INTRODUCTION:

Today’s pharmaceutical industry is driven by the necessity to generate and execute effective and efficient processes for generating new product.¹

Drug discovery is cost, time and risk intensive process. It takes more than 500 million dollars and about 10 years to bring drug from concept to clinic. However, only 20% of the medicines that enter clinical trials are eventually approved. It is for these reasons that more funds are devoted to the investigation of new medications than are being spent on efficient manufacturing. ²

Pharmaceutical manufacturing needs to have innovation, cutting edge scientific and engineering knowledge along with the best principles of quality management to respond to the challenges of new discoveries. Manufacturing and regulatory efficiency of a product can be improved with effective use of the pharmaceutical science and engineering principles.

In conventional pharmaceutical manufacturing, there is a batch processing to evaluate quality. However, today significant opportunities exist for improving development, manufacturing and quality assurance through innovative product and process analysis. ³Innovation is the key to all-around success.

The high regulatory burden in pharmaceutical industry prevents continuous process optimization and process adaptations for increasing manufacturing efficiency. To overcome these regulatory barriers, the FDA has launched the Process Analytical Technology (PAT) Initiative in 2003. ⁴

Quality by design is an established concept in Europe. PAT has been implemented for years, particularly by the chemical industry for the control of chemical processes. More recently, PAT has become a cornerstone of the US Food and Drug Administration’s (US FDA) Quality by Design initiative for both the design and control of quality processes.

The term PAT is defined by US FDA as follows: “the agency considers PAT to be a system for designing, analyzing and controlling manufacturing through timely measurements (i.e., during processing) or critical quality and performance attributes of raw and in–process materials and processes, with goal of ensuring final product quality. It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical and risk analysis conducted in an integrated manner.”

PAT uses real time information to reduce process variation and manufacturing capacity. PAT is real-time testing and adjustment based on the complete understanding of how the components and related processes affect the final product.

PAT is a method of analysis/ or tool which involves correlation of processes and materials/ products, it not only determines quality of finished product but also assures the quality by monitoring and also control it. ²

DEVELOPMENT OF THE FDA’S PAT INITIATIVE:

The FDA initiated a proactive approach to include innovation and the public health benefits associated with it into pharmaceutical manufacturing process.

An initiative was developed at the FDA’s, Centre for Drug Evaluation and Research (CDER). The PAT initiative was then discussed publicly for the first time at an FDA; Advisory Committee for Pharmaceutical Science (ACPS) meeting in July 2001. A formal presentation to the FDA’s Science Board took place in November 2001, after which the Board endorsed the CDER’s plan.

The agency formed a subcommittee on PAT under the CDER’s ACPS. In addition to FDA representatives, the subcommittee also included industry experts, (e.g. From Pfizer, Bristol-Myers Squibb and Astra Zeneca) and representatives from academia (e.g. Purdue University). The tasks of the subcommittee, which was chaired by Tom Layoff, were defined as follows:

· Current status and future trends involving PAT in pharmaceutical development and manufacturing. This includes available technologies, applications in domestic and foreign plants and perceived and real regulatory hurdles.

· General principles for regulatory applications of PAT, including methods validation and specifications and feasibility of parametric release concepts.

· Case studies about PAT, most likely using NIR technologies

· Research and training needs of FDA and the industry.

A guiding force in the FDA’s PAT movement was the CDER’s Office of Pharmaceutical Science (OPS) Deputy Director, Azaz Hussain, who is the chair of the PAT steering committee.

In addition to three other representatives of CDER’s OPS, Ali Afnan, an industrial chemist hired by the FDA in May 2003 who had previously been employed at Astra Zeneca, was also active in the original PAT Policy Development Team. He is one of the three pharmaceutical/ chemical engineers with expertise in PAT who has recruited by the FDA.

Figure 1. Dimensions of PAT

The American Society for Testing and Materials (ASTM) established the Committee E55 on Pharmaceutical Application of PAT in February 2004. This committee addresses issues related to process control, design and performance, as well as quality acceptance/assurance tests for the pharmaceutical manufacturing industry. ²

PAT GOALS:

One of the most important goals of PAT initiative is to achieve process understanding. Process is generally considered well understood when

Ø All critical sources of variability are identified and explained

Ø Variability is managed by the process

Ø Product quality attributes can be accurately and reliably predicted over the design space established for materials used, process parameters, manufacturing, environmental and others conditions.

