Quality by Design—a Fundamental Paradigm Shift in Pharmaceutical Manufacturing

Surveying the Landscape of Solid-Dosage Manufacturing

Experts take a look at the journey travelled thus far and where pharmaceutical manufacturing is heading over the next decade.

Quality by design (QbD) has been a topic of discussion in the pharma world for the past decade, ostensibly because it places an emphasis on deeper process understanding and knowledge from a first-principles baseline as opposed to meeting product quality parameters post manufacturing.

Designing oral solid dosage forms to meet the fitness-for-use requirements of a given patient population for a particular medicine has required engineers and scientists to realise the need for basic models that will allow them to predict powder and product properties and design the processes to deliver those properties. Greater understanding of powder rheology, the compaction process and the role of tablet and compression tool design has allowed pharmaceutical engineers to more effectively use granulation techniques to yield a powder and ultimately, an oral solid dosage form that will meet the user requirements for research clinicians. Given the reality that many current API candidates have lower solubility and permeability properties, this greater understanding of the unit operations is paramount to successfully use the new chemical entities produced by the discovery scientists that are handed off to the development scientists for appropriate formulation.

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QbD has impacted the evolution of basic formulation unit operations by imparting the responsibility of delivering a capable process apparatus to the designers of the particular machine and implicit to that responsibility is the knowledge of how to control a given unit operation to target. Armed with more knowledge of basic operations, the manufacture of tablets and capsules is responding to the ever present pressure from healthcare payers to lower the cost of unit doses by evolving to the use of continuous manufacturing.

Continuous manufacturing of drug products is a common theme at most of the recent pharmaceutical industry trade shows and accounts for an ever increasing percentage of publications in the scientific literature. Linking well-understood unit operations together with a carefully designed control strategy to enable continuous manufacturing of tablets is a monumental task that is seeing remarkable progress and pace.

For a continuous manufacturing process, the measurement of the many variables of each given unit operation are accomplished with various process analytical technology monitors as inputs to a variety of feedback, feed forward and model predictive control schemes to enable the production of acceptable dosage forms. Providers of compression equipment and compression tooling must be aware of the need for improvement of their products so that tablet presses offer capable data monitoring and instruction input pathways to affect compression control based on the properties of the output of the preceding unit operation. Better control provides a more capable process, thus, yielding higher quality. Compression tooling must evolve to provide more robust tool life, resistance to sticking and tool innovation that will enhance continuous manufacturing capability indices.

Communication of needs is a key to innovation no matter the subject. It is sometimes the case that what the innovator develops turns out to be a solution in search of a problem, and the patient is, therefore, not served by the effort.

Next time a problem is encountered with a product used in tablet compression, which in reality should not be an issue for the purchaser, feedback to the developer is in order and should be valued by the manufacturer. Cost reductions in medicine manufacturing are the responsibility of all vendors, but without open and honest feedback concerning medicine manufacturing, hardware progress is limited to that which the innovator thinks is important, but may not hit the real target from the view point of the consumer.

About the Author
Charles N. Kettler is director of Natoli Scientific