capability to perform method installation of a wide array of physiochemical, microbiological, and biochemical assays. This may involve the transfer of established methods from the sponsor or the development and validation of stability-indicating methods (and verification of compendial methods). These activities and assays encompass a broad range of skill sets, expertise, equipment, and instrumentation.
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.
Simultaneous studies are often performed; therefore, careful thought should be given to finding a balance between batching efficiency and unrealistic sample volumes. Other considerations such as freeze-thaw logistics should be covered in the protocol as well. Further, studies performed in support of development and clinical trials may have different objectives than those for marketed products, and these differences need to be considered. Photostability, stress stability, and thermal cycling are all typically covered in a comprehensive program, and therefore, the contract organization should have experience with these types of studies. The development of a stability protocol is ideally carried out in a collaborative manner between the laboratory and sponsor.
Lastly, as important as the capability, capacity, and stability protocols are to the project, strong project management is paramount. large stability programs can be logistically challenging and require a tremendous amount of planning, forecasting, scheduling, follow-up, and communication. Regular calls and meetings between the sponsor and the lab are crucial at least in the lead up and during the early time points of a study. A well-run meeting should be agenda-driven and followed up with minutes and action items in a timely manner. Key discussion topics include: planning for upcoming pulls, sample status, OOS results, “anomalous” results, investigations, and reference standards management. A proficient project manager must be able to effectively interface with the various testing laboratories, Quality Assurance, stability storage, and the sponsor. Therefore, the laboratory should have a proven track record in managing biologics stability programs.
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. Available at: http://www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines/Quality/Q5C/ Step4/Q5C_Guideline.pdf. Accessed August 27, 2014.
Dr. Jon S. Kauffman is Sr. Director of Biochemistry, Method Development & Validation and Protocol Development and Technical Writing at Lancaster Laboratories. His teams are responsible for developing and validating methods and performing analysis of clinical and commercial samples for stability and release purposes. This includes methods for the testing of residual impurities in biopharmaceutical products and in-process samples. Dr. Kauffman’s departments also perform mass spectrometric characterization and leachable and extractable studies. Dr. Kauffman’s key roles are to interface with clients and his team to ensure positive project outcomes by maintaining compliance and a high level of quality; meeting milestones and delivery requirements; and finding cost-effective, value-added solutions. He earned a doctorate in chemistry from the University of Delaware and has over 25 years of experience in the analytical testing field.