An attention to the process understanding can lower the burden for validating system by providing more options for justifying and qualifying systems intended to monitor and control biological, physical and/or chemical attributes of materials and processes. ^{2, 3}

Real time release:

Real time release is the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process data. Typically, the PAT component of real time release includes a valid combination of assessed material attributes and process controls. The combined process measurements and other test data gathered during the manufacturing process can serve as the basis for real-time release of the final product and would demonstrate that each batch conforms to established regulatory quality attributes.

Dimensions of PAT:

PAT comprises more than just measurements (sensors with control electronics) and analysis (calibration with on-screen or paper reporting). PAT consists of four segments: design, measurements, prediction and control. (Figure I) When each of these is brought together to optimize quality, safety and cost, the true aim of the PAT initiative is achieved to enhance real-time process understanding for better risk management.

PAT provides a base for reducing risk by making processes “self-validating“ and checking quality at the source.

PAT TOOLS:

There are many tools available that enhance process understanding for scientific, risk-managed pharmaceutical development, manufacture and quality assurance. In the PAT, these tools can be categorized according to the following:

· Multivariate tools for design, data acquisitions and analysis

· Process analyzers

· Process control tools

· Continuous improvement and knowledge management tools

Multivariate tools for design, data acquisitions and analysis:

Using multivariate projection of methods, the number of charts can be reduced. These methods reduce the dimensionality of the problem by taking advantages of the correlated structures of databases.

The use of multivariate charts based on latent variable methods has revolutionalized the idea of statistical process control for multivariate processes. The performance of an entire unit, or even a plant, can be monitored by the operators looking at only a few multivariate control charts.

Industry quickly adopted the multivariate methodology in the development of soft sensors, where real time sensors for measuring a product quality response are not available. These soft sensors can either replace the hardware sensor (analyzer) or they can be used in parallel with it to provide redundancy and verify whether the hardware sensor is drifting or has failed.

Multivariate projection methods for analyzing batch process databases (multiway principal component analysis and multiway partial least squares) are available; they were initially presented by Nomikos and Macgregor in a series also be applied to fermentation, batch distillation, drying, batch annealing and mixing/blending additives for a finite time.

There are multiple steps in pharmaceutical manufacturing and each step involves multiple unit operation. Such cases also are assessed with latent variable models. Rather than building a model for each unit, one can build a model for the full process that will take into account the interactions between units and their relative importance to the final product quality by weighting them differently.

Multivariate image analysis (MIA) is a relatively new technology for real-time monitoring and feedback control. The aim of this approach is to extract subtle information related to product quality from the image, and use such information for prediction, monitoring and control.

Figure 2. PAT instrumentation Demand, 2005

It is hoped that the pharmaceutical industry will adopt quickly the multivariate approach to process analysis and understand this and hence not only avoid the mistake of dealing with univariate control charts, but also improve process performance while achieving excellent product quality. ⁵

Process analyzer

Process analysis has advanced significantly during the past decades, due to an increasing appreciation for the value of collecting process data. Industrial drivers of productivity, quality and environmental impact have supported major advancements in this area. Some process analyzers provide non destructive measurements that contain information related to biological, physical and chemical attributes of the materials being processed. These measurements can be,

· At-line: measurement where the sample is removed isolated from and analyzed in close proximity to the process stream.

· On-line: measurement where the sample is diverted from the manufacturing process and may be returned to the process stream.

· In-line: measurement where the sample is not removed from the process stream and can be invasive or non-invasive.

Process analyzers typically generate large volumes of data. Certain data are likely to be relevant for routine quality assurance and regulatory decisions. In a PAT environment, batch records should include scientific and procedural information of high process quality and product conformance measurements collected from these process analyzers need not be absolute values of the attribute of interest.

Advances in process analyzers make real-time control and quality assurance during manufacturing feasible.

For certain applications, sensor-based measurements can provide a useful process signature that may be related to the underlying process steps or transformations.

Installation of process analyzers on existing process equipment in production should be done after risk analysis to ensure this installation does not adversely affect process or product quality. ³

Process Control Tools:

Process monitoring and control strategies are intended to monitor the state of a process and actively manipulate it to maintain a desired state.

