Wednesday, June 17, 2009

Process Analytical Technologies

The term "Process Analytical Technologies (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". The PAT initiative focuses on building quality into the product and manufacturing processes, as well as continuous process improvement.

New US Food and Drug Administration (FDA) directives that seemingly arrive with little warning and that carry tight deadlines because problems with budgets result in confusion within laboratories and production facilities and inversely affect the credibility of the quality assurance (QA) and regulatory affairs units. For some companies, the announcement of 21CFR Part 11 represented an unwelcome surprise. Vendors and users were suddenly faced with new requirements for signature verifications, archiving and date stamping procedures that had not been anticipated in system design or purchase. A subsequent rescinding of Part11guidance and consequent reissuing of clarifications and modifications increased confusion and resulted in further demands for advance warning. PAT is an approach to monitoring manufacturing (and other) processes on a continuous rather than discrete basis. Traditionally, quality assurance (QA) monitors the safety and cleanliness of production facility at all stages, but examines product only at end (or predetermined interim)-stage. If the final sampling process indicates contamination, dosage error or other problem, the affected batch is destroyed (or reprocessed) and the cause is identified and corrected to avoid future problems. The procedure is not unlike taking a snapshot photograph of an event – a single moment is frozen in time for detailed observation and analysis. PAT replaces the photograph with a streaming video. A process is monitored on a continuing basis (as well as at end-point) to instantly detect and movement in automobile assembly, largely touted and occasionally implemented, is an attempt to introduce PAT into that environment – assembly line workers are empowered to monitor progress and halt and correct a problem, rather than passing it on to a final quality inspector.

Process analytical technology (PAT) is one of the objectives contained in the Initiative for Pharmaceutical CGMPs for the 21st Century published by the Food and Drug Administration (FDA). In a few words and according to the FDA’s guideline, PAT can be defined as a system for designing, analyzing, and controlling pharmaceutical Manufacturing through the measurement of critical quality and performance parameters. The measurements performed on raw and in process materials or process Parameters are intended to enhance final product quality. Process analytical technology encourages technological innovation, specifically the adoption of new analytical techniques by the pharmaceutical industry designed to improve the understanding and control of manufacturing processes. Both the FDA and industry experts expect benefits over conventional manufacturing practices: higher final product quality, increased production efficiency, decreased operating Costs, better process capacity, and fewer rejects. Correspondingly, fundamental Changes are also expected within the regulatory framework. The future of pharmaceutical production will require innovative technological approaches and more science - based processes. PAT will boost collaboration between research and development(R & D) and manufacturing departments inside companies and increase overall efficiency. Approvals and inspections will increasingly focus on scientific and engineering principles. As a result, regulators will set higher expectations for new products from the outset.

1.What Motivated Process Analytical Technology (PAT)?

In September2004 the FDA released a document for the industry entitled “PAT Guidance for Industry: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.” PAT is clearly anchored in FDA corporate culture. Pharmaceutical companies are facing growing demands for increased productivity and reduced manufacturing costs. They also have to meet the evolving need for higher quality standards and higher drug expectations. At the same time the quest for new active substances remains a significant issue. Reducing the attrition rate among selected candidates will bring more new medicines onto the market. In terms Of drug marketing, the goal is to improve formulations so as to offer patients innovative and more efficient solutions, and thus achieve commercial success or breakthrough.

By prioritizing science based design and introducing novel or improved Process techniques, backed by the generation of increased critical data throughout A drug’s life cycle, the aim of the emerging PAT strategy is to direct the drug industry Toward these essential goals. Because they have been used for many years, a variety of existing experimental methods and manufacturing processes are considered well established. They are trusted to generate few errors and make only modest contributions to process variation. Due to their longevity; they continue to be widely used in recent drug developments. Improvements in existing technologies are always possible and are constantly being made. However, this makes it difficult to consider or identify potential technological alternatives without critical review or a voluntary management decision to replace well - established techniques. The FDA noticed that nearly all recent drug developments lacked the possibility of enhancing and extending process capabilities toward newer or alternative technologies. More specifically, the FDA wanted to encourage drug manufacturers to achieve more innovation and improve risk management when releasing new medicines on the market. When a quality problem arises in present - day production, it is increasingly difficult to identify the root cause. Thorough understanding of process and product performance often comes up against knowledge barriers, whether due to the escalating Documentation burden, lack of time, or loss of expertise. The goal of PAT is to enhance process control and understanding so that procedures can be performed differently and more efficiently. The PAT initiative facilitates and encourages the Introduction of innovative approaches. It makes it possible to consider shifting from Validation to continuous verification. The next step is effective real - time release with continuous processing as an alternative to the conventional batch after batch scheme.

