Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Clinton Chichester

Abstract

The objective of this research topic is to show QbD and PAT tools such as multivariate analysis can perform “Continued Process Verification by using a Real-Time Multivariate Process Monitoring (RT-MSPM) system. There are not one but many challenges The pharmaceutical and bio-pharmaceutical manufacturers are facing multiple challenges such as changing regulatory requirements, healthcare reforms, economic pressure and availability of advance manufacturing technology to make better quality products at reduced costs.

Due to the recent technological developments, significant opportunities exist for improving pharmaceutical development, manufacturing and quality assurance through innovation in product and process development, process analysis, and process controls. The latest FDA guidelines such as QbD, PAT and the 2011 process validation have opened the doors for “Real-Time Process Monitoring” concepts for “Continued Process Verification”.

The regulatory agencies have taken the initiative by providing guidelines in last ten years such as, Pharmaceutical cGMPs for the 21st Century - A Risk Based Approach, Final Report in September 2004 [1], Guidance for Industry: PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance [2], Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations [3], Internal Commerce for Harmonization (ICH) - guidelines [4, 5, 6, and 7], QbD, a perspective from the “Office of Biotechnology Products” (OBP) [8] and lastly, Guidance for Industry Process Validation General Principles and practices utilizing three stages during Process Validation [9].

The objective of agency is to ensure that the most up-to-date concepts of risk management and quality systems approaches are incorporated into the manufacturing. The application of multivariate statistical models for process monitoring can provide information on the challenges that are routinely encountered by drug manufacturers and process can be monitored in real-time to achieve continued process verification (CPV). The outcome of the study is intended to become a benchmark for biological manufacturers who are interested in applying the “PAT tools” for existing legacy products or any new manufacturing process to address challenges [10, 11] such as raw material variation and control of process variability, identifying and monitoring of relevant process parameters in the operating space, RT-MSPM with early fault detection and diagnosis of process upsets and trends.

PCA (Principal Component Analysis (PCA) and PLS (Projection to Latent Structure (PLS) are the two popular techniques are used to create the multivariate (MV) models. MV statistical models for process monitoring are used in this study to address the challenges in biologics manufacturing process such as raw material variation and control of process variability, identification and monitoring of relevant process parameters in the operating space and RT-MSPM for Early Detection and Diagnosis of Process Upsets and Trends.

The implementation of RT-MSPM assists in meeting the latest process validation guidance requirement to achieve continued process verification (CPV) by monitoring each and every batch in real time. With the use of RT-MSPM tool, every run can be considered as a process validation run. If the process is monitored in real time then the sampling frequency can be reduced significantly, which can result in tremendous cost saving.

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