In process control , validation of large scale process and Case Studies.pptx

In Process
Process control in pharmaceutical process chemistry is essential for ensuring the quality, safety, and efficacy of pharmaceutical products. It involves the monitoring and regulation of various parameters throughout the manufacturing process to maintain consistency and meet regulatory standards. Here are some key aspects of process control in pharmaceutical process chemistry:
Critical Process Parameters (CPPs): These are the key variables that have a significant impact on the quality of the pharmaceutical product. CPPs include factors such as temperature, pressure, pH, agitation rate, and reaction time.

Process Analytical Technology (PAT): PAT involves the use of real-time monitoring techniques to measure and control critical process parameters during manufacturing. PAT tools include spectroscopy, chromatography, mass spectrometry, and other analytical methods that provide rapid and accurate data on process performance.
3. Quality by Design (QbD): QbD is a systematic approach to pharmaceutical development that emphasizes the understanding of how formulation and process variables influence product quality. QbD principles guide the design of robust manufacturing processes with built-in controls to ensure consistent product quality.

4. Risk Assessment and Mitigation: Identifying and mitigating risks associated with the manufacturing process is crucial for ensuring product safety and compliance with regulatory requirements. Risk assessment techniques such as Failure Mode and Effects Analysis (FMEA) help identify potential failure modes and develop strategies to prevent or mitigate them.

5. Process Validation: Process validation is the process of establishing documented evidence that a manufacturing process consistently produces a product that meets predetermined specifications and quality attributes. Validation studies involve process qualification, process performance qualification, and continued process verification to ensure ongoing control and compliance.

1. In process control , validation of large scale process and Case Studies Presented By: Divya Ashok Dhule M. Pharm.(Pharmaceutical Chemistry) 1 st Year Rashtrasant Tukadoji Maharaj Nagpur University Nagpur-440033

2. In Process Control Process control in pharmaceutical process chemistry is essential for ensuring the quality, safety, and efficacy of pharmaceutical products. It involves the monitoring and regulation of various parameters throughout the manufacturing process to maintain consistency and meet regulatory standards. Here are some key aspects of process control in pharmaceutical process chemistry: Critical Process Parameters (CPPs): These are the key variables that have a significant impact on the quality of the pharmaceutical product. CPPs include factors such as temperature, pressure, pH, agitation rate, and reaction time. Process Analytical Technology (PAT): PAT involves the use of real-time monitoring techniques to measure and control critical process parameters during manufacturing. PAT tools include spectroscopy, chromatography, mass spectrometry, and other analytical methods that provide rapid and accurate data on process performance.

3. 3. Quality by Design ( QbD ): QbD is a systematic approach to pharmaceutical development that emphasizes the understanding of how formulation and process variables influence product quality. QbD principles guide the design of robust manufacturing processes with built-in controls to ensure consistent product quality. 4. Risk Assessment and Mitigation: Identifying and mitigating risks associated with the manufacturing process is crucial for ensuring product safety and compliance with regulatory requirements. Risk assessment techniques such as Failure Mode and Effects Analysis (FMEA) help identify potential failure modes and develop strategies to prevent or mitigate them. 5. Process Validation: Process validation is the process of establishing documented evidence that a manufacturing process consistently produces a product that meets predetermined specifications and quality attributes. Validation studies involve process qualification, process performance qualification, and continued process verification to ensure ongoing control and compliance.

4. 6. Control Strategy Development : A control strategy outlines how critical process parameters will be monitored and controlled throughout the manufacturing process. It includes procedures for deviation management, corrective actions, and change control to ensure product quality and regulatory compliance. 7. Regulatory Compliance: Pharmaceutical manufacturing processes must comply with regulatory requirements set forth by agencies such as the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) in Europe. Compliance involves adhering to Good Manufacturing Practices (GMP), following established guidelines, and maintaining comprehensive documentation of process controls and quality assurance activities. Overall, process control in pharmaceutical process chemistry is a multifaceted discipline that integrates scientific principles, advanced technology, and regulatory compliance to ensure the production of safe and effective pharmaceutical products.