2.When to Introduce Process Analytical Technology (PAT)

Building quality into a pharmaceutical product has to be considered from the very Beginning of the product’s life. Essential preconditions are the equal involvement Of and seamless communication between R & D and manufacturing. One purpose of PAT is to provide a motivating framework to bring quality into a product from the outset. It is thus essential for it to be involved in the R & D phase. If product Quality requirements are understood and implemented from the beginning root - cause analysis of quality or process failure after scale - up to commercial manufacturing will be much easier. This is why PAT could play an even more important role in the design and analysis of manufacturing processes, enabling performance control to be based on timely measurement of well - described critical processing data. Data processing needs should also be considered in the context of overall process Analysis strategy to meet emerging requirements for the speed and volume of data Collection. Real - time analysis supported by knowledge management requires collecting and gathering all production batch information, for example, by data warehousing. Thus, a PAT data management strategy based on online process analysis or data mining can be set up long before generating large sets of measurement data.

Historical data analysis should aim to cover method development, method validation And ongoing performance monitoring, as well as routine results for a given Manufacturing process Changing Current Practice Using PAT An approach integrating R & D and manufacturing will enhance process understanding and make acceptable risk management possible. By establishing transferable process models, it will be possible to develop and implement adequate measurement technologies that match process needs rather than vice versa. More efficient and cost - effective technology transfers will facilitate process knowledge, continuous process verification, and compliance, thereby enhancing final product quality. Better process understanding makes it possible to operate by continuous process verification instead of three - batch validation. Measurement technique selection and integration occur very early. Accumulated pertinent knowledge is readily available through data - mining techniques to confirm or control processing. A series of dynamic closed control/compliance loops at the process steps identified as critical will increase confidence in final product quality. In addition knowledge accumulated overtime will provide a basis for immediate and rapid intervention in the event of deviation or failure.

A typical illustration of a PAT approach to quality improvement is the use of Near Infrared Spectroscopy (NIRS) to qualify excipients and active pharmaceutical ingredients just before they enter the production process, E.g. for example, in dispensing. As discussed in the next part, near - infrared (NIR) spectra are informative about product structure and overall quality. Because with substances such as excipients the quality Range was investigated at some time in the past and fixed into a calibration, NIR Measurement can provide simultaneous non-destructive confirmation of the predominant physical and chemical parameters. This is an effective method of reducing uncertainties about possible causes of failure or poor quality during production. Each time a given excipient fails its quality requirements at the moment of use, immediate action can be taken. Control is possible before the risk of failure is increased. Such an approach is complementary to container wise identification of materials on delivery to a warehouse.

3.Basis For Process Analytical Technology

Despite the fact that the FDA ’ s PAT framework (and guidance) began to take form just ahead of the creation of the twenty - first - century cGMPs initiative in 2001, it is well known that several of the core concepts were pioneered decades ago by other manufacturing industries such as fine chemicals, semiconductors, petroleum, and consumer products. The main concepts that differentiate PAT from the traditional industrial pharmacy skill set (including pharmaceutical and materials science, chemistry, and engineering) are process analytical chemistry (PAC) and advanced manufacturing science (Figure 1).


