What controls do you need over the apertures?
GSK identified four potential quality attributes throughout the development lifecycle to ensure consistent and robust performance
of the product: presence, size, position, and depth of the apertures.
The effect these have on the performance of the product are dependent on the API and core formulation. Those products with
greater robustness are evidenced by a wide tolerance of the aperture size (± 1 mm) with little impact of aperture position
and depth, which provides a broad manufacturing control strategy using generic process controls. Those products that require
more rigorous process controls around the aperture formation will require a unique process recipe, for instance, a high sensitivity
to aperture depth, ± 10 µm, would require specific drill movement parameters to ensure precise aperture formation. Typical
process controls maintain the aperture size within ± 0.2 mm, the position to within 0.3 mm and the depth to within 50 µm of
target.
The online inspection systems, visual imaging, and laser displacement, measure every aperture formed in terms of size, position,
and depth. The recipe-controlled specifications are used to categorize the product as acceptable or nonacceptable. Products
that do not meet the specification are automatically removed from the process flow with a confirmation of removal. During
routine production, the current process efficiencies are being measured at greater than 99.9%.
Does the drilling process affect uniformity or stability?
Figure 4: Dissolution performance of the initial product and after 56 months storage at 30 °C/65 % relative humidity (RH).
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For the products developed to date, GSK typically observed no change in release profile on stability for the drilled products.
Figure 4 shows stability dissolution performance of one product over 56 months with no discernible difference indicating very good
stability and reproducibility. Since the drilling process only exposes a small surface area of the product while the remainder
is coated with a reduced permeability enteric film coating, the shelf life does not appear to be, nor is expected to be, any
different to a cosmetically film coated product.
Dedusting and metal checking are used as part of manufacturing, similarly to compression, reducing potential operator exposure
and contamination downstream. The potential for product damage on downstream processing, such as packaging, was investigated
showing that, using typical equipment, the process was optimized to eliminate potential defects.
How do you scale up the process for commercial production?
Figure 5: Development equipment with on-line inspection systems.
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Post PoC, a development machine has been purpose built to manufacture these products (see Figure 5). This machine will manufacture up to 10,000 units per hour with online inspection of the product quality attributes impacting
performance.
Figure 6: Commercial manufacturing equipment with online inspection systems.
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For commercial production, GSK uses machines that are currently installed in its global manufacturing facility in North Carolina
(see Figure 6). These machines have the same functionality and process parameters as the small-scale equipment, thereby eliminating scale-up
and increasing output (approximately 120,000 units per hour). The process is scale-independent, and the final development
process is transferred directly to the commercial machines. The current manufacturing process exhibits consistent content
uniformity with good variability (mean = 99%, standard deviation = 0.82, based on 14 commercial batches).
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