Industrial Regulation and Quality CHMG 751

1. Industrial Regulation and Quality CHMG 751 Manhattan College Fall 2012 Class 6

2. Agenda • Midterm Exam • Process Validation • Break • Processing Monitoring and Control • Homework

3. Midterm Exam • What did you think about it? • Review exam questions next class after grading • Final exam will be similar but in class

4. Process Validation How do you know if a manufacturing process is in control?

5. Process Validation How do you know if a manufacturing process is in control? • Good design of the process • Good construction of the facility and equipment • Trained personnel • Raw materials into the process are of the required quality • Control critical parameters of the process

6. Process Validation • Purpose • Process Validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.

7. Process Validation • Industries using formal validation • Pharmaceutical • Biotechnology • Medical devices • What about the other industries • If it is not formal done or required, what do they do? Building quality into the process

8. Process Validation • Regulatory Basis • For the U.S., cGMPs 21 CFR 211.110 (a) Control procedures shall be established to monitor output and to validate of the manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

9. Regulatory Basis • Regulatory Basis • Guidances • http://www.fda.gov/cder/guidance/index.htm • General Principles of Process Validation Final 5/1987 • Process Validation: General Principles and Practices Draft 11/17/2008 • ICH Q11 Process Validation

10. Process Validation • When is Validation Required? • Commercializing a new product • Pharmaceutical Development • The goal of pharmaceutical development activities is to design a product and its manufacturing process to consistently deliver the intended performance and meet the needs of patients and healthcare professionals, and regulatory authorities and internal customers’ requirements. Approaches to pharmaceutical development are described in ICH Q8. The results of exploratory and clinical development studies, while outside the scope of this guidance, are inputs to pharmaceutical development

11. Process Validation • When is Validation Required? • Commercializing a new product • Technology Transfer • The goal of technology transfer activities is to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realisation. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach and ongoing continual improvement. commercializing a new product

12. Process Validation • When is Validation Required? • Commercializing a new product • Commercial Manufacturing • The goals of manufacturing activities include achieving product realisation, establishing and maintaining a state of control and facilitating continual improvement. The pharmaceutical quality system should assure that the desired product quality is routinely met, suitable process performance is achieved, the set of controls are appropriate, improvement opportunities are identified and evaluated, and the body of knowledge is continually expanded. • State of Control: • A condition in which the set of controls consistently provides assurance of continued process performance and product quality. (ICH Q10)

13. Process Validation • When is Validation Required? • When changes occur in: • Primary packaging • Formulation • Equipment • Process • Raw material • Supplier of excipient or active So is Process Validation = Change Control?

14. Process Validation • How do you validate a process • Understand the process • What does it require to meet the production volumes? • What are the required unit operations to process. • Each unit operation will have requirements • Materials • Equipment • Environment • Personnel considerations

15. Process Validation • How do you validate a process • Qualify resources that support the process • Process equipment • Supplier material • Operator training • Information/Documentation Lifecycle • Conduct a series of test • Simulation of actual process • Evaluate the data and ensure each step is performing within the defined specifications • Product Testing

16. Process Validation • Process Knowledge • What are the critical process parameters (CPPs) • What is the relationship between product attributes and the process parameters • Need to define targets and ranges of all CPPs

17. Process Validation • Process Design • Check and Balance between design and construction and the verification and testing of all elements • Culminating in a final overall running of the process mimicking the actual process

18. Process Validation • Documentation Methodology • Validation Master Plan • Documents scope of what is validated, overall strategy and governance • Validation Plans • Documents approach to how will manufacturing and support systems will be validated • Validation Protocols • Actual procedure to conduct tests on the process • Collect data • Analysis and Decision on Validation State

19. Process Validation • Manufacturing Process • Cleaning Process • Computer System Validation • Analytical Methods Validation

20. Process Validation • Manufacturing Processes • Ensure all unit operations and material handling steps are consistently executed to produce results which are reproducible and repeatable. • Ensure the environment supporting the manufacturing processes are maintaining the appropriate levels of control including temperature, humidity, particles, microbiological contamination • Ensure support systems are able to support the utility requirements of the process (i.e. steam, chill water, compressed air, etc.)

21. Process Validation • Manufacturing Process • Types of processes • Washing • Sterilization • Compounding Formulations • Solid Dosage Forms • Liquid/Cream Dosages Forms • Sterile Dosage Forms • Lyophilization • Inspection • Packaging Operations • Filling • Container Closure Systems • Labeling

22. Process Validation • Cleaning Process • Need to ensure raw materials and product of previous batches are reduced to levels that will not impact future batches of the same or different product

23. Process Validation • Analytical Methods Validation • Ensure the methods for testing the active ingredient, intermediates, raw materials and excipients and the finished product are accurate and reproducible

24. Process Validation • Computer System Validation • Ensure the computer systems controlling the process or information regarding the product is under control and supports repeatable steps

25. Process Validation • Need to revalidate • Changes to the actual process that affect product quality or its validation state • Negative trend(s) in quality indicators • Changes in the product design which affects the process • Transfer of processes from one facility to another • Change of the application of the process (i.e. another product run on the same equipment)

26. Break

27. Process Monitoring and Control • Basic Statistical Concepts • Definition of Statistical Process Control • Advantages of Decreasing Process Variability • Statistical Control Charts • Process Capability

28. Process Monitoring and Control • Basic Statistical Concepts • Using a sampling methodology ( a portion of the population), a set of characteristics would be calculated to predict the actual population characteristics • The characteristics would represent the population based upon a probability • Smaller sampling would be a lower probability of representation • If all the population is sampled, in essence 100% then the probability is also 100%, impractical in almost of all cases • Central Tendency ( mean, mode, medium) • Distribution (standard Deviation)

29. Process Monitoring and Control • Basic Statistical Concepts • Central Tendency • Mean (average) : arithmetic midpoint • Mode: most frequent number • Medium: 50% of data is above and 50% is below the medium • Main concept: Beware of averages!!!

