Rodolfo J. Romanach

It has been almost 3 years since I received the first phone call from a company requesting a 'PAT-trained' student, and industrial interest and investment in PAT is continuing to grow. In my recent visits to industry, human resources (HR) personnel have been keen to learn where future PAT personnel will come from, to develop job descriptions for these positions and to learn which skills the new hires will have.

This article discusses four facets of PAT and HR:					

How to involve current personnel in PAT initiatives.

How PAT, Quality by Design (QbD) and the new Quality Systems Initiative can enhance pharmaceutical productivity.

Before hiring a PAT-trained student, companies should first assess the capabilities of the current personnel involved in the PAT effort. PAT hires should complement the skills of those already on board to bond as a good PAT team. Without the support of the team, he/she will be ineffective. PAT requires establishing a work plan, which should be a goal for an entire company rather than a single operating unit. Furthermore, companies should discuss their PAT plans with the FDA as usually only one person at a manufacturing site is authorized to contact the FDA.

The PAT hire also needs to have a wide range of interests that encompass the different aspects related to pharmaceutical manufacturing. For example, the PAT hire may have a strong background in chemometrics, but will also require a desire to learn about pharmaceutics and concepts of interest to industrial engineers (efficiency, down time and scheduling). Additionally, he/she will need to work with data management personnel to determine how data should be stored and evaluated. While the PAT team starts a new project, there will also be quality control (QC) personnel trying to implement risk management throughout the company. The PAT hire does not have to be an expert in risk management, but should be interested in understanding its relationship with PAT.

PAT is about understanding pharmaceutical processes. Therefore, interest in pharmaceutics and visualizing interactions between the different components in formulations are essential; for example, the new PAT hire should not develop a method to determine blend homogeneity without first discussing mixing with industrial pharmacists and pharmaceutical engineers. The PAT hire must be able to organize efforts to extract relevant data from a pharmaceutical process.

A PAT hire must be able to obtain and interpret data relevant to the manufacturing process. Many situations require an initial observation of the data, a cursory evaluation or simple exploratory analysis before initiating additional efforts. HR personnel are hearing the new word 'chemometrics', which is linked with data, equations and a possible recruiting difficulty as chemometrics courses are relatively rare. Chemometrics is the chemical discipline that uses mathematics, statistics and formal logic to: 					

Design or select optimal performance experimental procedures.

Provide maximum relevant chemical information by analysing chemical data.

The ability to work with data is intimately related to attention to detail; for example, in near-infrared spectroscopy and many of the spectroscopic methods used in PAT, subtle differences in spectra can be very important. An unskilled analyst might look at the spectrum shown in Figure 1 and not see any difference, but the trained analyst will find differences such as those observed between 8866–8666 cm

 Skilled practitioners would recognize that these near-infrared spectral differences are important in developing a method to determine the drug concentration of tablets. 

The PAT team should include a veteran member who is thoroughly familiar with the manufacturing processes and challenges. This person should be capable of outlining the critical problems in manufacturing processes. They could provide feedback such as: "The real problem is that this product constantly sticks to the punches; we can monitor and control previous steps, but if the product continues to stick we still have the same problems and bottleneck." The veteran must provide feedback on the daily problems that affect manufacturing and possess the process knowledge needed to improve it. Many personnel frown upon change as, for them, a change in a process means that it was not adequately validated. The veteran should be thoroughly familiar with company procedures and capable of convincing personnel of the importance of the PAT initiative so that they do not hinder its progress.

Pharmaceutical companies often have much more in-house expertise to support PAT initiatives than they realize, as current personnel may include scientists who worked with chemometrics or made real-time measurements as graduate students, but have now focused on other areas such as separations, after joining the industrial environment.

In pharmaceutical manufacturing plants, technical support groups work with formulators to transfer processes to the manufacturing site. Once this has been accomplished, the formulators turn their attention to the future new products in their company pipeline and the 'technical support' or 'product support groups' work with the transferred product in the manufacturing plants.

Unfortunately, most technical support groups do not have analytical instrumentation to help them gather new process knowledge to improve or troubleshoot their processes. When manufacturing problems arise, technical support groups carefully observe the manufacturing process, attempt to identify any minor variations in procedures that may have led to the manufacturing problems, and evaluate results received from the QC laboratory to identify trends in the data. Some production problems are serious enough to warrant a full investigation, and perhaps a process change, while others are never resolved and last throughout the entire life cycle of the product, limiting the manufacturing plant's efficiency and affecting its lead times. Technical support personnel have often told me they are restricted by the fact that "in the pharmaceutical industry, you cannot make any changes after a process is validated".

