Advanced Manufacturing and Process Analytical Technology–for Competitiveness and Resilience in Pharmaceutical Manufacturing

Introduction

Process Analytical Technology (PAT) is often seen as an approach that provides valuable process knowledge during the development of a new product contributing to its approval. However, PAT may also be started by manufacturing operations interested in improving process efficiency and creating competitive advantages.^1-3

The success of PAT requires the training of manufacturing personnel.^4,5 PAT must be implemented within the Quality System of the manufacturing site.⁶ This article describes a series of capacity building modules that are being offered to industrial participants from companies in Puerto Rico free of charge to stimulate investment in Process Analytical Technology (PAT) and Continuous Manufacturing (CM). This project is currently funded by the Economic Development Administration (EDA).

In general, the economy in Puerto Rico is comprised 50% of manufacturing activities.⁷ Puerto Rico’s pharmaceutical cluster is essential to the United States supply chain of medicines. This sector includes over 50 manufacturing sites that provide close to 20,000 direct jobs and at least 78,000 direct and indirect jobs.^7,8 Puerto Rico includes 12 of the world’s top 20 pharmaceutical companies such as AstraZeneca, Abbott, AbbVie, Amgen, Bristol-Myers Squibb, Merck, Pfizer, and Eli Lilly.^7,8 Furthermore, seven of the top 10 medical device companies are operating on the island. This cluster has been in constant development for over 60 years and is now the largest exporter of biopharmaceuticals in the United States with over $93 billion in exports.⁸ As of 2020, Puerto Rico is the world’s fifth largest pharmaceutical manufacturing hub by volume with over 80 companies.

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The trainings are also available to the many local companies that service the pharmaceutical industry. The acronym EVAS has emerged for these companies that provide engineering, validation, and automation services. These companies have grown in recent years as the outsourcing of services has increased in pharmaceutical manufacturing and are now an important element within the island’s ecosystem.⁹ The EVAS are usually small businesses which attract larger companies to the area creating jobs and helping in the economic development of communities.¹⁰ In a case study conducted in Puerto Rico for the industrial ecosystem, it was determined that the competitiveness and success of an industrial region are dependent on many factors, including “the existence of related industries and institutions that support the core industry” such as the EVAS.¹¹

The first training sessions were conducted from May 15th to June 19th, 2020. These sessions involved 17 pharmaceutical manufacturing companies, and eight EVAS. The trainings are now being offered for the second time. During the remainder of the project the focus will be on working with the participating companies to build business cases for PAT and continuous manufacturing. The team will also provide more hands-on training using a mobile training unit which is currently under development and prepare for a third cohort of participants starting in January 2022.

The program involves a multidisciplinary group of faculty and students from four departments at the University of Puerto Rico, Mayaguez campus. Experts from chemistry, chemical engineering, industrial engineering, and business administration are working together to help the pharmaceutical industry using PAT or CM. Regulatory issues, opportunities and other PAT topics are being covered. The trainings will also include mentoring for business case definition and development. The project has also provided a way to connect the EVAS, through a mapping of the different companies on the island, with major pharmaceutical and biopharmaceutical companies in need of their specialized services.

Description

The program currently includes eight weekly one-hour training sessions on:
• Process Analytical Technology

• Discussion of FDA guidance and significance.
• Discussion of emerging technologies as well as the ICH guidances related to PAT and the ICH Q12 guidance.

• Opportunities for PAT

• Discussion of several PAT applications that have been successful and could be implemented in pharmaceutical and biopharmaceutical manufacturing to increase competitiveness and resilience.
• Discussion of the benefits of using spectroscopic techniques such as Raman spectroscopy in biopharmaceuticals.

• Raw Material Identification:

• Theory and applications of near infrared and Raman spectroscopy.
• Discussion of the importance of the correlation coefficient in material identification and the development of a spectral library.

• Defining the Business Case for PAT

• Discussion of the identified expected costs, benefits, and their categories.
• The importance of risk management in different applications.
• Prepare participants to start developing the business case for PAT application.
• Description of the support system provided when developing business cases.

• Challenges and Difficulties

• Discussion of factors that may delay the implementation of a PAT or continuous manufacturing project.

• Introduction to Continuous Manufacturing

• Discussion of the advantages of continuous manufacturing, and reductions in costs, time, and yield improvement.
• Discussion of the regulatory aspects when implementing continuous manufacturing.

• Introduction to Chemometrics

• Discussion of methods such as principal component analysis (PCA) and partial least squares (PLS) regression
• Description and application of spectral pretreatments
• Sampling errors that may delay PAT implementation.

Description of Mobile Training Unit

Figure 1 is a schematic of the PAT and Continuous Manufacturing unit that is currently under construction. This unit is for hands-on training for local companies working on business cases for investments in PAT and continuous manufacturing. The unit will consist of three feeders, a continuous blender, a stream sampler12-14 and a tablet press. A training on material characterization will also be given, since powdered materials should be handled according to their physical properties. This training will also include the use of a powder rheometer for material characterization.

The Business Case for PAT

The approval of a PAT project in industry requires a business case.15-17 A thorough understanding of the analytical chemistry involved in PAT is essential but is not sufficient for a successful PAT project. PAT projects will not start without a detailed business case. The team has received substantial valuable input from local pharmaceutical leaders while learning about the elements of a business case. The business case must include:
• Cost analysis

• Implementation costs
• Installation costs
• Personnel training

• Plan for execution and costs
• Investment in facilities
• The economic evaluation methods

• Net Present Value (NPV)
• Internal Rate of Return (IRR)
• Return on Investment (ROI)

• Any applicable tax incentives
• Determining how the costs will be distributed among work units at the manufacturing sites.

Lessons Learned

The business case is usually seen as an internal document in an industrial setting. However, addressing the issue of business cases for PAT and continuous manufacturing has helped this academic team to better understand the needs of pharmaceutical scientists.

Several participants have already implemented the identification of excipients through Raman or near infrared spectroscopy in their plants. Raw material identification could be considered as a starting point for PAT projects. Companies can acquire expertise in non- destructive methods of analysis (Raman and NIR spectroscopy) with commercially available handheld systems.18 This experience is then very valuable for more complex projects which require real-time process measurements.

We have also found significant diversity in the EVAS that we have worked with. Computer validation is one of the strengths of the EVAS. Most of these companies are focused on pharmaceutical outsourcing; nonetheless, some are developing innovative solutions for pharmaceutical manufacturing. However, most of the EVAS are not currently involved in PAT projects. Through this project, a detailed mapping of the entrepreneurial ecosystem will be done with interviews with key stakeholders in the different sectors. The importance of the EVAS in the pharmaceutical manufacturing ecosystem will be discussed in future articles.

Acknowledgments

The authors thank EDA for funding through Project Award Number 01-79-14889 “Advanced Manufacturing to Increase Competitiveness and Resilience”.

References

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