Contract development and manufacturing organizations (CDMOs) have long played a critical role in the global biopharmaceutical industry. While CDMOs have historically not been the most visible or recognized contributors to the development and delivery of medicines to patients around the world, the emergence of the COVID pandemic helped place a well-deserved spotlight on these companies. One particular CDMO service offering that has been strongly impacted by the pandemic is sterile manufacturing. The need to rapidly and safely develop, manufacture and deploy novel vaccines on a global scale created a dramatic spike in demand for sophisticated sterile manufacturing services. Combine this once-in-a-generation global health crisis with a consistent acceleration in development activities related to other therapeutic subclasses of biologics which require complex sterile manufacture and lyophilization solutions, and it is easy to see that the biopharmaceutical industry will be increasingly looking for trusted CDMO partners in this area. When it comes to sterile manufacturing, those CDMOs will be charged with leading innovation, identifying and overcoming challenges and delivering a high-quality, personalized and timely service.

Sterile Manufacturing Overview

Patients, healthcare providers, manufacturers and regulators have an intrinsic expectation for effective and safe parenteral drug products. This expectation requires that they be produced to standards of quality, purity and sterility that are uncompromising.

One means to ensure sterility of products which are filled in vials and syringes is terminal sterilization. This process requires exposing a product to very high heat or irradiation in its final container or packaging so that living microorganisms are not present in the end product. It works well for a range of stable drug products that are not susceptible to heat, including small molecule drugs. However, parenteral drug products, which are often fragile and susceptible to heat or irradiation, and which present other challenges as it relates to filling, storage and shipping, require a more specialized and complex fill-finish process that ensures sterility of all components from beginning to end.

Aseptic manufacturing, which is increasingly accounting for more and more of the overall sterile manufacturing market, is able to address the sterilization challenges for those drug products that are unable to withstand the harsh terminal sterilization process. It is a technical, stepwise method that involves cleaning, sterilization and isolation to ensure the drug product and its container/packaging are free of contaminants throughout the entire process.

Many of these more sensitive drug products that require aseptic manufacturing for the means of fill-finish also benefit from lyophilization (freeze drying) as part of their manufacturing process. Lyophilization helps significantly increase product stability and extend shelf life, which can be particularly beneficial for biologics and global vaccine deployment in particular.

Key Considerations for Successful Aseptic Manufacturing and Lyophilization

The ability of a CDMO to offer high-quality, reliable aseptic manufacturing and lyophilization services to its pharmaceutical industry partners hinges on four core components: equipment/facilities; people; robust, mature quality systems and regulatory track record; and customer trust.

Equipment/Facilities: One of the most significant recent innovations in the field of aseptic manufacturing has been a near-complete shift toward automation. The development of single-use equipment that enables complete isolation of the process, in combination with the incorporation of advanced robotics, has dramatically shifted how this work is undertaken, allowing for more flexibility, sensitivity and reliability. This automation is applied to all steps of the aseptic manufacturing process, from formulation to fill-finish to inspection, labeling and packaging.

The role of best-in-class equipment is vital for the lyophilization (or freeze-drying) portion of aseptic manufacturing. This process has several steps, each requiring careful optimization to maintain a product’s quality and function after lyophilization. A successful strategy will balance various key factors, including formulation, temperature and pressure. Of these, temperature selection and control can prove most challenging. Control and characterization of the temperature used for super-cooling are critical for addressing challenges with freeze-drying scale-up. The ability to increase the degree of super-cooling can have a dramatically beneficial impact on drying behavior. One recent advance in this area is controlled nucleation technology, which allows for freezing, or ice crystal formation, to begin at warmer temperatures. The latest controlled nucleation equipment has shown numerous benefits that can be translated into significant quality improvements and cost savings at the production scale level. Experienced CDMOs are able to incorporate these advanced lyophilizers into their automated aseptic manufacturing processes, providing benefits across both freeze-drying and fill-finish processes.

The facilities that house this equipment are another element of a successful aseptic fill-finish and lyophilization operation. Leading CDMOs are adept at designing, creating and maintaining aseptic suites within a very controlled environment that allows for differential pressure and meets proper ISO classification.

