Meeting Manufacturing Challenges Tied to Extended-Release Injectables - Pharmaceutical Technology

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Meeting Manufacturing Challenges Tied to Extended-Release Injectables
Industry experts working with extended-release injectables discuss challenges and solutions to formulating and manufacturing these complex products.


Pharmaceutical Technology
Volume 36, Issue 5, pp. 40-47

Regulatory challenges

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.

Technological challenges

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 desired.

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 production.

(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.


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