Process analytical chemistry generally describes the science and technology associated with displacement of laboratory based measurements with sensors and instrumentation positioned closer to the site of operation. Although industrial process analyzers have been in use for more than 60 years, the modern period of PAC essentially began with the formation of the Centre for Process Analytical Chemistry(CPAC) in 1984 , the goal of PAC is to “ supply quantitative and qualitative information about a chemical process ”for monitoring, control, and optimization: they went on to define five “ eras ” of PAC:1) off line, (2) at line, (3) online (4) inline, and (5) non-invasive, which describe the evolution of sensor technologies. The industrial PAC movement has been bolstered by two decades of advances in materials science, electronics, and chemo metrics. Since the inception of CPAC the pace of innovation in sensors, instrumentation, and analytics has quickened dramatically. The development of more robust, sensitive photo detector materials, micro electro mechanical systems (MEMSs), and fibre optics and the perpetual advancement of computing power (as predicted by Moore’s law) have both increased the performance and reduced the cost of PAC. As a result, PAC is now a critical part of routine operations within the realm of industrial chemistry.

4.Drivers in Process Analytical Technology (PAT)

The goal of the PAT-oriented approach is to continue to ensure patient health by the availability of safe, effective, and affordable medicines. A key driver of PAT comes from the regulatory side, where the FDA ecognized that its traditional approvals procedures were actually hindering manufacturing innovation. With increased guidance and assurance from the FDA, PAT is expected to encourage innovation and to reassure manufacturers that moving toward PAT- based manufacturing is in their best interest. While the benefits are clear, the hesitation toward adopting PAT is not without reservations. Of specific concern is the fear of FDA reprisals should companies implement PAT on existing processes only to find problems in the system that wouldn’t have been discovered in normal process monitoring. The FDA recognizes this concern and is working to alleviate manufacturers’ fears, as noted in the FDA’s draft guidance document for PAT: “FDA does not intend to inspect research data collected on an existing product for the purpose of evaluating the suitability of an experimental process analyzer or other PAT tool. FDA’s routine inspection of a firm’s manufacturing process that incorporates a PAT tool for research purposes will be based on current regulatory standards (e.g., test results from currently approved or acceptable regulatory methods).” Another important driver for PAT is the pressing need within the industry to reduce production costs and speed time-to-market. Pharmaceutical companies have historically taken a conservative approach when it comes to implementing process changes and upgrading technology. But business models are changing and the importance of manufacturing’s role in the financial performance of pharmaceutical companies is increasing. While the cost of restructuring production lines may be daunting to smaller companies, the savings gained from more efficient use of resources, reduced waste, and faster product.

4.1 Regulatory Drivers

• Assurance of affordable, safe, and effective drugs for all citizens ensuring a high quality of drugs

• facilitating manufacturing process innovations

Only efficient research of new drugs, optimized processes, and dedicated quality control procedures will provide, in the future, affordable, safe, and effective drugs for all. The implementation of PAT principles and tools enables efficient manufacturing, while maintaining today’s stringent quality standards.

Drug quality depends more on best development, production, storage, and distribution strategies than on expanded quality testing. With PAT, there will be a shift from lab-based end-product quality testing to better formulation and process design leading potentially to more in-line, on-line, or at-line testing. Innovation transfer to routine production ensuring “state of- the-art” manufacturing processes should be accelerated by regulatory authorities. Potentially there should be fewer post approval regulatory submissions supporting process improvements.

4.2 Regulatory Benefits

• Time to approval.

• improved process understanding.

• reduced inspection frequency.

Time to market means in a first step “time to approval.” Regulatory authorities are committed to reducing time for administration of Chemistry, Manufacturing, and Controls (CMC)/dossiers for new drugs as well as for submission changes of approved drugs. The key to reaching this goal is the appropriate presentation in the dossier of increasing complexity. Improved process understanding helps both industry and authority with running, controlling, and monitoring processes on a well assessed science-and risk-based level. Process understanding is the basis for process control and assured end product quality. Finally, time and frequency for extended audits or inspections can be reduced if the process Understanding meets the desired level. Up to now, this could to be detected in the available case studies.

