The Desired State: PAT and the Road to Enlightenment

By focusing on the pharmaceutical manufacturing process, ASTM standards for process analytical technology (PAT) promise to bring engineering rigor and proactive decisionmaking to pharmaceutical quality.

By Ajaz S. Hussain, Ph.D., Deputy Director, Office of Pharmaceutical Science, CDER, the U.S. Food and Drug Administration (FDA)

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Process understanding can be a foundation for innovation and continuous improvement in pharmaceutical development and manufacturing. FDA’s Process Analytical Technology (PAT) initiative, part of the Agency’s 21st Century cGMPs [1-5], reaffirms that message [5-7], but also aims to help the global pharmaceutical community reach a “desired state,” where:
  • Product quality and performance are achieved and assured by design of effective and efficient manufacturing processes;

  • Product specifications are based on a mechanistic understanding of how formulation and process factors impact product performance;

  • Manufacturers are able to effect continuous improvement and continuous "real time" assurance of quality.
The phrase “desired state” was first articulated two years ago, at the International Conference on Harmonization (ICH) in Brussels, where the idea of a global, harmonized pharmaceutical quality system began to take shape. The system would be based on science and applicable across a product’s life cycle. First, however, the pharmaceutical community would have to overcome the hurdles—historical, traditional, and cultural—that have prevented it from reaching this nirvana.

ICH emphasized the importance of taking an integrated approach to regulatory review, assessment and inspection, based on principles of sound scientific risk assessment and risk management [5]. An expert working group was established to develop guidance for sharing pharmaceutical development information in regulatory submissions (ICH Q8), to begin to define the desired state and to outline the steps needed to reach it.

The ICH vision provides the global pharmaceutical industry the opportunity to move from a reactive to a proactive decision system for pharmaceutical quality (Table 1), a system that can meet patients’ current and future needs. This article discusses the opportunities to create this new framework for quality decisions, and outlines progress that is being made.

Current standards don’t facilitate continuous improvement

Any pharmaceutical quality system must ultimately be judged by how effectively it serves society. Developing a common, science-based framework for the entire community, regulators and manufacturers alike, can only benefit society by improving decision efficiency. And extending this framework internationally, through consensus building, as was seen with ICH Q8, extends those benefits.

Clearly, today’s pharmaceutical quality system shows much room for improvement. Many regulatory decisions on quality assurance and control—for example, the drug dissolution rate—are based predominantly on test data from a relatively small sample; robust estimates of sample and population variance are often not obtained. At a time when process control technology has advanced considerably, the industry’s process control strategy and decision criteria still reflect traditional compendial standards.

Compendial standards were intended to be “market standards,” since they are applied to many different manufacturers, and cover different manufacturing processes for the same monograph product. By definition, compendial or market standards have to be absolute — pass/fail, with no room for uncertainty or risk-based decisions [8].

These are minimal standards, sufficient for ensuring quality fit for intended use of a product. They do not, and were never intended to, provide a way to recognize the level of process understanding and control achieved. Therefore, decisions primarily based on these standards cannot facilitate continuous improvement in efficiency or productivity.

In addition, there is a growing concern about applying some of these standards to address quality decisions on increasingly complex products. For example, composite and complex physical functionality, as evidenced by dissolution rate, is generally influenced by many physical factors, such as hydrodynamics. It is sometimes difficult to define one set of test conditions for several products that may differ in certain formulation and manufacturing characteristics.

Furthermore, forcing different manufactures to conform to one set of test conditions can be unfair; the equipment and test conditions optimally defined for the first drug product of its type may not be optimal for testing and interpreting test data for other products; this can impose non-value added constraints on products that follow [9].

Building consensus through ASTM

In December 2003, FDA took concrete steps to help advance the development of science-based standards for process quality by joining a diverse group of stakeholders from the pharmaceutical community to establish the ASTM International Technical Committee E55 on the pharmaceutical application of PAT [10].

Having broad-based stakeholder representation from various segments of the pharmaceutical community establishes the most effective venue to develop science-based consensus standards for process quality. ASTM International allows the pharmaceutical community to integrate fundamental scientific and engineering principles to standards development. Other industrial sectors, notably chemicals and petrochemicals, have taken this approach and achieved outstanding results by collaborating on standards within the organization.

Involving stakeholders with multidisciplinary expertise allows for consensus development with an appropriate focus on the manufacturing “process,” providing a fundamental engineering dimension that has traditionally been missing from pharmaceutical quality decision making.

Structurally, Committee E55 is organized as other ASTM International Technical Committees, with a main Executive Committee (E55.90), and several subcommittees (E55.01, E55.02, and E55.91) that are tasked with addressing specific topics concerning the pharmaceutical application of PAT.
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