Delivery by way of the respiratory system creates new stability issues. We know that protein structure determines bioactivity,
and the generation of an aerosol for inhalation can subject a molecule to new modes of structural degradation. Metered-dose
inhalers, familiar to asthmatics, don't work with biopharmaceuticals because of the harsh conditions they present to a formulation
in the form of propellants and their mechanism of action. Some stabilizing excipients cannot be used for inhaled biopharmaceuticals
because they may cause cough or bronchitis side effects, which may be dangerous as well as unpleasant for some patients. Formulation
components cannot be allowed to interfere with aerosol generation, but the protein must be stabilized to survive the delivery
process. Nebulizers expose a lot of the product's surface area for possible interactions, which must be minimized. If the
delivery device is too customized, it may need to be approved through FDA's Center for Devices and Radiological Health as
a medical device before the product's Biologics License Application can be approved. Patient factors (such as lung anatomy,
breathing patterns, and possible pulmonary obstructions) can also affect the efficiency of delivery.
Four key questions are on the mind of a formulator developing a biopharmaceutical for inhalation:
(1) How much drug will exit the device as an aerosol?
(2) What is the size distribution of particles in the aerosol?
(3) How reproducible is the aerosol generation process?
(4) How do the device and its aerosolization process affect the quality and efficacy of the drug formulation?
The first three questions will be addressed by laser diffraction for nebulizer clouds. For the last question, characterization
techniques (as used in preformulation) should be performed on the product that exits the device as well.
Like parenteral drugs, inhaled biopharmaceuticals come in liquid and lyophilized forms. No matter which form the basic formulation
takes, it will go through three main steps toward incorporation into the delivery device:
- Choose the device
- Choose excipients
- Determine related manufacturing issues.
Step 1: Choosing the device. Various types of nebulizers use compressed gas (usually nitrogen because oxygen can degrade proteins) or sound waves to create
droplets and force them out of the device. Potential degradation pathways include high concentrations and heat build-up with
the ultrasonic method and product recirculation with the gas. Mechanical methods of extrusion through tiny holes can cause
Few multidose powder formulations are in development because of humidity and crystallization problems over time with the micronized
(a process that reduces the particles to FPF size) particles. Unit-dose foil blister packs or "multidose" disks and tapes
(really unit-dose multipacks) provide patient convenience. Unit-dose packaging (in blister packs) is usually preferred in
liquid formulations because multidose products require preservatives. Complete sterility is not required for such products
by US or EU regulatory authorities. Instead, inhaled biopharmaceuticals must conform to microbial limits measured in colony-forming
Patients prefer hand-held nebulizers to larger, more complex devices. Most devices are patient-driven, but some companies
are working on powered nebulizers. In this case, the choice depends more on delivery requirements than molecular characteristics.
Because the digestive system is very adept at disassembling proteins, accidental swallowing of the product is avoided more
for cost than safety.
Step 2: Choosing the excipients. The drug indication matters — most asthmatics are sensitive to a range of excipients. Most buffers are known to cause coughing,
an adverse reaction that can expel the drug, so no buffer can be used in an inhaled biopharmaceutical even though pH control
is needed because degradation is often pH-dependent (>5 is best). At 1-6 µm, the dry particles of powdered formulations often
act against each other, requiring excipients or carriers for the larger ones. Formulators must weigh flow and dispersal rates
against each other to determine the optimal conditions for a given formulation.
Multidose liquid formulations require preservatives that can interact with proteins to denature, aggregate, precipitate, or
change their efficacy. Europe is stricter than the US on preservative use, citing that some preservatives can cause bronchoconstriction.
Salt included as an isotonicifier can interact with stainless steel storage of bulk formulations to cause metal-chelated oxidation.
It may be helpful to add sugars, but some can cause bronchoconstriction.