Frank Manella, Alex Garner, and Khanh Ngo Courtney, Element12.09.21
From manufacturing to administration, pharmaceutical products are exposed to several potential sources of contamination, including during the process of filling vials, cartridges and syringes. If not sterile, some drug products can cause harm to patients simply due to their route of administration. Consequently, per FDA requirement, drug manufacturers need to ensure their fill-finish process for certain drug formulations is performed using aseptic techniques. A collaborative partnership with a trusted aseptic processing and sterile fill-finish contract development and manufacturing organization (CDMO) will go a long way towards successfully bringing sterile therapies to market.
As more products that carry a heightened risk of contamination reach the clinic, biomanufacturers need to ensure their fill-finish process is performed in a sterile environment. Sterile fill prevents the growth of bacteria that can degrade the product and reduce its shelf life. In addition to parenteral and injectable products, otic, ophthalmic, and specific topical products must be aseptically processed. Specifically, topical products that cannot contain preservatives, or those with the potential to come in contact with the eye, may require aseptic processing.
How Aseptic Fill-Finish Works
At the most basic level, the fill-finish process involves sterilizing the drug product, container and closure before moving the sterilized products to a cleanroom where they are combined, typically using self-contained equipment. This process requires significant resources and expertise. In fact, aseptic manufacturing and sterile fill-finish for biologics and conventional drugs is a complex and highly specialized discipline that requires purpose-built facilities, equipment and processes, meticulous planning and careful execution and a highly skilled and experienced team.
Manufacturers must be meticulous in their decontamination practices. They must terminally sterilize the drug product, filling components and equipment, sanitize the cleanroom and most importantly, decontaminate the cleanroom personnel.
Cleanroom personnel, simply by living and breathing, are the greatest source of contamination in a cleanroom. All personnel must wear sterile gowns and use proper donning and doffing techniques to limit the spread of contaminants and the cleanroom must have unidirectional air currents to sweep away contaminants.
The best way to avoid contamination is to remove personnel from the room. Manufacturers can automate portions of the fill-finish process using robotics; in fact, most large-scale operations are highly automated today to minimize human intervention and other potential sources of contamination.
Considerations for Large Molecules
Sterility is not the only factor that impacts the safety and effectiveness of a pharmaceutical product during fill-finish. The filling process itself can also impair the behavior and stability of a product, especially if the active pharmaceutical ingredient is a large molecule. Large molecules are more fragile, making it more likely that the wrong protocol will lead to degradation that reduce its potency. Therefore, manufacturers must be aware of the critical attributes of the large molecule they are working with as environmental insults can easily impact the molecule’s structure, and in turn, its function and stability.
Large molecules are especially susceptible to shearing produced by rotary piston pumps that are used to fill vials. Due to the vulnerability of large molecules to force and temperature, manufacturers working with large molecule solutions must take into consideration gentle handling and careful temperature control to mitigate the risk of degradation. The sterile fill process must be validated for the large molecule product to ensure, for example, that its potency and structural integrity are not compromised simply by going through the pump and the fill line.
Finding a Strategic CDMO Partner
Many of the sterile fill labs around the world cater to large batch sizes, making it difficult for smaller companies with a smaller target population to find a collaborative CDMO partner that can assist them with development of formulations for clinical trials. For instance, gene and cell therapies are often produced in small batches, and innovators in this space must compete with developers of larger commercial batch sizes for bandwidth from a sterile fill CDMO. But when selecting a CDMO that specializes in small batch manufacturing, drug developers will want to partner with an organization that has proven expertise in tech transfer for large scale clinical needs and commercial manufacturing to ensure a smooth transition of validation of both manufacturing and analytical methods. Therefore, a CDMO with experience in large batch manufacturing and expertise in small batch manufacturing would be the perfect partner for producing large molecule drug product therapeutics.
In selecting an aseptic CMDO, a client should examine an organization’s relationship with the local FDA/DEA District Office as well as the reputation of their overall quality assurance program and the experience of their management and technicians. A developer should also consider a CDMO’s equipment and capabilities to determine if the organization can fill their desired configuration (vials, syringes, cartridges, etc.). Furthermore, manufacturers should consider if the CDMO has the correct certifications to manufacture and support the product in its current phase and should assess the turnaround time the partner requires to manufacture and release test the product for use in humans.
Developers should consider if the CDMO has experience with working with large molecules. Filling large molecule therapeutics, especially advanced therapeutics such as gene or cell therapy, operates on a much smaller and different scale and unit than small molecules. The CDMO who has experience working with large molecules would also take into consideration the pump and fill rate, size of tubing to accommodate the larger viral particles or cells, different methods of sterilization, etc. as they consult with the client to design the sterile fill process.
In addition to evaluating technical expertise and experience, robust quality programs, and reputation with local FDA and regulatory agencies, drug developers should also evaluate how easily they can access their chosen CDMO. Several factors should be considered beyond proximity, including whether the CDMO offers clients the ability to view all steps of the manufacturing process remotely via a large viewing window into the aseptic core, local camera set-up, or comparable arrangement.
With personalized medicine becoming more prevalent, small batch fill-finish will become more of a necessity. A trusted, experienced CDMO partner will be able to provide manufacturers the skills, techniques and attention they need to ensure their products remain safe and shelf-stable from the moment they get packaged in the manufacturing plant to when they are administered to patients.
Frank Manella, Consultant, Element
Frank’s expertise extends to the design, construction, and operation of contract manufacturing facilities (CMOs) capable of filling potent and non-potent sterile compounds. The growth of several aseptic CDMO businesses, as well as the successful licensing of various new chemical entities and ANDA and NDA filings, have been accelerated as a result of his technical background and deep understanding of the pharmaceutical, biotechnology, and IVD/medical device industries.
Alex Garner, Director of Formulation and Clinical Trial Manufacturing, Element
Alex Garner’s experience extends from Chemistry and Manufacturing Controls (CMC) development, process and formulation development, clinical trial batch manufacturing, through packaging and documentation. His background provides a wealth of knowledge and comprehensive support to biopharmaceutical clients whose product portfolios include small and large molecule development.
Khanh Ngo Courtney, Ph.D., Sr. Director of Biologics, Element
Khanh Ngo Courtney’s experience extends from R&D to analytical method development, validation, implementation, method transfer, and optimization of test methods for the cGMP setting per USP and ICH guidelines. These skills provide her with the foundation for effective authorship of INDs, BLAs and MAAs for biological therapeutic molecules, as well as responses to requests and questions from the FDA, EMA, and PMDA. Khanh holds a PhD in Biochemistry from the University of Wisconsin-Madison.
As more products that carry a heightened risk of contamination reach the clinic, biomanufacturers need to ensure their fill-finish process is performed in a sterile environment. Sterile fill prevents the growth of bacteria that can degrade the product and reduce its shelf life. In addition to parenteral and injectable products, otic, ophthalmic, and specific topical products must be aseptically processed. Specifically, topical products that cannot contain preservatives, or those with the potential to come in contact with the eye, may require aseptic processing.
How Aseptic Fill-Finish Works
At the most basic level, the fill-finish process involves sterilizing the drug product, container and closure before moving the sterilized products to a cleanroom where they are combined, typically using self-contained equipment. This process requires significant resources and expertise. In fact, aseptic manufacturing and sterile fill-finish for biologics and conventional drugs is a complex and highly specialized discipline that requires purpose-built facilities, equipment and processes, meticulous planning and careful execution and a highly skilled and experienced team.
Manufacturers must be meticulous in their decontamination practices. They must terminally sterilize the drug product, filling components and equipment, sanitize the cleanroom and most importantly, decontaminate the cleanroom personnel.
Cleanroom personnel, simply by living and breathing, are the greatest source of contamination in a cleanroom. All personnel must wear sterile gowns and use proper donning and doffing techniques to limit the spread of contaminants and the cleanroom must have unidirectional air currents to sweep away contaminants.
The best way to avoid contamination is to remove personnel from the room. Manufacturers can automate portions of the fill-finish process using robotics; in fact, most large-scale operations are highly automated today to minimize human intervention and other potential sources of contamination.
Considerations for Large Molecules
Sterility is not the only factor that impacts the safety and effectiveness of a pharmaceutical product during fill-finish. The filling process itself can also impair the behavior and stability of a product, especially if the active pharmaceutical ingredient is a large molecule. Large molecules are more fragile, making it more likely that the wrong protocol will lead to degradation that reduce its potency. Therefore, manufacturers must be aware of the critical attributes of the large molecule they are working with as environmental insults can easily impact the molecule’s structure, and in turn, its function and stability.
