Antibody-drug conjugates (ADCs) are an important, emerging class of Biologics that exploit antibody specificity to achieve targeted delivery of a small molecule drug. In contrast to traditional small molecule drug products, which typically consist of pure chemical substances that are easily analyzed after manufacture, the complex structure of ADCs makes identification of clinically relevant components extremely difficult. For this reason, ADCs are defined by their manufacturing process, necessitating thorough process characterization to assure product efficacy and patient safety1.
Because they afford such specific drug delivery, ADCs have significant potential to address unmet medical need and make a remarkable impact on patients’ lives. For this reason, ADC programs can accelerate rapidly from early to late stage clinical development. This highlights the importance of preparing for commercial launch early on to avoid incurring delays. Through careful planning of process/analytical development and characterization, commercial manufacturing site selection, and manufacturing-scale process performance qualification (PPQ), the introduction of an ADC to market can be expedited.
ADCs are widely recognized as newcomers to the biopharmaceutical marketplace, with just five products granted FDA approval to date2, 3. Yet with many more ADCs in the pipeline, a range of innovative technologies are currently under investigation to develop these drug products. Irrespective of the route chosen, it is essential that the associated manufacturing processes are well understood, scaled up, and fully optimized to support clinical and commercial demands throughout the entire ADC lifecycle. To reduce the risk of manufacturing failures and regulatory delays, it is sensible to partner with a CMO offering a strong Biologics foundation.
To benefit from the various approaches introduced by the FDA4 to expedite the availability of essential therapeutics such as ADCs, it is important to develop phase-appropriate processes to supply the clinic. In particular, the timeliness of the Phase 1 supply is key to entering the clinic as soon as possible.
An experienced CMO can rapidly transfer a process from the laboratory and bring it into a GMP suite. Performing development at small scales (1-10 mL) to create a basic understanding of process sensitivities is essential. This can include high throughput multivariate screening to optimize parameters such as buffer matrix, concentration, reaction time, temperature, and reagent equivalents. Further process development at a scale of 10-100mL to refine factors like temperature control and agitation; and transition to a scale of 0.1-10L using appropriate scale-down systems to confirm process parameters from smaller scales and generate laboratory-scale lots for toxicology studies. This paves the way to successful GMP production of 10-500L clinical and commercial lots. By running each stage of the conjugation development and scale-up process under conditions that simulate manufacturing as closely as possible with phase-appropriate analytical methods, the resulting data can expedite transition to the Phase 2 clinical trial.
As a result of the opportunity for accelerated approval, the Phase 2 clinical study can be the pivotal clinical study, meaning that the Phase 2 manufacturing supplies could likely be the pivotal supplies to an ADC program. It is therefore critical that the process characterization strategy is well thought out to ensure commercial readiness from the Phase 2 manufacturing process. Although process characterization is typically performed during the late stages of drug development, following Phase 2 clinical trials, the implementation of a tiered approach to process characterization is an effective way to compress program timelines. One means of achieving this is to introduce some overlap with PPQ runs; these are typically performed after process characterization, yet a savvy CMO will carry out essential PPQ activities early on to avoid program delays.
CMOs as process characterization partners
With process characterization being such an important stage of the lifecycle of a drug, it is vital that it is carried out properly to avoid manufacturing failures or costly regulatory delays. However, many companies simply do not have the necessary expertise, resources or facilities for process characterization, and instead choose to partner with a CMO for faster progression to market.
Having performed many previous process characterization studies, an established CMO offers a robust platform to support market approval. This includes everything necessary to deliver on planning, assessment, analytical studies, data analysis, review, and not least the diversity of specialized and often expensive equipment required for biopharmaceutical testing. Utilizing the knowledge and expertise of highly skilled personnel to support every aspect of process characterization, a trusted CMO partner is a practical choice to deliver a launch-ready ADC within accelerated timelines.
Leveraging Biologics processes/know how throughout the manufacturing of an ADC
Like all Biologics, ADCs are defined by their manufacturing process. In selecting a partner for ADC development and manufacture it is therefore wise to choose a CMO with a strong Biologics foundation. Offering rapid scale up, phase-appropriate method development, and comprehensive process characterization, only a CMO experienced in Biologics processing can truly provide the depth of knowledge necessary to ensure success for an ADC program.
As an example, rapid scale up of a new ADC design with unique purification needs requires intricate knowledge of Biologics processing and purification. A CMO practiced in this field can enable rapid scale up in areas such as filtration to remove small molecule impurities, chromatography to purify the species of interest, and formulation to enable downstream processing, backing this with the full range of analytical procedures necessary to characterize the process and the product variants.
Thorough process characterization provides a full understanding of a Biologic such as an ADC and the processes under which it can be efficiently, compliantly manufactured for safety, purity, and potency. With the ability to develop all the necessary phase-appropriate methods, an experienced CMO can accelerate timelines to not only supply the clinic but also to minimize costly method changes later in development. This benefits the ADC manufacturer, the regulatory agencies and ultimately the patient. In contrast, process characterization that has not been performed correctly can lead to issues with regulatory compliance or manufacturing performance. These can force costly re-work and substantial delays in getting to market or can result in tight tolerances for the proven acceptable ranges, greatly restricting manufacturing.
AbbVie CMO leverages comprehensive experience to provide partners with unparalleled expertise in delivering launch-ready ADCs that can support accelerated timelines. To learn more about how AbbVie CMO can support the development and manufacture of your ADC, contact us at 1-847-938-8524 or visit www.abbviecontractmfg.com for more details.
2.) Antibody-Drug Conjugates: Pharmacokinetic/Pharmacodynamic Modeling, Preclinical Characterization, Clinical Studies, and Lessons Learned, Hedrich WD et al, Clin Pharmacokinet. 2018 Jun;57(6):687-703