The Desired State: PAT and the Road to Enlightenment

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 improvementAny 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 ASTMIn 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.The Executive Committee consists of elected officials and appointed members-at-large, and oversees the general direction and administration of Technical Committee E55. Subcommittee E55.01, “PAT System Management,” is tasked with developing strategic documents that provide a framework for the pharmaceutical application of PAT. Some work items currently under development within E55.01 include:

• “Standard Practice for Process Understanding Related to Pharmaceutical Manufacture and Control”
  
  
• “Standard Practice for Risk Management as it Impacts the Design and Development of Processes for Pharmaceutical Manufacture.”

Subcommittee E55.02, “PAT System Implementation and Practice,” addresses a more detailed need for the implementation of PAT. For example, this subcommittee is currently addressing topics such as “measurement system fitness-for-use” and “data management.”Subcommittee E55.91, “Terminology,” has established, and will continue to develop, a common terminology for use throughout the committee.Active participation from drug manufacturers and equipment and sensor vendors, regulators and academics will be crucial to the success of this endeavor. This broad base will create a standardized language, recommended best practices and performance standards for the pharmaceutical application of PAT. Success, in turn, will facilitate the development and implementation of future innovations in pharmaceutical manufacturing, advancing a scientific approach toward process understanding, control, and consequently flexible manufacturing. The ICH and ASTM processes are complementary and collectively outline information to be submitted in regulatory applications and the scientific standards for achieving a higher level of process understanding and control to facilitate our journey towards the desired state.First steps on the journeyTo facilitate continuous improvement and innovation, relationships between in-process controls, final product control limits, and regulatory specifications and/or standards must be clearly understood by all stakeholders. Applying appropriate measurement tools so that product quality consistently exceeds the minimal standard should provide both regulatory and technical flexibility for continuous improvement.However, quality improvement is facilitated if this improved ability to control is not penalized by narrowing the regulatory acceptance criteria. Regulatory concerns that often narrow these criteria can be addressed through science-based quality systems that effectively utilize tools such as statistical process control to provide a means to evaluate trends so as to prevent deviations due to “special causes” (e.g., under cGMPs).Significant opportunities exist today to build upon the current regulatory decision system and to further improve its effectiveness and efficiency, mainly by:

• (a) utilizing pharmaceutical development information (e.g., ICH Q8) in regulatory decisions
  
  
• (b) using new technologies for more effective control of the formulation and manufacturing variables that impact product performance
  
  
• (c) taking a comprehensive systems approach to regulatory quality assessment — for example, synergistic collaboration between CMC review, clinical pharmacology and biopharmaceutical review and cGMP inspections.

An effective and efficient decision system for pharmaceutical quality should integrate all discrete decisions to ensure consistent delivery of therapeutic objectives over a product’s life cycle. The system will be proactive, and worthy of regulatory flexibility, when its:

• (a) characteristics deliver the intended goals, reliably and efficiently
  
  
• (b) decision reliability, transparency and efficiency improve continuously
  
  
• (c) characteristics accommodate increasing system complexity
  
  
• (d) decisions facilitate continuous improvement in all applicable operations.

However, for the most part, the pharmaceutical community is still using a “reactive” approach to quality. Table 1 contrasts what is with what might be.

Editor's Note: To access a 2-page PDF containing Table 1 and other graphics for this article, click the Download Now button at the end of this story.

