INTRODUCTION:

The term “Process Analytical Technology (PAT)” has been used to describe “a system for designing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes for raw and in-process materials and also processes with the goal of ensuring final product quality into the product and manufacturing processes, as well as continuous process improvement. Process analytical technology (PAT) has been defined by the United States Food and Drug Administration (FDA) “as a mechanism to design, analyze, and control pharmaceutical manufacturing processes through the measurement of Critical Process Parameters (CPP) which affect Critical Quality Attributes (CQA)” ^[1-2].

PAT allows for and encourages continuous process manufacturing improvement. It uses real-time information to reduce process variation and manufacturing capability and demands a solid understanding of the various processes involved in the operation. Simply put PAT is a real-time testing and adjustment based on the complete understanding of how the components and related processes affect the final product. This is in accordance with the fundamental principle that quality cannot be tested but is instead built into the medicinal product by design ^{[2, 4]}.Quality by Design (QbD) and Process Analytical Technology (PAT) promise to deliver a bigger, brighter future in terms of encouraging “the voluntary development and implementation of innovative pharmaceutical development, manufacturing and quality assurance” ^[3] while ensuring patient safety and increasing profitability for the life sciences industry. And relation with QbD) has been debated and described in many venues (e.g., conferences, social media, article etc.). In these enthusiastic discussions, one point that is frequently overlooked is that PAT tools are firmly attached in the pharmaceutical workflows that underpin development and scale-up, for both drug substance and dosage forms. The term Process Analytical Technology (PAT) was introduced by the US FDA as an initiative to bring an improved understanding of pharmaceutical manufacturing processes to increase the quality of their products^{.[ 5]}

PAT is a system and application at following sites^[6]

1. Designing, analyzing and controlling manufacturing.

2. Timely measurements.

3. Critical quality and performance attribute.

4. Raw and in-process materials.

5. And processes.

6. RM Testing (warehouse based)

7. Packaging Components

8. Blending (at- line or on- line)

9. Drying

10. Tableting (potency and CU)

11. Encapsulation (Coating thickness)

12. Packaged product

13. Equipment cleaning

14. Equipment cleaning (surface monitoring).

Fig. 1: Main area covered by PAT

What is PAT?:

Process analytical technology (PAT) has been defined as “a system for designing, analyzing, 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” ^[5]. A desired goal of the PAT framework is to design and develop well-understood processes that will consistently ensure a predefined quality at the end of the manufacturing process. A process is generally considered well understood when:

1. All critical sources of variability are identified and explained;

2. Variability is managed by the process; and

3. Product-quality attributes can be accurately and reliablypredicted over the design space established for materialsused, process conditions, manufacturing, environmental,and other conditions.

The objective for PAT implementation could be one or more of the following ^{[5, 16–20]}:-

1.Better process understanding

2.Improved yield because of prevention of the scrap, rejects, and reprocessing

3. Reduction in the production cycle time by using online/at-line or in-line measurements and control

4. Decrease in the energy consumption and improved efficiency from conversion of the batch process into a continuous process

5.Cost reduction because of reduced waste and reduced energy consumption

6. Real-time release of the batches From an implementation perspective, perhaps, PAT can be visualized as the three-step process ^{[19, 20]}. The design phase starts early in process development when the given unit operation is being designed and then later optimized and characterized ^[21,22]. In this phase, the critical quality attributes (CQA) that are being affected by the process step are identified along with the critical process parameters (CPP) that have been determined to affect the CQA. This process understanding is the essence of PAT and critical for the next two phases. In principles of the method validation, specifications, use, and validation of the chemo metric tools; and

7.Discuss the need for general FDA guidance to facilitate the implementation of the PAT.

PAT Goals:-^[7,8]

The goal of PAT is to understand and control the manufacturing process, which is consistent with our current drug quality system; quality cannot be tested into products; it should be built-in or should be by design . In August 2002, recognizing the need to eliminate the hesitancy to innovate, the Food and Drug Administration (FDA) launched a new initiative entitled “Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach.” This initiative has several important goals, which ultimately will help improve the public's access to quality health care services.

The goals are intended to ensure that:

1.The most up-to-date concepts of risk management and quality systems approaches are incorporated into the manufacture of pharmaceuticals while maintaining product quality.

2. Manufacturers are encouraged to use the latest scientific advances in Pharmaceutical manufacturing and technology.

3.The Agency's submission review and inspection programs operate in a coordinated and synergistic manner.