Design and Optimization of drug formulations and manufacturing processes within the PAT framework can include the following steps:

1. Identify and measure critical material and process attributes relating to product quality.

2. Design a process measurements system to allow real-time or near real-time (e.g. on-, in-, or at-line) monitoring of all critical attributes.

3. Design process controls that provide adjustment’s to ensure control of all critical attributes.

4. Develop mathematical relationship between product quality attributes and measurements of critical materials and press attributes.

Continuous Improvement and Knowledge Management:

Continuous learning through data collection and analysis over the life cycle of a product is important. These data can contribute to justifying proposals for changes. Approaches and information technology systems that support knowledge acquisitions from such databases are valuable for the manufacturers and can also facilitate scientific communication with the Agency.

Opportunities need to be identified to improve the usefulness of available relevant product and process knowledge during regulatory decision making.

A knowledge base can be of most benefit when it consists of scientific understanding of the relevant multifactorial relationship as well as a means to evaluate the applicability of this knowledge in different scenarios. Today’s information technology infrastructure makes the development and maintenance of this knowledge base practical. ³

BENEFITS OF USING PAT WITH ITS CHARACTERISTICS:

Some of the potential benefits of pharmaceutical manufacturing based on PAT include:

· Enhancing process understanding and reducing process failures.

· Yield improvement opportunities.

· Ensuring quality through optimal design, continuous monitoring and feedback control.

· Reducing cycle time to improve manufacturing efficiency.

· Identifying the root causes of process deviations.

· Basic regulatory scrutiny on process knowledge and scientifically based risk assessment.

· Reduce production costs.

· Improve consistency of production.

· Decrease burden of final product testing.

· Reduce the non-value added time in laboratory testing and associated paperwork.

· Faster time to release to market potential. ^6,7,8

A PAT system is characterized by three inter-related factors: continuous, cybernetic and remote monitoring.

Continuous control provides an early warning mechanisms; cybernetic control provides a self- correcting mechanism; and remote monitoring allows multiple and efficient quality assurance control mechanisms. Together, these three factors minimize the cost of pharmaceutical production while maximizing the end-quality of those products. It is in the interaction of the three- continuous, cybernetic, and remote monitoring – that the quality, safety and cost benefit accrue. ⁹

SCOPE OF PAT:

The scope of the PAT involves enhancing product and process understanding and controlling of pharmaceutical manufacturing processes. This will encompass applications of PAT in both the manufacturing and RandD environments including but not limited to the following:

· Drug substance/API route development and manufacturing control

· Drug Product/Formulations and process development and manufacturing control

· Raw materials

· Excipients

· Biologicals

· Animal Health products

· Generic products

The PAT applied throughout the lifecycle of a product including:

· RandD

· Scale-up

· Technology Transfer

· Commercial Manufacturing

· Also cases involving CRO's

PAT REGULATORY APPROACH:

One goal of PAT is to tailor the Agency’s usual regulatory scrutiny to meet the needs of PAT-based innovations that

1. Improve the scientific basis for establishing regulatory specifications

2. Promote continuous improvement and

3. Improve manufacturing while maintaining or improving the current level of product quality. To be able to do this, manufacturers should communicate relevant scientific knowledge to the Agency and resolve related technical issues in a timely manner. ³

The historical regulatory context acted as a drag anchor on changes in the manufacturing process, since companies have to face the uncertainty, delay and extra cost of fresh regulatory approval each time they reform their manufacturing process. Innovation that could result in safer, more stable processes, and ultimately better public health, was being hindered by regulation.

It was the FDA’s realization of the potentially inhibiting effect of regulation that led them to reform their approach to validation and introduce the new PAT guidance. ¹⁰

AUTOMATION AND PAT:

To implement PAT effectively, automation needs to support the effort of continuously and automatically collecting data not just from the sensors directly associated with the process, but from all of the other factors that could influence the results. ¹¹

INSTRUMENTATION:

Near Infrared Spectroscopy (NIR):

Near infrared (NIR) spectroscopy is one of the modern process analyzers. It is perhaps the most dominant technology within this group of process analyzers. NIR is one of the most powerful PAT tools available and the increasing number of applications will also provide the economic incitement for the vendors to improve their instruments. There are, in particular, two key areas in which instrument development will support the PAT evolution; these are: sampling and interfacing with process control systems. ¹¹

