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Continuous tablet manufacturing
 
Q: Why is there so much interest—and investment—in continuous manufacturing of oral solid dosage forms these days?
 
 
imageYou're right. Interest in continuous manufacturing—as an alternative and/or addition to traditional batch manufacturing—is significant. In April 2016, the FDA approved Janssen Pharmaceutical's transfer from batch to continuous manufacturing for Prezista, a drug product that treats HIV. The Agency also approved Orkambi, Vertex's cystic fibrosis drug, in July 2015, which the company will manufacture via continuous processing. Therefore, the stage is set for additional continuous-process approvals of more prescription products in tablet form that typically have been manufactured via the batch process.
 
Continuous manufacturing
Before I identify the main reasons for that shift, I want to define and describe continuous manufacturing. The OSD Community of Practice (COP) at the International Society for Pharmaceutical Engineering (ISPE) offers a definition: "Continuous manufacturing is a set of closely coupled unit operations that transform incoming material by imparting physical or chemical changes—mixing, agglomeration, consolidation, densification, separation, crystallization, evaporation, filtration, or chemical reactions—into a new material or product" [1].
 
Additionally, the OSD COP notes the fundamental differences between continuous and batch processing. Continuous manufacturing:
  • Closely couples all unit operations, with no work-in-process between major units.
  • Uses gravimetric or volumetric feeders, replacing the conventional weigh and dispense function in batch manufacturing.
  • Balances the flow of the various unit operations, operating like one equipment train.
  • Uses integral process analytical technology (PAT) between unit operations to ensure that tablets discharged from the end of the train meet specifications.
  • Reduces manufacturing cycle time from weeks to hours.
  • Defines capacity by throughput versus nominal equipment volumes used in batch manufacturing.
 
imageFigure 1 shows a typical continuous OSD process.
 
The reasons for the paradigm shift are becoming clearer and more defined as more and more pharmaceutical companies begin product development using continuous process methods and technologies or transfer products to that process. The continuous process provides numerous process and business advantages.
 
Five reasons for the shift
The FDA's strong support. The FDA and international regulatory bodies are advocating the adoption of advanced manufacturing applications and technologies, with an emphasis on the continuous process, which is consistent with quality initiatives that the FDA has proposed in recent years.
 
Several factors have contributed to that support. The process:
  • Implements modern manufacturing approaches.
  • Potentially improves overall drug quality and consistency.
  • Enables quality by design and full process understanding.
 
Improved product quality and safety. The primary manufacturing objective is to ensure the highest levels of product quality, safety, and consistency in drug products. Using continuous processing, pharmaceutical manufacturers can improve quality and safety.
 
Continuous processing:
  • Enables manufacturers to build quality directly into the process design.
  • Allows real-time process monitoring and adjustments.
  • Results in stable and robust process operations.
 
Reduced costs. The pharmaceutical industry is under intense pressure to control drug costs and improve overall operational efficiencies, which are significantly lower than those of other manufacturing industries.
 
The use of continuous processing offers opportunities to reduce costs because it:
  • Requires a much smaller overall footprint for the facility and supporting areas.
  • Reduces capital equipment cost and overall operating cost.
  • Uses significantly less API during product development.
 
Reduction in the gap between product development and commercial manufacturing. Taking new products from the lab and clinical phase to commercial manufacturing is one of the biggest challenges the industry faces in terms of time and cost.
 
The application of continuous manufacturing closes the gap between those two sectors and actually ties them together. The process:
  • Eliminates scaleup and tech transfer because it uses the same system and equipment for development as for commercial manufacture.
  • Makes it easier to develop and control the design of experiments to assess critical attributes.
  • Provides a means to accelerate product development, which is ideal for the breakthrough therapies that the FDA is seeking.
 
Operational efficiency and processing enhancements. Traditional batch processing has inherent inefficiencies and challenges for unit operations that can be overcome through continuous processing.
 
Those improvements include:
  • System closure and integration and better containment of the processing operation
  • Quicker movement from powder in to tablet out, possibly just minutes or hours in a continuous process as compared to days or weeks in a batch process
  • Flexible and quick reactions to variations in product demand and changes to marketing forecasts
  • FDA-supported, real-time release testing through use of an in-process data PAT and sophisticated process modeling
 
Summary
Continuous processing brings many advantages to the industry from both process and business standpoints. Furthermore, it provides a viable alternative to the conventional batch process that has remained relatively unchanged since 1843 when William Brockedon patented the compression of sodium and potassium carbonate tablets. With continuous processing, the pharmaceutical industry now has a means to modernize its manufacturing approaches, improve product quality and safety, reduce cost, tie product development and commercial manufacturing together, and improve operational efficiencies.
 
By working together in support of the effort to transition from batch to continuous processing, pharmaceutical companies, engineering firms, equipment vendors, and many others can improve the quality and availability of medicines to patients.
 
References
  1. COP group's discussion, Oral Solid Dosage Community of Practice Focus Group, International Society of Pharmaceutical Engineers.

Dave DiProspero is the director of pharmaceutical process technology at CRB and an associate in the company's Philadelphia, PA office. He has more than 25 years of pharmaceutical engineering experience, with a specialty in manufacturing OSD forms. He is a long-term member of ISPE and is currently chair of the Facility of the Year Award Committee and a steering committee advisor to the OSD COP, which he was involved in forming. He is also the steering committee manager and a contributing author for the revision of the OSD Baseline Guide, Volume 3. DiProspero received ISPE's Max Seales Yonker Member of the Year award in 2006.

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