Many companies are paying highly skilled personnel to observe processes that they have no intention to improve. One of the main benefits of PAT and the current FDA initiatives is that pharmaceutical scientists are allowed to use their technical capabilities to improve pharmaceutical processes. 

The post-PAT view is that change is necessary for process improvement. Change control is no longer seen as a documentation practice, but as a mechanism to facilitate process improvements.

 The new PAT hire should not be solely restricted to observing processes where he/she cannot make any changes.

The company should address the training needs of the entire PAT team, not just the new hire. Continuous learning is necessary for the new hire's development in areas not addressed in formal academic training such as pharmaceutical regulations and risk management, and is also essential for the new hire to become familiar with the company's products and processes. A valuable resource that is often overlooked is discussions with company veterans and experienced scientists. Technical reports and other documents describing previous validations or troubleshooting efforts are also of great worth, as are training/education sessions provided by a number of associations.

There is a need for in-house discussions of relevant FDA guidance, EMEA documents, QbD, International Conference on Harmonisation (ICH) guidelines and business objectives.

 Discussions with other companies are also very productive; for example, sharing experiences in discussing PAT or QbD projects with FDA. Communication of this type has been encouraged locally through a PAT forum, which was initiated in December 2004, with bi-monthly meetings where companies and academic laboratories share their experiences in developing and implementing PAT.

PAT will also involve a learning curve with new pharmaceutical analytical applications. The pharmaceutical industry thoroughly understands its high performance liquid chromatography methods. At recent conferences, a number of presentations have reflected the fact that industrial groups are progressing along the learning curve and implementing methods using near infrared, Raman spectrometers and other instruments. While many academic laboratories have helped to develop these spectroscopic methods and demonstrated their feasibility, some problems will only come to the surface with daily industrial experience. Using a certain method for product release requires a thorough understanding of it and the parameters that may affect it. Transferring methods from one laboratory to another will bring additional instrument calibration and wavelength accuracy problems not anticipated in feasibility or validation studies.

The hiring of a PAT-trained student should not be an isolated decision: it must be accompanied by a strategy to implement PAT in the company and assemble a team to support the efforts of the new hire. A commitment to process knowledge and a move away from the 'you cannot make any changes' paradigm is necessary. These combined efforts will increase the productivity of the entire technical support team.

The author thanks Manuel L. Hormaza, Dr Carlos Conde and Dr Manel Alcalá for their helpful comments.

is Professor of Chemistry at the University of Puerto Rico (Puerto Rico).

., Handbook of Chemometrics and Qualimetrics: Part A (Elsevier, Amsterdam, The Netherlands, 1997), p 1.

4. Quality Systems Guidance, US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM) and Office of Regulatory Affairs (ORA), September 2006.

5. Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM) and Office of Regulatory Affairs (ORA), September 2004.

7. EMEA — Reflection Paper: Chemical, pharmaceutical and biological information to be included in dossiers when Process Analytical Technology (PAT) is employed, March 2006. 

9. Forum sponsored by INDUNIV, Puerto Rico Industry Research and Government research consortium. 

Articles

The biggest benefit of PAT and the current FDA initiatives may be in allowing pharmaceutical scientists to use their technical capabilities to improve pharmaceutical processes.

PAT — a team effort

Pharmaceutical companies have followed quality improvement programmes, implemented planning and scheduling tools, and introduced just-in-time and lean manufacturing approaches, but in spite of these efforts the efficiency or level of utilization in pharmaceutical manufacturing is only 15%, according to a study.

  The success of these programmes is often limited because pharmaceutical materials and processes are not thoroughly understood.  

Many pharmaceutical processes are based on empirical knowledge, not on fundamental understanding of the physical and chemical interactions. Quality control (QC) laboratories do not generally provide information on the physical aspects that dominate pharmaceutical processes, such as flow properties or particle size distribution of the materials. These important characteristics are frequently ignored, and lack of process understanding limits the efficiency of pharmaceutical manufacturing.  

FDA has indicated that product quality is generally adequate for its intended purposes, but the process by which the quality is achieved is inefficient.