4.Regulations and manufacturing standards are applied consistently by the Agency and the manufacturer.

5.Management of the Agency's Risk-Based Approach encourages innovation in the pharmaceutical manufacturing sector.

Agency resources are used effectively and efficiently to address the most significant health risks. The approach is based on science and engineering principles for assessing and mitigating risk related to poor product and process quality. The desired state of Pharmaceutical manufacturing and regulation may be characterized as follows:

v Approaches recognize Product quality and performance are ensured through the design of effective and efficient manufacturing processes.

v Product and process specification are based on a mechanistic understanding of how formulation and process factors affect product performance.

v Continuous “real time” quality assurance.

v Relevant regulatory policies and procedures are tailored to accommodate most current level of scientific knowledge.

v Risk-based regulatory,

A)The level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance.

B)The capability of process control strategies to prevent or mitigate the risk of producing a poor quality product.

PROCESS ANALYTICAL TECHNOLOGY – HISTORICAL, BUSINESS AND REGULATORY PERSPECTIVE:

Historical View of Process Analytical Technology (PAT) ^[10,11]:-

Because they have been used for many years, existing experimental methods and manufacturing processes and quality control parameters are considered well established and trusted to generate few difficulty and errors and make only simple contributions to process variation and different process parameters. Historically, pharma lab develops a product, describe the product, improve the quality of product, maintain the quality of product for a sufficient time, describe the process materials and methods in great detail in the regulatory filing, and validate the process through various batches. The quality of the product would remain consistent as long as nothing was changed. With this data industries are having little pressure to improve manufacturing efficiency and rate.

Business view of Process Analytical Technology (PAT)^[12-15]:-

To pharma with its paper-based control systems PAT is different technology, but it is old that to industries such as food and beverage, petrochemicals and semiconductors etc. US drug companies have had the ability to use process control for 20 years, but they have not used it because it is more expensive in term of the cost of the equipment, the cost to develop qualification, validation and quality systems. There are no industry leaders yet demonstrating the value of PAT, so pharma companies are approaching PAT with uncertainty.^[19] Although PAT increase production efficiency and rate, this may not be viewed from a business standpoint as a strong impetus for change due to the perception that the implementation costs may outweigh the return on the investment in various cases, especially for small pharmaceutical companies which manufacturing drug product and dosage forms that are already struggling with tight or nonexistent margins. With limited available capital, equipment, and talented human assets, maximizing asset utilization and return on assets is becoming vital to future success and survival.¹²Although benefits of PAT in the long-term are generally recognized, the short-term uncertainty and risk, at least in these early days of the FDA guidance, boil down to how much time and resources a company should invest in a pharmaceutical product that faces an uncertain future in terms of clinical efficacy, regulatory approval, and commercial success. Accounting pros and cons of technology companies should determine when the investment in process development does benefits the company and when it does not make any business sense. For example, a process step is not under any time constraints, does not represent a potential bottleneck, does not consume costly reagents and resources, and does not pose a risk of contamination or introduction of impurities, and then there may be little justification for investing in the monitoring, control, and optimization of that particular process step. ¹³ Further available analyzers are not suitable for pharma industry which requires instrument development. The sensors available as analysis tools are not compatible with the process. Analyzer dependability, having small expertise in high specialized technology, inadequate validation of analyzer/software add with all these makes PAT associated risks too high and creates hesitance over change and remains as big hurdles for PAT implementation. ¹⁴ But business models are changing and the importance of manufacturing’s role in the financial performance of pharmaceutical companies are important. While the cost of restructuring production lines may be daunting to smaller companies, the savings gained from more efficient use of resources, reduced waste, faster product approvals and a lower risk of product recalls would outweigh the cost to implement PAT. ^[15]

Main Pharmaceutical Business Benefits from PAT:-

In Pharmaceutical R&D:

• A deeper scientific and engineering understanding of manufacturing processes

• Reduced product development times, more robust licensing packages, faster scale up, and faster time-to market for new products

• Implementation of innovative manufacturing and quality strategies

In Pharmaceutical Manufacturing:

• Reduced waste, right-first-time manufacturing, higher production asset utilization

• Real-time quality assurance and validation

• Movement toward real-time release of products

• Lean manufacturing practices for reduced raw material, work-in-progress, and finished goods inventories