Figure 1 illustrates a process for re-evaluating the inherent assumptions in current regulatory policies pertaining to quality assurance and identifying opportunities for improvement [9]. It also illustrates a proposed relationship of this re-examination to the journey towards the “desired state.” Since a higher degree of process understanding and control—for example, control of variability — is the critical directional vector towards the “desired state,” this vector is visualized in three dimensions as the Z axis, where the X and Y axes define the plane, or the minimal standards, on which the current state rests.Benchmarking progress: “milestones”The efficiency of our journey towards the desired state will depend on how rapidly the pharmaceutical community can develop a common understanding of that state, identify and address challenges to moving forward, and develop metrics or “milestones” to benchmark progress and guide this journey.With every passing milestone, the global pharmaceutical community should continually improve our ability to deliver, as efficiently as possible, the high pharmaceutical quality that patients expect and demand of us. Broadly, the milestones necessary to benchmark our progress have to gauge scientific and technical progress and measure efficiency improvements. The measures of efficiency will be essential to make the business case in terms of cost savings or return on investment. Efforts such as the 2005 Pharmaceutical Manufacturing Team of the Year Award competition also help to benchmark our progress [11].The matrix in Table 2 identifies some of the key scientific and quality system issues and challenges to be addressed [5]. Systems and tools that address these challenges effectively will be significant milestones in the journey towards innovation and continuous improvement in pharmaceutical manufacturing.FDA initiatives create a number of opportunities for the pharmaceutical manufacturing community, and make it possible to move from reactive to proactive pharmaceutical quality decision making. There will be many hurdles to clear on this journey to the desired state, but a science-based framework and consensus development, and shared global vision developed under ICH, can help overcome some of these hurdles.To facilitate continuous improvement and innovation, a common understanding of the relationships between in-process controls, final product control limits, and regulatory specifications and/or standards will be necessary. Development of standards for “process quality” may be a means to achieve a common understanding on process control in the context of pharmaceutical quality, and ASTM’s International Committee E55 plays a critical role in making these standards a reality.Our progress toward the desired state will depend on how rapidly we all can agree on what that state is, identify and address challenges, and develop metrics to benchmark progress. The path to enlightened, proactive decisionmaking lies before us. It is up to us to follow it.References

1. The PAT Initiative. http://www.fda.gov/cder/OPS/PAT.htm
   
   
2. Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach, Final Report, Fall 2004. http://www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm
   
   
3. The Critical Path to New Medical Products. FDA, March 2004. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html
   
   
4. Guidance for Industry. PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. http://www.fda.gov/cder/guidance/6419fnl.htm
   
   
5. Innovation and Continuous Improvement in Pharmaceutical Manufacturing. The PAT Team and Manufacturing Science Working Group Report. http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf
   
   
6. Hussain, A. S. Process Analytical Technology: A First Step in a Journey towards the Desired State. The Journal for Process Analytical Technology. January 2005. http://www.patjournal.com/main.aspx
   
   
7. ICH Q8: Pharmaceutical Development. http://www.fda.gov/cder/guidance/6672dft.pdf
   
   
8. Torbeck, L. D. In defense of USP singlet testing. Pharmaceutical Technology. February 2005
   
   
9. Quality-by-Design Approach for Regulatory Decisions: Seeking Applications for Establishing Drug Dissolution/Release Specifications, Creating Flexibility for Continuous Improvement and for Assessment of Therapeutic Equivalence. Food and Drug Administration Advisory Committee for Pharmaceutical Science, May 3-4, 2005. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4137b1_Index.htm
   
   
10. ASTM International. Committee E55 on Pharmaceutical Application of Process Analytical Technology. http://www.astm.org/cgi-bin/SoftCart.exe/COMMIT/COMMITTEE/E55.htm?E+mystore
    
    
11. Shanley, A. and Thomas, P. Team of the Year: Our Finalists Tell Their Stories. Pharmaceutical Manufacturing, April 2005. http://www.pharmamanufacturing.com/articles/2005/261.html

About the AuthorAjaz Hussain, Ph.D., is Deputy Director, Office of Pharmaceutical Science (OPS) in CDER, FDA, which has oversight responsibilities for the development of science-based regulatory policies and the management of both review and research activities in the offices of New Drug Chemistry, Generic Drugs, Clinical Pharmacology & Biopharmaceutics and Testing & Research. He also holds adjunct faculty appointments at the School of Pharmacy, Purdue University and School of Engineering, University of Michigan. He received his Ph.D. degree in Biopharmaceutics from the University of Cincinnati, where he also held a faculty position before joining FDA.