Addressing the challenges
Potential solutions would be to increase the dose concentration to fit within the classic 1-mL volume limitation, or to expand
the dose to a larger volume. Concentration has apparently been the choice for many products to date because dosages have increased
in the cases of products like Bristol-Myers Squibb's Orencia, although the 1-mL paradigm has not been broken. In fact, some
recently introduced self-injected products, such as UCB's Cimzia, have concentrations of up to 200 mg/mL.
The exponential relationship between product concentration and viscosity, which often becomes readily apparent above 100 mg/mL,
may limit this strategy significantly because the product either may not be deliverable by self-injection or may not be amenable
to existing fill–finish processes if it is too viscous. Concentration to the necessary level in the final product may not
be possible for all products because in many cases, upstream purification and manufacturing processes may limit the maximum
concentration for the final drug product more than delivery and fill–finish process concerns. Additionally, drug-product properties,
such as pH and osmolality, along with the use of certain excipients, may limit the most appropriate drug-product concentration.
These properties may need to be kept within certain ranges to prevent patient discomfort and site reaction upon injection.
Certain emerging formulation technologies, including the use of nonaqueous solutions, have shown promise towards mitigating
such concerns, but are awaiting regulatory approval.
Increasing the administered volume of drug product offers the ability to deliver a larger dose, but this approach can have
disadvantages. There are limitations to how rapidly a volume of drug can be injected subcutaneously. Although the optimal
injection time may vary greatly by individual drug product, and the literature regarding the relationship between injection
volume and speed is limited, the subcutaneous space cannot necessarily tolerate rapidly injecting larger and larger dose volumes
as tissue disruption and site reaction may occur. Second, if the injection is rapid and the volume is too large, there is
potential for the product to leak back from the injection site, reducing the bioavailability relative to the total dose. Lastly,
a larger volume of product may require a larger device for self-delivery, and, potentially, a longer injection time, neither
of which is likely to be desirable, especially in a crowded therapeutic class.
A potential solution to large-volume injection challenges is the development and use of systems that administer the dose into
the subcutaneous space more slowly. Such systems have the potential to expand the possibilities for self-injection. Due to
the longer duration of injection, the device or system may need to be temporarily attached to the body at an appropriate injection
site; thus, the current industry interest in patch-injection technologies.
Such systems use a bladder, cartridge, or other container for the drug product, which may either be prefilled or user-filled.
The mechanism to force the drug product into the body may be purely mechanical or electromechanical. Due to the widely varying
properties of drug products, which can influence the optimal injection time, systems should be easily adaptable to the demands
of the drug-product developer (e.g., changing the system mechanism or varying the programming of an electromechanical system).
Patch-injector systems specifically can potentially allow for less frequent administration of products already approved for
self-injection and for porting of products approved for IV administration to subcutaneous self-injection. In the case of the
former, a larger dose can be given by a single injection less frequently than currently approved, more frequent regimens,
except in the case where dose-limiting toxicities may exist. The latter can be performed by concentrating the existing formulation
or by using the already formulated dosage strength in conjunction with a larger-volume injection.
Technologies that allow for delivery of higher drug product doses may be applicable to certain emerging needs for mAb products.
For instance, the potential to coformulate (i.e., containing more than one mAb product in a single dose), may be a significant
area of investigation to create next-generation therapeutic options. A major limitation for some solutions is viscosity, which
can be significantly higher than would be expected for a normal mAb solution. The ability to deliver such products in higher
volumes may increase the attractiveness of pursuing combination drug products.
Conclusion
In conclusion, the development of mAb products to address patient needs is complicated by the many physical and chemical factors
inherent to such drug-product solutions. Limitations imposed by existing formulation strategies and the dose volume that can
be delivered by devices may make some products less attractive than currently approved therapies or less likely to gain user
acceptance, even in areas of unmet need. Innovative delivery systems that address the challenges of higher-volume delivery
may enable drug manufacturers to develop products that use more desirable dosing and IV administration regimens.
Bart E. Burgess is manager of business development, self-injection systems, at West Pharmaceutical Services, tel. 610.594.3295, bart.burgess@westpharma.com
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