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Quality by Design:
the Co-Development Toolbox Elements
by Maxim Puchkov
1. Introduction
Several years ago the
Food and Drug Administration of Department of Health and
Human Services of United States of America has decided to pursue
the goal for improved quality of final pharmaceutical product
by setting up the PAT Initative (Process Analytical Technology).
The start-up of the PAT programs by pharmaceutical industry
was followed by the tremendous progress in this area and
had unleashed new terms and concepts such as Quality by Design
(QbD) and Right First Time initiative. Numerous conferences,
events, and meetings were dedicated to find an optimal way
of integration of these new concepts and novel analytical
techniques into QbD-oriented product design and manufacturing.
Acceptance of these initiatives and concepts is leading the
industry to drug development paradigm shift: the development
process is becoming dynamic, involving the gained experience
into new development through process understanding.
The major
QbD prerequisite is formulation robustness. Nowadays formulation
can not be understood as simple “recipe” but
it is expanding to process design and performance. Thus
the robust formulation is a science-based “alloy” of
process understanding and material knowledge.
Process robustness
can be well explained with six sigma concept. In terms of
sigma values the champion among manufacturers is the semiconductor
industry with its six Sigma performance, i.e. with an amount
of defective samples ≥ 2 ppb. The performance
of the pharmaceutical industry is around 2 Sigma (≥ 4.6
% defectives). Such a low performance is extremely affecting
the emerging areas of healthcare, especially combined therapy
against such a threats as HIV, cardiovascular diseases,
cancer, etc. The factors that are delaying the polypills
to market are usually due to formulation issues (Simon
Frantz, The trouble with making combination drugs, Nature
Reviews Drug Discovery, November 2006). There is obviously
a room for an improvement.
The development of a dosage form
production of the first formulation in the preclinical
research up to registration of the commercial form is very
costly and lasts between 8 to 12 years, thus to reduce
time to market it is important to think about an integrated
approach and a better connectivity between pharma R&D
and manufacturing. The obvious source of a poor connectivity
is that “companies tend
to operate in silos – R&D,
manufacturing, marketing. This is a very proprietary culture.
Knowledge and information sharing is the basis to overcome
inefficiencies . . . ” (John Moore, Analyst,
Catching up with Reengineering June 2, 2003 Chemical & Engineering
News, Vol. 81, N° 22). The step towards to improved
connectivity is Co-Development Strategy (Figure 1).
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| Figure 1. Co-Development
Strategy (Courtesy of Dr. Jurgen Werani, Pfizer) |
Following up with co-development strategy one can identify
that the major input factors affecting the formulation
robustness are:
– material understanding
– process equipment and parameters understanding
– process changes
– floor operators (human factor).
In this respect one can clearly identify three important needs
to be satisfied on the way to quality by design:
– Need for robust formulation and process design
• Formulation screening is costly and time consuming
• Non-robust formulation will jeopardise full-scale production
– Need for mechanistic models and expert systems
– Need to reduce possibility of human error
• Batch-wise production is an ”agar plate” for
growth and flourish of manufacturing failures
• Floor operators skill assessment
and continuous education
To fulfil these needs the development
of the co-development toolbox is a step towards to QbD-oriented
production. The toolbox consist of two major parts: in silico
formulation design and assessment (Research&Development
Tool) and virtual equipment simulators used for training
and setting up the manufacturing design space (Manufacturing & Quality
Operations Tool), see Figure 2.
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| Figure 2. Co-Development
Toolbox |
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