• More robust product supply to the public

Regulatory View of Process Analytical Technology (PAT)^[9]:

A major contributor to inhibition of PAT adoption is concern over how regulatory agencies will react to the technology during a facility review. If the technology requires the agency to develop an understanding of the potential impact on the product, this could result in a protracted approval of the facility and thus delay the introduction of a new product to the market. Pharma industries are accepting new technology on the R&D side, “it lags behind on the manufacturing side for fear of delaying approval,” There is concern within the industry that there is lack of worldwide harmonization of regulatory expectations relative to PAT that could lead to PAT being accepted by one regulatory agency while another might not share the same level of acceptance, resulting in quality control strategies that are specific to a given market. However FDA has participated in international conferences as a means of creating harmonization on the PAT approach. These types of activities should also be conducive to harmonization on the PAT approach. The agency’s intention was not to dictate how companies should implement PAT, but rather to create a flexible regulatory process that would involve regular meetings with regulators, at which time companies could present and discuss individual strategies and innovative approaches.

Regulatory framework:

Process analytical technology (PAT) is a key element of the “Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century—a Risk Based Approach” initiative announced by the FDA in August 2002 to improve and modernize pharmaceutical manufacturing ^[1]. The PAT initiative was first proposed by the United States Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) with the objective of achieving significant health and economic benefits by application of modern process control and tests in pharmaceutical manufacturing ^[2,3]. Shortly thereafter, with an endorsement from the FDA’s Science Board, the PAT subcommittee under the Advisory Committee for Pharmaceutical Science (ACPS) was formed in November 2001 and consisted of the following four working groups with representatives from the FDA, industrial experts, and academic representatives ^[3–5]

§ PAT applications working group.

§ PAT products and the process development working group.

§ PAT process and analytical validation working group.

§ PAT chemometric working group.

The key objectives of the ACPS subcommittee were to^[6]:

1. Identify and define the technology and regulatory hurdles, possible solutions, and strategies for successful implementation of PAT in pharmaceutical development

and manufacturing.

2. Discuss the general principles of the regulatory application of process analytical technology including the principles of the method validation, specifications, use, and validation of the chemo metric tools.

3. Discuss the need for general FDA guidance to facilitate the implementation of the PAT.

Fig 2:-Process Analytical Technology Framework

Quality by Design:

The engine through which PAT objectives are to be accomplished is known as Quality by Design (QbD). The idea behind the FDA Quality by Design initiative is to better understand the process and build quality into the product rather than “test it in” at the end. When QbD is absent, an organization is forced to “test quality into the product,” which is an expensive and unreliable way to achieve quality requirements. It also demonstrates that they have failed to mitigate the product risks that occur due to lack of design, poor planning and inadequate control of the manufacturing process. In any system, the absence of design leads to slipped deadlines, overextended budgets, frustrated employees, disappointed stakeholder expectations and possible harm to the public. Thus, it is imperative that an organization budget “design phases” into their project, not as a one-time activity, but as an ongoing re-occurring activity to be met throughout the project. This implies that regular design reviews focused on QbD be included as part of the project life cycle development model.

Quality by Design, however, goes well beyond simple project development. It also implies that:^[3]

v The intended therapeutic objectives; patient population; route of administration; and pharmacological, toxicological and pharmacokinetic characteristics of a drug are understood and managed.

v The chemical, physical and biopharmaceutical characteristics of a drug are accounted for.

v Design of a product and selection of product components and packaging based on drug attributes include:

– Understanding the mechanisms of degradation, drug release and absorption

– Understanding the effects of product components on quality

– Knowing what sources of variability are critical

– Understanding how the process manages variability

v The design of manufacturing processes using principles of engineering, material science and quality assurance to ensure acceptable and reproducible product quality and performance throughout a product’s shelf life.

