Tuesday, July 24, 2012

Is Continuous Processing in Pharma’s Future?

The answer to the question is “May be and depends”. This is not the answer everyone would be expecting from anyone who is proponent of “continuous processing”. “May be or depends” needs further explanation. I describe pharmaceutical manufacturing processes as follows.

    API (drug) + Formulation processing/packaging = Dispensable drug dose

We all know that each component and the resulting product must meet the established performance and quality standards and that is a must. Annual volume, process design and equipment are some of the factors that direct us to the right process selection.

Table 1 illustrates the amounts of API (active pharmaceutical ingredient) needed for various dosages to serve variable population size. This table directs us to the answer to the “May be and depends” question between batch and continuous processing in pharmaceutical manufacturing. Breaking down the overall manufacturing process described above assists in rationalization. 



                                                               Table 1

A quick review of the table suggests that between API manufacture and formulation/packaging later has the highest potential to be a continuous process. This observation is based on annual volume of the tablets needed. It is expected that the formulation and packaging process steps are adequately designed. Quality by Design (QbD) will be the rule for such processes.

To serve 10 million population using 0.1 milligram dose tablet, API volume is not large enough to have a continuous process. If the equipment used to produce the APIs is going to stay the same as currently used, less than optimum processes will stay in place. Since the companies with the current manufacturing practices are able to achieve their profit margins they do not have any incentive/justification to change their manufacturing practices even if the methods are inefficient and highly un-sustainable. Such operations present an excellent opportunity to improve yield, create sustainable processes, lower manufacturing costs and improve profitability.

For continuous process to become a reality for APIs while using the current equipment technologies, production volumes have to be about 750,000 pounds or higher per year per site or the size of equipment used has to change to produce for lower volumes i.e. a complete paradigm shift is needed. A single plant operating continuously (24/7/50) producing (750,000 pounds per year) would produce about 110 pounds product per hour. Such plants, if they become a reality, could significantly reduce the regulatory load significantly and would produce highest quality product.

To serve 10 million people taking 0.1 milligram tablet per day per year about 3.65 billion tablets would be needed. This is producing about 8500 tablets per minute (80% operating rate) from a single manufacturing train. A single continuous train that takes the API to a finished tablet is very feasible provided the equipment is properly designed. Depending on the size of the tablet, commercially available equipment can produce up to one million tablets per hour. Through campaigns this particular train could also be used to produce other drugs following cGMP practices. Multiple tableting and packaging trains can be used to fulfill higher tablet needs.

As the dose and frequency needs increase, the needed API volume increases and manufacturing trends toward continuous processes. Increased per site production volume and process technologies can justify better manufacturing methods that have higher yield and are sustainable. It is possible that the companies might still use batch processing even if the total API production volume could justify continuous manufacturing. This can happen if the companies do not want to invest in better process technologies. If the companies do not change their methods competition will force the change.

Based on the above review one can conclude that better than 70-80% of the APIs needed would be produced by batch process using existing type of reactors, heat exchangers and other processing equipment unless the existing equipment can be used creatively to develop continuous processes. This is definitely possible. On the other hand better than 85-95% of the formulations can be produced using continuous processes.

Above quick review demystifies “May be or depends” mystery and shows us a clear path. The choice is ours to act.

Girish Malhotra, PE

EPCOT International

No comments: