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Quality By Design: Myth Or Reality?

In the United States, the FDA’s initiative on nudging the pharmaceutical industry to invent, develop and commercialize products using technologies that will result in product quality by design (QbD) is a challenging task.

In the United States, the FDA’s initiative on nudging the pharmaceutical industry to invent, develop and commercialize products using technologies that will result in product quality by design (QbD) is a challenging task. It is also a noble task that will have major business process implications and ultimately high financial impact on healthcare costs.

Through presentations and pilot programs, the FDA is making its case to move the industry toward a win-win situation for all involved, especially consumers. These outlined items if submitted would assist in the approval process and allow continuous improvements. Since this is uncharted territory for drug developers and reviewers, it is necessary for the developers to present information that will convince the reviewers that the process will produce QbD “the desired state” rather than quality by inspection (QbI) “the present state”. Because this is a change in process and mindset, there will naturally be apprehension on the part of industry as it has traditionally worked in a defined comfort zone and is not sure about the value of change.

QBI Versus QBD
With that said, processes are developed and commercialized by chemists and engineers with the involvement of regulatory personnel to comply with the FDA, EPA and OSHA rules and regulations. In this evolution, one has to optimize the impact of their actions when it comes to the total business process. The current QbI methodology creates business processes and inventories that need infrastructure to support quality pharmaceutical production. This costs money and the consumers pay for it. QbD can be equated to Just in time (JIT) as the industry will have total control of the manufacturing process. Volumes have been written about the value of JIT and we all know that it smoothes out the total business process.

The FDA in its expectation of process analytical technology (PAT) framework and QbD stipulate a complete understanding of the interaction of raw materials and intermediates and control of process parameters. In a commercial operation, this will result in a QbD rather than QbI product. This is easier said than done. It requires combined application of knowledge, common sense and stepping out of bounds to establish a new paradigm.

Improving The Manufacturing Process
In this paper, I am reviewing a chemistry outlined in a patent and sharing some of the opportunities to improve the manufacturing process. Process controls can be applied which will produce consistent quality product with no or minimal in-process testing. Similar methods and observations can be incorporated in the development of new chemistries so that we have a QbD process from the outset.

I have chosen production of an active ingredient rather than the formulation of the active pharmaceutical ingredient (API) with excipients. The reason for choosing reaction chemistry is its complexity and the length of time it takes to produce an API. In addition, much has been written about the formulation aspects and very little to none has been written about the manufacture of APIs. Thus, it needs proper consideration.
For the development of a process and chemistry of API’s an alternate approach could be considered. This is “out the box” thinking but worth consideration. Instead of having a mindset that we are developing a “pharmaceutical”, it might be easier to consider that we are developing a “specialty chemical” that might have pharmaceutical value. This should simplify many of the drug development processes.

In this alternate approach, once an optimum process has been developed for a specialty chemical where we know the interaction of each raw material and intermediates, the critical parameters and how to control them, every regulatory requirement can be included to meet the necessary standards. Since we have to apply regulatory requirements only on one process, the product and process development is simplified. Such an approach might also be a way to reduce the “time to market”. I believe that if we are able meet quality and performance specifications all the time, we might have to contend with fewer regulations also.

By using the “right” process we will produce a “quality” product, which in turn will reduce waste, work in process inventories, regulatory oversight and bureaucracy i.e. simplify the business process. Doing it right the first time, by a repeatable process is the key and has to be the method of choice. If we are able to accomplish this from the outset, we would not have to live with 2.5 Sigma processes, and the process of continuous improvement would be less expensive compared to after the fact improvements.

Process Considerations
The following considerations are necessary in the development, simplification and commercialization of the “right” process. Most of these are being used in the manufacture of chemicals. The understanding and application of these also allows the control of processes using commercially available process control technologies. The following are taught in chemical engineering curriculum, thus these are not new.
1. Total process feasibility. Each unit process step has to be reviewed individually and collectively.
2. Is the stoichiometry optimized?
3. Are the heat and mass balance optimized?
4. Are the reaction kinetics understood and applied to simplify the process?
5. Are proper unit operations being used?
6. Are the necessary steps in place to reduce the cycle time?
7. Can a single solvent be used for the whole process? This economizes solvent recovery and the related investment.
8. Can we eliminate isolation of intermediates?
9. Are the raw materials to be used easy to handle?
10. How can the phase separation be improved and simplified, if it is part of the process?
11. How can I improve the conversion of each process step? Lower conversion means that there is raw material loss, which has to be recovered and/or treated in the effluent system or disposed of as hazardous waste. Lower conversion also means that unless the unconverted raw materials or impurities are removed prior to the subsequent reaction steps, additional impurities will be created adding to the process complexity.
12. Are the safety requirements met and is the process safe?
13. If the developers were operating the process, what process modifications and/or additions would be included to have the simplest process?
14. Is the process meeting all of the environmental standards?
15. Is the rework eliminated and/or minimized?
16. Is the process economical?

A thorough understanding of every interaction allows one to have a complete grasp of the impact of every process change and its influence on the product quality. If above considerations are followed all the time QbD becomes a natural part of the development process. In addition to the above considerations, each chemistry and process has its nuances and if recognized and implemented can simplify the manufacturing processes further. The incorporation also allows one to have complete control of the process. One can react to any unexpected changes and deliver quality. From my experiences, it also allows one to repeat the mistakes. If this can be done, developers will have done an excell