On-line HPLC:

By transferring the specificity of HPLC to an on-line analyzer, it is possible to directly measure the critical quality attribute in near real time, thus allowing the process decision (i.e., when to start and stop collection of the product eluting from the process chromatography column) to be based on the critical quality attribute rather than being based on a surrogate measurement that is impacted by the process variability. ¹²

Acoustic-Resonance Spectroscopy:

Acoustic-resonance spectrometry (ARS) is accurate and precise as well as inexpensive and nondestructive, and the sensor is constructed from readily available parts, suggesting utility as PAT. The wide-ranging measurements that can be made by ARS include sample compaction and axial strain, deformation, hydration and drying endpoint, elasticity, molecular stacking, and homogeneity, making ARS a very descriptive method of sample analysis. In addition, ARS provides a rapid and efficient way to nondestructively identify and quantify an analyte with no sample preparation. ¹³

Raman Spectroscopy:

Commercially available Raman spectrometers designed for PAT-type applications are available with up to 60 fibre optic inputs allowing potentially 60 individual points on the production line to be monitored simultaneously. Use of a suitable optical 'relay' can potentially increase this degree of multiplexing further. Encouraged by the opportunities that will arise as a result of the PAT initiative; the Raman instrument manufacturers and scientific community are now putting considerable effort to develop the technique as a PAT tool. Indeed, a range of proprietary Raman PAT instrumentation is already available. ¹⁴

IMPLEMENTATION OF PAT:

Implementation of PAT for pharmaceutical manufacturing has continued to advance and enable operations that monitor, control, and analyze critical quality attributes of processes and products while manufacturing is in progress, i.e. continuous quality verification. Implementation of PAT challenges the current validation paradigm to change towards supporting quality by design so that a balance is maintained between compliance and innovation. ¹⁵

For the implementation of PAT, FDA has outlined the following steps:

· First, a comparability protocol can be submitted to the FDA outlining PAT research, validation, and implementation strategies. Following FDA approval of this comparability protocol, one or a combination of the following regulatory pathways can be adopted for implementation.

· PAT can be implemented under the facility's quality system; cGMP inspections by the FDA follow.

· PAT can be implemented following cGMP inspection whereby the FDA's PAT Team conducts a pre-operational review of the PAT-based facility or application.

· A supplement (CBE, CBE-30 or PAS) can be submitted to the FDA prior to implementation, and, if necessary, the FDA's PAT Team can perform an inspection before implementation.

For PAT method validation, sufficient data must be acquired with a qualified system in routine operation including the process or product interface.

Periodic review of PAT systems and methods in use should identify trends in results that require preventive or corrective actions, as well as analyzing the cumulative effect of changes relative to original specifications. ¹⁵

Three striking themes- backward process PAT, narrow PAT and inward PAT-spring out from literature that how pharmaceutical companies are implementing PAT. First, there is a tendency to work backward, getting priorities reversed by an undue focus on the analytical technology at the expense of the business outcomes and the process frameworks. Second, PAT is often viewed too narrowly, with a focus on the technology alone without proper consideration of the wider context in which it has to be implemented. Third, much of the discussion around pharmaceutical PAT in inward with little is learning from outside the industry, despite the fact that the pharmaceutical sector is relatively late in its introduction of PAT. ¹⁶

PAT in outsourced manufacturing:¹⁷

Implementing PAT in outsourced manufacturing benefits both customers: the sponsor, and the regulatory body. The key benefits fall into the following areas:

· Flexibility in manufacturing configuration

· Asset utilization through more effective campaigning of batches

· Reduction in paperwork

· Greater Productivity and Improved Quality

· Lower Regulatory Scrutiny

PAT MARKET DEMAND:

Strategic Directions International, Inc. (SDi) report, PAT Instrumentation: The Pharmaceutical and Biotechnology Market for Process Analytical Technology, provides a detailed and unbiased perspective on the developing market for PAT instrumentation and software. The report covers each of the disparate analytical technologies that are seeing significant application in the PAT market. (Figure II) ¹⁸

CONCLUSION:

PAT involves a fundamental shift from testing the quality of the finished drug product, to building quality into products by testing at several intermediate steps. It specifically requires that quantifiable, casual, and predictive relationships be established amongst raw materials, the manufacturing process, and final product quality. It is believed that PAT may not bring dramatic changes overnight, but years from now, it may be seen as an initiative that helped foster a period of innovation, efficiency, and expansion for the pharmaceutical industry. ¹⁹

A critical appraisal reveals that in certain circumstances PAT possesses a number of compelling practical advantages in the pharmaceutical industry. PAT will surely lead to become an integral tool in the pharmaceutical industry's analytical armory.