5. Validation of Large Scale Process The collection and evaluation of data from the process design stage through commercial production ,which establishes scientific evidence that a process is capable of consistently delivering quality products. (FDA) Documented evidence which provides a high degree of assurance that a specific process will consistently result that meets predetermined specifications and quality characteristics.(WHO) T he documented evidence that the process operated within established parameters can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications attributes.

6. Validation of large scale process Traditional New Paradigm VS Development Basic Pilot Batch Manufacturing Process Validation – 3 Batches Post Approval Changes /Change Controls/Risk Analysis Enhanced –Development And Process Qualification Continuous and extensive monitoring of CQAs and CPPs for each production batch ICH Q8, QbD Control Stratergy ICH Q9 and Q10

7. Process Validation Phases Pre-validation Phase Protocol Preparation Validation Phase Protocol execution Post Validation Phase: Review of process, deviations, failures, need for improvement, scale up etc …. Information from primary/clinical manufacturing (scale up information) Information from product development studies (identification of critical attributes) Process risk assessment information (identification of critical steps) Includes demonstration of content uniformity of the clinical batch

8. Latest Guidelines:

9. Types of Process Validation and Dossier Requirements:

10. Process Validation –Role of Assessment Design Qualification Operational Qualification Performance Qualificati on Process Validation Dossier GMP

11. 1. Design Qualification verification process to meet particular requirement relating to the quality of Pharmaceutical and manufacturing process. DQ plan covers user requirement, user specification, Technical specification and DQ report 2.Performance qualification (PQ) (process qualification) process of testing to ensure that the individual and combined systems function to meet agreed performance criteria on a consistent basis and to check how the result of testing is recorded. The purpose is to ensure that the criteria specified can be achieved on a reliable basis over a period of time. 3. Operational Qualification (OQ) process of testing to ensure individual and combined systems function to meet agreed performance criteria and to check how the result of testing is recorded. The purpose is to ensure that all the dynamic attributes comply with the original design. 4.Process Validation Owners are responsible for Validating Their Processes (personnel, equipment, methods, SOPs) to ensure compliance to cGMP/GLP regulations.

12. Case study Process Development for Labetalol Production Background : Labetalol –antihypertensive, 30,000 Kg p.a. produced by Schering-Plough. Labetalol Manufacturing Process Mono-pot reaction in jacketed, glass-lined 10,000 L reactor. Addition of liquid reagents and jacket temperature computer controlled. Solid reagents charged manually via handwhole . Phase separation using sight-glass. Solid product from second step isolated by centrifugation. Product tested to determine if recrystallisation necessary. When required purity achieved, product is dried

13. Labetalol Process – St ep 1 Solvent system modified to isopropanol / ethyl acetate containing hydrogen bromide from methanol / ethyl acetate to reduce formation of third impurity. Original process used chloroform. Concentration was increased threefold increasing throughput and reducing solvent waste. Figure 1: Main Impurities

14. Labetalol Process - Step 2 : Process Development Large excess of dibenzylamine used to ensure reaction driven to completion. Propylene oxide added as it reacts with HBr side-product as it’s produced. Presence of HBr would neutralise dibenzylamine and no reaction to give product would occur. Propylene bromohydrin side-product easily washed out. Use gentle reflux to ensure propylene oxide doesn’t escape.

15. References: TEXTBOOK PROCE SS CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY BY KUMAR G. • Sitompul , Johnner & Lee, Hyung & Kim, Yook & Chang, Matthew. (2013). A Scaling-up Synthesis from Laboratory Scale to Pilot Scale and to near Commercial Scale for Paste-Glue Production. Journal of Engineering and Technological Science. 45. 9-24. 10.5614/j.eng.technol.sci.2013.45.1.2.

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