30. Process Monitoring and Control • Basic Statistical Concepts • Distribution • Profile of variability of the data in the sample or in the population • Calculated measurement is called standard deviation

31. Process Monitoring and Control • Basic Statistical Concepts • Normal Distribution • Characteristics • Bell-Shaped • Symmetrical • Mean = Median = Mode • Allows us to extend the use in many situation • Allows many statistical tests to be conducted • t Test • ANOVA

32. Process Monitoring and Control • Definition of Statistical Process Control • Application of statistical methods to the measurement and analysis of variation in a process • Statistical Quality Control; similar term, sometimes more specific to quality measurements in the lab

33. Process Monitoring and Control • Advantages of Decreasing Process Variability • Improved product performance • Less defects • Higher revenue • Better Competitive position in the market • Compensate for other areas where higher variability is experienced • Less process control investment • Less final product inspection

34. Process Monitoring and Control • Statistical Control Charts • How to create control charts • Select parameter which will be measured • Sampling Plan (frequency, location) • Plot value of sample versus time or sequential method (i.e. batches produced) • Calculate Upper Control Limit and Lower Control Limit (=/- 3 standard deviations, or other formulas depending on control charts) • Derived from the actual data • Do not confuse with specifications • Analyze and interpret the results

35. Customerneeds (Specs) Process Monitoring and Control • Most often used for continuous data where each data point represents a single measurement (“individuals data”), but can be used for count data… Note: Do not place Specs on a Control Chart. Control Limits

36. I - M R C h a r t 1 4 0 ) s d 1 n a 3 0 s u U C L = 2 7 . 0 5 o h t ( 2 0 _ X = 1 6 . 8 8 Cases 1 0 L C L = 6 . 7 0 J a n M a r M a y J u l S e p N o v J a n M a r M a y J u l S e p N o v M o n t h 1 2 0 e g 1 5 n a R U C L = 1 2 . 5 0 g 1 0 n i v o M _ _ 5 M R = 3 . 8 3 0 L C L = 0 J a n M a r M a y J u l S e p N o v J a n M a r M a y J u l S e p N o v M o n t h Process Monitoring and Control

37. Process Monitoring and Control How do you know if a manufacturing process is in control?

38. Process Monitoring and Control How do you know if a manufacturing process is in control? Monitor the process

39. Process Monitoring and Control • Statistical Control Charts • Different control charts provide different views of the data • X: actual data • Xbar: Average of X (if multiple samples are taken at one time for example in a process tank taking 10 samples across the batch • X double bar: average of the averages • Range: how does the overall range of values change

40. Process Monitoring and Control • Statistical Control Charts • Types of Charts • Variable: continuous data (40.3, 50.6, 35.4) used for process parameters such as tablet hardness • Attribute: count data (1,2,3,4,5) used for defects or nonconformities

41. Process Monitoring and Control • Statistical Control Charts • Examples • Lets go to Gryna Chapter 18

42. Process Monitoring and Control • Statistical Control Charts • Interpretation of Charts

43. Process Monitoring and Control • Statistical Control Charts • Interpretation of Charts • Special and Common Cause Variation • All processes have natural variability (common causes) • Potentially “unnatural variability” (special causes) • We use SPC to monitor and/or improve our processes by quickly DETECTING special cause variation. • These out of control signals CANNOT tell us WHY the process is out of control, only that it is.

44. Process Monitoring and Control • Statistical Control Charts • Interpretation of Charts • Tests for Special Causes • 1 Point outside of the control limits (> +/- 3 Sigma) • 6 Points in a row either increasing or decreasing (Trend) • 8 Points in a row on the same side of the mean (Shift in the process) • 14 Points in a row alternating up & down (Possibly 2 “different” processes)

45. Process Monitoring and Control • Statistical Control Charts • Demonstrate JMP • Set of data • Generate Individual and Range chart with control limits

46. Homework • Readings • Nash, Pharmaceutical Process Validation • FDA Guidance: Process Validation • GHTF Quality Management System – Process Validation Guidance • Gryna Chapter 18

47. Homework • Paper/Presentation • Select your topic immediately… • Submit a draft of an abstract by next week: • Describe what the paper will be about • Scope of the paper • Include why the topic is important to regulatory and quality • Some perspective on the results of the paper • Need to revisit abstract and finalize after the paper is finished • Need to select day of presentation • 11/27/2012 (5 individuals) • 12/4/2012 (5 individuals)

48. Homework • Homework No. 8 • Chapter 18 Questions • Problem 18.8 • Problem 18.11

49. Next Week • Quality Improvement Methodologies