  Low manufacturing efficiency leads to high compliance costs with a significant proportion of FDA resources required to ensure adequate product quality. Recurring quality problems are common at many pharmaceutical sites. FDA also maintains a website that lists drug shortages, the majority of which relate to manufacturing problems.

FDA has started the critical path initiative (CPI), where the critical path is defined as all those activities that occur once a company decides to develop a drug candidate molecule into a product and seek its approval.

  The critical path studies indicate that the number of new molecular entities (NMEs) for both small molecules and biotechnology-derived products submitted to FDA has decreased in recent years. The decrease in new products has been accompanied by a significant increase in the cost of bringing a new product to market, and FDA has diagnosed a 'pipeline problem'. The critical path report also discusses the industrialization stage defined as developing the capacity to reliably manufacture a high-quality product at commercial scale. Industrialization is also seen as a frequent hurdle in the critical path-delaying trials, and limiting and delaying access to new products.  

Recognizing the difficulties in pharmaceutical manufacturing is an important first step. This article reviews FDA initiatives to improve pharmaceutical manufacturing, and discusses two significant research efforts to develop a future environment based on scientific understanding of pharmaceutical materials and processes.  

FDA started the PAT initiative to increase pharmaceutical process understanding and encourage innovation in pharmaceutical manufacturing.

  The efforts to develop this initiative involved several activities to seek industrial feedback. Table 1 lists some of the actions that occurred between the start of discussions on PAT and the guidance issued on September 2004. The table also shows that the PAT initiative served as a first step towards other FDA initiatives. 

 Table 1 Developments in PAT and GMPs.			

PAT has been defined as a "system for designing, analysing and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality."

  For example, in current pharmaceutical processes fixed blending times are specified. In a PAT system mixing would occur until the system indicates that the blend is homogeneous. A blending period or range would be specified based on the variability that may be expected in the excipients and API. The technology to monitor blending processes is already available and several researchers have shown the feasibility of using near infrared (NIR) spectroscopy to monitor blending processes.

  The analytical technology to monitor the process is only one aspect of PAT because its concept also encompasses process design and control.  

The PAT guidance describes FDA's regulatory framework to handle PAT proposals from the pharmaceutical industry, and is now part of the broader 

 that FDA has summarized as: "A science and risk-based approach to product quality regulation incorporating an integrated quality systems approach."  

PAT contributes to QC by providing a framework for using technology to monitor and control critical quality parameters in processes. Therefore, PAT cannot be implemented without studying and understanding pharmaceutical processes. If a process is not understood, sensors or instruments could be used to monitor all the nonimportant parameters, wasting the effort and investment without any improvements.  

Process understanding requires comprehending the fundamental structural properties of excipients and the API, the manner in which these materials interact, and the effect of processing steps on materials. In the majority of formulations, excipients and the API are solids, providing a significant challenge to chemists that have learned chemistry in curricula that focused on liquid and gaseous state reactions. Some of the exciting pharmaceutical process research opportunities are related to the formation of amorphous or crystalline materials,

  or to controlling the crystal form of the API.

  Other efforts are geared to understanding the physics involved in mixing granular materials,

  and the role of nanoparticles to improve material flow.

  Without doubt, research is needed to understand the physical and chemical properties of materials involved in pharmaceutical processes.  

The PAT concept emphasizes that product quality should be achieved through the design of effective and efficient manufacturing processes.

  ICH Q8 describes how to include quality by design (QbD) and PAT in a regulatory submission.

  The design space will need to address variations in the chemical and physical properties of excipients and the API, and show that these variations can be managed by the process resulting in a final product that meets the approved specifications. QbD will require additional pharmaceutical process research to understand pharmaceutical materials.  

The National Science Foundation (NSF [VA, USA]) recently approved a $15-million (€10.9-million), 5-year grant to implement the Engineering Research Center (ERC) to improve the manufacturing of pharmaceuticals, food and agricultural products. This award was given to more than 30 researchers from Rutgers (NJ, USA), New Jersey Institute of Technology (NJ, USA), Purdue University (IN, USA) and the University of Puerto Rico (Mayagüez, Puerto Rico). The principal objective of this large project is to incorporate materials science and engineering methods in pharmaceutical manufacturing.  

Figure 1 shows the engineering approach the ERC is currently following. Once the administration and delivery requirements of an API are known, then engineering is used to obtain an integrated framework with predictive models to systematically design the particles of the API, composites and their manufacturing processes with a reduced number of supporting experiments. The engineering system will be demonstrated in three core technology platforms dedicated to developing specific types of products with predetermined functionalities. 

