Release profile and control strategy
PharmTech: What additional comparability concerns need to be addressed so that the release profile of these products is not affected?
(Herbert, Alkermes): Scale-up is associated with significant attention to comparability. Any changes in scale or unit operations are subject to
significant regulatory oversight and require buy-in from the various regulatory bodies. Comparability becomes especially important
when a change of manufacturing site is considered. Finally, having a good handle on the long-term stability of a product and
its performance characteristics is a key component of comparability analysis over time. The key performance aspect, the extended
release, is critically important because any loss of control or drift of release rate is potentially impactful: if, for example,
the release rate increases over time on storage, such a change would be cause for concern about durability of efficacy and/or
safety of the drug.
Stickelmeyer (Lilly): Ideally, during development of an ER injectable product, an appropriate in-vitro assay can be developed that correlates with animal and human pharmacokinetic studies. In addition, consideration of orthogonal
methods to characterize critical quality attributes such as particle size, for instance, is highly desirable to confirm that
changes during development have not impacted the release profile.
Tipton (Evonik): In all cases of new formulations, stability data is needed. In some cases, the new dosage form may be more stable as compared
with an immediate-release formulation. For example, a drug that has been supplied as a ready-to-inject solution may be more
stable when formulated into a solid crystalline drug form in a microsphere. It is possible that the new formulation may present
new stability issues. For example, perhaps an ingredient is a polymer with a low glass-transition temperature. So accelerated
stability at elevated temperature may not be possible. Or, a novel formulation may be a suspension and additional data may
need to be developed on the settling characteristics of that suspension. Also, items that may not have been important in the
immediate-release formulation may be important in the ER formulation. For example, conventional syringes are lubricated with
silicone oil. This small amount of silicone oil may interact with the formulation and result in unexpected properties, such
as plasticizing a polymer used in the ER formulation.
PharmTech: What considerations do manufacturers need to keep in mind when developing and carrying out a control strategy for these products?
Stickelmeyer (Lilly): The technical risks encountered during development of complex, ER parenteral dosage forms can be addressed by incorporating
a thorough understanding of the product quality attributes into the formulation and process design. This, in turn, will result
in a robust manufacturing control strategy. For example, understanding the release mechanism (e.g., molecular weight of polymers,
diffusive, and degradation properties) is critical to ensuring that there is no unintended or burst release. The use of orthogonal
techniques during development to fully characterize the formulation and process design space should be considered to assess
the impact of changes in formulation, primary packaging, process and/or devices. Data should be tied to clinical data to ensure
that safety and efficacy are maintained.
Development of discriminating in-vitro tests may require nontraditional approaches such as a modified flow-through cell with low flow rates. With ER rates, the
test may need to be performed over a long time period and thus include measures to minimize evaporation and assure stability
of the active ingredient during the test period. Sufficient time points that characterize the release profile should be obtained.
Multiple tests may need to be developed including a quality control test for release, an accelerated release to assess safety,
and a test for assessing comparability for changes that reflects the actual release period.
Finally, an understanding of inherent microbial activity of the formulation and the impact of processing and hold times should
be assessed. Assessment of equipment and facilities for acceptable microbial and extrinsic particulate control should also
Tipton (Evonik): There will certainly be additional analytical methods required for an ER product. Most importantly, a method will be needed
to confirm the extended release. A product that claims one-month duration, has to be tested to show that one-month delivery.
A microsphere product will need a technique to confirm particle size. A liposome formulation likely will require a test for
free lipid. In many cases, a test for free drug is desired. Depending on the technology used, additional testing for drug
uniformity is likely. Finally, sterility testing may need to be adapted for a more complex formulation or geometry—for example,
how to test that the inside of an implant is sterile.
(Thiel and Loffredo, Hospira): Manufacturers need to identify the product's critical product attributes and process parameters. For example, for PLGA microspheres,
the particle-size distribution might be a critical product attribute due to its potential impact on the release profile, and
the batch size, volume ratio of oil and aqueous phases, temperature of these phases, type of mixer, mixing speed, and duration
of mixing may be critical process parameters that could impact the resulting particle size distribution. The PLGA molecular
weight (perhaps measured by intrinsic viscosity) may be another critical product attribute.