31 August - 3 September 2021
GMP News No. 713
27 April 2006
The End of Process Validation?
The "FDA Guideline General Principles on Process Validation" is now 19 years old, and the process validation concept described in it "may now be ready for the trash bin" - or at least that is what Laura Bush writes in her article on process validation in the online edition of the US magazine Pharmaceutical Technology. Since many companies endeavour to understand their processes better, traditional process validation becomes less important.
Experts agree that, in the course of time, the issue of process validation has gradually turned into extensive documentation instead of focussing on its proper meaning: assuring quality. A whole branch of industry has emerged around the topic of process validation, leading to an inflated documentation. And still there are processes that do not "work correctly".
The new keyword is process understanding. Up till now, many processes were not thoroughly understood. However, validation activities based on insufficient process understanding do not make sense, according to Professor Muzzio from Rutgers University. As further weaknesses of the current validation model, Muzzio sees the practice that the Quality Control has the task to guarantee product quality by discarding bad batches. In his opinion, that is inefficient.
Another expert, Dr Philippe Cini from Tunnel Consulting, states that medicinal products do reach a high standard relative to the Six Sigma quality approach. However, this high quality is not built into the product during production, but is achieved through quality management systems discarding bad products.
A further weakness of the current validation concept lies with the avoidance of changes at the cost of even preventing improvements, since changes could always be relevant on a regulatory level. This can go as far as to refrain from generating new data in order to avoid the impression (which could be evoked by the new data) that the company does not understand its own processes.
In case of new products, the firms often know relatively little about the corresponding processes, since the development phases are kept as short as possible in order to be able to market the products soon. Every day passed without the new product being on the market is considered as a financial loss. Consequently, it is not until commercial-scale production begins that larger amounts of data on the process are generated.
With regard to this practice, we are witnessing a change at present. The companies have begun to invest more time in developing and improving their processes.
Application examples of PAT studies by Pfizer, AstraZeneca and Genentech confirm this change. Interestingly, these companies have different objectives: Pfizer puts the emphasis on reducing deviations, AstraZeneca aims at "real-time release", and Genentech places special focus on early stages of process development. Here, Genentech chooses Design of Experiments (DoE) as a means to achieve process understanding. Surprisingly, when this method was first used for the development of the monoclonal antibody Avastin, time could be saved because the really critical parameters (in a narrow range) were found using DoE. Further tests then focus on just these parameters.
For Genentech, this approach was also the key to quickly obtaining the marketing authorisation, as their way of proceeding enabled them to hand in statistically valid data and validation could be limited to a small number of parameters.
In the future, industry and authorities will concentrate more on "good science". To Ron Branning from Genentech, it is less important to practise exhaustive science than to focus on the issues at hand. Prof Muzzio, too, sees that, as soon as a new quality standard is achievable, it leads to higher expectations.
Click here for the complete Pharmaceutical Technology article:
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