Erika Porcelli- Regulatory Services, Regulatory Compliance Associates®
Introduction
In the evolving field of pharmaceutical development, the implementation of Process Analytical Technology (PAT) for manufacturing is an essential competitive advantage. PAT offers widely accepted methods to safeguard quality assurance and the general safety of pharmaceutical products. The goal of this article is to provide a summary of PAT, best practices of principles and adoption of PAT, and how to leverage increased process knowledge in your regulatory submission.
Understanding Process Analytical Technology (PAT)
Efficient pharmaceutical manufacturing is a significant facet of the global healthcare system. The well-being of patients is contingent on the accessibility of safe and effective treatments. The U.S. Food and Drug Administration (FDA) framework1 for process analytical technology was originally established based on insights to facilitate quality improvement. It includes risk-based regulatory outcomes that have been validated by both life science manufacturers and FDA regulators.
The Agency framework is based on two primary drivers:
- Scientific principles and tools that support the development of innovation
- Regulatory strategies that accommodate innovation during the submission process
Principles of PAT
CMC (Chemistry, Manufacturing, and Controls) is one of the most influential facets of drug product development. Traditional drug development in pharmaceutical manufacturing is completed using batch processing and production sample lab testing to evaluate quality. This approach has been effective in delivering quality pharmaceuticals to patients in need.
However, modern technologies now offer life science employees the opportunity to improve pharmaceutical development. Specifically, PAT principles and technologies focus on increasing quality assurance during the product development process. This often involves the use of unique quality controls from different types of technologies.
PAT and CMC
The implementation of process analytical technology encourages drug manufacturers to create a team-based regulatory approach to chemistry, manufacturing and controls. Further, the review of current good manufacturing practices (cGMP) is also essential to the success of process analytical technology.
Finally, in-depth CMC training is important to achieve certification in process analytical technology. This is important considering the regulatory inspection review by Agency auditors for each new drug in development. The ability to demonstrate regulatory compliance is a foundational training strategy that supports the use of process analytical technology in 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 the 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 the FDA.
Recognizing the need to reduce this ambiguity by 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 the 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 of 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
Adoption of PAT
Equally important, for the manufacturing team's 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 the 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
- 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 documentation of quality assurance delivered by the manufacturer.
Innovation in development, manufacturing and quality assurance that leverages process analytical technology should help answer these common regulatory questions from FDA experts:7
- What are the mechanisms of degradation, drug release, and absorption?
- What are the effects of product components on quality?
- What sources of variability are critical?
- How does the process manage variability?
Regulatory Submission
Regulatory considerations that can help document quality assurance improvements from process analytical technology often are found in:
- Reducing production cycle times by using on-, in-, and/or at-line measurements and controls
- Preventing rejects, scrap, and re-processing
- Increasing automation to improve operator safety and reduce human errors
- Improving energy and material use and increasing capacity
- Facilitating continuous processing to improve efficiency and manage variability
Regulatory Documentation
Quality assurance improvements are centered around the manufacturing process and system processes involved. FDA considers a process to be well understood if regulatory documentation shows:8
- Why sources of variability can be identified and explained
- When production variability can be managed by owners of the process
- How quality attributes can be accurately and reliably predicted
This type of regulatory documentation provides insights for FDA regulators into materials used, an understanding of process parameters, changes in manufacturing, and environmental conditions.
The ability to predict these three items can show a high degree of process understanding. The goal is for your regulatory application to demonstrate your team and company understand how to reproduce process capability data and maintain a consistent state of control.
Conclusion
Process analytical technology is used to improve the scientific basis for regulatory specifications and promote continuous improvement. The ability to enhance manufacturing while retaining or improving product quality is essential to helping patients and population's health in general. Life science manufacturers should document technology improvements to the FDA and demonstrate the ability to quickly resolve production-related technical issues.
For more insight about how RCA can support your team, please visit us online at www.rcainc.com.
References
- https://www.fda.gov/media/71012/download
- https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/ pharmaceutical-quality-21st-century-risk-based-approach-progress-report
- https://www.fda.gov/media/71012/download
- https://www.fda.gov/media/71012/download
- https://www.fda.gov/media/71012/download
- https://www.fda.gov/media/71012/download
- https://www.fda.gov/media/71012/download
- https://www.fda.gov/media/71012/download
Author Biography
As Vice President of Regulatory Services for Regulatory Compliance Associates® (RCA), Erika Porcelli touches all aspects of the customer experience. RCA provides consulting services to life science organizations for the resolution of compliance and regulatory challenges. RCA is a global business unit of Sotera Health, a trusted partner to more than 5,800 customers in over 50 countries, including 40 of the top 50 medical device companies and 8 of the top 10 pharmaceutical companies.
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