Pandemic Influenza Vaccines—An Unprecedented Manufacturing Challenge
Figure 1. A timeline for manufacturing vaccines in response to a pandemic
|
The "on your mark, get set, go" manufacturing challenge for pandemic vaccine production is unique and unprecedented. The simplified
timeline in Figure 1 illustrates key activities, starting from declaration of a Phase 6 pandemic alert and continuing to production
and release of the first batch, leading to first vaccinations.
It is expected that following a Phase 6 alert, there would be a lead time of about 3 to 4 weeks for the WHO to generate a
master bank of the pandemic strain, which would subsequently be issued to manufacturers. From this point, it would take an
estimated development period of about 6 weeks—which would include process adaptation or optimization of the cell-line to the
new strain and generation of the master seed and working virus banks—to begin production. On a realistic schedule, these 6
weeks of development with concurrent bulking up of cells, plus an optimistic 2- to 3-week quality assurance (QA) release post-production,
allows for a 17- to 18-week manufacturing campaign to produce enough doses to cover 100% of the target population. This is
the best-case scenario, based on a 26-week timeline. In the worst-case scenario, the manufacturing campaign should be able
to produce sufficient doses to cover the first dose of vaccinations before the second wave erupts.
A key challenge in meeting such a demand will be the capability to develop scalable manufacturing processes that are capable
of rapidly deploying a surge production campaign in a facility designed to handle high-risk pathogens (such as H5N1), which
require satisfactory biocontainment. Thus, three design factors—scalability, speed, and biocontainment—would typically form
the conceptual basis of any multipurpose vaccine facility.
Scalability: The Process Engineering Challenge
The influenza vaccine industry has traditionally manufactured seasonal vaccines using an embryonated egg–based process that
has not changed fundamentally since the 1950s. Although an egg-based vaccine offers some advantages and is considered to be
the best strike-back option at hand in the event of an immediate pandemic, production at scale has two significant drawbacks:
aseptic processing limitations from a good manufacturing practice (GMP) point of view, and inefficient process scale-up issues
from an engineering point of view.
In addition, with highly pathogenic avian flu strains that require operating classification levels of laboratory biosafety
level 2 or higher (BSL2+), there would be limitations to biocontainment. These limitations increase with scale for egg-based
processes, and they conflict with operator-environment safety. In addition, demand for a pandemic flu vaccine would have a
surge characteristic, and it would pose an impractical case for responsive egg supply to meet the target of millions of doses
in a very short time. Egg-based production also runs the risk of severe shortfalls in sourcing eggs from biosecure flocks
and of culling of at-risk chicken populations. Also, if the pandemic strain were to target the chicken population (which is
highly possible), egg-based manufacturing may not be feasible, because the eggs themselves might have antibodies against the
circulating strain.
Cell-culture–based and alternative technologies currently in development aim to address drawbacks of the traditional egg-based
platform for influenza vaccine manufacturing. By eliminating the constraints on egg supply, and by drawing on the benefits
of large-scale bioprocessing with enhanced process control and quality assurance, cell-culture–based processes can be ramped
up responsively. Traditional vaccine purification processes based on (ultra)centrifugation techniques are not easily scalable,
and they are operationally difficult when closed processing conditions are required. Filtration and chromatography-based processes,
on the other hand, can be engineered to scale with relative ease. In addition, with single-use units available today that
are capable of handling high throughput, it is possible to have a purification train comprising partially enabled or completely
disposable units for up to 8 out of 10 steps. Disposables-enabled unit operations are central to offering flexibility of scale
to multipurpose facilities designed for meeting fluctuating market demands.
|