4.3 Additional Industry Drivers

• Reduced manufacturing costs

• More flexible manufacturing processes

• Real-time release

PAT efforts could generate competitive advantages (i.e., abetter corporate image, increased quality, and efficient management of risks). The costs of manufacturing or QA could be decreased by increasing productivity and greater availability of production equipment. Moreover, PAT offers the opportunity for interdisciplinary communication and for bridging the gap between the R&D, Manufacturing, QA, QC , and IT departments. Manufacturing processes could become safer and more flexible under PAT. A defined design space for production processes offers flexibility for raw materials used, APIs, and even process controls. Because the influence of raw material variations is well-known, the process control strategy allows adaptation to the variability of the raw material quality attributes. Process understanding results in an appropriate management of variability and improved operational efficiency (e.g., “Lean Manufacturing,” “Right First Time” strategies). This leads to safer processes because the control strategies are optimized both from a pharmaceutical manufacturing and an operator point of view. Real-time release could help to reduce the time in warehouses of raw materials, final and intermediate products, or bulk (work in progress). PAT projects may starting single unit operations or could cover the whole production site. Incremental deployment is also enabled. In summary PAT should lead to a more efficient and reproducible supply chain improved communication between the industry and the regulatory authorities is provided by the Regulatory Authorities’ PAT teams (“pre-approval” activities).

4.4 Industry Benefits

• Use of “state-of-the-art” technologies in manufacturing

• guaranteed quality level (“unit-to-unit”)

• reduced documentation

• Risk mitigation

• Real-time data acquisition and integration

• Knowledge management

The implementation of “state-of-the-art” and innovative production and control technology is encouraged. Knowledge transfer from other industries (e.g., IT, food, automotive, electronics) is reasonable and useful. A reduced transfer time from development to production by using PAT tools seems quite possible. Reduced personnel placement, less Out-of-Specification (OOS) batches, reduced lead time, cleaning, set-up, or maintenance time, will lead to an increased Return on Investment.


5. A Change in Strategy

The traditional approach to regulating quality in pharmaceutical manufacturing involved a laboratory analysis to verify quality after manufacturing the finished product. Many of these inefficiencies are based on traditions, cost considerations and a general reluctance to change. The disadvantages of this approach are continual process optimization, high levels of rejected product and limited adoption of new technologies The key to the success of PAT is applying the process monitoring tools needed to analyze each of the critical product attributes. Equally important is having the process controls in place to make production adjustments based on the analysis. Detecting errors or process deviations and correcting them while the product is being made is more cost-efficient, and can help justify flexible regulatory paths for innovations in manufacturing and post-approval changes. The pharmaceutical industry has historically been lab-centric with minimal closed- loop, real-time control and limited enterprise-wide data availability. A key to optimizing manufacturing in the future will be to make data visible in the context it is needed. Similarly, the ability to cost-efficiently manage data with connectivity to the point of use will be important both within the company and with the FDA as part of the approval process. For example, one of 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. In today’s environment of open-system architecture, access to data is becoming less of a challenge. However, legacy systems persist, and the underlying technology of the legacy system often does not support the open-system philosophy. Fortunately, control system vendors and third-party support companies have developed communication drivers in support of industry standard communications for many of the older control system platforms. To provide consistency and seamless connectivity to the enterprise, many pharmaceutical companies are turning to technology suppliers like Rockwell Automation for single, integrated platforms. These modular, scalable and open platforms help reduce lifecycle costs while assisting manufacturers with ever- changing compliance regulations

6. PAT Implications on Organization and Process

The PAT approach is influencing the organizational structures and the business processes as detailed below.

6.1 Implications on the Organization

6.1.1 Implications on Personnel

• Demand on qualification and/or skills of employees may change:

  1. PAT may have an impact on qualification profiles in respect to scientific data analysis, statistics, process control, etc. Similar to implementing Six Sigma, implementing a PAT program may require dedicated training
  2. On methods and tools, including project management and statistics. (Probably at all levels of the company comparable with the Six Sigma training structure – master black belts, black belts, green belts, white belts?)

• Structural change within the organization:

  1. There may be a need for the implementation of a new department or restructuring of departments to deal with the new demands.
  2. Interactions and collaborations between departments and functions may need to be increased (e.g., quality, regulatory, development, commercial production). Contact with regulatory authorities may need to be increased
  3. The implementation of PAT within the organizational structure requires accountability, roles and responsibilities to be specified (clearly defined process owners, project managers, subject matter experts, and process analysts).
  4. Depending on the structure of the company, employees working for a PAT project could remain members of different departments or be integrated in a separate. PAT team or department.
  5. Depending on the PAT approach (holistic or more specialized), an interdisciplinary project team with members from QA, R&D, Engineering, QC, IT, Manufacturing may be useful.
6.1.2 Implications on Management

The management also is involved since it has to support the PAT process commitment of management:

1. The management has to be committed to PAT to deal with the early phase of PAT, which could mean more investment.

2. However, in later phases, when processes are more efficient due to PAT elements, companies will be able to

3. Maintain quality at lower costs, and will be prepared for any future regulatory demands from agencies and thus be on top of the trend.

