Pharmaceutical Technology Magazine: Continuous production progress, problems and challenges in solid preparations.

Recently, the FDA's official website published a signed article by Director Stephen Hahn.
article said that in order to address supply chain pressures, the need for flexible manufacturing systems, in the context of the return of manufacturing to the United States, the FDA fully supports the application of advanced manufacturing technology in the industry, and continuous production (Continuous manufacturing, CM) is an important way.
Pharmaceutical Technology, a specialized journal in the U.S. pharmaceutical industry, conducted an exclusive interview on the application of continuous production in the pharmaceutical industry, and industry experts described progress made in the continuous process of oral solids.
interview background oral solid preparation continuous production has the following advantages: faster development, smaller equipment footprint, greater flexibility in production scale, more stringent process control and real-time release potential.
Vertex Pharmaceuticals, one of the few FDA-approved companies to produce continuously, began working with Hovione in 2016.
Hovione is a U.S. commissioned manufacturer responsible for the production of Vertex products using continuous production equipment.
pharmaceutical technology magazine spoke with Hovione's continuous production team members: Alexandra Adao, head of continuous production QA; Sarang Oka, process development engineer; and Jose Luis Santos, head of continuous pharmaceutical production, described their experiences in implementing CM.
and Challenges of Pharmaceutical Technology: What benefits have been realized with the commercialization of cm processes for solid drugs? What are the challenges? Santos: CM is a great opportunity to bring drugs to market compared to traditional mass production, and further improves product quality based on an understanding of the process and a richer data environment.
1) The investment is huge, not only in terms of the equipment itself, but also in terms of integrated software, which should include a robust Process Analysis Technology (PAT) framework, the facilities where the equipment is placed, and all relevant public systems.
2) team formation may be very different from the standard team for solid preparation batch production.
, the team should now include a strong background in process modeling, automation, and control, and PAT is a mandatory role in the team.
quality team should adapt itself to the new model, or form a new focused QA team.
3) Development is more difficult and requires more complex process understanding, including process modeling.
given the steep learning curve of most companies, development may not be as fast as batch production processes.
but throughout the drug's development cycle, it shows significantly faster potential than batch production, as development is always carried out on the same equipment and scale.
our experience is still limited, but in terms of equipment occupancy, it has shown significant advantages over batch production processes.
, CM can make better sustainable use of assets than batch production methods.
Pharmaceutical Technology: What are the challenges of sending materials into the system and what are some of the best practices that have been implemented? Oka (Process Development Engineer): The feeding challenges that plagued CM technology in the early days had two cores: feed at very low flow rates and feed of poorly flowing powders with significant electrostectronic adhesion.
that while substantial progress has been made in addressing the challenges, there has been little change in powder feeding technology.
weight loss (LIW) helix feed is still the main feeding technology.
For example, a few years ago, an academic team prototyped a salt-shaker feeder, a technique that showed only limited success, so we continue to be thwarted by spiral feeders without any innovative improvements in LIW helix feeds.
as mentioned earlier, we have made some substantial progress in addressing the challenge of feeding poorly liquid powders or at low flow rates.
the main challenge of poor powder fluidity is that the pitch is not filled consistently.
suppliers have tried a variety of agitator and screw geometry to improve screw filling, which shows encouraging results.
, however, certain powders, such as certain levels of silica, are very low in accumulation density and have a high trend of electrostitive adhesion, which still poses a challenge.
technique is to treat the illiquid powder with the aid and introduce it into the feeder.
, for example, the active ingredients with poor fluidity are premixed with silicon dioxide to improve their fluidity before entering through a spiral feeder.
in the accessories, has been designed and developed ideal for continuous production of accessories, and did not encounter the above challenges.
in the case of low flow feed, we are largely constrained by physical limitations.
has a physical floor, and even for the most complex load cells, the signal-to-noise ratio becomes too low for effective weight control, which prevents us from feeding at too low a flow rate.
management strategy is to premix the low-content ingredients in the formula with another ingredient.
Technology Transfer and Expansion of Pharmaceutical Technologies: What are best practices for technology transfer or expansion of CM processes? Oka (Process Development Engineer): These advantages are many when developing CM products.
development is done on a scale-by-scale scale, without the need for rigorous scale-up studies like batch production.
technology transfer is usually made between very similar (size and other characteristics) or the same units.
when developing on non-commercial equipment, challenges arise.
we still don't have correlations that can help us transfer processes between different equipment or process columns.
Process Modeling Pharmaceutical Technology: How are process models/digital mapping used in CM process development/process control? What will be done in the near future? Oka (Process Development Engineer): The development of digital mapping is being carried out in earnest for continuous production process training and individual unit operations, and its basic modeling framework includes methods based on discrete elements (DEM), balancing models, or other empirical and semi-empirical methods.
popular application for digital mapping is to experiment with in-computer dwell time allocation (RTD).
these experiments can be performed at the unit operating level or at the entire process family level.
of RTD enables people to track the evolution of process disturbances, which is a key element of today's control schemes.
if the model is well calibrated, it can also allow the operator to "involve" directly and verify the required RTD, all of which can be done from a comfortable desk.
applications also include understanding the impact of material characteristics and process parameters on process performance and the quality of the final product.
digital mapping and even predicts product performance, i.e. the performance of the drug in the body.
real-time release of Pharmaceutical Technology: Is real-time release happening? What obstacles remain? Adao (QA Head): Hovione has introduced all required elements to enable real-time release inspection in quality systems.
already have companies that have successfully implemented it, and we believe we have all the conditions in place to execute it.
there are technologies for real-time release inspection, such as online and inline PAT functions, automated control system design (e.g., equipment monitoring, material tracking).
control strategy combining these two functions is a key element in implementing real-time release in CM.
in Hovione, these features are already in place and have been systematically confirmed, taking into account the requirements for real-time release inspection.
potential challenges in real-time release implementations is the solubility test.
in order to achieve real-time release, based on process parameters and key quality attributes (CQA), model solubility predictions are required, and therefore appropriate model maintenance procedures are required.
maintain parallel inspection procedures in the model and conduct a controlled study of the appropriate laboratory/regulatory testing methods.
, in addition to performing confirmation work, there is important work related to the life cycle of many models.
As a commissioned processing company, we have been preparing for this type of release, and we recognize the benefits of doing so because it improves quality assurance, reduces release times, and brings overall benefits to patients.
Ref: Gaining Experience in Continuous Manufacturing. August 14, 2020.Jennifer Markarian. Pharmaceutical Technology.