Beyond containment: integrated line design reduces risk and complexity

In ADC manufacturing, pooling or formulation ensures that the recipe is adhered to while providing the highest level of operator and product safety and minimizing product loss. © Syntegon

External cleaning of filled containers removes highly potent residues from the exterior to protect personnel and downstream processes. © Syntegon

Syntegon supports customers around the globe with integrated vial lines for highly potent pharmaceuticals. © Syntegon

Glove ports allow for necessary interventions in the isolator environment while protecting both product and operating personnel. © Syntegon

The vials are thoroughly cleaned before they are transferred to the highly potent filling process. © Syntegon

For highly potent vial filling lines, an integrated isolator is the preferred, and often the most robust, choice. © Syntegon

Sarah Springer is Global Product Manager Vials, Ampoules and Filling Systems at Syntegon. © Syntegon

Highly potent active pharmaceutical ingredients (HPAPIs) and highly potent drug products such as antibody-drug conjugates (ADCs) are becoming increasingly important. As demand grows, pharmaceutical and biotech manufacturers as well as CDMOs are under increasing pressure to combine containment, product and operator protection, regulatory compliance, and operational efficiency in fill-finish manufacturing. The key to success lies in a seamless line that addresses these challenges through one holistic solution.

The pharmaceutical industry is experiencing strong growth in highly potent active pharmaceutical ingredients (HPAPIs) and highly potent drug products such as antibody drug conjugates (ADCs). According to a recent report from GlobalData1, innovative biopharmaceutical ADCs are currently transitioning from a niche drug class to a major therapeutic and commercial modality. In fact, an increasing number of ADCs are set to reach blockbuster status, while the total number of ADCs that are actively being developed or marketed has tripled over the last five years. While most ADCs developed so far are treating cancer, there is also enormous potential in other areas such as autoimmune and infectious diseases as well as cardiovascular and metabolic disorders.

Currently, China is one of the leading markets for early-stage ADC development and trial initiation, with above-average patent filings, and a growing installed base of production lines. In comparison, the U.S. and Europe are placing a stronger focus on late-stage execution and final approvals. Global regulatory engagement reflects the growing confidence in the clinical value and differentiation of ADCs, while strong industry investments confirm these highly potent drugs as a long-term strategic priority with high growth potential. Between 2017 and 2024, global sales increased from 1.6 to 13.6 billion USD, corresponding to a CAGR of 35.8%. By 2031, the market is expected to reach 65.2 billion USD, driven by both a growing number of approved ADCs and an increasing share of high-revenue products.

Main challenges in fill-finish operations

While this market outlook offers significant potential for pharmaceutical and biotech manufacturers and CDMOs, they also face a number of challenges when pooling, filling, and further handling these cost-intensive, highly potent drugs. ADCs are almost exclusively produced as lyophilized solutions to ensure stability and prolong shelf life before they reach patients. From an economic perspective, every single drop counts. Only by keeping product loss to an absolute minimum and ensuring that every vial is filled accurately can manufacturers turn ADCs into viable commercial products.

In addition to product yield, robust protection of both products and operators in line with international regulations is one of the most important prerequisites. For example, EU GMP Annex 12 mandates strict separation of the aseptic process zone from operators. In the case of highly potent drugs, containment is essential not only to ensure consistent product integrity, but also to protect people from contact with HPAPIs and the final drug product. Isolators, as well as effective and practical cleanability and washdown, are crucial to reducing human intervention and ensuring that ADCs are delivered to patients in the highest possible quality. This requires a consistent design for highly potent vial processing along the entire line, from pooling, cleaning and sterilization to filling, freeze-drying and capping, external cleaning, and beyond.

Containment by design

When designing a new vial line for highly potent drugs, containment and consistent process control must be considered from the outset. This applies not only to the main fill-finish operations, but also to the upstream process steps. In ADC manufacturing, pooling or formulation plays a critical role: It ensures that the HPAPI, i.e. the concentrated active substance that will turn into the highly potent drug product afterwards, is safely mixed with the required additives while maintaining strict separation between product and operators. This requires appropriate redundancies, for example for measuring devices and air filtration, as well as dedicated interfaces between pooling and fill-finish.

The filling and closing equipment itself also requires adequate containment in line with regulatory guidelines. For highly potent vial filling lines, an integrated isolator is the preferred, and often the most robust, choice. Integrated filling stations, minimized toxic zones, and highly automated operations reduce manual interventions. For example, automated, tool-less changeovers, gentle transport systems, and automated loading and unloading equipment for the freeze-dryer make operations much safer for both products and people and can boost yields significantly. Moreover, cleanability must be designed into the line from the beginning to ensure that no highly potent residues remain in the process zone after each batch. A combination of external cleaning and washdown of all non-removable components is currently the best option and should be assessed during the mock-up phase of a new line.

One line, many options

Integrated barrier technology and additional functions further support safe and efficient processing. Automated filter test racks for pre-use post-sterilization integrity testing (PUPSIT), for example, help increase patient safety and prevent batch losses by detecting filter defects before product exposure. Automated active and passive viable monitoring can extend settle plate change intervals, reducing manual intervention while improving process safety and machine availability.

Other important options include offline and stand-alone online glove testing systems, as well as smart filling features designed to improve product yield. Precise weighing and filling during start-up and at the end of the production cycle help increase the number of correctly filled containers and helps make full use of the highly valuable product. In addition, automatic detection and correction of underfilled containers supports an efficient production flow and further minimizes product loss. To make full use of their potential, these options should ideally be considered and integrated during the planning stage of a new line. At the same time, existing equipment can often be upgraded at a later stage, allowing manufacturers to enhance performance and process safety over time.

An integrated approach from a single source

By combining pooling, filling, handling steps, and additional options in one holistic line, pharmaceutical manufacturers and CDMOs benefit from numerous advantages. All equipment can be tailored to the specific requirements of highly potent drugs from the outset. Clearly defined interfaces across the line help accelerate production ramp-up and streamline overall processes. Working with a single supplier also reduces project and regulatory complexity, as it minimizes potential weak points between machines and suppliers. This, in turn, supports faster qualification and validation, ultimately helping manufacturers bring new ADCs to market more quickly.

For highly potent vial lines to perform reliably from day one, manufacturers need more than an equipment supplier. They need a partner with in-depth industry knowledge, a clear understanding of regulatory requirements, and the in-house expertise to provide further value-adding services such as product assessments, testing and qualification concepts, washdown verification, and lifecycle services. As a strategic lifecycle partner to the pharmaceutical and biotech industry, Syntegon helps customers reduce risk and manage complexity through a pragmatic, integrated approach. As ADCs are moving toward significant commercial potential, Syntegon is already supporting customers worldwide with integrated vial line solutions to bring their highly potent drugs to market quickly and at the highest quality. 

1 https://www.globaldata.com/store/report/antibody-drug-conjugate-market-landscape/ 
2 https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf