Biomedical Engineering Reference
In-Depth Information
Changes to processes are avoided, variability has been viewed as inherent and
controlled by testing and rejection rather than by adaptive processing, and quality
and process performance suffer as a result. Admittedly, much of this stems from
legitimate concerns for patient safety on the sides of both manufacturers and
regulatory authorities, but in the end the greatest benefit to patients is perceived to
be an industry, which is able to manufacture high-quality products in an efficient
manner. These efficiencies would enable it to focus its resources on the continued
advancement of new modalities rather than wasting them on ineffective processes,
particularly when compared to manufacturing from other industries such as food,
microelectronics, and petrochemicals.
Given that the most frequently quoted reason for reluctance to introduce innovations
was the regulatory environment, the FDA established several initiatives, including the
process analytical technology (PAT) initiative, with the objective of removing obstacles
to innovations which could lead to superior quality and manufacturing efficiencies. PAT
is essentially an approach to secure quality and process consistency through a combina-
tion of process understanding and real-time responsive control. It begins with initial
process design, allows dynamic processing, minimizes waste, and supports continuous
improvement throughout the product life cycle.
More recently, additional communications from the FDA have focused on the
broader area of pharmaceutical cGMPs for the twenty-first century, and ICH guidelines
have further developed the concepts of Quality by Design (QbD) and design space. The
original FDA PAT team has been restructured, leaving some to wonder if the original
commitment to PAT and the promise of regulatory flexibility still stand.
In this chapter, we shall review briefly the development of PAT and QbD in FDA,
EMEA, and ICH guidelines, describe how industry initiatives in developing standards
and guidelines are intended to support and elaborate on the guidelines, and discuss
approaches for the implementation of PAT in securing quality, reducing variability, and
supporting continuous improvement in biotechnology processes.
13.2 EVOLUTION OF PAT AND QUALITY BY DESIGN (QbD):
EMERGING GUIDELINES AND STANDARDS
To understand how the emphasis may have seemed to shift away from PAT, it is helpful
to consider the broad time line of events as the agency developed its program to reshape
the way in which the pharmaceutical industry approached lifecycle management of
manufacturing science and technology (Fig. 13.1), see also Chapter 2.
In summary, although the initial dialogue seemed to focus mostly on PAT [1, 2], as
the agency produced additional documents [3, 4] it became apparent that although the
agency continued to state its support for PAT, the PAT initiative was part of a grander
scheme to address quality, and what was perceived as stagnation in the delivery of new
therapies andin manufacturing technology and innovation. In 2005, the agency initiated
the Officeof New Drug Quality Assessment (ONDQA) CMC Pilot Program to revamp
the way in which filings were submitted and reviewed. The new Pharmaceutical Quality
Assessment System (PQAS) placed greater emphasis on scientific knowledge and
