The unique targeting capabilities and encouraging clinical trial results of antibody drug conjugates (ADCs) have made them an exciting and promising treatment in the fight against cancer. According to recent analysis, experts anticipate the ADC market to be worth $10 billion annually by 2025. Drug makers face a number of challenges in the manufacturing process for ADCs. Here we provide you with five key areas where pharmaceutical manufacturers may face the biggest uphill battles.
1. CONJUGATION TECH TRANSFERS
An ADC is the result of an antibody and a small molecule toxin linked together. This means on the one hand, a manufacturer is faced with the typical challenges associated with the biologic itself, such as maintaining the activity and physical state of the molecule, keeping endotoxin levels low, and maintaining sterility/low bioburden; on the other hand, the manufacturer is subject to challenges arising from the handling highly potent molecules that require high containment, as well as carrying out the chemical conjugation steps which typically use a mixture of aqueous/organic solvents. Any company that plans to work with ADCs must have specialized containment equipment, such as isolators, as well as access to experts who are trained in conjugation chemistry and biologics processing, and robust safety procedures for working with highly potent compounds.
Multiple conjugation chemistries are employed to make ADCs, and some methods may be more susceptible to raw material and process variations than others. This can be true for non-site-specific conjugation methods that typically result in a stochastic distribution of different component species that must be consistent from batch to batch. These variations are less problematic for site-specific conjugations in which the resulting ADC contains significantly lower levels of heterogeneity. In any case, the manufacturing process must be able to produce the same product profile every time. Ideally, during process tech transfer, the ADC produced by the CDMO at small scale or during an engineering run is analyzed by both the client’s QC lab as well as by the QC testing lab that will be doing the release testing. Both labs must be able to verify that both the transferred analytical methods are comparable. Verification runs should also be carried out with the same raw materials to be used for GMP manufacturing in order to eliminate any impact of differences in raw material quality.
As with analytical method transfers, having a project team with bioconjugation experts from both organizations who are in frequent communication is key to resolving any potential technical issues. Frequently, the client sends a person-in-plant (PIP) for the first few manufacturing campaigns to ensure a successful tech transfer. In-person training may also be required.
2. ANALYTICAL METHOD TRANSFERS
As with any pharmaceutical, a drug manufactured under cGMP has to meet certain specifications. Ensuring the product can be manufactured and tested to meet those specifications is necessary to initiate clinical studies. With ADCs specifically, there can be challenges in method transfer to the manufacturing and testing sites. For example, the product must meet the drug-to antibody (DAR) ratio. With DAR, for some conjugation chemistries and assay methods, both the conjugation reaction and the assay may each have some variability. Minimizing these ensures the drug will fall within the necessary specifications. DAR is important as it impacts the potency of the drug.
In addition, the FDA recommends cell-based potency assays used for ADCs in Phase I clinical trials. Cell-killing is part of the mechanism of action of an ADC and a cell-based assay is used to demonstrate the drug’s ability to do this. These types of assays have more inherent variability than non-cell-based assays and as this is a very specialized service, most clients prefer to manage
these assays themselves to limit complexity.
To complete a successful analytical method transfer for an ADC, both the client and the CDMO must produce comparable test results from the same sample. In some instances, an in-person method transfer and appropriate training is needed to ensure success. In any case, having a project team with analytical experts from both organizations who are in frequent communication is the key to resolving any potential technical
One of the most notable challenges of scaling-up ADCs is the process variation caused by changes in equipment, scale, and raw materials. Like the scale-up of many biologics, a process carried out at a milligram scale multiple times with consistent results does not necessarily mean the same outcome will occur at larger scales. There may be instances when the reasons for variations at scale are not clear; however, the expert process development team should be able to identify what changes are needed to make the results consistent from milligram to gram-andbeyond scales. Identifying these changes can be especially challenging with ADCs due to their relative complexities and the resulting variations that are often seen upon implementation of different processing equipment and raw materials, addition rates/mixing, reactor geometries, largerscale purification and even dissolved gasses in the conjugation reaction with some chemistries.
