Antibody-Drug Conjugates (ADCs) are a relatively new class of therapeutics, with the first promising clinical trial results dating back to the 1980s. Since then, ADCs have undergone robust and exponential growth. Recent market analyses forecast that the ADC market will reach USD 15 billion by 2025 and is projected to exceed USD 40 billion by 2030.
Key drivers behind this growth
The following factors are primarily responsible for the expansion of the ADC market:
- rising global cancer incidence;
- expansion in certain regions, supported by favorable national policies, especially in Asia-Pacific;
- growing interest in dual-payload ADCs to overcome treatment resistance;
- potential efficacy of ADCs in treating multiple cancer types;
- Expanding applicability to other pathological conditions beyond oncology.
ADCs are engineered to selectively target and destroy cancer cells while sparing healthy tissue. This precision, however, comes with increasing potency and complexity, making their production a high-stakes endeavor in terms of containment and safety. Today, the applications of ADCs have expanded to include not only cancer treatment but also autoimmune disorders and infectious diseases. ADCs are continuously evolving and increasing their efficacy to eliminate the targeted cells – e.g. cancer cells – while preserving healthy tissue. This feature leads to its success and to its rapid growth, which in turn leads to greater higher production. The end result is an increase in containment complexity. Typically, ADCs consist of three elements – a monoclonal antibody, a linker (that could be cleavable which are almost 80% or non-cleavable) and a cytotoxic payload – where the antibody is conjugated to the cytotoxic payload via a linker.
Innovations in cancer research have also led to the development of dual-payload ADCs. This new class is highly promising, as conjugating two payloads with different mechanisms of action (MOAs) can significantly enhance therapeutic efficacy and reduce relapse rates. However, the more complex the structure, the more intricate and challenging the manufacturing process becomes. The production of antibody drug conjugates involves many critical phases starting from cell culture (such as CHO cells for example) to produce the antibody. It then progresses thought the synthesis of the anti-cancer drug(s) and of the linker(s), followed by conjugation, purification, formulation, final filling, and packaging of the finished therapeutic dose. Each phase presents inherent different risks and requires specific containment strategies.
Production phases and related risks
Monoclonal antibodies (mAbs) are proteins synthesized in the laboratory to mimic the function of antibodies found in the human immune system. They are usually made by animal/mammalian cells (such as CHO, Chinese Hamster Ovary) which are cultivated under strictly controlled conditions. The next step involves the clarification of the solution and the antibody purification. This phase poses minimal health risks, as mAbs are not inherently toxic. However, depending on the production method, there may be potential exposure to biological agents (e.g., bacteria, viruses), so containment strategies must be evaluated on a case-by-case basis. cGMP cleanrooms and closed systems as well as BSCs or aseptic containment isolators are therefore necessary to preserve the sterility of this process and prevent contamination. While mAb production poses relatively low risk to operators, the same cannot be said for the synthesis of the cytotoxic payload. This is unquestionably the most hazardous phase in ADC production.
Payloads are often rated OEB 5 up to OEB 7, they can be lethal in infinitesimal quantities, and may pose a risk of DNA damage. Due to their extreme toxicity, this phase requires the use of aseptic high-containment isolators to simultaneously protect operators, the environment, and the cytotoxic compound from contamination. These isolators typically operate under positive or negative pressure. Those isolators are equipped with glove ports, HEPA filters, closed transfer systems, and integrated cleaning and decontamination systems. In contrast, linker toxicity depends on its chemical structure, and its synthesis poses safety risks because it implies the handling of active chemicals and solvents. Therefore, aseptic containment isolators are also used in this phase, with containment depending on OELs. Next, we move to the conjugation, purification, and quality testing phases, all of which share similar safety risks for operators due to the presence of cytotoxic payloads, while also requiring strict process sterility. For these reasons aseptic high-containment custom isolators (from OEB5 up to OEB 7) play a critical role in ensuring safe and sterile operations.
The final phase is formulation and fill-finish, where the ADC is prepared in its final buffer and filled into vials or syringes. Fill-finish operations are conducted in Grade A isolators, which provide a sterile environment and high containment. FPS Pharma custom fill-finish isolators can be easily integrated with automated filling lines and equipped with CIP and SIP systems to ensure the utmost safety and efficiency. As we’ve seen, ADC is a multi-phase process that demands strict aseptic conditions, high-potency API containment, and full compliance with regulatory guidelines to ensure both operator safety and product quality. Each phase presents distinct challenges and risks, requiring a comprehensive approach to risk management, along with the right containment strategies and safety protocols.
FPS Pharma is globally renowned as a trusted partner in the engineering and manufacturing of innovative, custom high-containment isolators used for handling and producing highly potent and sterile pharmaceutical ingredients, such as ADCs, a class of HPAPIs. Given that every ADC manufacturing process presents unique requirements, only custom aseptic containment isolators designed for toxic applications can ensure full regulatory compliance and meet all necessary safety and quality standards. FPS Pharma recognizes how critical Occupational Exposure Limits (OELs) are in the production of ADCs due to the unique and ultra-potent nature of these compounds. For this reason, FPS Pharma engineers Occupational Exposure Band (OEB) isolators, from OEB 4 up to the latest OEB 7, equipped with advanced safety and monitoring systems tailored to your specific process and OEL requirements, ensuring safe and compliant ADC operations.
Fonte: https://www.fps-pharma.com/adcs-manufacturing-isolators/