• Definition of PAT and development strategy:

  1. Define the general approach.
  2. Define the team.
  3. Define which processes or products should be subjected to PAT first.
  4. Define the goals and objectives and the expected benefits.
  5. Plan and commit the resources (i.e., personnel, program money, and equipment).
  6. PAT means a paradigm shift from black/grey box to white box processes.
  7. The development strategy may need to be revised; therefore, the specific requirements concerning PAT need to be analyzed.

• Risks concerning the company:

  1. If PAT is ignored, there may be a risk of being left behind in the industry (competitive disadvantage) as well as a risk of image or business loss due to lower operational efficiency in sustaining reproducible product quality.
  1. Regular review of benchmarks to stay on top of the project.

• Outsourcing:

Outsourcing partners need to be chosen and reviewed very carefully. Points to consider are: their ability to perform projects according to PAT

  1. • Knowledge transfer (content, interfaces, patents, etc.)
  2. • Definition of accountabilities, roles, and responsibilities communicational structure

• Communication:

  1. Communication between all kinds of different partners (e.g., departments departments, vendor company, company agencies, etc.) may need to be intensified.
6.1.3 Implications on the QA Approach
  1. There may be an impact on the existing QA structure.
  2. Change in regulatory processes

With PAT, communication between regulatory authorities may have to begin earlier and become more regular (and possibly less formal).

• Audits

1. Regulatory scrutiny will challenge the scientific understanding of quality-relevant factors and how quality relevant risks are mitigated. Developing departments will get increasingly more attention from regulatory authorities. Continuous improvement and a clear structure for documenting changes and deviations need to be demonstrated. Comparison between real design space and documented design space will be in the focus of an audit.

• Validation

1. Validation will be demonstrated by continuous measurement of critical-to-quality parameters in real/near real time instead of the traditional three batch validation. The continuous validation process improvement will reduce today’s validation efforts by more in-depth understanding of process variability in the future.

• Documentation

1. Better knowledge of the impact of raw materials may change specifications.

2. Specifications for submissions probably need to include design space and control space relevant to the product and process in which they are being used.

The PAT approach links together the four areas of Process Understanding linked to Risk Management, QA/QC, Technology, and IT –By applying such an approach, the process is controlled and fully understood, and the right data for real time release enables continuous process verification and improvement via knowledge management.

6.2 PAT Impact on the Process

6.2.1 Impact on Process Understanding

• Development of process models:

  1. The analysis of the process should define which parts have some flexibility and which are very rigorous. In order to define system/process boundaries, (re-)structuring of complex processes may be helpful.
  2. Situation analysis is the evaluation of historical data for marketed products (from specification results, corrective actions).
  3. Impact analysis is the identification and evaluation of process steps, sources of variation, and the variables that are critical to quality.
  4. Critical process parameters need to be identified using appropriate techniques (e.g., FMEA, statistical analysis, risk analysis, and root cause analysis).
  5. Monitoring/controlling of the process through definition and implementation of relevant measurements. This is necessary to obtain data which can be reviewed for better process/product understanding and control.
  6. Verification of the control cycle is necessary to understand the impact of process parameters on process/product quality.
6.2.2 Impact on Production-Related QA/QC

• Specifications

  1. Quality control testing will evolve from testing against a discrete specification (pass/fail) to real-time comparison of process/product signatures against a reference. This reference will be a specification which will look totally different in a PAT approach as the process set values are flexible and based on a control strategy incorporating the design space.

• QC testing

1. Parametric release and in-line control could have an impact on QC headcount and work.

2. There may be a necessity for additional verification of parameters and definition of prerequisites for parametric release.

3. In order to recognize a slow deviation from expected requirements (e.g., raw materials, wear of materials, etc.), additional controls may be needed.

