REGULATORY ISSUES IN VACCINE MANUFACTURING

Vaccines are generally (although not always) prophylactic biomolecules, therey making their development and commercialization complex. A set of basic regulatory criteria from the WHO applies to vaccine manufacture, regardless of the technology used to produce the products. Licensure of a new vaccine is based on the demonstration of safety and effectiveness, and the ability to manufacture in a consistent manner. The manufacturer facilitates the development and evaluation of new vaccines by anticipating and addressing the regulatory issues involved. General regulatory issues that are applicable to other biologicals, such as detection of adventitious agents and improved test methods that are reliable and sensitive, are valid for vaccines as well. Additional vaccine-specific issues include determining correlates of protection necessary for evaluating efficacy, improving assays for potency, or finding animal models that can be used for the evaluation of efficacy when human clinical trials are not feasible or unethical (17).

Although the use of animal-cell culture for manufacturing viral vaccines is the current practice, regulatory challenges tied to this protocol are extensive. The WHO requires additional reports to ensure safety of the population receiving vaccines generated out of cell culture. Required tests include confirming tumorigenicity, checking for extraneous agents of the cell substrate, residual HCP and residual DNA, equivalence of cell culture and egg-based vaccines (i.e., antigenic characterization by cross-reactivity of specific antisera and animal protection studies).

Generally speaking, single-use technologies reduce bottlenecks in manufacturing environments. Implementation of single-use technologies in vaccine manufacturing should be the gold standard. Single-use steps eliminate the need for cleaning and validation, which automatically eliminates any kind of cross-contamination, while maintaining the aseptic path. Apart from eliminating cleaning and validation, the reduced set-up time associated with these systems is crucial to meeting the time-sensitive demands of vaccine manufacturing. Single-use process steps can be easily assembled and are quickly configurable, thereby reducing downtime and capital investment in facility and equipment.

Aseptic processing has always received attention from regulators in the biopharmaceutical sector because of the high risk of microbial contamination that can affect patient health, particularly when the molecule is a prophylactic material. Traditionally, aseptic processing is done in critical or controlled areas, depending on the risks associated with certain steps in the manufacturing process (16).

Interestingly, discarding a device, without having to prove that it has been sufficiently cleaned, is one step that both regulatory authorities as well as manufacturers seem happy to embrace (18). This approach is especially beneficial for vaccines, because vaccinating large, healthy populations, carries much greater risks than treating relatively small groups of people with conventional drugs.

For manufacturers attempting to minimize the risks of vaccine-batch contamination, single-use technologies provide an important avenue for enhanced safety. Single-use systems that the supplier presterilizes and bundles together can further simplify set-up. With fewer opportunities for operator error, single-use technologies can improve safety and production economics. Some single-use products, such as bags, also save space, because they lie flat and can be stacked before use. Unlike permanent storage tanks, single-use bags are typically ordered on an as-needed basis to avoid excess unused equipment (18).

Although single-use technologies can play a prominent role in egg-based vaccine manufacturing, in the areas of filtration, storage, and at connection points, their use multiplies in cell-based applications. More specifically, single-use technologies can be used for media preparation, clarification, and cell harvesting in upstream processes as well as in buffer preparation, capture, and polishing chromatography steps, purification and filling in downstream processes. Single-use bioreactors are an example of the increasingly growing role of single-use technologies in upstream processing (18). A recent study demonstrated the successful development of a complete single-use downstream process by implementing depth filtration, UF/DF, and membrane chromatography for the purification of recombinant baculoviruses (12).

Finally, environmental concerns have been cited as key motivators for moving toward single-use systems in biomanufacturing (19). This belief stems from the observation that although single-use systems require significant energy to produce them and generate plastic waste, the amount of energy and water consumed in the production of water-for-injection and steam used in clean-in-place/steam-in-place operations can more than offset the waste issue. When waste-to-energy plants are considered for disposal of the plastics, the environmental benefits of single-use technologies are further enhanced (20). By one estimate, the commutes of the plant employees account for more than 50% of the total carbon emissions associated with biomanufacturing (19).

The above observations demonstrate that single-use technologies make it possible to develop and scale up processes quickly and facilitate manufacturing by reducing the cleaning-validation burden.

CONCLUSION

Despite the advances in vaccine manufacturing across the globe, regulatory, technical, and manufacturing hurdles still stand in the way of companies seeking to take a candidate product to the clinic and eventually to market. The identification of suitable vaccine candidates is only one of many hurdles involved in the translation of a vaccine candidate from the bench to the clinic (21). Identifying suitable antigens, adjuvants, and delivery methods are just the beginning of vaccine development (22). Public demand for safe and effective vaccines continues. In addition, regulatory requirements have led to an emphasis on well characterized, safe vaccines (21).

The need for well defined, single-use platform processes to reduce complexities, ensure safety, and maintain timelines to market, therefore, is only growing. Additionally, because process development provides a technological foundation for manufacturing, analytical methods and assay development for characterization and potency determination must be part of a company's approach. Such an approach helps to lay the groundwork for successful commercialization (22).

SUMA RAY is a senior process development scientist at Sartroius Stedim India Private, Ltd., suma.ray@sartorius-stedim.com
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