WhenPharmaceutical Technology Europewas established 20 years ago, PAT was not a hot topic in the industry. It was started in 2002 by FDA to modernize pharmaceutical
manufacturing and increase the efficiency of manufacturing processes.1,2It consists of controlling and monitoring critical process parameters using timely measurements and an understanding of the
process's physical and chemical phenomena, and the properties of excipients and APIs. Many of the elements of PAT were under
development 20 years ago, but they lacked the driving force to encourage industry to innovate and implement these concepts.
FDA's concern with the efficiency of manufacturing processes may not seem to be consistent with the usual drug evaluation,
inspection and compliance activities of the agency. However, FDA's mission statement includes a commitment to making safe
and affordable products accessible to citizens. The PAT guidance states: "Efficient pharmaceutical manufacturing is a critical
part of an effective US healthcare system. The health of our citizens (and animals in their care) depends on the availability
of safe, effective, and affordable medicines."2
The availability of drugs cannot be taken for granted, as FDA's list of drug shortages usually contains several products,
and many are usually related to manufacturing problems.3The availability of 'affordable' medicines is also a subject of significant discussion.Pharmaceutical manufacturing processes comprise a series of unit operations. However, the quality of the product is evaluated
by analysis of the final dosage form at the end of the process. Current processes are characterized by fixed blending and
lubrication times where the excipients and APIs received are expected to have the same physical and chemical properties as
the previous batch. Most current processes are not designed to control the unavoidable variation in the properties of excipients
and APIs.PAT systems are part of the 'quality by design' (QbD) efforts outlined in the ICH Q8 guidance on pharmaceutical development,
and can be used to improve process knowledge and efficiency of currently marketed products. The majority of the applications
discussed in this article are PAT systems for small molecule pharmaceutical processes, but PAT may also be used for manufacturing
APIs and biotechnology-derived drug products. PAT efforts must consider:
- Regulatory framework to evaluate PAT projects.
- Process understanding and QbD.
- PAT implementation and development of control strategy.
- Inclusion of PAT in quality system.
Evaluating PAT projects
On the go...
|
The PAT guidance provides FDA with a regulatory framework to evaluate manufacturing processes that involve PAT. Many of the
approaches described in the PAT guidance were outlined by Callis and collaborators in 1987.4The guidance does not describe any new scientific or technical approaches, but it provides an opportunity to use PAT and other
innovative approaches to improve pharmaceutical manufacturing.The guidance was preceded by a number of pharmaceutical research efforts that could be considered the beginning steps for
the current PAT initiative. For example, vision systems were evaluated to inspect the correct printing of lot numbers and
expiration dates during packaging.5There were also projects showing that near-infrared (NIR) spectroscopy could be used to identify placebo and drug-loaded tablets
used in clinical studies, and identify raw materials for pharmaceutical manufacturing.6–9The majority of the projects focused on achieving quality through inspection or substituting established quality control methods
with faster ones that did not require sample preparation.10However, it became increasingly difficult to justify these innovative projects because of concern that FDA would think their
driving force was recurring problems within the company rather than quality improvement.
The PAT initiative has provided a window for innovation in pharmaceutical manufacturing. There is now a framework for regulators
to consider and discuss innovative projects that will, ultimately, lead to higher quality products. This window of opportunity
includes the possibility of having pharmaceutical processes where critical processes parameters are monitored and controlled
leading to real time release of the product.
