Donald Paquette
Senior Director CMC | BrevisRefero
The innovation process of a biological product is inherently founded on the validation of a Mode of Action, the product’s capacity to achieve a defined biological effect and, ultimately, on the establishment of a reliable correlation between the output of its potency-representing assay and the observed clinical response. This intrinsically makes biological activity a biopharmaceutical critical quality attribute and compliance to a predefined potency acceptance criterion is a regulatory requirement for batch release and its stability program. Potency assays represent somewhat of a special class of quantitative measure since they are designed to elicit a response as a result of a specific binding event. For biologicals, this typically involves assaying the integrity and accessibility of a binding surface on a target protein using an affinity reagent, which is also usually a protein, such as an antibody-antigen interaction. The implication of using protein-based reagents to identify and assess the status of finite features on a biological molecule fundamentally makes potency assays complex, highly sensitive and variable in nature. In large part, this is because the binding event is compounded by the properties of both the product and the affinity reagent – which is classified as a critical reagent (CR) in potency assays. Just like the product, a protein-based CR is not only subject to batch-to-batch variability but also to instability in terms of its physicochemical, biophysical, conformational, adsorption, and other properties. Instability can be an intrinsic feature of a CR or potentially a result of storage conditions and handling. While the degree of instability from in-test handling that contributes to assay variability can be minimized through in-depth method development and standardization, method precision is also significantly enhanced by the implementation of a CR Program in the early stage of drug development.
So, what constitutes a CR Program? The main aspects include a strategy and the establishment of well defined protocols for sourcing, qualification, stability monitoring, and resupply.
"Potency assays represent somewhat of a special class of quantitative measure since they are designed to elicit a response as a result of a specific binding event."
Sourcing
With the onset and progression of clinical activities comes a growing emphasis on supply-chain risk management such as long-term availability of quality raw materials, consumables, and reagents at sufficient quantities to meet production demands for projected market requirements. In this light, the criticality of employing batches with appropriate biological activity, and the direct reliance on potency assay performance to demonstrate this, necessitates careful consideration to the selection and supply chain of CR(s) in the late pre-clinical or early Phase 1 clinical period. A particular CR (be it an antigen, antibody, enzyme, receptor, etc.) can be generated in-house, produced from out-sourced services or obtained from a commercial vendor. Each of these avenues come with advantages and disadvantages. For instance, the practicality of commercially available CRs is offset by uncertainties in long-term availability that are sometimes due to volatility in vendor business operations, or product quality consistency issues. Out- and in-sourcing CR production can provide more assurance/control on accessibility and quality aspects but it requires to be managed through internal resources with appropriate infrastructure and expertise. Quality drift or sourcing changes to a CR can have a profound impact on potency assay output, so having an established platform for CR sourcing is a great safeguard. For production of in-house or out-sourced CRs, a well-documented production/purification procedure should be in place and be amenable to tech transfer.
"The test panel, at minimum, must include assessment of all relevant attributes for its use as the CR, such as concentration, integrity, and bioactivity."
Qualification
Establishment and application of a qualification protocol that confirms a batch is deemed fit-for-use as a CR is a fundamental aspect of a potency assay’s life-cycle management. The protocol should outline requirements such as chain of custody, shipping requirements, handling procedures, storage conditions, identity confirmation, appropriate aliquoting, and test panel acceptance criteria. The test panel, at minimum, must include assessment of all relevant attributes for its use as the CR, such as concentration, integrity, and bioactivity. CRs obtained commercially usually come with a Certificate of Analysis (CoA) or a Report of Analysis (RoA), and depending on the extent of confirmed quality attributes provided in such a document, a qualification protocol may deem the certificate sufficient, or it may require supplemental testing to ensure the reagent meets expected characteristics for use as the CR. The protocol for CR produced in-house or from an out-source service should be designed with consideration to the presiding level of quality management at the source laboratory. Lastly, documentation declaring a CR is qualified for use should be generated and kept on file for future use and reference.
"Having an established resupply protocol that outlines the replacement of a CR helps streamline the transition and avoids compliance issues."
Stability Monitoring
Instituting and executing a formal stability protocol provides assurance that a CR is not significantly changing through long-term use and storage. Ideally, pre-defining alert limits in relation to stability acceptance criteria on key CR attributes help to establish the need to initiate a resupply protocol. A monitoring protocol may be employed in concert with the stability study which describes the trending practices and criteria for a CR through routine product batch release and stability testing.
Resupply
The necessity to resupply a CR usually results from evidence of its instability or concerns over its shrinking inventory level. Having an established resupply protocol that outlines the replacement of a CR helps streamline the transition and avoids compliance issues. Key elements of the protocol include defined triggers for starting resupply activities such as alerts on existing CR instability or inventory limits, details on what procurement/production request procedures to follow, inventory refreshment volume, and the obligation for qualification of the new CR. As a final measure of assurance, the protocol should stipulate that adoption of a new replacement CR undergoes a successful bridging event with the retiring CR, such as demonstrating comparability between both CRs over three product stability time points.
In summary, the importance of CR sourcing is often underestimated until variability and/or unexpected assay results become a significant factor in mid or late stage drug development so don’t overlook the importance of your potency assay’s CRs – they should receive the same care and attention as your product!
If you would like a free, no-obligation consultation to talk about your biologic drug development outsourcing, planning, budgeting, or execution then please reach out to us at:
contact@brevisrefero.com or call us at (905) 636 - 6559.
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Donald Paquette
Senior Director CMC | BrevisRefero
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