Transcript Validation &Sample Size Selection

Validation &
Sample Size Selection
Quality Day Orange Empire ASQ – November 1, 2013
Larry Bartkus
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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?
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 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.
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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.”
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Product Development Phases
Phases in the Product Development Process
1
Concept and
Feasibility
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Design and
Development
3
6
Final Validation
& Ramp-up
4
Market Launch
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!
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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 13485
Design 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 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.
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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
not regulated.
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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 Continuum
Lots
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.
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Pharmaceutical Guidance
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Simple Validation Decision Diagram
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Discussion: Validation or Verification?
•
Sterilization processes
Validation
•
Manual cutting processes
Verification
•
Aseptic filling processes
Validation
•
Testing for color, turbidity, total pH for
Verification
solutions
•
Heat treating processes
Validation
•
Visual inspection of printed circuit
Verification
boards
•
Numerical control cutting processes
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
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
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!
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