A common mistake occurs when a company undertakes some type of PAT and simply thinks that it can be achieved by the sheer amount of software and equipment that is purchased. They may achieve the collection of real-time data only to dump it into a statistical analysis package post-batch requiring an army of statisticians to interpret the data; and then engineers to make recommendations on how to improve the process. They end up with a statistical representation of what is happening in the batch and are probably utilizing some type of Statistical Process Control but do not realize the goals (e.g., real-time release) envisioned by PAT. In R&D or early development it is critical to model processes to gain the understanding of what the key performance indicators are for the product. This is the time when the model is used mostly for gathering data, trending and building the “golden batch.” Commercial production should have the requisite process data to understand what Key Performance Indicators (KPIs) are crucial to the process and what the “Golden Batch” criteria should be. The Golden Batch profile is critical to quality parameters and contains allowable deviations to produce an “ideal” batch. A rigorous process model is used as a comparison during actual batch manufacture and has the ability to generate statistical process control (SPC) alarms in real time. Real-time data and comparisons are fed back to an operator who can then make decisions about the trajectory of the batch. If the batch is trending away from the “Golden Batch” parameters, then the operator can make adjustments to bring the batch back in line. This is open loop feedback. As the controls and understanding become more sophisticated, closed loop feedback can be used to automatically make the necessary adjustments to keep the process within the Golden Batch profile. This level of batch understanding allows for more sophisticated forms of Operational Excellence. This is where Process Optimization and Automated Release come in. Process Optimization is an off-line program that understands the trends and patterns of the process. This tool can not only show where the process can be optimized for better performance, but can also see the degradation effects of the process equipment and suggest modifications. The ultimate goal of these initiatives is an understanding of the process that allows for automated release. The principles behind this are that if you know the inputs and understand the effects of key variables, then you should be able to accurately predict the quality of the final product before it gets tested. In fact, given the randomness of most sampling methods, this can be a better predictor of uniform quality within a batch.

When implementing QbD and PAT Framework Technologies a life sciences company should consider the following kinds of QbD and PAT developmental requirements:-

• Development of process modeling capabilities that allows for real-time monitoring, feedback and control versus statistical packages that only provide data after the fact

• Consider applicable modeling and optimized processes from other industries

• Provide an end-to-end solution…from PAT to modeling to visualization to optimization and ultimately to automated release capabilities

• Develop and maintain a library of strong process models. This allows for fewer deviations, higher quality product, less waste or rejects and provides a shorter time to product release

• Create a PAT framework that provides an integrated harmony with Quality by Design, legacy/new equipment, data analysis, process control and regulatory compliance.

Fig3:- Quality by Design and Process Analytical Technology

Four key elements in PAT implementation:

1. Building a science:-based knowledge base complete process understanding at the mechanistic and first principle level

2. Process monitoring and control: determination of critical process parameters and critical quality attributes and selection of measurement, analysis and control mechanisms to adjust the process to provide the predicted quality of the product.

3. Validation of PAT system.

4. Regulatory strategies.

1. Building a science – based knowledge base:

The PAT guidance emphasizes the need to develop a deep understanding of the underlying scientific principles behind pharmaceuticals manufacturing processes to determine the parameters critical to process and product quality. The knowledge base provided by the PAT approach is valuable in three main ways:

A. It is a foundation for robust process and product design.

B. It facilitates continuous learning throughout the product life cycle.

C. It is supports and justifies flexible regulatory paths for innovative new approaches.

The design of experiments, and the capture and evaluation of analytical measurement data are essential parts of building the knowledge base.

Examples of sources of variation:

· Variation in the raw material supplier manufacturing processes that impact the chemical and physical attributes of the supplied materials.

· Time based variation in manufacturing performance (e.g., between equipment maintenance events).

· Effects linked to planned changes to equipment / analyzer hardware and software of the system.

· Individual ways of working (i.e., variation attributable to people in manufacturing area).

· Change in the local environment (e.g. temperature, humidity and other environmental condition).

· Long term equipment ageing and degradation effects.

2. Process monitoring and control:^[39]

The understanding of the interaction between process and product is the basis for the design of the process monitoring, process control and QA strategies used in Manufacturing PAT is an integrated approach in which the results obtained from the real time analysis of critical process control points are used to control the process in some way. During manufacturing, process parameters are adjusted (within clearly defined limits) to produce the desired product quality attributes at the process end point. The automation system required for this level of process control are available today and are used extensively in the chemical and petrochemical industries.

Technologies used in PAT include:

Near infra red (NIR), Raman spectroscopy, UV – visible Spetrophotometry, Fourier Transform Infrared (FTIR), XRay Powder Diffraction (XRPD), Terahertz Pulse (TP) spectroscopy, NIR microscopy, Acoustic Resonance (AR) spectrometry, thermal effusivity, etc. NIR spectroscopy is the most popular and widely used technique.

