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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.
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:
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.1
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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:
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–1 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.3
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.4 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.4–8 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.9
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.
Rodolfo J. Romañach is Professor of Chemistry at the University of Puerto Rico (Puerto Rico).
1. S. Hernández et al., Journal of Process Analytical Technology, 3(6), 20–23 (2006).
2. D.L. Massart et al., Handbook of Chemometrics and Qualimetrics: Part A (Elsevier, Amsterdam, The Netherlands, 1997), p 1.
3. R.J. Romañach, Journal of Process Analytical Technology, 3(1), 22–25 (2006).
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.
6. F. Erni, Journal of Process Analytical Technology, 2(2), 23–26 (2005).
7. EMEA — Reflection Paper: Chemical, pharmaceutical and biological information to be included in dossiers when Process Analytical Technology (PAT) is employed, March 2006. www.emea.europa.eu
8. S.V. Hammond, Journal of Process Analytical Technology, 2(4), 15–7 (2005).
9. Forum sponsored by INDUNIV, Puerto Rico Industry Research and Government research consortium. www.induniv.org