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Quality Day Orange Empire ASQ – November 1, 2013

Larry Bartkus

Validation &Sample Size Selection

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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.

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What Does This Mean?

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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.

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Other DefinitionsProcess 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.

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Qualifications

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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.”

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Product Development Phases

Phases in the Product Development Process

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Concept and Feasibility1

Design and Development2

Final Validation & Ramp-up3 Market Launch4

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DRDs, CTQs

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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!

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Laws and Regulations FDA 21 CFR §820.75

§820.75 Process Validation(a) 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.

(b) 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.

(1) Each manufacturer shall ensure that validated processes are performed by qualified individual(s).

(2) 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.

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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.

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Standards ISO 13485 Clause 7.5.2

Validation of Processes for Production and Service Provision 7.5.2 of ISO 13485

Clause 7.5.2.1 General RequirementsThe 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.

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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.

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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

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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.

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Why Process Validation is important?

Process Validation sets the optimal range and determines the process control requirements to ensure long-term success.

Process Validation Continuum

Process Parameters

Lots

Product/Process Development

Process Validation (IQ/OQ/PQ/PPQ)

Process Control

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Pharmaceutical Guidance

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Simple Validation Decision Diagram

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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

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Attribute Data

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Variable Data

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Categories of Quality Levels

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Risks

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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”

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AQLs vs LTPD

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Binomial Distribution

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Binomial Distribution – Zero Table

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Calculations using Software (Attributes)

From Minitab

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Using the k-value

From National Bureau of Standards Handbook 91

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k-values One-Sided

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k-values Two-Sided

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From ISO 16269-8

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Calculations using Software (Variables)

From Minitab

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Power Analysis

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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.

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Power Analysis

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Sample Selection Example

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Sample Selection Example

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Sample Selection Example

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Sample Selection Example

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Sample Selection Example

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Sample Selection Example

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Questions?

?

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Thanks!

Thank You for Your Time and Attention !- Uncle Larry

Uncle Larry’s a Cool Dude!