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Title: ??FDA??????

1

??FDA??????
Denis Kluba ??
??? ??

2
??Table Of Contents

????
CGMP??????
???????
????
????????
???????
?????????
??????
????
????
???
??

3
Part One What is Validation?
????????
?
4
What is Validation?
??????

For this Seminar??? it refers to two things
1. The USA FDA requirements that must be met in
order to successfully and continually sell drug
products in the USA
2. Activities that will contribute to the success
of the company in the manufacture of drug products

5
Validation
????????

Anything which you cannot understand is
indistinguishable from magic.
Arthur C. Clark
Validation may not be magic!
C. Edwards

6
Validation Is.....
FDA??????
Documented evidence which provides a high
degree of assurance that a specific process will
consistently produce a product meeting its
predetermined specifications and quality
attributes.
7
Why Do We Validate?
?????/??

To Consistently Produce A Desired Known Product

Product Compliance
Confirm Design
Test within Specification
Establish Operating Boundaries
Establish Baselines
8
How Do We Validate?

Details Will Follow But This is the General Model

?????
Identify Equipment Systems
Develop Tests
Amend Test
Conduct Tests
Write Protocols
Amend Protocol
Collect Data
Evaluate Data
Results OK?
No
Report Results
yes
Validated System
System Modified?
9
First three steps to CGMP compliance
??CGMP??????

document
document
document

10
Boundaries of Validation
?????/??
Validation
Operations / QA
Engineering
COMMISSIONING START-UP TROUBLE SHOOTING
TRIAL RUNS CYCLE DEVELOPMENT PROCESS
DEVELOPMENT ENGINEERING STUDIES
VENDOR SERVICE REPORTS FACTORY
ACCEPTANCE TEST AS-BUILT DRAWINGS
STANDARD OPERATING
PROCEDURES MFG BATCH RECORDS
PERSONNEL TRAINING
CALIBRATION PREVENTATIVE MTCE
CHANGE CONTROL COMPLIANCE
VENDOR AUDITS ANNUAL REVIEWS
COMPLAINTS SAFETY
11
Validation Life Cycle Approach
New / Revised Process / Product
Prospective / Concurrent
?????? ??/??????/??
Define Specifications Equipment Process
Requirements
Procedures
12
Validation Life Cycle Approach
Existing Process / Product
?????? ????/??
Retrospective
Define System Specifications Equipment Procedures
13
Benefits of Validation
???????

Increased Throughput
Reduction In Rejections and Reworks
Reduction In Utility Costs
Avoidance Of Capital Expenditures
Fewer Complaints About Process Related Failures
Reduced Testing In-process and Finished Goods
More Rapid / Accurate Investigations Into Process
Upsets
More Rapid and Reliable Startup Of New Equipment
Easier Scale-up From Development Work
Easier Maintenance Of The Equipment
Improved Employee Awareness Of Processes
More Rapid Automation

14
Elements Of Contemporary Validation In The US
???????????

Equipment Calibration - Process and Validation
Equipment
Equipment Qualification - Installation and
Operational
Process Development
Process Documentation
Performance Qualification - "Validation"
Maintenance of Validation - Process and Equipment
Change Control

15
cGMP and ISO-9000 - Similarities
CGMP? ISO 9000?????

Aimed at Quality
Require Documentation
Require Specific Quality Program
QA and QC Included

16
cGMP and ISO-9000 - Differences
CGMP? ISO 9000?????

cGMP Aimed at Product
ISO-9000 Includes Design and Service, as well
cGMP Covers Activities Directly Related to
Manufacturing
ISO-9000 Covers Broader Range of Activities
(e.g.. Purchasing)
cGMP Requires Formal Validation
ISO-9000 Requires Applicable Statistical Methods

17
Benefits of the Systems Approach to Validation
?????????

More Rigorous Control Over Operations
Centralized Planning for all Validation Related
Aspects
Ties Existing Sub-elements into Cohesive System
Establishes Validation as a Program, not a
Project
Provides for Continuity of Approach
Affirms Validation as a Discipline Much like
Others
Allows For Personnel Growth within the Validation
Expertise
Usually Results in Centralization of Validation
Expertise
More Compatible with the Accomplishment of a
Corporate??? Objective for Validation

18
The Validation Program
????/??

Establish Goals and Objectives as to What Must be
Validated
Qualify or Re-qualify the Equipment
Establish Validation Protocols for each, and
obtain Approval of the Protocols
Establish Personnel Requirements and Training
Records Procedure
Design and Conduct Experiments. Collect Data
Evaluate the Data
Prepare Summary Reports Outlining the Results of
the Experiments. Obtain the Necessary
Approvals
Establish and Maintain Validation Files Including
Raw Data
Institute a Change Control Procedure to Insure
the Ongoing Acceptability of the Work

