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You Can’t Keep a Good Drug Down

Reducing Mutagens, Carcinogens & Other Genotoxins to Improve Safety Profiles

There are a number of process modifications API manufacturers can make to improve safety profiles, reduce production costs, improve capacity planning and more.  Here are four aspects of API production that often arise in our work at Neuland:

  1. Alternate Route Selection
    Let’s face it: early discovery & development work doesn’t often concern itself with late-stage or post-approval challenges. It is common for an API contract manufacturer to see molecules with 15-step routes.

    Alternate route scouting aims to find the safest, simplest, least expensive and/or most consistently reliable production route for a molecule. It may involve reducing the number of required processing steps, shortening process duration, or finding alternate chemicals or solvents to control the formation of an impurity. At Neuland for instance, we’ve performed a good deal of work on route development to avoid or reduce the formation of genotoxic impurities (GTI).

    In some cases, alternate route scouting may be undertaken to identify greener processes that reduce environmental impact, waste management costs or other infrastructure challenges.

  2. Early Route Design
    While the entire production route matters, of course, it’s what’s happening during the first few steps that often counts most. Making sure to introduce any potentially toxic reagents or raw materials as early as possible in the process is a commonly-overlooked aspect of route design.

    A focus on early route design can spell the difference between a successful product and an out-of-spec one. When introduced at the final stage, for instance, toxic materials such as genotoxic reagents or raw materials are generally retained as-is, and possess the same toxicity as before introduction. Elimination of toxicity at late or final stages can also be difficult due to the difference in the solubility patterns of each compound.

    Front-loading certain reagents or materials at the beginning of the route allows for toxicity reduction to occur across the remaining route processing steps. Introduced at the early stages, toxic materials may undergo further reactions and convert into low-toxic compounds.

  3. Fate & Purge
    Once API production processes have been developed, they should be subjected to Fate & Purge studies. In Fate and Purge, contaminants are introduced into the process. Studies are then conducted to determine how successfully the introduced contaminants are purged across the process. And, since impurities can also be modified or transformed by the manufacturing processes, they – too – should be tracked across the process (to determine their ‘fate’).

    Understanding how impurities form – and what happens to them during the process under evaluation through final compound elimination – allows manufacturers to control contaminants at the source.

  4. Operating Range Design
    Last month, I mentioned Quality by Design (QbD) and Process Analytical Technology in a post on 5 Trends in API Design & Production. Both of these quality systems involve the understanding and control over production operating ranges, whether its equipment operating within certain established parameters or successful reduction of contaminants below threshold limits.

    A limited understanding of process parameters – the upper threshold for the addition of specific chemicals, or the upper temperature and longest time allowed at a given stage of processing, for example – can lead to regulatory, production or even Environment, Health & Safety (EHS) challenges down the road.  Knowing the operating ranges of process parameters helps minimize the generation of genotoxic impurities (GTIs).

What steps have been taken to optimize the production of APIs in your Company’s drug?


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