The recent emphasis on continuous improvement, operational excellence and Process Analytical Technology (PAT) within the pharmaceutical and biotech industries has driven us to evaluate the basic tenets of our approach to quality. Historically, the ability to ensure that a drug will meet its intended form, fit and function has been achieved through the combined application of quality infrastructure (SOP’s, policies, specifications), qualification or validation (commissioning, IQ, OQ, PQ process Validation) and Testing (in-process and final release). Despite this rigid environmental approach, the number of drug recalls continues to rise, escalating from 176 in 1998 to 354 in 2002 [US CDER website]. In a break from tradition, the FDA recognized that the methods that lead to this problem could not be part of the solution. In 2002 the FDA issued its revised cGMP guidance document entitled Pharmaceutical cGMP’s for the 21st Century- A Risk Based Approach. This guidance advocated a shift in industry reliance on a rigid punitive quality structure to achieve regulatory compliance (with increasing failures) toward a more rigorously scientific argument for product development, quality and production. The revised guidance for the 21st century is included as part of Presidential Executive Order 13329; an order that is designed to encourage innovation in manufacturing and includes PAT. As inventing, developing and bringing new therapies to the marketplace has long been considered a core strength of the pharmaceutical and biotech industry, and given the increasing pressure and scrutiny from patient, shareholder, government and regulatory entities, the industry has never been more driven to look at their core business practices for solutions.
The current model for ensuring product quality is based upon the establishment of six major quality systems1.
The intent of PAT was to advocate a more scientific and methodical approach to product development, scale-up and production. The impact of PAT will be felt in all sectors of the organization, and if applied correctly, will increase granularity in the quality and quantity of data being created throughout the product development lifecycle. This data becomes the basis for process understanding and ultimately ensuring product quality. In the PAT guidance document issued by FDA the agency discusses several of the key elements required to be successful in deploying PAT. Specifically, the guidance document discusses PAT Tools, the need for Process Understanding, Risk-Based Management, Integrated Systems Thinking and Real-Time Product Release. The reduced time and operational cost of taking a product from the end of manufacturing to the marketplace has captured both the imagination and interest of the industry.
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Real-Time Product Release
The FDA guidance document3 describes PAT as:
“A system for continuous analysis and control of manufacturing processes based on real time measurements or rapid measurements during processing, of quality or performance attributes of raw and in-process materials and processes to assure end product quality at the completion of the process.”
The challenges in integrating PAT with manufacturing hardware are significant. Sampling technology, cleanability, assay specificity, accuracy and linearity and comparability to bench top methods and previous production methods must all be addressed before proceeding to implementation.
Blending Case Study
In a recent PAT deployment a blender was equipped with in-line hardware in an effort to determine Content Uniformity of the API and key rate controlling excipient.
The project was driven by intermittent dissolution failures in the product. Data revealed that 1/3 of the tablets failed S1 testing, while 1 out of 12 tablets failed S2. Subsequent analysis found that the tablets that failed dissolution had significantly different amounts of lubricant required for the formulation. The PAT study attempted to integrate in-line FT-NIR analytical technology in the final blending stage. The data were correlated against the bench top method that utilized ICP-MS.