Sterile manufacturing
PharmTech:
What would you identify as the most significant advances in parenteral manufacturing in the past 10 years?
Figure 2: Industry roundtable participants, from left to right: James Agalloco, president of Agalloco & Associates and a member
of the Pharmaceutical Technology Editorial Advisory Board; Ryan Hawkins, vice-president and chief operating officer at Cook
Pharmica; and Bernd Stauss, vice-president of production & engineering at Vetter.
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Agalloco:
The single most important change in parenteral manufacturing has to be the maturation of isolation technology. Ten years ago
there was still a lot of trepidation regarding isolators; it wasn't clear to the industry that expected operational advantages
would overcome their added complexity. With the passage of time, we've better understood decontamination practices, defined
realistic leak testing criteria, and most importantly gained sufficient operating experience. In addition, quantifiable cost
benefits are now well documented, so perhaps the last hurdle to isolators increased adoption has now been cleared. We're starting
to see the next generation of isolators emerge that provide even greater sophistication and performance. That wouldn't have
been possible without the success we've witnessed in the last decade with this technology.
Hawkins (Cook):
Decontamination cycles for barrier isolator technology are significantly shorter today. While cycles were 12–16 hours in the
past, they are now 2–4 hours for equivalent isolator size. We also have conquered the learning curve of how to get things
in and out of isolators and improved the ergonomics. We have met the goals of removing the risk of human contamination and
having a validatable cleaning cycle.
Automation has helped industry remove the need for human intervention. For example, it wasn't long ago that we manually fed
nested syringe tubs onto the line and manually removed lids and liners, but today these steps are commonly fully automatic.
Continuous manufacturing: Solid-dosage manufacturing
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Another advance of just the past few years is that use of disposables has gone from talk to action and is yielding significant
savings in cleaning and time for set-up and tear-down.
Stauss (Vetter):
The most important advance has been the increase in sterility in product manufacturing. New technology—such as isolators and
restricted access barrier systems (RABS)—and conceptual approaches to manufacturing have significantly reduced the need for
direct human contact with the product, thus reducing this key risk factor. Because of comprehensive automation in peripheral
areas (e.g., transport and freeze dryer loading/unloading), manual interventions in aseptic production are kept to an absolute
minimum. Automated cleanroom sanitization and the increased use of more complex disposable systems (e.g., filling pumps) contribute
to reliable sterility. Fully automated visual inspection now allows for steady and high-level testing standards for millions
of units. All combined, the continuing automation in parenteral manufacturing has allowed for a notable increase in quality
and safety of drugs.
PharmTech:
What may be the most significant advances of the next 5–10 years?
Continuous manufacturing: Integrated API and solid-dosage manufacturing
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Agalloco:
Single-use disposables, which simplify set-up, cleaning, and system integrity, will become more prevalent. A gradual shift
from glass to plastic containers will virtually eliminate breakage, avoid delamination and glass particles, reduce shipping
costs, and lower utility costs, among other potential benefits. The next generation of filling equipment will operate in isolators
with internal automation and robotics that will essentially eliminate the need for human intervention.
Hawkins (Cook):
Further implementation of robotics technology will lead to advances in equipment. For example, prototypes exist today for
lines that can run vials, syringes, or cartridges, rather than having separate lines for each. Ten years from now we expect
to be using this type of combination line.
From a supply chain standpoint, 10 years from now, companies will be more focused on where they can add value. For example,
fill–finish lines will use ready-to-use vials rather than having vial washing at the start of the line. This is already occurring,
but it will be several years before it really takes hold. We also expect to see more innovation in components and delivery
systems, such as retractable needles and the blurring of the line between syringes and cartridges. While the benefits of plastic
components compared to glass are documented, we see their higher cost as a significant barrier.
Stauss (Vetter):
An important task over the coming years will be to work in close cooperation with packaging suppliers to further align quality
parameters in order to achieve higher quality levels throughout the entire supply chain. For example, using a laser in a cut-to-length
process for the manufacture of glass barrels can meet increasing glass-breakage requirements. Another example is in the manufacture
of components (e.g., stoppers), in which fully automated visual inspection can be used to check for defects (e.g., particles,
inclusions).
PharmTech:
What do you think the influence of QbD will be in the upcoming years?
Agalloco:
The early adopters of QbD are well ahead of everyone else and making it evident there's much to be gained through it. Regulatory
support, and certainly some prodding as well, is pushing the rest of industry to introduce it as a matter of routine. The
benefits of QbD are well known, but it requires almost a cultural shift within the industry before it becomes standard practice.
Once folks get comfortable with it, they won't want to develop any product or process without it.
Hawkins (Cook):
Regulatory authorities are clearly leading this effort, but like anything else, it takes time for everyone to understand how
to implement it.
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