Sonocrystallization & Advanced Particle Engineering technologies from Prosonix meets many of the guidelines laid out by the FDA with respect to their Quality by Design (QbD) initiative, aimed at guiding (the ICH Q8 guidelines of 2004) the pharmaceutical industry to improved invention, development and commercialization of structured products using technologies that will result in superior product quality.

QbD is a scientific, risk-based, holistic and proactive approach to pharmaceutical development and improvement, covering structured product design through to drugs used by the consumer. An understanding of how the API (Active Pharmaceutical Ingredient) attributes and manufacturing process relate to its performance should be sought.

New Chemical Entities (NCE) are selected by considering clinical efficacy, bioavailability, stability and processing. Within this selection process the physical form and solid-state chemistry (polymorphs or diverse crystal habits), raw material consistency and synthesis should be well documented and understood. An improved appreciation of manufacture and design space could also lead to better asset utilisation, quality and lower failure rates. With respect to solid-state chemistry sonocrystallization approaches can transform productivity and at the same time assist in improving flexibility and manufacturing compliance. Rather than using the historic approach to design, manufacture and optimisation of an API process via a ‘process down' view, we need to use a newer approach via a molecule-to-product philosophy whereby there is in essence molecular design of the product property.

Crystallization is a ubiquitous and critical manufacturing unit operation in the manufacture of APIs and almost every chemical process that produces solid form involves at least one crystallization step, either for intermediate separation, final product purification, or for the removal of key impurities. Yet crystallization processes are poorly understood and are difficult to control. With Prosonix methods we can:

• Control the crystal nucleation event, which is key to process control and robustness
• Improve process productivity and economics
• Improve the drug product quality and effectiveness by improving physical form
• Avoid the problems of classic series based approach to isolation and development
• Eliminate downstream problems by controlled crystallisation

For each unit operation of the crystallization or particle engineering process the following issues are considered:

• - Understanding how process parameters affect CQAs (Critical Quality Attributes)
• - Conducting a risk analysis/assessment to:
•     o Identify critical process parameters and materials attributes
•     o Develop risk reduction strategies
•     o Establish appropriate control strategy to minimize effects of variability on CQAs
•     o Evaluate risk in terms of severity, likelihood, and detectability

Critically we should understand sources of variability for each material, component, and processing used in the delivery (device) and evaluate the impact of this variability on delivery performance for the drug product. In serving our customers Prosonix considers rational Design of Experiments (DOE) and will work with our clients to ensure appropriate in-process controls for your pre-formulation drug products.

Successful collaboration with Prosonix can maximize the chances for success as part of a rational risk assessment program.

Prosonix Sonocrystallization & Advanced Particle Engineering technologies are potentially "best available" for API solid-form manufacture.