What Was Old is New Again

Thirty-six years ago as a young Pharmacy post-graduate, I was introduced to the “Continuous Process”. Merck commissioned the plant housing this process in the late 1970’s in the Shenandoah Valley of Virginia. Building on the company’s experience with continuous chemical processing, the plant manufactured a blockbuster (at the time) anti-hypertensive “Aldomet”, Methyldopa Tablets, USP. At the peak of production, 2-4 million tablets were produced per shift, dependent on strength. In a 3 floor facility, raw materials were fed from bulk hold hoppers, granulation was continuous. Film coating was applied in large fluid bed coaters, and final tablets were packaged from tote bins, feeding the packaging lines below. The entire process was computer controlled, but, since computers of the time frequently crashed, a back-up synaptic panel was available. A picture of the Control Room for the process was featured in Remington, The Science and Practice of Pharmacy. Analytical testing was the largest lag time, as the batch was finished within a day and had to wait for release to package. The facility ran well into the 1990’s aided by the reduced manpower requirements of an automated process. It even claimed an electronic batch record and early day elements of Computer Validation, well ahead of the time.

Flash forward to 2016; at the ISPE Annual Meeting in Atlanta, Georgia last month, several sessions were given to Continuous Manufacturing (CM) and its advantages and challenges. This included a presentation by Michelle D. Baily from Vertex on “Validation for Continuous Manufacturing and Inspection Readiness.” Both Vertex and Janssen have approved products made by Continuous Manufacturing.  These efforts in automation were facilitated by the Draft Guidance “Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base, December 2015”. The ISPE has also published a White Paper on “Regulatory and Quality Considerations for Continuous Manufacturing” in January 2015 to help guide firms through the Quality and Regulatory considerations of the evolving technology.

In the 1980’s, the concerns with Quality and Processing for CM were Batch/Lot configuration, start-up and stops of the process, changing raw material characteristics, cleaning of the process/carryover, training, and change control. Today’s list of concerns reads much the same; however, advances in Process Analytical Technology aided by today’s computer/automation platforms have minimized some concerns. The possibility of real-time release eliminating testing lag is a real possibility. A robust Supplier Quality Management Program combined with continuous monitoring of critical control parameters can minimize material drift. The FDA is collaborating with industry in such forums as the OPW Regulatory Science Program on Continuous Manufacturing, BARDA-FDA Continuous Manufacturing Innovations Initiative, and CSOPs (an industry-academia initiative researching continuous manufacturing). The Biotechnology Industry may be further along the learning curve with many current biotech processing adaptable to Continuous Manufacturing, especially in monoclonal antibody processes, which already use elements of continuous processing. Several generic companies have moved to elements of processing, such as continuous coating for large volume OTC medications.

The day of the blockbuster product warranting an entire facility may be over, but a small nimble module with PAT can offer unsurpassed control and throughput. As Jannsen and Vertex have shown, it could be the right solution once again for the right molecule.