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CDMOs address the unique challenges of liquid and lyophilized forms as well as preparing for the large capacity needed for COVID-19 vaccines.
Biologic drug products are typically formulated into a liquid or lyophilized powder form for the fill/finish step during biomanufacturing. As the much-anticipated COVID-19 vaccines move through the pipeline, and some are already in use under emergency authorization, manufacturers will need to optimize vaccine formulation and establish robust fill/finish operations.
In general, biomanufacturers face challenges in the fill/finish step when dealing with biologics that have been formulated into either a liquid form or a lyophilized powder. One main challenge is understanding the product’s characteristics and behavior under different circumstances, including what parameters may be necessary to lyophilize the product, for instance, says Dhaval Patel, senior manager, Manufacturing Science & Technology, Catalent. It is also important to understand the inspection requirements for the product because there could be different criteria for liquid vs. lyophilized drug products, he adds.
“From a mechanical perspective, the challenge is to procure the required equipment based on any product’s characteristics and batch size; some products require higher rotations per minute during mixing, which necessitate high-speed mixers, while varying batch sizes will need different vessels because of the required minimum working volume,” he states.
The difference in formulation may also require different approaches to fill/finish. For instance, Patel notes that different sizes of filters and membranes for sterile filtration may be required. “For a manufacturing partner, the biggest challenge is to build a catalogue of capabilities that cover different customer and product needs, and to be able to incorporate realistic lead times associated with having to source any new or additional equipment/components needed for manufacturing,” he says.
Christy Eatmon, senior scientist, pharma services, at Thermo Fisher Scientific says that, sometimes, liquid biologic products have stability challenges that can be overcome by formulating the product as a lyophilized biologic. “Lyophilization may be necessary to decrease prohibitive storage temperature requirements, allowing for shipment and storage in areas of the world where refrigeration isn’t as easily accessed. Lyophilization also extends the shelf-life of the biologic and can protect a labile molecule from degradation in an aqueous environment,” she says.
Eatmon does note that lyophilized and liquid biologic drug product vials are both filled in a similar manner, but the different formulations do pose different processing challenges. “The hold times during compounding of a lyophilized product are typically shorter than those of a liquid product and affect the production timeline and planning that must be done in advance of the API addition,” she explains.
A major difference regarding these two types of formulations for biologic drug products, Eatmon points out, is the varying fulfillment times for each project. For instance, liquid products require less time for development and, thus, have shorter lead times. On the other hand, she emphasizes, the lead time for lyophilized products must incorporate the freeze-drying cycle and characterization of that cycle. “Characterization is important because the parameters of that cycle affect the production of a high-integrity cake, and producing a cake without collapse, melt-back, or shrinkage requires additional development,” she explains.
In both cases, Eatmon continues, it is necessary to understand the stability of the formulation, but for lyophilized products “we need to develop the cycle through calorimetric measurement, define critical process parameters, and optimize the cycle,” she says. “We also must do characterization of the lyophilized product and complete the stability profile work.”
A main technical challenge lies in the development work that occurs prior to filling a clinical batch, Eatmon adds, stating that “lyophilized products require more preparation in choosing the right excipients, bulking agents, and cryoprotectants as well as the cycle development.” The lyophilized process also requires additional characterization testing.
Fill/finish for vaccines requires a similar approach to biologics, Patel notes. In addition, the nature of the incoming vaccine drug substance will determine what equipment, filters, and other components are needed for formulation. “From a fill/finish perspective, vaccines and typical biologics require either a thaw, pool, and filtration process of the final product; or a thaw, pool, dilution with buffer, and then filtration of the final product. The configuration of the vial or syringe components, together with any additional packaging requirements, will determine what labeling or packaging of the vaccine or biologic is necessary,” he states.
It is also important to note that some of the COVID-19 vaccines are multidose and require the use of an evaluated preservative, includes Eatmon. For example, messenger RNA (mRNA) vaccines use nanoparticle technology to enhance stability, as opposed to the aqueous-soluble molecules that are typical of standard biologics. Furthermore, with recombinant protein vaccines, the use of an adjuvant could be needed in order to stimulate immune response. There are also unique differences between live vaccines and attenuated or inactivated vaccines, Eatmon notes.
“These differences require considerations in terms of facility classification and engineering controls as live viruses must be separated from other types of vaccines,” Eatmon says.
At the end of the day, COVID-19 vaccines are no more challenging than any other biologics from a fill/finish perspective, assures Patel. Where the real issue sets in, however, is in the management of time when the vaccines are out of controlled storage. This time management issue poses an additional challenge because of the requirement to freeze the filled product within a certain amount of time, he observes.
“Ensuring operations are managed in a timely manner means all the necessary resources for the process must be staged and be ready to perform manufacturing activities as soon as product moves to the next stage, minimizing the time out of storage,” Patel emphasizes.
