In routine manufacturing, PAT will enable continuous and real-time quality assurance to ensure consistently high product quality and performance, batch after batch^1-6.

2. PAT-PIONEERS:

With the discussed technology, regulatory and business issues, have there been changes that will encourage the implementation of process analytical technology? The answer to this question is yes. As a direct consequence of the "cGMPs for the 21st Century" initiative, the pharmaceutical industry is experiencing pressure from the regulator to address concerns around limited process understanding, process inefficiencies and continuous process improvement through the adoption of PAT. Since FDA released its PAT initiative, few pharmaceutical companies are willing to talk about their efforts to implement PAT. To encourage industry for PAT implementation FDA introduced the "safe harbor" or "research exemption" concept which is designed to encourage the industry to investigate tools that will provide increased process information without the fear of having a negative impact on the ability to release products that meet all aspects of the company's current quality control strategy. Technology vendors says that many of their pharma customers are in the planning stages of adopting PAT, but few have actually implemented new manufacturing technology and they are in testing phase⁶.

Novartis is running sensor technology side-by-side with the old process and doing lot of pioneering cutting edge work. Once a company learns how to apply the key fundamental types of analytical control technologies effectively to one process and product then the knowledge can be transfered to others. TechniKrom has implemented PAT in critical liquid handling/blending steps, such as buffer supply, pH adjustment, LC gradient elution, and solvent feeds. The company helps clients monitor process operations and demonstrate that variability in feeds leads to variability in production yields. Eli Lilly researchers presented some ideas about the analytical methods that could be adapted for real-time analysis of steps in the pharmaceutical manufacturing process. These methods include Fourier transforms infrared (FTIR) spectroscopy for reaction analysis, Near-IR (NIR) spectroscopy to measure product dryness and uniformity, HPLC, GC, NMR spectrometry, and MS for reaction analysis and product identity, Ultrasound to measure sample granularity. NIR use has been increasing in PAT-style testing and has been particularly useful in on-line analysis. Multiple measurements is possible with a single NIR instrument and will able to follow a variety of processes in a chemical reaction simultaneously such as changes in reactant concentration, byproduct formation, and product generation which further allows to make minor adjustments to the process on the fly. Likewise, strong differences in the NIR spectra of various polymorphs of a single API allow scientists to quantify polymorph formation during both preformulation and formulation processes. This ability is critical to a drug’s success, because subtle changes in form can result in significant differences in drug behavior in vivo. Astra Zeneca described how new Raman spectroscopy instrumentation is making extensive inroads into the pharmaceutical manufacturing sector. According to them it is a highly selective method that allows researchers to easily and accurately determine the active pharmaceutical ingredient (API) content of a formulation while largely ignoring the physical parameters of the samples or sampling conditions. As an example, they cite a study in which aspirin tablets were assayed for both the API and the main degradation product, salicylic acid. The study compared the results obtained using Raman spectroscopy with those achieved using more standard HPLC method and found a good correlation between the two methods. To understand or know what PAT is, one has to look outside pharma to the chemical industry which offers an excellent resource for process analyzer expertise. Scientists at Sigma-Aldrich Biotechnology used a DOE approach to develop a cell culture medium optimized for a variety of Chinese hamster ovary (CHO) cell lines, which biopharmaceutical firms use to produce protein-based biologics. The researchers used statistical software to identify the best-performing culture media in their arsenal and develop methods to further increase cell growth and productivity. New equipment, tools (e.g., SOA, XML), or applications may be needed to enhance data acquisition and analysis. Infrastructure, databases, and software should enable easy data mining. New methods (e.g., MVDA, DoE, process modelling) including knowledge base maintenance must be implemented to enhance data and process analysis⁴.

3. POSITIVE IMPACT OF PROCESS ANALYTICAL TECHNOLOGY (PAT):

From a business perspective, increasing operational efficiency in manufacturing is clearly of interest. This may occur through cycle time reductions and increasing process yields. There is strong belief that variability reduction will be added by increased process capability and by minimized risk of producing out of specification product. Because whenever process variables deviate from the specifications, the result will be the loss of one or several batches and an extensive investigation process, which all adds up to very long cycle times. All of these identified issues can be positively impacted through the use of process analytical technology. Designing in PAT upfront can offer substantial, long-lasting benefits for optimizing productivity across an organization. Process analytical technology (PAT) is a key enabling technology to deliver huge savings. It has been estimated that reducing inventory levels across the pharmaceutical industry to those already achieved by the very best pharmaceutical manufacturing facilities could deliver one-off cash release of $76 billion. The key components of this knowledge-based approach are better understanding of the product manufacturing process, data analysis, process analytical tools, process monitoring, and continuous feedback during the manufacturing process. The prominent techniques of PAT is online monitoring, which means it’s not only recording information, but it’s also closing the loop and making adjustments to the process as the product is being manufactured. In other words, the ability to analyze the production stream is pointless if you can’t respond to what the results are telling you. While process monitoring traditionally involved temperature, pressure, flows, pH and other physical parameters, PAT focuses on the use of in-line testing using near infrared, Raman, or other physiochemical techniques as a primary means of process monitoring. The data retrieved would provide information on the properties of blends, cores, and other stages in the process. Through the use of probes in the process, uniformity, drying, and mixing endpoints, and other targeted stages can be pinpointed to a high degree of certainty. Sampling error would be minimized with in-line probes placed strategically through out the production process. Unlike the batch processing common on today’s drug manufacturing, PAT will allow continuous process streams to be digitally measured, monitored, and controlled. By reducing the need for trial and error, FDA regulators expect that PAT will allow companies to more easily improve the manufacturing process and thereby reduce product development times. Without strong manufacturing operations, many of the new drugs will produce less revenue than their full potential as a result of longer-than-necessary process start-up and scale-up times, too many lost batches, process instability and quality problems, and fines and recalls. PAT contributes in offering solution to these issues to greater extent. With PAT system Bacterial Endotoxin Testing (BET), microbial growth and presence testing, ion chromatography, etc can be converted to on-line or at-line testing methods with no human intervention. Labor-intensive laboratory preparation and testing will be Outmoded as the automation sequencing is refined and standardized. The increased process information with PAT will lead to increased process understanding and better product^1-5.

