Alex Garner, Director of Formulation and Clinical Trial Manufacturing, Element
Frank Manella, Consultant, Element
Khanh Ngo Courtney, Ph.D., Sr. Director of Biologics, Element
It may seem counterintuitive, but the often-reported shortage of large batch CDMOs and the resulting backlogs in production actually may hit small batch manufacturing companies the hardest. The competition for available sterile fill large batch slots means companies requiring less capacity may unfortunately slip through the cracks in the process.
And yet, advanced and personalized therapeutics (like cell and gene therapies) generally use large molecules and are produced in small batches. That’s where the market seems to be headed.The ideal solution, therefore, would be for these smaller companies to partner with a CDMO specializing in small batch manufacturing when producing large molecule drug product therapeutics. In time, it’s likely that more such CDMOs will come online as the advanced and personalized therapeutics market matures.
When finding the right partner, it’s important to fully understand the ins and outs of sterile fill, to be able to match the CDMO’s capabilities with the pharma manufacturer’s needs. Together the organizations can arrive at a strategy to develop formulations for clinical trials at smaller scales.
There are several aspects to consider when understanding sterile fill and finish:
- The fundamentals of a sterile fill and types of products that need sterile fill
- Manual processes versus automation
- Challenges associated with sterile fill for large molecule formulations
- Considerations when partnering with a sterile fill lab
Let’s take a look at each of these considerations more closely.
Sterile Fill Fundamentals
All FDA-approved drug products must comply with Current Good Manufacturing Processes to ensure they are safe, pure, effective, and fit for intended use. To meet these requirements, drugs that cannot contain preservatives must be produced in a sterile fill lab, which manufacturers, packages and labels these drugs under strict aseptic conditions.
Sterile fill and finish is essential to prevent infections in patients caused by contaminated drug products. But as previously indicated, most large-scale sterile fill labs are currently operating at capacity to produce COVID-19 vaccines as well as various COVID-19 treatments, and that poses a challenge to small-batch manufacturers looking to develop a new drug on a small scale for early-stage clinical studies.
Pharmaceutical products are susceptible to many types of contamination, particularly when filling vials, cartridges, and syringes. Complicating matters, an increasingly greater number of products on clinic shelves now actually carry a heightened risk of contamination, because they cannot contain preservatives. This increases the demand on biomanufacturers to have a sterile environment for their fill-finish process.
Aseptic processing is particularly important for otic, ophthalmic, and topical products. For example, topical products that cannot contain preservatives must use sterile fill, to prevent bacterial growth that may reduce the effectiveness of the product or shorten its shelf life. Therefore, the FDA requires that drug manufacturers ensure their fill and finish process for certain drug formulations, using aseptic techniques.
At its core, the fill-finish process requires the sterilization of the drug product, container, and closure. The sterilized products are then moved to a cleanroom to be combined (in most cases, using some type of self-contained equipment).
Understandably, aseptic manufacturing and sterile fill finish for biologics and conventional drugs is a complicated process demanding highly specialized capabilities. This extends not only to having purpose-built facilities, equipment and processes, but also to well-trained and experienced teams that can execute the meticulous plans involved in the process.
Decontamination practices are of utmost importance. The drug products, filling components and other cleanrooms must be scrupulously sterilized, the cleanrooms must be sanitized – and the cleanroom personnel themselves must be decontaminated. The significance of proper decontamination procedures for cleanroom personnel cannot be understated; most industry observers agree that personnel are often the greatest source of cleanroom contamination.
To limit the spread of contaminants, cleanroom personnel must, obviously, wear sterile gowns and use appropriate techniques for donning and removing those gowns. The cleanroom itself must be designed with unidirectional air currents to avoid inadvertently re-introducing contaminants into the room.
Of course, the best possible way to remove the risk of personnel contaminating the cleanroom would be to remove personnel from the cleanroom. That’s why many manufacturers have chosen to automate portions of the fill-finish process using robotics. Most large-scale operations today are highly automated, which minimizes the risk. For small batches, however, many operations are still be done by hand, so meticulous cleanroom sanitation practices are essential.
Manual Processes Versus Automation
As an extreme quality control measure, the sterile fill/finish process relies more on manual processes compared to most drug manufacturing.
However, aseptic processing has come a long way in 50 years and automation is heavily used in aspects of the process, such as closed vial filling, blow/fill/seal, and so on. Many of the larger commercially available sterile filling lines are automated, with the exception of preparing the bulk drug product. Such lines, however, are most commonly in large scale commercial manufacturing.
In smaller scale operations, a number of processes must still be done by hand. These include the addition of ingredients to a blender for uniform mixing, and transferring this blended mix to a sterile filler. Once the vials are filled, the next manual step is to transfer the vials to a capper to seal the vials.
As discussed earlier, human intervention can lead to contamination unless workers undergo and adhere to special aseptic training and procedures. This training emphasizes proper operation of equipment to ensure sterile conditions in the manufacturing rooms and to guard against “shedding.”
Sterile Fill Considerations for Large Molecules
It’s not just sterility in the fill-finish process that affects a pharmaceutical product’s safety and effectiveness. Large molecules are much more susceptible than small molecules to degradation by agitation, sheer stress, and prolonged exposure to high room temperatures or more direct heat sources.
In cases where the active pharmaceutical ingredient is a large molecule, the filling process itself is a factor in the behavior and stability of the product. Because large molecules are inherently more fragile, using the wrong protocol can hamper the effectiveness of the finished product. And because small batch sizes require the same amount of QC testing as large batches, smaller batches can be more expensive to produce, on a per-unit basis.
The shearing forces from rotary pistons pumps used to fill vials can also damage large molecules. Furthermore, because large molecules can create a more viscous product, inconsistent filling is not uncommon. As the viscosity of the product increases, sterile filtering becomes more difficult.
To guard against instability or degradation of the product, large molecule solutions must be handled gently, under carefully controlled temperatures. Unless the sterile fill process is approved for large molecule products, just going through the pump and fill line may be enough to compromise the product’s potency or structural integrity.
These are not inherently obvious problems. A lot of knowledge and experience is involved. Manufacturers need to understand as much as possible about protein physiology and the ways in which production processes can adversely affect molecular structures – and the function and stability of the finished product.
Finding a CDMO partner
As may be clear by now, there are many moving parts to the challenge of sterile fill/finish, not just for companies working with large molecules, but especially for companies manufacturing such products in small batches. Coordinating all those moving parts and levels of experience is difficult, and thus identifying a CDMO partner that can assist in development of formulations, and appreciates the challenges described above, is critical.
Finding the right partner can be its own challenge, though. Many sterile fill labs focus on large batch sizes, so they may lack the skill set to meet the needs of smaller manufacturers. What’s more, larger companies occupy much of the already-scarce space available in sterile fill CDMOs, making smaller companies – for example, makers of cell and gene therapies – scramble for what’s left over. That’s why a CDMO specializing in small batch manufacturing would also be the ideal partner for producing large molecule drug products.
So, how should a company go about selecting an aseptic CDMO? The right partner should have a solid relationship with the local FDA/DEA District Office, along with a positive reputation for their overall Quality System Program, managed and run by technicians with appropriate demonstrated experience.
Is the CDMO’s equipment suited to fill product in the desired configurations (vials, syringes, cartridges, etc.)? Does the CDMO have the proper certifications to manufacture and support the product in its current phase? Can they meet the turnaround timetable required to manufacture and release the product for human testing?
The CDMO must have experience with working with large molecules. The filling of large molecule therapeutics uses a much smaller and different scale and unit than small molecules.
A CDMO with experience in large molecules will make designing the sterile fill process that much easier. They will innately understand the necessary pump and fill rates, the size of tubing required for larger viral particles or cells, and the different methods of sterilization demanded by the operation, for example.
Perhaps the bandwidth shortage among large batch CDMOs is actually opening up a new market for companies focused on serving small batch developers. As personalized medicine starts taking up more market share, more companies catering to small batch fill-finish will need to emerge.
For now, it’s incumbent on the developer to ensure they work with a CDMO that is experienced in small batch skills and techniques – and has the available time to devote to the particular needs of small batch producers. That is the best way to ensure that products are safe, pure, effective, and fit for intended use, and stay that way from the manufacturing plant through their use by patients.
About the Authors:
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.
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.
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.
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