“The challenge posed by the COVID-19 vaccines at the fill/finish stage of manufacturing stems from the fact that these candidates are dispersions,” adds Eatmon, who explains that the dispersion factor makes the vaccines sensitive to shear stress because they are a lipid nanoparticle rather than a solution.
“CDMOs/CMOs [contract development and manufacturing organizations/contract manufacturing organizations] must account for the different types of COVID-19 vaccines,” Eatmon states. “For some of the mRNA-based vaccines, once the drug substance has been manufactured, it must be frozen to maintain stability. The temperature-sensitive liposomes typically require additional monitoring during processing to ensure that filtration pressures are not exceeded and that temperature excursions do not occur,” she explains.
Eatmon further explains that facility capacity and suite segregation must be considered, noting that these vaccines must also be filled almost immediately after the end of the compounding process.
“For this type of drug product manufacturing, you want to make sure your CDMO/CMO has end-to-end experience and is knowledgeable in starting from drug substance production. A skilled CDMO/CMO will have the experience to know how to handle specific vaccine challenges that increase substantially as these products become more complex,” Eatmon adds. For example, it is strategically beneficial for a CDMO/CMO to understand that facility design is integral to efficient manufacturing, not only due to rapid hold times, but also due to the need for segregated suites for live viruses and compounding areas that require organic solvents, she says.
The use of particular excipients also plays a factor in developing the most conducive formulation for ensuring vaccine stability as well as bioavailability in vivo, but determining which excipients to use may itself be a challenge. Some excipients used to enhance the stability of a vaccine, such as polysorbate, for example, are often foamy, Eatmon points out. As a result, the manufacturer or CDMO/CMO must pay close attention to foaming during liquid formulation filling and must reduce the rate of vial filling to accommodate excipients that foam, she notes.
Other excipients can also be adhesive, Eatmon explains, meaning that they cling to the product contact surfaces, such as filter membranes and disposable tubing. “Excipients such as these can dilute the concentration in the formulation, so we must compare component compatibility prior to use in fill/finish,” she states.
“In some cases, the need for an adjuvant could pose significant challenges to the process as a proper recirculation loop needs to be included as part of the line and can impact the overall filling strategy,” she adds.
Patel, meanwhile, explains that, for vaccines, the API itself can be considered the most conducive component. “All vaccines are based on a different platform; some are based on antigen and some of the recent COVID-19 vaccines are based on mRNA. Other than the API, excipients sometimes include: antibiotics, to prevent contamination by bacteria; adjuvants that help stimulate a stronger immune response; and stabilizers, to keep the vaccine potent during transportation and storage,” he notes, further explaining that the types of API used all help to ensure the product’s stability, and that each type plays a different role while in storage.
As fill/finish operations are predominantly outsourced to CDMOs/CMOs, these organizations are well suited to handle fill/finish of COVID-19 vaccines as they start to hit the market. Catalent is an example of a manufacturing partner that is well positioned to deliver on both scale-up and meeting demand, Patel notes. He says that additional capacity can be created by effective management and by expediting expansions.
“The supply of excipients and drug substance is obviously critical to the scale-up of drug product manufacturing, but the procurement of components used in manufacturing, such as vials, stoppers, seals, filters, labels, cartons, and other consumables is also important,” Patel says. He emphasizes that creating partnerships between suppliers can help alleviate some of these challenges as well as streamline manufacturing efficiencies to meet demand and timelines.
“Additionally,” he continues, “storage can become a challenge for vaccines without sufficient warehouse space, especially where specific storage conditions are necessary.” Normal production of a typical biologic, in contrast, does not require storage of both empty and filled components in such large quantities, which makes it much easier to manage. The situation with COVID-19 vaccine production, however, is slightly different because of the extremely high number of doses needing to be manufactured. “This constraint can be rectified by utilizing a third-party storage partner,” Patel asserts.
Eatmon points out that one of the biggest challenges for CDMOs/CMOs, even before the COVID-19 vaccines and therapies entered clinical trials, is capacity. “At Thermo Fisher, we have continued to invest in our facilities and build new lines. We are currently expanding sites across North America, APAC [Asia Pacific], and Europe to add development and CGMP [current good manufacturing practice] commercial production lines to support a range of capabilities, including live virus, aseptic liquid, and lyophilized vial filling,” she says. Equally important, she adds, is maintaining robust quality standards.
An additional consideration for CDMOs/CMOs is the ability to handle different types of product formats, including capacity for liquid, lyophilized, and prefilled syringes, Eatmon says. It is also important to have access to the right type of capacity across different geographies worldwide.
Feliza Mirasol is the science editor for BioPharm International.
Vol. 34, No. 2
When referring to this article, please cite it as F. Mirasol, “Meeting Fill/Finish Challenges for COVID-19 Vaccines,” BioPharm International 34 (2) 2021.