Validation & Sample Size Selection

1. Validation &Sample Size Selection Quality Day Orange Empire ASQ – November 1, 2013 Larry Bartkus

2. Verification and Validation • Verification: • Confirmation by examination and provision of objective evidence that the specified requirements have been fulfilled. • Validation: • Establishing objective evidence that something consistently produces a result or product meeting its predetermined requirements.

3. What Does This Mean? Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. Validation can use tools such as: Verification uses: Design of Experiments Examination Regression Analysis Test Worst case testing Inspection This entire process requires a careful analysis of materials, processes, requirements, and test capabilities to determine what exactly can be verified and what cannot be verified.

4. Other Definitions • Process validation – establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications. • Design validation – establishing by objective evidence that device specifications conform with user needs and intended use(s). • Installation Qualification – Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. • Process Performance Qualification – Establishing confidence that the process is effective and reproducible. • Product Performance Qualification – Establishing confidence through appropriate testing that the finished product produced by a specified process(es) meets all release requirements for functionality and safety.

5. Qualifications Qualifications are really a subset of Validation. These address the specific equipment, process, and product. Webster refers to qualification as “a restriction in meaning or application” and “a limiting modification” and also “a condition or standard that must be complied with”. We are then talking about very specific equipment, processes, and product characteristics. The specificity is demonstrated in the Regulations as follows: • “Installation qualification studies establish confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.” • Each process shall be defined and described with sufficient specificity so that employees understand what is required. • ‘it is necessary to demonstrate that the specified process has not adversely affected the finished product.”

6. Product Development Phases Phases in the Product Development Process Concept and Feasibility Design and Development Final Validation & Ramp-up Market Launch 1 2 3 4

7. DRDs, CTQs • It is essential to quantify all important quality characteristics and test for them. Design Requirement Documents or Product Matrices are a must. • The CTQ (Critical to Quality) Tree can be a good tool for this effort!

8. Laws and Regulations FDA 21 CFR §820.75 §820.75 Process Validation • Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented. • Each manufacturer shall establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met. • Each manufacturer shall ensure that validated processes are performed by qualified individual(s). • For validated processes, the monitoring and control methods and data, the date performed , and where appropriate, the individual(s) performing the process or the major equipment used shall be documented. (c) When changes or process deviations occur, the manufacturer shall review and evaluate the process and perform revalidation where appropriate. These activities shall be documented.

9. Standards ISO 13485 Clause 7.3.6 • Design and development validation Clause 7.3.6 of ISO 13485Design and development validation shall be performed in accordance with planned arrangements (see 7.3.1) to ensure that the resulting product is capable of meeting the requirements for the specified application or intended use. Validation shall be completed prior to the delivery or implementation of the product (see Note 1). • Records of the results of validation and any necessary actions shall be maintained (see 4.2.4). • As part of design and development validation, the organization shall perform clinical evaluations and/or evaluation of performance of the medical device, as required by national or regional regulations (see Note 2). • NOTE 1 If a medical device can only be validated following assembly and installation at point of use, delivery is not considered to be complete until the product has been formally transferred to the customer. • NOTE 2 Provision of the medical device for purposes of clinical evaluations and/or evaluation of performance is not considered to be delivery.

10. Standards ISO 13485 Clause 7.5.2 Validation of Processes for Production and Service Provision 7.5.2 of ISO 13485Clause 7.5.2.1 General Requirements The organization shall validate any processes for production and service provision where the resulting output cannot be verified by subsequent monitoring or measurement. This includes any processes where deficiencies become apparent only after the product is in use or the service has been delivered.

11. GHTF Overview of N99 The Global Harmonization Task Force Quality Management Systems - Process Validation Guidance This process validation guidance is intended to assist manufacturers in understanding quality management system requirements concerning process validation and has general applicability to manufacturing (including servicing and installation) processes for medical devices. The guidance provides general suggestions on ways manufacturers may prepare for and carry out process validations. This guidance provides general suggestions on ways manufacturers may prepare for and carry out process validations. Other ways may be equally acceptable; some regulatory requirements place the responsibility on the manufacturer to specify those processes which require validation and the qualification of personnel who operate validated processes. Regardless of the method used to validate the process, records of all validations activities should be kept and the final outcome documented.

12. Validation in Software • This guidance applies to: • · Software used as a component, part, or accessory of a medical device; • · Software that is itself a medical device (e.g., blood establishment software); • · Software used in the production of a device (e.g., programmable logic controllers in manufacturing equipment); and • · Software used in implementation of the device manufacturer's quality system (e.g., software that records and maintains the device history record). • This document is based on generally recognized software validation principles and, therefore, can be applied to any software. For FDA purposes, this guidance applies to any software related to a regulated medical device, as defined by Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) and by current FDA software and regulatory policy. This document does not specifically identify which software is or is not regulated.

13. Process Validation in Pharmaceuticals • The CGMP regulations for validating pharmaceutical (drug) manufacturing require that drug products be produced with a high degree of assurance of meeting all the attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)). • Process Validation and Drug Quality • Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. This principle incorporates the understanding that the following conditions exist: • Quality, safety, and efficacy are designed or built into the product. • Quality cannot be adequately assured merely by in-process and finished-product inspection or testing.

14. Lots Why Process Validation is important? Process Validation Continuum Process Parameters Product/Process Development Process Control Process Validation (IQ/OQ/PQ/PPQ) Process Validation sets the optimal range and determines the process control requirements to ensure long-term success.

15. Pharmaceutical Guidance

16. Simple Validation Decision Diagram

17. Discussion: Validation or Verification? • Sterilization processes • Manual cutting processes • Aseptic filling processes • Testing for color, turbidity, total pH for solutions • Heat treating processes • Visual inspection of printed circuit boards • Numerical control cutting processes • Validation • Verification • Validation • Verification • Validation • Verification • Verification, but validation may be preferred

18. Attribute Data

19. Variable Data

20. Categories of Quality Levels

21. Risks • Alpha Risk is the probability of rejecting a good lot. It can be expressed as: Alpha=1-Probacc (at the AQL level). It can also mean in hypothesis testing rejecting the null hypothesis when it is true. Alpha is also known as a Type I Error or the “Producers Risk” • Beta Risk is the probability of accepting a bad lot. It can be expressed as: Beta=Probacc(at the LTPD level) It can also mean accepting a hypothesis that is false. Beta is also known as Type II Error or the “Consumers Risk”

22. AQLs vs LTPD

23. Binomial Distribution

24. Binomial Distribution – Zero Table

25. Calculations using Software (Attributes) From Minitab

26. Using the k-value From National Bureau of Standards Handbook 91

27. k-values One-Sided

28. k-values Two-Sided

29. From ISO 16269-8

30. Calculations using Software (Variables) From Minitab

31. Power Analysis The power of a statistical test is the probability, given that Ho is false, of obtaining sample results that will lead to its rejection. “Power of a test” is clearly an important characteristic. To put it in other words, a powerful test is one that has a high probability of claiming that a difference exists when it really does. -The larger the effect size, d, the greater the power. -For any given effect size (other than zero) the larger the sample size, the greater the power of the test.

32. Power Analysis

33. Sample Selection Example

34. Sample Selection Example

35. Sample Selection Example

36. Sample Selection Example

37. Sample Selection Example

38. Sample Selection Example

40. Thanks! Thank You for Your Time and Attention ! - Uncle Larry Uncle Larry’s a Cool Dude!