3. Validation of PAT system^[38]

The validation plan for a PAT system will typically include the validation of Software packages for data analysis Process analyzer hardware and software Process control software IT systems for the management, storage and backup of

results

4. Regulatory strategies^[40,37]

A PAT policy development team of four subject matter experts has been established to work with industry to facilitate discussion on proposed pat approaches at an early stage and support FDA’s sciences and risk based approaches to PAT. PAT is a joint initiative of the centre for Drug Evaluation and Research (CDER), Office of Regulatory Affairs (ORA) and the Centre for Veterinary Medicine (CVM) within the “cGMPs for the 21st Century”

framework.

Figure4 :- The different unit operations that comprise a typical pharmaceutical process. Each step can potentially benefitfrom implementation of one or more PAT applications.

Table 1:- Examples of PAT applications in the pharmaceutical industry

Application	Process analyzer	Statistical tool	Observation
Rapid and accurate tablet identification	Acoustic resonance spectroscopy	Principle-components analysis (PCA)	A fast and non-destructive method for on-line analysis and label comparison before shipping, to avoid mislabeling of drug [23]
Active determination of content of uncoated pharmaceutical pellets	NIR	Partial least-squares (PLS) analysis	NIR method was developed and validated for determination of active content ranging from 80-120% of the usual active content of the uncoated pharmaceutical pellets [24]
Mechanical property determination of the drug tablet	Air-coupled excitation and laser interferometric detection	Iterative computational technique	Examination of the vibrational resonance frequencies can be directly correlated with the mechanical properties of the tablet providing a non- destructive technique for physical characterization of the tablet [25]
Analysis of sustained-release tablet film coatings using terahertz pulsed imaging (TPI)	Terahertz pulsed spectroscopy (TPS)	-	Tablet coating thickness, coating reproducibility, distribution, and uniformity can be easily determined. The method was validated against optical microscopy imaging [26]
Roller compaction process of dry Granulation	Thermal effusivity measurement using the effusivity sensor	-	Effusivity measurement were used to monitor the roller compaction process [27]
Evaluation of content uniformity for low-dose tablets	NIR	PCA	NIR/PCA was used to predict content uniformity of low-dose tablets manufactured by a direct compression process [28]
Powder flow characterization	NIR	PLS	Real time information on the flowing cohesive powder mixture was used to avoid powder segregation or agglomeration and thus to maintain product quality [29]
NIR measurement of the potency of an API	NIR	PLS	Potency of heparin active pharmaceutical ingredient was determined by this non-destructive method [30]
Active drug identification and content determination	NIR	PLS	NIR method was used for qualitative and quantitative determination of ranitidine in granules for compression, cores, and final tablet [31]
Monitoring capsule manufacturing at small-scale level	NIR	PLS	PAT was utilized for testing of identity and quality of raw materials, for blend uniformity analysis, and for final content analysis of busulfan pediatric capsules [32]
Prediction of dissolution for a sustained-release dosage form	NIR	PLS	This method was used to identify differences in the composition of the coating polymer used for a tablet and thus assist with prediction of dissolution behavior [33]
Analysis of liquid formulations containing sodium chloride	Laser-induced breakdown spectroscopy (LIBS)	-	Method does not need any sample preparation and is less time-consuming [34]

Table 2:- Benefits associated with implementing PAT in Pharmaceutical industry ^[35,36]

Industry Application	Process analyzer	Observation
Analysis of organic content of waste water	NMR Spectroscopy	Less time and cost effective method
Raw material identification and quality control	Near infrared (NIR) Spectroscopy	Fast and cost effective method
Simultaneous monitoring of solute concentration and polymorphic state of crystal	Raman Spectroscopy and Attenuated total reflectance(ATR) and FTIR	Know how the rate of addition of reactant affects the Polymorphic state of crystal
Catalysis reaction involving conversion of acetone to Methyl isobutyl ketone (MIBK)	In-line NIR	Affects Productivity, selectivity, and yield of MIBK

Table 3: PAT application in chemical industry Application[^35,36]

Industry Application	Process analyzer	Observation
Analysis of organic content of waste water	NMR Spectroscopy	Less time and cost effective method
Raw material identification and quality control	Near infrared (NIR) Spectroscopy	Fast and cost effective method
Simultaneous monitoring of solute concentration and polymorphic state of crystal	Raman Spectroscopy and Attenuated total reflectance(ATR) and FTIR	Know how the rate of addition of reactant affects the Polymorphic state of crystal
Catalysis reaction involving conversion of acetone to Methyl isobutyl ketone (MIBK)	In-line NIR	Affects Productivity, selectivity, and yield of MIBK