People: The key advances that have been made in equipment have significantly impacted the role that people play in the aseptic manufacturing process. The shift toward automation and robotics has dramatically reduced the number of individuals required to successfully operate a state-of-the-art aseptic manufacturing line. However, the complexity of this latest equipment necessitates that the individuals overseeing its operation be experienced and well-trained. As such, while the overall labor force directly involved in aseptic fill-finish operations is shrinking in size, the technical requirements of the personnel responsible for maintenance of new, complex equipment and associated utilities have increased significantly. In addition to technical expertise, it is important that these individuals create and operate within a culture of aseptic responsibility. Adopting the proper mindset and implementing the appropriate practices are key to maintaining a sterile environment free of contamination.

Robust, Mature Quality Systems and Regulatory Track Record: Biopharmaceutical companies face multiple risks as they develop new products from within their pipeline.  There are clinical risks, financial risks, manufacturability risks and quality/regulatory risks, among others. It is important that CDMOs support the products they are manufacturing for their clients by having deep, established quality systems which are suitable for all phases of clinical development as well as being able to support product approval inspections and ongoing in-market compliance requirements. The biopharma landscape is littered with product candidates that were stalled or even abandoned due to the manufacturers’ inability to demonstrate to FDA or other regulatory authorities that the processes in place were performed consistently in a compliant manner. The importance of this capability within the CDMO a drug developer selects cannot be overemphasized.

Customer Trust: While CDMOs can choose to utilize the industry’s newest, most advanced equipment and commit to hiring the best and brightest individuals, one of the most valuable and differentiating characteristics it can provide to its drug development partners is trust. Offering customers a proven track record of CDMO service success, regulatory excellence and uncompromising standards of quality, purity, sterility and stability are key avenues for building that shared trust. Combining those characteristics with cultural and technical fit and a shared commitment to improving the lives of patients provides the foundation for a strong and long-lasting relationship, particularly one involving the complexities of aseptic manufacturing.

The Challenges that Lie Ahead

Despite the significant strides made in recent years, providers of aseptic manufacturing services face several challenges as they work to establish themselves leaders in this area.

Equipment Maintenance and Oversight: With state-of-the-art automated equipment comes the need for diligent maintenance and oversight. This is even more critical in aseptic environments that must remain free of even the slightest contamination. Unlike other CDMO service areas that can be cleaned and shut down without attention for periods between use or requalification, an aseptic manufacturing suite must be vigilantly maintained in a controlled environment at all times regardless of production. These maintenance activities require significant effort and expertise to ensure aseptic environment.

Training of Professionals: The latest and greatest automated aseptic manufacturing equipment continues to get more complex as manufacturers of this equipment strive for greater speed, accuracy and isolation levels. With that comes the need to consistently train the team members responsible for its operation. As new equipment is added, new training is required. Personnel training also extends more broadly to fundamental sterile techniques required for day-to-day operation within aseptic suites. This ongoing focus on training can be a costly, time-consuming process. Against that backdrop, the retention of highly skilled, well-trained team members is important.

Industry Capacity: As aseptic manufacturing continues to increase in complexity with requirements for specialized expertise, it becomes more likely that drug developers, particularly small-to-midsize companies, will increase the rate at which they outsource these activities to CDMOs. Combine this with the continual increase in the number and scope of drug development programs that require aseptic manufacturing, and the challenge of industry capacity becomes very clear. Until more capacity is brought online to align with industry needs, those CDMOs with established and trusted aseptic manufacturing offerings will have no shortage of demand for their services.

Finding The Right CDMO Partner for Aseptic Manufacturing

With the expectation that more and more drug developers will continue to turn to CDMOs for their aseptic manufacturing needs, the CDMOs best able to differentiate themselves stand to benefit most from this increase in demand. Societal CDMO is well positioned in this area following its launch of new, dedicated aseptic fill-finish and lyophilization services earlier this year. A new aseptic fill-finish suite features some of the industry’s most advanced equipment, including a sterile, automated vial filling system with the capability to fill up to 2,000 pre-sterilized vials per hour at a range of volumes, nitrogen overlay/purge, 100% automated weight check, and trays loading capabilities. Additionally, its lyophilization offering incorporates a novel, patented approach to uniformity and instantaneously induces nucleation via pressurization and depressurization. This equipment provides the capacity for lyophilization of approximately 9,500 10 mL vials during each 3–5-day freeze-drying cycle.

The company pairs this cutting-edge equipment with a decades-long track record of quality, reliability, regulatory filing expertise and customer service. Societal CDMO’s team of experienced professionals provides high-touch, personalized service to all of its customers in each area of expertise of the company, including its work in aseptic manufacturing.