The first development programme, Continuous Manufacturing of Macrocomposites, improves and upgrades two current manufacturing methods: direct compression and roller compaction. The second, Engineered Particle-Based Delivery Systems, focuses on innovative stable suspensions of nano- and microparticles with desired properties. The third, Multilayer Architectures, emphasizes highly innovative product synthesis methods intrinsically suitable for personalized medicine. 

The National Institute of Pharmaceutical Technology and Education (NIPTE [

]), was established as a nonprofit multi-university consortium for interdisciplinary research and education in pharmaceutical science and engineering. Its aim is to develop, manufacture and deliver pharmaceutical products faster, safer and at a significantly lower cost to the patient. 

The NIPTE's current goal is "to become the pre-eminent interdisciplinary national resource for research and education on science- and engineering-based understanding of pharmaceutical development and manufacturing. Scientists, researchers and engineers from academia, FDA and the industry will collaboratively engage in developing state-of-the-art science and technology to enable the pharmaceutical industry to develop products faster, and at a significantly lower cost with less variability and higher predictability of performance." The executive committee of the NIPTE has estimated that about $25 million (€18 million) is needed annually for the NIPTE to make a significant contribution and meet its goals.  

The NIPTE will not be dedicated to the discovery of new pharmacologically active molecules; it will focus on improving pharmaceutical technology, which has been defined as: "Pharmaceutical technology addresses design, development, and manufacturing of all components of drug products, diagnostics, and pharmaceutical devices, including organic molecules, proteins, and other biologics. It also encompasses the physical and engineering sciences of scalable drug delivery platforms." 

The NIPTE is developing pharmaceutical manufacturing and education roadmaps, which will pinpoint a number of problems that delay the approval of drug products, increase the cost of their development and lower the efficiency of manufacturing processes. They will also include a vision of the desired state of pharmaceutical development and manufacturing. The path from the current state to the desired state will require overcoming a number of barriers, and advances in various research areas. These research areas are being identified and classified in terms of their importance, with a preliminary estimate of the time and financial resources needed to advance them.  

The PAT initiative marked the beginning of a consistent FDA effort to emphasize innovation and science-based pharmaceutical manufacturing. The research initiatives described in this article also support science-based pharmaceutical manufacturing. These regulatory and scientific efforts — and those of many other researchers — are expected to lead to a future science-based pharmaceutical manufacturing environment.  

The author thanks Dr Prabir Basu at NIPTE and Dr Manel Alcalá at the University of Puerto Rico, Mayaguez for reviewing the manuscript and providing suggestions.  

1. D. Dean and F. Bruttin, "Productivity and the Economics of Regulatory Compliance in Pharmaceutical Production", PricewaterhouseCoopers, Food and Drug Administration Advisory Committee for Pharmaceutical Science (28 November 2001). 

2. A.S. Hussain, "The Subcommittee on Process Analytical Technologies (PAT): Overview and Objectives", FDA's Advisory Committee for Pharmaceutical Science (25 February 2002). 

4. "Innovation or Stagnation. Challenge and Opportunity on the Critical Path to New Medical Products", US Food and Drug Administration, 2004. 

5. "Innovation or Stagnation. Critical Path Opportunities Report", US Food and Drug Administration, 2006. 

6. "Innovation or Stagnation. Critical Path Opportunities List", US Food and Drug Administration, 2006. 

7. "PAT — A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance", in Center for Drug Development and Research (US Food and Drug Administration), 2004. 

14. N. Rodríguez-Hornedo and D. Murphy, 

16. T. Shinbrot and F.J. Muzzio, "Mixing and Segregation in Tumbling Blenders", in J. Swarbrick, J.C. Boylan, Eds., 

Encyclopedia of Pharmaceutical Technology

 (Marcel Dekker, New York, NY, USA, 2002) p 1795.  

19. ICH Q8, Pharmaceutical Development, US Food and Drug Administration, 2006. 

Recent regulatory initiatives have emphasized the need to improve pharmaceutical manufacturing. PAT marked the beginning of a number of regulatory efforts to encourage innovation and a transition towards science-based manufacturing. This article reviews the progress of the regulatory initiatives and describes two significant research initiatives to develop a future pharmaceutical manufacturing environment based on scientific understanding of pharmaceutical materials and processes.