Basic Benefits of Implementation of PAT:

v Cost reduction in manufacturing

v No rework, no scrap, no or little waste

v Higher throughput

v Higher yields, less rejection to no rejection

v Less Validation, tighter process parameters

v No lab interference with product quality

v Process and product uniformity

v Easier transfer of master manufacturing

v SOPs, documentation, and data

v Global manufacturing capacity utilization

v Cursory FDA inspections

v Easier regulatory adherence and compliance

v Technology transfer

v Less validation expenses

Benefits category	Specific PAT benefits
Reduced operating costs	Increased Operating efficiencies, improved cycle time, Decreased operating costs, continuous processing, Real-Time monitoring, Feed-Back controls and Result, inventory reduction, increased capacity utilization, attain production schedule, Reduced reprocessing expenses
Quality improvements	Increased quality, increased regulatory compliance, increased product uniformity, Process finger printing, increased process understanding, Quality designed into process, use of scientific, risk-based approach, Recall prevention, No sampling requirements, Critical process control provided, Rapid identification of counterfeits, substances.
Positive regulatory impact Increased occupational safety Minimize environmental impact Positive research and discovery impact	Moderate regulator burden on FDA, improved scientific basis for regulatory functions. Decreased occupation exposure to toxic substances Reduced environmental impact, Minimize waste generation during manufacturing Reduced product development life cycle/time to market.

REFERENCES:-

1. Rakshit V Thumar, Vidhi N Kalola, Nishendu P Nadpara, Parula B Patel. A complete review of process analytical technology. Int J Pharm Sci Rev Res 2012;17;57-65.

2. http://www.fda.gov.[Last accessed on 10 Oct 2015].

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 - Center for Drug Evaluation and Research (CDER) - Center for Veterinary Medicine (CVM) - Office of Regulatory Affairs (ORA) - Pharmaceutical CGMPs - September 2004.

4. Bakeev KA. Near-infrared spectroscopy as a process analytical tool. Part II. Atline and on-line applications and implementation strategies. Spectroscopy 2004;19:39–42.

5. U.S. Department of Health and Human Services, Food and Drug Administration: Guidance for industry: PAT – a framework for innovative pharmaceutical development, manufacturing and quality assurance www.fda.gov/down loads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf, Accessed 25 may 2013.

6. Plant Automation in Pharma An Asian perspective, Process Analytical Technology Application in precipitation processes available at http://www.pharmafocusasia.com/manufacturing/pharma_pat_precipitation_process.htm Accessed on 25 may 2013.

7. Goal for process analytical technology visit. Available from: http://www.fda.gov/cder/OPS/PAT.html. [Last accessed on 09 Aug 2012].

8. Validation of pharmaceutical process. 3rd. Edition by James. Agalloco, Frederic J Carleton; 1925. p. 585-93.

9. Scott P, Process Analytical Technology: Applications to the Pharmaceutical Industry, Quality Assurance Analytical Services, Astra Zeneca, Westborough, MA available atwww.dissolutiontech.com/DTresour/0802art/Article_1.htmAccessed on 25 may 2013.

10. Spiegel R, Pharma Industry Sees Process Innovation at Last, February 2006 38.

11. Rick EC and Egan JC, the Impact of Process Analytical Technology, (PAT) On Pharmaceutical Manufacturing, 2009.

12. PAT-Ready production scale for the pharmaceutical industry from processing solution for the process industries, available at http://www.pharmainfo.net/reviews/process-analyticaltechnology-pat-impact Accessed on 25 may 2013

13. Benson RS, McCabe JD A practical approach to PAT implementation-Pharmaceutical Technology, Pharm. Eng, July/Aug2004.

14. A practical approach to PAT implementation Highlights of Advances in the Pharmaceutical Sciences: An American Association of Pharmaceutical Scientists (AAPS)Perspective2007.www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm128080.htm Accessed on 25 may 2013.

15. Slow Adoption of PAT for Bio processing- Challenges Emanate for Technology Development and Design of Processes, genetic engineering and biotechnology news, (Vol. 26, No. 16), 2006, available at www.genengnews.com/gen-articles/slow-adoption-ofpat- for-bioprocessing/1891/ Accessed on 25 may 2013.