• Continuous improvement

1. Under PAT, manufacturing processes are monitored and controlled on-line, which – as opposed to a static process validation – leads to continuous process improvements. A continuous improvement and control of design space will be increasingly important

• Equipment validation, including the control cycle

1. In contrast to the common validation approach, where testing the functionality of the immediate equipment is sufficient; with PAT, the complete control cycle of the equipment is included.

6.2.3 Impact on Process Technology

• Continuous production

1. New equipment may be needed to enhance data acquisition and process understanding. Better knowledge of the process could lead to continuous production and faster release.

2. Due to design space, production equipment could be used more flexibly.

3. Availability of suitable sensors/methods

4. After the identification of critical process parameters, the availability of suitable sensors and methods has to be verified.

Impact on PAT-Related Data Management/IT

• New software/tools and new methods

  1. 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.
  2. New methods (e.g., MVDA, DoE, process modelling) including knowledge base maintenance must be implemented to enhance data and process analysis.

• Software validation

There will be increasing scrutiny on software validation at regulatory audits.

  1. The requirement for complete validation of software may start even earlier during research

7. Steps to Implementation

The implementation of process analytical technology (PAT) is occurring in what is perhaps the most exciting period of change in pharmaceutical manufacturing of the past three decades. A host of technological, regulatory, and market forces have converged during the last five years, yielding new opportunities for innovation in the development and operation of pharmaceutical production processes. A major driving force for change is the Food and Drug Administration (FDA) initiative to implement a modern, risk based framework for regulation and oversight of pharmaceutical manufacturing.

While the emergence of PAT is not new, it does require a shift in organizational structure, including the development of in-house expertise and training; changes to existing inspection and validation methodologies; and reliance on specialized PAT support teams. The implementation of a PAT program requires identifying the relevant technologies that can be applied and the creation of an integrated data management infrastructure capable of handling the volume of data to be recorded. It also requires advanced automation, visualization and analysis tools to manage the continuous identification and prediction stages in the process. For the majority of manufacturers, the transition to a PAT strategy is too monumental to be made in a single effort. Instead manufacturers should look to implement PAT programs in phases, starting with a specific project or production line and then gradually expanding to other areas. The first step is to conduct a productivity improvement appraisal (PIA) to analyze existing product lines and determine those that may benefit most from PAT. It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, systemic, control and risk analysis conducted in an integrated manner. A PIA report identifies possible productivity improvement opportunities such as:

  • Identification of best practices
  • Reusable engineering components
  • Cost reduction
  • Key performance indicators (KPIs)

Potential costs and benefits can then be generated, which will help create a list of financially viable projects. By carefully analyzing likely opportunities and implementing PAT projects in phases, companies more accurately assess the potential impact of process changes while managing investment costs. Defining the business drivers and potential benefits from a PAT initiative are essential for a successful project. This effort also will establish the framework for continuous quality improvement. Risk assessment, change management systems and a process monitoring plan are created during this effort to establish the importance of the investment strategy. Once a specific project is identified, the next step – discovery phase – involves re- evaluating work practices, process chemistry, manufacturing techniques, and inspection and validation methods. New products are one area where companies are concentrating their efforts and activities. Products with recurring quality issues are other good candidates, because process deviations or exceptions often result in lost or poor product quality leading to higher costs, especially with expensive and hard to acquire raw and intermediate materials. Management of processes by operators not fully understanding the process is another issue prompting analysis. Partial PAT adoption is suitable for processes which can benefit from new technology to correct or prevent a problem in the production process. In the analysis phase, engineers perform a thorough and systematic review of product filings, exception history, manufacturing and quality data and other sources for each product to verify if the original critical process parameters (CPPs) are still valid, or whether other parameters not originally identified are now more critical. The emphasis is on CPPs that affect in-process product quality rather than quantitative measurements. The analysis also involves looking at the critical operator data (COD) necessary and/or for integrated system control or required by an operator to effectively manage the process. The identification and confirmation of CPPs is accomplished by using neural net, mathematical modeling and statistical software to find correlations between key quality attributes and measured real-time process parameters. By using real-time methods, the process endpoint no longer needs to be a fixed time, but rather can be the time required to reach a specific state or condition. The definition, analysis, and documentation of CPPs require competent engineering and compliance expertise. Activities include:

  • Preparation of a formal project plan; submit for approval
  • Identification and setup of toolsets necessary for project implementation
  • Identification of product process specifications and limits
  • Identification of at-line or in-line or on-line process controls and tests
  • Acquisition of necessary information and data
  • Preparation and delivery of a CPP analysis report assessment report,

Which includes high-level recommendations for improvement preparation and delivery of productivity improvement appraisal (PIA) the results of the analysis provide the basis for determining which manufacturing technologies and quality assurance tools will comprise the PAT solution? This might include: data acquisition and analysis technology; modern process analyzers or process analytical chemistry tools; knowledge management systems; and process and endpoint tools for real-time or near-real time monitoring and control of all critical attributes. It’s important that the risk and impact assessments be completed on the basis of data and not on opinions or theories. Design strategies should address:

  • The attributes of input materials
  • The ability and reliability of process analyzers or other instrumentation like NIR sensors to measure critical attributes,

8. Factors Limiting Implementation Of Pat

Despite the evidence of fiscal and competitive benefits enjoyed by the various industries which have embraced process analytics, pharmaceutical companies’ have been notoriously restrained in their efforts to deploy PAT. Indeed, the pharmaceutical industry has slipped so far behind peer industries before indicting the industry for gross negligence; however, it is important to consider the various factors which have acted over time to create the current state of affairs. Over the years, dozens of excuses have been provided for the industry’s lack of manufacturing innovation; many of the reasons are well known and have been published elsewhere For the sake of simplicity, the factors limiting the adoption of PAT can be distilled into three categories: real and perceived technological barriers, lack of economic incentive, and regulatory disincentives.

8.1 Real and Perceived Technological Barriers

Changes of improbable magnitude would be recognized with statistical confidence despite the fact that near infrared spectroscopy (NIR) has been used industrially for decades there has been hesitance to accept and trust “new” process analytical measurement technologies as equivalent or superior to traditional methods.

8.2 Lack of Economic Incentive

A common refrain within the industry has been that there simply is not sufficient financial return from investment in process analytics or manufacturing technology Upgrades to justify spending. In some respects, this is a valid argument.

9. Importance of PAT

Cost control, resulting partly through more efficient production processes, and partly through the minimisation of the necessity of final discard (or reprocessing) at the QA final test point, is an important justification for exploring PAT. In a world in which financial issues have entered a triage of decisions, cost control has become tightly entangled with patient treatment and cure, PAT brings other important advantages, however. Even the most rigorous military sampling of end product has a statistical chance of missing a problematic situation. In fact, in the most dangerous of circumstances – human blood processing, for example – regulation and practice call for testing of all end products rather than a representative sample. However, the addition of monitoring during production as well as at end stage, even if redundant, can only enhance the likelihood of catching aberrant situations and increasing patient safety Perhaps most removed but of great potential, PAT also carries the future promise of new methods of production. Continuous monitoring allows more controlled processes and a finer control of interim production steps. In vaccine production and protein separation technologies, the continuous monitoring of PAT could potentially enhance the speed and quality of end- product development.

10. Approach to the PAT and Awareness Project with Case Studies

The basis for the PAT awareness document was the evaluation of 11 PAT case studies. The identification and evaluation of benchmarking parameters concerning PAT applications is important for various aspects:

• To raise acceptance in the management

• To proof the maturity of projects

• For monitoring project progress

For this purpose, a catalogue of standardized questions for evaluating and assessing the case studies was created. The following categories have been defined and considered for this assessment:

• Category 1: Quality

• Category 2: Process

• Category 3: Risk

• Category 4: Cost

• Category 5: Personnel

• Category 6: Tools

• Category 7: Time

• Category 8: Validation

• Category 9: Organization

• Category 10: Regulatory.