4. STEPS TO IMPLEMENTATION:

There are following steps for implementation of PAT as per FDA guidelines⁵:

1. Preparation of a formal project plan; submit for approval

2. Identification and setup of toolsets necessary for project implementation

3. Identification of product process specifications and limits

4. Identification of at-line or in-line or on-line process controls and tests

5. Acquisition of necessary information and data

6. Preparation and delivery of a CPP analysis report assessment report

5. APPLICATIONS OF PAT:

There are several types of PAT applications that can accompany the lifespan of a product or process. The drivers, challenges and benefits associated with these types of methods can be very different from process research and development through to full-scale production. Some methods are only applied to the initial phases of the development with the goal of defining and understanding critical process parameters or product quality attributes. In this early phase of process development, a broad range of PAT methods can be used to gain process understanding, with no intention of retaining all possible methods during the transfer to full-scale production manufacturing. This phase is often called process optimization – finding the most efficient and robust operating conditions that allow the process to produce quality product. The requirements for hardware and the procedures are typically aligned along those of other R and D technologies. In these types of applications, only a subset of stakeholders are involved in the PAT implementation compared with the number involved in implementation for a full-scale production plant. For example, maintenance, automation and control, and quality organizations may not be involved in multi-purpose systems used in the research and development environment. The applicable project phases might be reduced to ‘project identification’ and ‘application development,’ with some modified aspects of a short-term ‘implementation phase,’ but without the need for a routine operations phase.

The next stage of process development is typically the scale-up phase. The goal of PAT in this phase is to continue to gain process knowledge and/or to verify scalability of the process by comparing process data obtained during initial development with pilot-plant or full-scale data. Depending on the scale, more stringent requirements for safety, installation and procedures are typical, especially when actual manufacturing equipment is utilized⁵.

Finally, PAT tools can be used in commercial manufacturing, either as temporary methods for gaining process information or troubleshooting, or as permanent installations for process monitoring and control. The scope of these applications is often more narrowly defined than those in development scenarios. It will be most relevant for manufacturing operations to maintain process robustness and/or reduce variability. Whereas the scientific scope is typically much more limited in permanent installations in production, the practical implementation aspects are typically much more complex than in an R and D environment. The elements of safety, convenience and reliability validation and maintenance are of equal importance for the success of the application. There are some applications are describe below.

5.1 The use of PAT in powder blending process

It was examined whether Raman spectroscopy can be used as PAT tool for the in-line and real-time endpoint monitoring and understanding of a powder blending process. A screening design was used to identify and understand the significant effects of two process variables (blending speed and loading of the blender) and of a formulation variable (concentration of active pharmaceutical ingredient (API): diltiazem hydrochloride) upon the required blending time (response variable). A Soft Independent Modelling of Class Analogy (SIMCA) model was developed to determine the homogeneity of the blends in-line and real-time using Raman spectroscopy in combination with a fiber optical immersion probe. One blending experiment was monitored using Raman and NIR spectroscopy Raman spectroscopy not only allowed in-line and real-time monitoring of the blend homogeneity, but also helped to understand the process better in combination with experimental design. Furthermore, the correctness of the Raman endpoint conclusions was demonstrated for one process by using a second independent endpoint monitoring tool (NIR spectroscopy).

5.2 The use of PAT in process development

Process Analytical Technology (PAT) is a system for design, analysis, and control of manufacturing processes, based on continuous monitoring/rapid measurements of critical quality and performance attributes of raw material, intermediates and products.

5.2.1 In-line FT-IR for Monitoring an Asymmetric Hydrogenation Reaction

In-line FT-IR technology was evaluated for real time monitoring the hydrogenation process at both lab and pilot plant scales. The FT-IR probe was inserted directly into the reaction vessel. Figure 1 shows the representative spectra collected during hydrogenation reaction. Clearly, the FT-IR can be used to distinguish between the starting material enamine amide and product freebase. By using multivariate statistical (chemometric) methods of Multiple Linear Regression and Partial Least Squares, as well as simple peak ratio data treatment, the real time reaction profiles of the enamine amide and freebase can be obtained (Figure 2). The data showed excellent agreements between the FT-IR and HPLC results and demonstrated the feasibility of using FT-IR to determine the end of reaction at pilot plant scale⁷.