16. Rathore AS (2009) Trends Biotechnol 27(12):698–705

17. Scott B, Wilcock A (2006) J Pharm SciTechnol 60(1):17–53

18. Rathore AS, Gerhardt AS, Montgomery SH, Tyler SM (2009) BiopharmInt 22(1):36–44

19. Read EK, Park JT, Shah RB, Riley BS, Brorson KA, Rathore AS (2009) BiotechnolBioeng 105(2):276–284

20. Read EK, Park JT, Shah RB, Riley BS, Brorson KA, Rathore AS (2009) BiotechnolBioeng 105(2):285–295

21. Van Hoek P, Hamrs J, Wang X, Rathore AS (2009) In: Rathore AS, Mhatre R (ed) Quality by design for biopharmaceuticals: Perspectives and case studies. Wiley Inter science

22. Seely J (2005) In: Rathore AS and Sofer G (ed) Process validation in Manufacturing of Biopharmaceuticals Taylor and Francis

23. Medendorp J, Lodder RA (2006) AAPS Pharm Sci Tech 7(1): E1–E9

24. Mantanus J, Ziemons E, Lebrun P, Rozet E, Klinkenberg R, Streel B, Eyrard B, Hubert P (2009) Talanta doi:10.1016/j.talanta.2009.10.019

25. Akseli I, Cetinkaya C (2008) Int J Pharm 359:25–34

26. Ho L, Muller R, Romer M, Gordon KC, Heinamaki J, Kleinebudde P, Pepper M, Rades T, Shen YC, Strachan CJ, Taday PF, Zeitler JA (2007) J Control Release 119:253–261

27. Ghorab MK, Chatlapalli R, Hasan S, Nagi A (2007) AAPS Pharm Sci Tech 8(1) Article 23 doi:10.1208/pt0801023

28. Li W, Bagnol L, Berman M, Chiarella R, Gerber M (2009) Int J Pharm 380:49–54

29. Benedetti C, Abatzoglou N, Simard JS, McDermott L, Leonard G, Cartilier L (2007) Int J Pharm 336:292–301

30. Sun C, Zang H, Liu X, Dong Q, Li L, Wang F, Su L (2009) J Pharm Biomed Anal doi:10.1016/j.jpba.2009.11.022

31. Rosa SS, Barata PA, Martins JM, Menezes JC (2008) Talanta 75:725–733

32. Paris I, Janoly-Dumenil A, Paci A, Mercier L, Bourget P, Brion F, Chaminade P, Rieutord A (2006) J Pharm Biomed Anal 41:1171–1178

33. Tabasi SH, Moolchandani V, Fahmy R, Hoag SW (2009) Int J Pharm 382:1–6

34. St-Onge L, Kwong E, Sabsabi M, Vadas EB (2004) J Pharm Biomed Anal 36:277–284

35. Mowery MD, Sing R, Kirsch J, Razaghi A, Béchard S, Reed RA. Rapid at-line analysis of coating thickness and uniformity using laser-induced breakdown spectroscopy. Pharm Biomed Anal 2002;28:935-43.

36. Zackrisson G, Ostling G, Skagerberg B, Anfalt T. Accelerated dissolution rate analysis (ACDRA) for controlled release drugs application to roxiam. J Pharm Biomed Anal 1995;13:377-83.

37. General Principles of Software Validation: Final Guidance for Industry and FDA Staff, US Food and Drug Administration (CDERandCBER), July 2013.

38. Good Automated Manufacturing Practice (GAMP) Guide 4.0,International Society for Pharmaceutical Engineering (ISPE), July2013.

39. U.S. Department of Health and Human Services, Food and Drug Administration Guidance for industry: PAT- a framework for innovative pharmaceutical development, manufacturing and quality assurance http://www.fda.gov/downloads/Drugs/Guidance Compliance Regulatory Information/Guidances/ucm070305.pdfAccessed 25 may 2013.

40. U.S. Department of Health and Human Services, Food and Drug Administration, www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/UCM071836 Accessed 13 may 2013.

Received on 04.03.2016 Accepted on 10.04.2016

Asian J. Pharm. Ana. 2016; 6(2): 122-130.

DOI: 10.5958/2231-5675.2016.00019.3