All opinions are my own.

Tuesday, April 6, 2010

Process Centricity is the Key to Quality by Design

It would be worth reviewing future of pharma’s most discussed acronyms (PAT, QBA and QBD). The following are my interpretation of these acronyms.

PAT (Process Analytical Technologies) means various analytical methods that can be used to convey the state of the sample as soon it is tested.

QBA (Quality by Analysis) is a methodology where the intermediates are tested by “off-line” sampling. The results tell us an “after the fact” state of the manufacturing process. Repeated testing is used to tweak the process till the desired quality product is produced. Such testing is manifestation of lack of complete understanding of the chemistry, process, equipment and any and all variables that interact to produce a product.

QBD (Quality by Design) tells us that the people, who have developed and designed the process, have complete understanding of the process, equipment and their interaction as the sample tested would meet specifications any and all the time. No intermediate sampling is necessary.

Around 2001, the above acronyms were coined for the Pharmaceutical world. They were an instant buzz and synonymous with the current and future state of manufacturing. However, based on reading much of the published literature, I get the impression that “PAT” is considered a cure all and by waving this magic wand, we will produce quality product all the time. This is far from reality.

Published literature also suggests many differing interpretations of these TLA’s and that could be the one of the reasons for very little progress toward QBD adoption.

Any analytical equipment, that costs more than $30,000 (just a number) and requires an analytical chemist to operate and interpret the results for a commercial operation, is expensive. As stated earlier an intermediate process sample tells the state of the sample tested i.e. is the process on track or not. This testing will not and cannot fix the manufacturing process automatically unless the analytical equipment delivers real time results and has feedback loops to control the process stoichiometry and operating conditions. In order to have this level of process sophistication one has to have complete understanding of the chemistry, process equipment and operating conditions i.e. one has to move from “chemistry centricity” to “process centricity”.

What is process centricity? Process centricity to me means moving away from “chemistry centric” laboratory practices and commercializing unit processes by applying appropriate unit operations. This would allow operating personnel to have complete command of the chemistry, process equipment and operating conditions. They can create a process error, observe the process change and can correct the error in minimal time without producing off-spec product. Chemists and chemical engineers have to have incorporated this level of knowledge in the process. This would be perfection (almost) and will not require complex analytical methods to check the process and the product, as we will produce quality. We will achieve QBD i.e. NIRVANA.

Since majority of the APIs are fine/specialty chemicals, their manufacturing practices are very similar. Due to dosage needs the API annual manufacturing production volumes are significantly different from fine/specialty chemical volumes. Thus, it is necessary that we evaluate the current manufacturing practices. Process centricity might necessitate that we change/alter API manufacturing practices. We have to implement methods that are simple and based on good chemical engineering principles and practices. Technologies and methods exist to achieve this change but due to “chemistry centricity” we have not made any significant progress.

As I have explained in a recent article and blogs companies most suited for implementing “Quality by Design” are the API producers and the formulating companies. They have to move away from “chemistry centricity” to “manufacturing centricity” during the technology transfer and incorporate methods that do not require any intermediate product sampling and analysis. This might not look or sound easy, but is the only way to produce a product based on “quality by design”.

It is a bit disheartening for many that almost after ten years, we are still discussing PAT, QBA and QBD. If more than 51 percent of the API producers and formulators stop intermediate sampling, I will consider QBD would become a way of future life in the pharmaceutical world. If this does not happen soon (let us say in the next two to three years) my conjecture is that PAT, QBA and QBD will disappear from the pharmaceutical vocabulary like any other fad. That would be sad because we collectively would have failed to implement a good idea that not only will improve profits but also might facilitate regulatory requirements.

EPCOT International