Wednesday, March 2, 2011

Process Wednesday: "Ruggedness"

In the process chemistry literature, there are many words that are liked, e.g. 'simple', 'efficient'. But our mentor-by-literature Neal Anderson (and others) seem to prize the word 'rugged' or 'robust' more than most. In his book "Practical Process Research and Development", Dr. Anderson describes a rugged process as such:
A rugged or robust process must included 3 qualities: high-quality product must be prepared within the expected time cycle; the process must accommodate relatively broad purity ranges for the inputs, whether prepared or purchased; and the process must operate within parameter ranges, e.g. temperature and pH, which are readily obtainable during the expected process time-cycle. Unless the process is rugged, additional time is incurred, and the quality of the drug substances may be jeopardized. Appropriate in-process controls (IPC) are necessary to maintain low operating costs. Processes must be as simple as possible, but superficially simple (simplistic) processes may be eventually prone to errors. 
In his recent review*, the R-words pop up again:
An "edge of failure", or the conditions at which process failure will result, lies at the limits of the PAR (proven acceptable range) or beyond them at some undetermined point. After appropriate optimization a robust manufacturing process will "tolerate the expected variability of raw materials, operating conditions, process equipment, environmental conditions, and human factors."**  
In general, rugged processes operate comfortable far from the edge of failure. 
Interestingly, (completely underappreciated blog) Kilomentor has a bittersweet answer as to 'why' ruggedness may be prized in our modern times:
The Kilomentor approach to process development is geared towards the simple, rugged and dependable process step and avoids the technically demanding step, which uses sophisticated and expensive equipment. This keeps with the tenor of the times wherein so much process work is being moved to the developing economies where at least for now labour is plentiful, so long as the work process is rugged.
*Anderson, N.G.; Burdick, D.C.; Reeve, M.M. "Current Practices of Process Validation for Drug Substances and Intermediates." Org. Process. Res. Dev. 2011, 15, 162-172.
**Process Robustness - A PQRI White Paper. Pharm. Eng. 2006, 26(6), 1; http://www.pqri.org/pdfs/06ND-online_Glodek-PQRI.pdf

2 comments:

  1. I would offer additional tolerance that comes with ruggedness as often come face-to-face with unexpected Murphy variants, especially with those human factors involved, so increases possibility of circumvention.

    Not only should one have concern about developing countries labor forces, further motivation for early process development is in majority of manufacturing often have to deal with engineers who have limited understanding of the actual chemistry/process but are more knowledgeable about equipments/controls aspects needed in production therefore having a rugged process permits greater opportunity for fuller optimizations at commercialization stage.
    CMCguy

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  2. I looked at Kilomentor, but I thought he wasn't blogging anymore.

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