Donald Paquette
Senior Director CMC | BrevisRefero
Embarking on a product development program initiates (among a multitude of other facets) the management of a dynamic interplay between preclinical/clinical studies and Chemistry, Manufacturing & Control (CMC) – and within CMC itself. This interplay is intrinsically rooted in the need to supply representative product to enable the train of studies, while undergoing a staged development, refinement, and eventual lock-down of a full-scale manufacturing process with associated analytics.
"Although initiating FD as early as possible is advantageous, starting too hastily may result in costly setbacks down the line."
Initiating Formulation Development
A vital consideration across the interplay is Formulation Development (FD): when to start and how to go about it. Fundamentally, a high-level document such as a Target Product Profile (TPP) that delineates the overall goal of a drug development program and key product characteristics, as well as its strategic plan, should be in place from the onset. While such a plan can undergo changes, as knowledge and experience through the drug development program is gained, the contents of TPP-like documents are an invaluable reference to the product developers. This can be critical for minimizing a short fall in the realization of a regulatory approved and commercially viable product. Upfront information on the intended Drug Product formulation, and its stability and compatibility expectations, provides important context to Drug Substance formulation requirements, which is where FD begins.
Although initiating FD as early as possible is advantageous, starting too hastily may result in costly setbacks down the line. Product formulations for preliminary preclinical screening studies are usually established based on dose levels of the Active Pharmaceutical Ingredient (API, i.e. the biologic) within a vehicle that is considered to be both compatible with the API and that is appropriate for animal model administration. At this phase of product development, minimum investment towards the development of a formulation meeting the TPP is warranted. However, the situation begins to teetertotter with progression through preclinical studies into the early clinical phase, as process and analytical development evolve.
"For biologics, the output of a batch production is a population of the API comprised of an ensemble of variants...as well as impurities of various types...and concentration levels."
Batch Selection for Formulation Development
For biologics, the output of a batch production is a population of the API comprised of an ensemble of variants (charge, size, glycoforms, etc.) as well as impurities of various types (host cell-derived, product-derived, process-related) and concentration levels. The overall compositional profile of batches can undergo significant refinement through early process development for yield, purity, potency, etc., and generally becomes more consistent as upstream and downstream process unit operations are selected, optimized, and locked. However, it is not unusual to experience changes in API variants distribution and/or impurity content through subsequent process scale-up. Since the compositional profile of a batch can have an important influence on its stability behaviour within a given formulation environment, FD should “ideally” be performed using late-development batches. But this is not always practically feasible as the drug development process requires formulated product batches through the clinical phases that are backed by demonstration of appropriate storage, handling, and administration stability. As such, the timely triggering of product-specific FD activities that will likely establish a formulation aligned with TPP expectation hinges on API generated from a production process that i) has shown consistent compositional and desirable quality batch profiles, and ii) bears a sufficient level of confidence that it will continue to make comparable batches through scale-up
"Whether performed internally or outsourced, thorough and efficient FD relies on the implication of strong technical and strategic expertise, sound study design and management, as well as access to a wide range of instrumentation and assays."
Selection of Excipients & Characterization Design
Once a batch (preferably multiple batches) has been identified for FD, screening and selection of a baseline buffer is normally undertaken. This is typically followed by iterative assessment of the stabilizing effect/performance of excipients through forced degradation conditions. Whilst forced degradation of the product provides important information (i.e., degradation profiles and pathways, degradant identity), the challenge conditions (thermal, oxidative, freeze/thaw, etc.) are often applied individually and some to levels that go well beyond the range that a product will experience through real-life storage and handling across its shelf-life. There is thus a probability that an excipient is unnecessarily included, or is excessively added, within the formulation – which needlessly adds to the burden of cost of goods sold (COGS), supply chain management and, in some cases, the requirement to monitor the stability of the excipient itself. Furthermore, evaluation of the product in the selected formulation through early product development is commonly focused on demonstrating that acceptable real-time long-term and short-term accelerated stability is achieved, with minimum consideration to product stability for end use.
A more fitting approach to consider for FD is to first characterize the sensitivity of the product in its baseline buffer against stress conditions in a Design of Experiment (DOE) based approach. The results of applying overlapping stress parameters (e.g., thermal + agitation + oxidation) to various degrees within, and just beyond, real-life excursion levels provide a more refined picture of the product’s practical weaknesses and thus permits a more targeted approach for the selection and assessment of stabilizing excipients. Follow-on experiments to spot check the formulation’s in-use stability performance (e.g., compatibility with the intended administration preparation procedure, delivery device, combination therapy, adjuvants, etc.) is a good way to proactively identify issues and to adjust the product’s formulation sooner rather than later. Indeed, recognizing that a formulation is inappropriate during the later stages of product development can be detrimental to the overall program. Changes to a product’s formulation during this period, depending on the gravity of the modification, may result in a requirement to requalify/revalidate analytical methods, reboot stability studies, and repeat clinical trials to demonstrate product comparability, increasing time, resources, and cost.
In summary, the recommended approach to FD should encompass the characterization of real-life stress-response profiles using i) early-stage development batches that are deemed likely to represent late-stage batches, ii) the selection of excipients that will safeguard against product evolution under real-time and anticipated excursion conditions, and iii) evidence that the chosen formulation is fitting for clinical administration with the delivery mode and matrix aligned with the TPP. Whether performed internally or outsourced, thorough and efficient FD relies on the implication of strong technical and strategic expertise, sound study design and management, as well as access to a wide range of instrumentation and assays. The success of your biologic depends on it!
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