APR Sept/Oct 2023 - 105

MANUFACTURING
Implementing PAT
In the past, many manufacturing procedures have been considered
static due to regulatory constraints. Proposed process changes
are often considered for feedback by FDA early in the regulatory
submission process. However, this can also lead to ambiguity of what
types of technology will be authorized or declined by the Agency going
forward. Life science manufacturers often stick with what is approved
to stay in compliance and not raise red flags with FDA.
Recognizing the need to reduce this ambiguity for embracing
innovation, FDA launched an initiative called Pharmaceutical CGMPs for
the 21st Century: A Risk-Based Approach.2
The goal of this program is
to ensure process analytical technology principles are known by life
science companies and include:
* Modern concepts of risk management
* Quality system approaches are incorporated into
pharmaceutical manufacturing while maintaining
product quality
*
Life science manufacturers are encouraged to use modern
innovations in pharmaceutical manufacturing technology
* FDA's submission review and inspection programs operate in a
coordinated manner
* Regulations and manufacturing standards are applied
consistently by FDA and the manufacturer
Benefits of Implementing PAT
FDA considers process analytical technology to be:
" a system for designing, analyzing, and controlling manufacturing
through timely measurements of critical quality and performance
attributes of raw and in-process materials and processes, with the goal
of ensuring final product quality. " 3
The primary benefit of implementing process analytical technology
is to enhance understanding and control the manufacturing
process. Consequently, the tools and principles of process analytical
technology should increase the level of manufacturing process
understanding in general.
Manufacturing Process
Further, meeting the regulatory requirement of validating the manufacturing
process can only benefit from this understanding of what
quality looks like. Five core ingredients of process analytical technology
strategy that should help users boost their understanding include:4
* Enhanced process understanding and knowledge
*
Improved process control and efficiency
* Reduction in production costs and waste
* Faster and more efficient product development
* Enhanced regulatory compliance
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American Pharmaceutical Review | September/October 2023
Adoption of PAT
Equally important, for manufacturing team adoption of new
technologies to be successful, employees must recognize the
importance of quality assurance and patient safety. Moreover,
proposing innovative approaches to pharmaceutical development
should not lead to a regulatory stalemate between FDA and the life
science manufacturer.
FDA encourages manufacturers to use the process analytical
technology framework in clinical documentation, so a stalemate
doesn't occur during the regulatory process. This can include clinical
evidence that helps demonstrate:5
* Process understanding and control strategy
* Real-time process monitoring
* Multivariate data analysis (MVDA)
* Process control and optimization
* Continuous manufacturing and quality by design (QbD)
PAT Manufacturing Examples
FDA has provided process analytical technology examples of the tools
available that facilitate manufacturing process understanding. These
converge at the intersection of scientific, risk-managed pharmaceutical
development, manufacture, and quality assurance.
When used within an effective manufacturing system, process analytical
technology can provide effective and efficient means for facilitating
process understanding. Further, continuous improvement, and development
of risk-mitigation strategies. In the PAT framework, PAT manufacturing
examples can be categorized according to the following:
* Multivariate tools for design, data acquisition and analysis
* Process analyzers
* Process control tools
* Continuous improvement and knowledge management tools
PAT and Quality Assurance
Process analytical technology and quality assurance go hand in hand
when it comes to manufacturing innovation. The above performance
metrics for measuring quality focus on designing, analyzing, and
controlling manufacturing through timely measurements of raw and
in-process materials and processes.6
For the same reason,
process analytical technology commonly
includes tools that can improve chemical, physical, microbiological,
mathematical, and risk analysis. Simultaneously, these quality
assurance tools that aid process understanding can also support
meeting existing regulatory submission requirements to validate the
manufacturing process.
PAT and Regulatory Approval
Achieving regulatory submission approval for a new product is rarely an
easy process. The clinical evidence needed to support efficacy must include
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