Large molecules are especially susceptible to shearing produced by rotary piston pumps that are used to fill vials. Due to the vulnerability of large molecules to force and temperature, manufacturers working with large molecule solutions must take into consideration gentle handling and careful temperature control to mitigate the risk of degradation. The sterile fill process must be validated for the large molecule product to ensure, for example, that its potency and structural integrity are not compromised simply by going through the pump and the fill line.
Finding a Strategic CDMO Partner
Many of the sterile fill labs around the world cater to large batch sizes, making it difficult for smaller companies with a smaller target population to find a collaborative CDMO partner that can assist them with development of formulations for clinical trials. For instance, gene and cell therapies are often produced in small batches, and innovators in this space must compete with developers of larger commercial batch sizes for bandwidth from a sterile fill CDMO. But when selecting a CDMO that specializes in small batch manufacturing, drug developers will want to partner with an organization that has proven expertise in tech transfer for large scale clinical needs and commercial manufacturing to ensure a smooth transition of validation of both manufacturing and analytical methods. Therefore, a CDMO with experience in large batch manufacturing and expertise in small batch manufacturing would be the perfect partner for producing large molecule drug product therapeutics.
In selecting an aseptic CMDO, a client should examine an organization’s relationship with the local FDA/DEA District Office as well as the reputation of their overall quality assurance program and the experience of their management and technicians. A developer should also consider a CDMO’s equipment and capabilities to determine if the organization can fill their desired configuration (vials, syringes, cartridges, etc.). Furthermore, manufacturers should consider if the CDMO has the correct certifications to manufacture and support the product in its current phase and should assess the turnaround time the partner requires to manufacture and release test the product for use in humans.
Developers should consider if the CDMO has experience with working with large molecules. Filling large molecule therapeutics, especially advanced therapeutics such as gene or cell therapy, operates on a much smaller and different scale and unit than small molecules. The CDMO who has experience working with large molecules would also take into consideration the pump and fill rate, size of tubing to accommodate the larger viral particles or cells, different methods of sterilization, etc. as they consult with the client to design the sterile fill process.
In addition to evaluating technical expertise and experience, robust quality programs, and reputation with local FDA and regulatory agencies, drug developers should also evaluate how easily they can access their chosen CDMO. Several factors should be considered beyond proximity, including whether the CDMO offers clients the ability to view all steps of the manufacturing process remotely via a large viewing window into the aseptic core, local camera set-up, or comparable arrangement.
With personalized medicine becoming more prevalent, small batch fill-finish will become more of a necessity. A trusted, experienced CDMO partner will be able to provide manufacturers the skills, techniques and attention they need to ensure their products remain safe and shelf-stable from the moment they get packaged in the manufacturing plant to when they are administered to patients.
Frank Manella, Consultant, Element
Frank’s expertise extends to the design, construction, and operation of contract manufacturing facilities (CMOs) capable of filling potent and non-potent sterile compounds. The growth of several aseptic CDMO businesses, as well as the successful licensing of various new chemical entities and ANDA and NDA filings, have been accelerated as a result of his technical background and deep understanding of the pharmaceutical, biotechnology, and IVD/medical device industries.
Alex Garner, Director of Formulation and Clinical Trial Manufacturing, Element
Alex Garner’s experience extends from Chemistry and Manufacturing Controls (CMC) development, process and formulation development, clinical trial batch manufacturing, through packaging and documentation. His background provides a wealth of knowledge and comprehensive support to biopharmaceutical clients whose product portfolios include small and large molecule development.
Khanh Ngo Courtney, Ph.D., Sr. Director of Biologics, Element
Khanh Ngo Courtney’s experience extends from R&D to analytical method development, validation, implementation, method transfer, and optimization of test methods for the cGMP setting per USP and ICH guidelines. These skills provide her with the foundation for effective authorship of INDs, BLAs and MAAs for biological therapeutic molecules, as well as responses to requests and questions from the FDA, EMA, and PMDA. Khanh holds a PhD in Biochemistry from the University of Wisconsin-Madison.