5.2.2 Process analytical Technology for monitoring a crystallization process

As an example, multiple in-line techniques were applied during process development of compound MK-A, which can exist as several polymorphs (A, B and C) with close thermodynamic stability. Figure 3 shows the setup of the crystallization vessel with three in-line analytical probes immersed: attenuated total reflectance-Fourier transform infrared (ATR-FTIR), Raman and Focused Beam Reflectance (FBRM)⁹.

Figure3. The 1L Vessel with FT-IR FBRM and Raman Probes immersed for crystallization development

ATR FT-IR was used to monitor the solution concentration of the MK-A compound during crystallization. FBRM can be used to detect the point of nucleation during crystallization. Figure 7 shows the real time profiles of fine count (1-10 microns) by FBRM during crystallization of MK-A using unmilled and milled material as seed (Fig. 5 to 7).

5.2.4 In-line NIR for Monitoring of an API Drying Process

The final step of preparation of the novel Carbapenem antibiotic, Ertapenem Sodium involves a drying process, in which the wet cake is dried to target organic solvent and water level to yield the final active pharmaceutical ingredient (API). Ertapenem is hygroscopic, thermally labile and readily degrades. Accordingly, in-line Near-IR spectroscopy was implemented for monitoring this drying process at manufacturing scale to minimize the sample handling and product degradation. NIR peaks necessitate the use of chemometrics for quantitative analysis. Using a calibration model developed by the Partial Least Squares method, NIR was able to reliably determine the water and residual solvent levels during Ertapenem Sodium drying. An example of the results obtained is shown in Figure 8. The data illustrate excellent correlations between NIR and reference methods Karl Fischer (KF) and Gas Chromatography (GC)^8,10. (Fig- 8)

6. FUTURE ASPECT OF PROCESS ANALYTICAL TECHNOLOGY:

The challenges for the pharmaceutical sciences are expanding over time as we seek to address increasingly complex medical needs and health care expectations.

Technical innovation in the pharma industry’s manufacturing sector has moved at a snail’s pace, with many methods technicians use for process analysis remaining largely unchanged for the past three or more decades.

The implementation of Process Analytical Technology is set to change this by bringing real-life benefits and improvements to many pharmaceutical processes. The aim of PAT is to generate product quality information in real-time. The advantages of PAT are many and varied.

One thing required by companies is they must be convinced that PAT makes good business sense before they will adopt organization-wide changes that, from a process and regulatory perspective, will change the way they do business. Perhaps the most persuasive argument for introducing PAT is a sense of inevitability. As can be seen in the above discussion, the use of PAT techniques can be a huge benefit to those who choose to use the technology⁹

7. REFERENCES:

1. Chauvel, J.P.; Henslee, W.W. and Melton, L.A., Teaching Process Analytical Chemistry; Anal.Chem. 2002, 74, 381A–384A.

2. Clevett, K.J., Process Analyzer Technology; Wiley-Interscience; New York, 1986.

3. Callis, J.B.; Illman, D.L. and Kowalski, B.R., Process Analytical Chemistry; Anal. Chem. 1987, 59,624A–631A.

4. Process Analytical Technology, ABB and compny, Rev2006(03)

5. Bakeev K.A., Process Analytical Technology, Blackwell Publication (2005) 1-37.

6. FDA Draft Guidance on Process Analytical Technology, Aug. 2003.

7. www.cpac.washington.edu/nessi/nessi.html

8. Eriksson, L., Johansson, E., Kettaneh-Wold, N. and Wold, S., "Multi- and Megavariate Data Analysis, Principles and Applications." 1^st Edition, Umetrics Academy, June 07, 2001, Ch 3-4.

9. http://www.fda.gov/cder/guidance/6419fnl.html

10. Workman J., Koch M. and Veltkamp D.J., Process Analytical Chemistry; Anal. Chem. 2003, 75, 2859–2876.

Received on 26.11.2010

Accepted on 15.12.2010

Research J. Science and Tech. 2(6): Nov. -Dec. 2010: 129-133

2Maliba Pharmacy College, Bardoli-Mahuva Road, Gopal Vidyanagar. Ta. Mahuva. Dist.-Surat, Pin-394 350,

2. PAT-PIONEERS:

3. POSITIVE IMPACT OF PROCESS ANALYTICAL TECHNOLOGY (PAT):

4. STEPS TO IMPLEMENTATION:

There are following steps for implementation of PAT as per FDA guidelines5:

6. FUTURE ASPECT OF PROCESS ANALYTICAL TECHNOLOGY:

²Maliba Pharmacy College, Bardoli-Mahuva Road, Gopal Vidyanagar. Ta. Mahuva. Dist.-Surat, Pin-394 350,

There are following steps for implementation of PAT as per FDA guidelines⁵: