OUTSOURCING CONSIDERATIONS


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


Table 2. Category


Assay pH


General


Appearance Osmolarity Moisture Turbidity


Reconstitution Time Quantity (strength/content) Protein Concentration by A280 cSDS (or SDS-PAGE) Purity /Identifi cation


Size Exclusion Chromatography (SEC) RP-HPLC cIEF (or IEF) Western Blot


Binding Activity ELISA Biological Activity Cell Based Assays HCP Process Related Impurities


Residual DNA Protein A


Product Related Impurities Methionine-Oxidation by Peptide Mapping Safety


Endotoxin Sterility


Particulates Container


Container Closure Integrity Testing Extractable volume


6 American Pharmaceutical Review | Biopharmaceutical Supplement 2014 (UV)


sponsor or the development and validation of stability-indicating methods (and verifi cation 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-specifi cation/ 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-fl ow imaging (MFI), light scattering, nonroutine LC detection (RI, CAD, and ELSD), and microbial identifi cation 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.


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