Assessment Category 1: Quality

The following benefits depend on the degree of the PAT implementation:


• Better quality definition and analysis methods

• Reduction of complaints and recalls

Assessment Category 2: Process

In all investigated case studies, the general process understanding has greatly increased, e.g., by an optimized adjustment of known process parameters. In some case studies, new Critical Process Parameters (CPP) also were identified and used for advanced process control. In most cases, the process cycle time was significantly reduced, while the productivity was increased. Introduction and implementation of new process automation technologies including sensors, analytical devices, and process control technologies is not a mandatory prerequisite for PAT. PAT also can be achieved with existing process and control equipment. The benefits of implementing PAT in the process have been estimated to be very positive.

Assessment Category 3: Risk

Risk assessment is a positive state-of-the-art methodology for risk detection and minimization, but currently in the companies sampled independent from PAT. Risk assessment will become a key integral method within PAT.

Assessment Category 4: Costs

Most of the case studies cannot give an answer to the question of ROI, and only one case study claims a ROI period of less than one year. In all other cases, it is still too early for a meaningful calculation. Practical experience, as far as available, revealed fewer rejected batches, fewer deviations, increased yield with higher Overall Equipment Effectiveness (OEE), fewer consumables, less waste, and fewer reworks.

Assessment Category 5: Personnel

Up to now, there has been no reduction in personnel. Production is less lab-intensive due to a higher degree of automation, but the personnel has shifted their tasks to implement and improve PAT. The shift to PAT-based thinking encourages the communication between different departments. A better process understanding is obtained. There are hints to a slight increase in personnel safety.

Assessment Category 6: Tools

A clear result of the investigation is that more process data is recorded, analyzed, and stored. The data is additionally used within the batch documentation. In most cases, the data is used for advanced process control and the prediction of process deviations.

Applied analytical methods: NIR, MIR, Raman, laser diffraction, mass spectroscopy, accelerated dissolution testing, etc. Applied statistical methods: MVDA, DMAIC, etc.

Assessment Category 7: Time

In summary, faster processes have been reported:

• Higher utilization of resources

• reduced lead time by reduced intermediate off-line testing

• Faster decisions for on-line quality assessment and faster and earlier decisions on waste material

• Due to automated data acquisition, shorter transition time from raw data to meaningful process information

• Material variability is detected earlier

Assessment Category 8: Validation

In total, a lower effort for validation is expected, but more effort has to be put into facility, equipment, and software validation during PAT implementation.

Assessment Category 9: Organization

PAT projects have an impact on the organization of pharmaceutical companies and increase the interdisciplinary communication between departments.

Assessment Category 10: Regulatory

Regulatory issues have a strong impact on:

•The frequency of scientific-based contacts and communications with regulatory bodies

• Earlier and more frequent contact before and during the implementation phase

• The kind of documentation that will undergo changes (more precise and deeply science-based, earlier documentation during design is expected)

• change control (a positive impact is anticipated)


Process Analytical Technology can be viewed as a constellation placing greater or less emphasis on a given activity depending on the current problem or situation there is no written rule or straightforward path to progress through PAT. Experience and expertise are necessary, together with a good knowledge of the pharmaceutical environment. Once a pharmaceutical company has decided to implement PAT, continuous management support for the development and Maintenance of PAT - related activities is critical. It is a strategic and necessary step for the future success of PAT to encourage, stimulate, and initiate scientific collaboration and interaction as well as the relevant education and training. Better understanding and control of chemical and pharmaceutical processes are greatly needed, as well as the development of advanced measurement tools and data analysis methods.

A summary of PAT benefits follows:

• Immediate action if quality is not met

• Better process control and understanding

• Less uncontrolled variation and less production waste

• Better and more stable products

• Data collection and improved historical knowledge

Process analytical technology continuously improves product quality, extends the Acquired knowledge base for new projects, and shortens time to market


  1. Guidance for Industry. PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.
  2. Weinberg Sandy “Process Analytical Technology-An Emergent Biomedical Regulatory Methodology “
  3. Schneidir Ray “Achieving Process Understanding –The foundation of strategic PAT programme”
  4. Hussain Ajaz “The desired state :PAT and road to enlightment”
  5. Mollan Matthew and Lodaya Mayur “Continuous Processing In Pharmaceutical Manufacturing”
  6. Cox Shayne “Pharmaceutical Manufacturing Handbook Regulation and Quality”
  7. Agalloco James and Carleton Fredrik “Validation of pharmaceutical Processes”

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