What are the key developments that have influenced solid dosage and sterile manufacturing during the past 35 years and the
technologies that will shape its future? Pharmaceutical Technology spoke to leading scientists, equipment manufacturers, and senior production executives to gain their perspectives. Offering
insight on solid-dosage manufacturing are Chris Moreton, PhD, vice-president of pharmaceutical sciences at FinnBrit Consulting
and a member of the Pharmaceutical Technology Editorial Advisory Board; Charles Kettler, PhD, director of Natoli Scientific, a division of Natoli Engineering; and from
Pfizer, Axel Knoch, senior director and team leader of product and process development; Cynthia Oksanen, director, PharmaTherapeutics
R&D; and John Groskoph, senior director, global chemistry manufacturing and controls. Providing perspectives on sterile manufacturing
are 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.
What would you identify as the most significant advances in solid dosage manufacturing in the past 10 years?
The evolution of new formulation techniques that allow poorly soluble molecules to press forward as potentially effective
treatments for patients is a significant advance.
Figure 1: Industry roundtable participants, from left to right: Chris Moreton, PhD, vice-president of pharmaceutical sciences
at FinnBrit Consulting and a member of the Pharmaceutical Technology Editorial Advisory Board; Charles Kettler, PhD, director
of Natoli Scientific, a division of Natoli Engineering; and from Pfizer, Axel Knoch, senior director and team leader of product
and process development, and Cynthia Oksanen, director, PharmaTherapeutics R&D.
There have been several incremental advances, such as improvements in cleaning, which allow shorter changeover times when
switching to another product, and developments in sensor technology for granulation, blending, and compaction. However, traditional
batch processing is very inefficient because the equipment is idle for significant periods of time. The most significant advances,
therefore, have been in beginning to apply continuous manufacturing methods.
The main advances have involved the application of advanced materials science and engineering tools to enable greater understanding
and heightened control of existing unit operations. Measurements of the material properties of APIs and excipients are now
routinely applied to the design of manufacturing processes to enrich understanding of potential sources of variability. Computational
models for pharmaceutical processing have made significant advances in modeling powder mixing, spray drying, and tablet coating.
The application of process analytical technology (PAT) has enabled heightened control of these unit operations and the ability
to adjust for variations in material properties.
What will be the influence of quality by design (QbD) on solid-dosage manufacturing in the years ahead?
As the reviewers and inspectors for regulatory agencies begin to get more comfortable with the concept of design space, they
will know how to rapidly review submissions and query the submitter directly about design space definition, robustness, and
process capability of equipment. Ultimately, if the agencies can retain sufficient numbers of experienced personnel for review
and inspection, the QbD process can hasten the decision process instead of being a barrier.
The influence of QbD will eventually be enormous. Some companies already understand the potential benefits and are working
towards it. Others will be forced into it by virtue of the questions FDA will raise if they do not include QbD elements in
their new drug or abbreviated drug (NDA, ANDA) submission. QbD has the potential to improve the supply of drugs eventually.
By definition, if we have undertaken our QbD development program properly and asked all the relevant questions, we should
be developing more robust products.
From its start, QbD has delivered more robust processes into the manufacturing environment. Regulatory and operational flexibility
(i.e., the ability to make changes without regulatory action), however, have been difficult to achieve. We do see a shift
in the approach towards reducing or eliminating the focus on design space and increasing the focus on control strategy. This
opens the door to apply the tools of QbD to existing products where significant manufacturing experience can replace proactive
developmental knowledge but achieve the same result of reduced variability of the end product.
We have learned how to implement process parameter changes in routine manufacturing in order to optimize yield and robustness.
As a global company, we are challenged by the fact that the QbD approach is not yet accepted in every country, and companies
still have to run QbD and conventional filings in parallel. With time, this hopefully will change.