PharmTech: What regulatory challenges do ER injectables manufacturers face compared with more traditional injectable products?
Stickelmeyer (Lilly): As noted, ER injectable preparations, such as those based on biodegradable polymers, liposomal preparations, micellar preparations,
or encapsulation, are considered to be complex dosage forms and as such, additional data (e.g., production scale data) may
be required in the marketing authorization dossier. Unfortunately, specific regulatory guidances have been limited for these
parenteral dosage forms. Typically, pharmaceutical scientists have applied the concepts used for modified oral products as
a guide. More recently, industrial groups have collaborated with regulatory groups to address the challenges.
Tipton (Evonik): There may be a challenge with the development of an in-vivo–in-vitro correlation for some complex products. But in any case, one must have some data on how batch-to-batch performance is achieved
for ER. The sterilization technique discussed above is an important regulatory aspect. Aseptic processes can be intricate,
and therefore, a solid development history and validation will be required for product approval. Cleaning methods should be
carefully reviewed as well. As the number of ingredients (polymers in particular) used increases, cleaning process equipment
can be more difficult.
In addition, filtration may not be a possible process step in many complex formulations, or may only be possible at an early
stage in production, so extra care is required for foreign particulates as well as bioburden. Many of these efforts in process
validation and product specification will be held in high regard by the regulatory reviewers.
(Herbert, Alkermes): In addition to comparability and mechanistic understanding, site-specific manufacturing is more complex for ER products than
for other injectables. A site change may necessitate additional clinical studies for ER injectables, for example.
In addition, the process development section of a company's common technical document submission tends to be longer and more
multifaceted when filing for an ER product. In general, we have found that regulators understand the processes for ER products
and are supportive of the technology.
PharmTech: What technological gaps exist for manufacturing ER injectables? What's needed going forward?
Stickelmeyer (Lilly): There are technological difficulties associated with the manufacture of very small particle-size ranges for nanoparticle
formulations. Improvements in achieving narrower particle-size distribution for more consistent release and improved injectability
are needed. Technology improvements for sterilization processes of fragile biological products and polymer systems are also
Tipton (Evonik): In some cases, market needs only require modest production levels, so full economy of scale has not been realized. For products
that require small-volume powder filling, there is a limited source of equipment. Isolation and drying of particles can require
significant equipment and facility time increasing cost. There remains a relatively small number of suppliers for some critical
raw materials, so backup sourcing can be a challenge in some cases.
Of note, using a continuous processing method can help to maintain the same equipment for both smaller scale and larger scale
(Herbert, Alkermes): For polymer-based ER injectables, a polymer that is stable at room temperature and can withstand the temperatures associated
with shipping and warehousing would be an important technological advancement. Most microsphere products use PLGA-based polymer,
which requires cold-chain distribution.
Sterilization and validation methods are also an area of near-term need. For example, the industry needs more refined ways
of performing gamma-irradiation. Another opportunity is tailoring of molecular structure for intrinsic control of release.