This is why it is ideal to have an established scaled down model (typically 0.1 g to several grams) that mimics as closely as possible the unit operations for clinical scale manufacturing. This applies to both conjugation as well as subsequent purification (by tangential flow filtration, chromatography, and the like). An example of a process that is difficult to mimic at milligram scale is ultrafiltration/ diafiltration, which is used to remove small molecule impurities from the ADC product.
4. CDMO FACILITY
For ADCs, a CDMO must have a facility designed with the proper engineering controls to provide product and personnel protection from the highly potent compounds. This includes isolators for highly potent powder handling for ADC conjugation, and, for ADC fill-finish, a fill line with lyophilization capability fully-enclosed in an isolator. Containment at the level required for handling ADC toxins and ADCs must be verified through surrogate testing, which can be challenging with the most potent toxins currently under development. ADCs must be verified through surrogate testing, which can be challenging with the most potent toxins currently under development.
An ADC manufacturing/fill finish facility is a substantial investment, which is why most ADCs are manufactured at CDMOs. Most smaller companies, and even some larger companies, do not have enough of a pipeline to justify the level of facility investment needed for ADC manufacturing and/or cannot keep the facility fully utilized. In addition, the supply chain for manufacturing ADCs is complex, including linker/toxin manufacture, antibody manufacture, conjugation/formulation/ QC and stability testing, and fill finish. The more of these supply-chain elements a CDMO can offer at a single site, the better for the client.
Single-source CDMOs offer multiple advantages. First, they eliminate the considerable risks often present in the supply chain for an ADC. If the “parts” of an ADC (antibody, linker, cytotoxin) are made at different sites, each has to be manufactured and shipped safely and on time. Given the globalnature of today’s manufacturing environment, this can pose a risk to not just the timeline but also potential damage to the product. Second, a single-source CDMO offers inherent flexibilities. For example, a client using multiple suppliers’ reserves facility space for an ADC’s antibody, drug/linker, conjugation, and then fill finish. If unexpectedly the site making the antibody falls a month behind schedule the client would then have to coordinate this change in schedule with multiple sites as opposed to coping with the delay at one organization. Finally, utilizing a single source CDMO reduces an ADC’s time to market. For example, if the client can perform both the conjugation to produce the ADC drug substance. conjugation to produce the ADC drug substance and the fill finish of the drug product at one location and with one CDMO, this saves a considerable amount of time in scheduling, testing, and release if those processes are well integrated, which ultimately helps get your product into the clinic faster.
As a single-source CDMO for ADCs, Ajinomoto Bio-Pharma Services has made significant investment into its new ADC high containment facility, technical staff, and manufacturing equipment. Additionally, at the same facility, Ajinomoto Bio-Pharma Services offer high quality fill finish services for a broad range of sterile dosage forms for liquid and lyophilized vials. The goal is to deliver both high quality ADC conjugation and fill finish contract manufacturing services to developers pursuing the ADC market.
As with any project, all teams involved must have clear lines of communication established from the beginning. Any issues need to be resolved in a timely fashion and in a collaborative manner. Good communication is essential to achieving a successful manufacturing campaign, especially for transferring complex processes that produce lifesaving medications.
There are ways to determine whether a potential partner can communicate effectively. When vetting partner can communicate effectively. When vetting a CDMO for your project, it is highly recommended to speak with references who are the CDMO’s previous or existing clients. In addition, it is important that a CDMO is willing to agree to the way the client wants their project executed in terms of the frequency of communication betweenthe client and the CDMO. For example, the CDMO should indicate if they allow the sponsor to assist with troubleshooting analytical issues or process issues or if the sponsor is able to have someone present at their facility for the initial manufacturing campaigns. This information as well as details on the CDMO’s experience, staff, available equipment, safety program, and more can be collected through the use of a questionnaire.
While many of these challenges exist with other biologics, the complexity of ADCs can make the drug development process and tech transfer process even more difficult. However, through the right expertise, fruitful partnership, strong communication, and working with a single source CDMO, such as Ajinomoto Bio-Pharma Services, for development through fill finish, these problems can be overcome and ADCs can continue to have an increased impact as targeted cancer therapies.