The emphasis in PAT is on manufacturing process to amplify the basic premise of the current drug quality system: The product is “engineered for Quality”, as opposed to “tested to quality.”

As well stated by US-FDA, “Quality cannot be tested into products; it should be built –in or should be by design.”

REFERENCES:

1. Koch MV. Optimizing the impact of developments in micro-instrumentation on process analytical technology: a consortium approach. Anal. Bioanal. Chem. 2006; 384: 1049-1053.

2. Hinz DC. Process analytical technologies in the pharmaceutical industry: the FDA’s PAT initiative. Anal. Bioanal. Chem. 2006; 384: 1036-1042.

3. Guidance for Industry PAT- A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. U.S. Department of Health and Human Services, Food and Drug Administration, September 2004.

4. Streefland M, Happe H, Beuvery EC. et al. PAT for vaccines: The first stage of PAT implementation for development of a well-defined whole –cell vaccine against whooping cough disease. Vaccine 2007; 25: 2994-3000.

5. Kourti T. The Process Analytical Technology initiative and multivariate process analysis, monitoring and control. Anal. Bioanal. Chem. 2006; 384: 1043-1048.

6. Yu LX, Lionberger RA, Raw AS. et al. Applications of process analytical technology to crystallization processes. Advanced Drug Delivery Reviews 2004; 56: 349-369.

7. Industrial^IT for Process Analytical Technology. [www.abb.com/lifesciences]

8. Ganguly J, Vogel G. Process Analytical Technology (PAT) and Scalable Automation for Bioprocess Control and Monitoring- A Case Study. Pharmaceutical Engineering. 2006; 26(1): 1-9.

9. Weinberg S. Process Analytical Technology- Regulatory Aspects and Checklist. Bioprocessing and Biopartnering. 2006: 11-12.

10. Liedekerke BV, Manager S. PAT: Evolution or Revolution? PMPS Journal. 2004. available from: www.samedanltd.com/magazine/15/peyperview/pdf

11. Skibsted E. Near infrared spectroscopy: the workhorse in the PAT toolbox. SpectroscopyEurope. 2006; 18(5): 14-17.

12. Cooley RE. On-Line Liquid Chromatography as a Process Analytical Technology for Monitoring and Control of Biotech Processes.[www.dionex.com/en-us/webdocs/40383_LPN%201856-01_PAT.pdf]

13. Medendorp J, Lodder RA. Acoustic-Resonance Spectroscopy as a Process Analytical Technology for Rapid and Accurate Tablet Identification. AAPS PharmSciTech. 2006; 7(1): E1-E9.

14. Webster S, Baldwin K J. Raman as PAT Tool. Pharm. Tech. Europe. Aug. 2005. available from:

http://www.ptemag.com/pharmtecheurope/article/article

15. Schadt R. Process Analytical Technology-Changing the Validation Paradigm. American Pharmaceutical Review. [www.taika.com/view_file.php?cl=contentandfn=filenameandid=97]

16. Maes, Liedekerke BV. The need for a broader perspective if process analytical technology implementation is to be successful in the pharmaceutical sector. J. Pharm. Innovation 2006: 19-21.

17. Radspinner D, Davies B, Kamal Z. Process Analytical Technology and Outsourcing- Impact on Manufacturing and Process Knowledge. GOR, 2005; 7(4): 55-58.

18. PAT Instrumentation: The Pharmaceutical and Biotechnology Market for Process Analytical Technology 2005-2010. [www.strategic-directions.com/pdf/PAT-ProcessAnalyticalTechnology.pdf]

19. Kanasakoski M, Kurkinen M, Weymarn NV. Process analytical technology (PAT) needs and applications in the bioprocess industry. [www.pharmamanufacturing.com/whitepapers/2007/004.html]

Received on 21.02.2009 Modified on 23.03.2009

Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 611-616