19
Part Two GMP Requirements
????GMP??????
20
GMP requirements
GMP??

Part 211 Current good manufacturing practice for
finished pharmaceuticals   211.68 - Automatic,
mechanical, and electronic equipment.   211.84
- Testing and approval or rejection of
components, drug product containers, and
closures.   211.110 - Sampling and testing of
in-process materials and drug products.
  211.113 - Control of microbiological
contamination.   211.165 - Testing and release
for distribution.   211.166 - Stability
testing.

21
cGMP in the Pharmaceutical Industry
?????cGMP

GMP is the abbreviation of Good Manufacturing
Practice which is adopted by the medical and
health related industries including the
pharmaceutical industry in an effort to maintain
the highest standards of quality in the
development, manufacture and control of medicinal
products. Since the industry standards are
subject to continuous improvement, the letter c
in the abbreviation cGMP refers more
specifically to the current or the latest version
of the GMP requirements.

22
Regulatory Requirements for Validation.....
??????????

The requirement of process validation is implicit
in the language of 21 CFR 211.100 of the Current
Good Manufacturing regulations which states
There shall be written procedures for product
and process control to assure that drug products
have the identity, strength, quality, and purity
they purport or are represented to possess."

23
GMP Regulatory Requirements for Cleaning
Validation
GMP??????????

1978 cGMP Regulations (part 211.67(a)) Equipment
cleaning and maintenance states
Equipment and utensils shall be cleaned,
maintained, and sanitized at appropriate
intervals to prevent malfunctions or
contamination that would alter the safety,
identity, strength, quality, or purity of the
drug product beyond the official or other
established requirements.

24
GMP Regulatory Requirements for Test Method
Validation
GMP????????????

Laboratory Controls 21 CFR 211.165(e) states
The accuracy, sensitivity, specificity and
reproducibility of test methods employed by the
firm shall be established and documented. Such
validation and documentation may be accomplished
in accordance with Part 211.194(a)(2).

25
GMP Regulatory Requirements for Test Method
Validation
GMP????????????

Part 211.194(a)(2) states
A statement of each method used. . . shall
indicate the location of data that establish that
the methods used in the testing of the sample
meet proper standards of accuracy and reliability
as applied to the product tested. The
suitability of all testing methods used shall be
verified under actual conditions of use.

26
GMP Regulatory Requirements for Test Method
Validation
GMP????????????

U.S. Federal Court decision
United States vs Barr Labs
Cleaning Validation . . . it was ruled
for cleaning to be effective, the specific test
methods had to be shown to be effective.

27
PROCESS VALIDATION
????

21 CFR 211.110
such control procedures shall be established to
monitor the output and to validate the
performance of those manufacturing processes that
may be responsible for causing variability in the
characteristics of in-process material and the
drug product

28
Part Three History and Expectations
?????????FDA???????????

As applied by the FDA and Implemented by Industry

29
History and expectations
?????

Learn for the experiences of the USA
manufacturers and industry organizations
Current applications
Past citations
Industry guidelines
ICH Q7A
ISPE
PDA
Etc.

30
Validation Targets
????

Recent Years
Biological Processes
Bulk Organic Synthesis
Developmental and Pilot Operations
Supporting Services
Currently
Total Operations
Review by Systems
Quality System
Production System Laboratory Controls
Packaging and Labeling, Materials and
Facilities
Equipment Manufacturing.

Early Years
Sterilization
Aseptic Operations
Middle Years
Non-sterile Processes
Oral Dosage Forms

31
History of Validation
????

Validation in The Early Years - 1972 to 1978
Regulatory Based to Satisfy FDA Pressures
Defensive to Protect Product Line
Validation in Its' Adolescence - 1978 To 1983
Primarily Defensive
Some Efforts at Process Optimization
Includes Some Peripheral Concerns
Validation in the US Today - 1983 to Present
Non- Regulatory in Many Areas Geared Towards
Optimization and focused on Systems

32
"validation" vs. "VALIDATION"
????????

"validation"
Defensive
Testing Oriented
Costly
Quality Control
Narrow Focus

"VALIDATION"
Optimization
Total Process Control
Cost Effective
Quality Assurance
Diverse Application

33
Elements of Contemporary Validation in the US
????????????/??

Equipment Calibration - Process and Validation
Equipment
Equipment Qualification - Installation and
Operational
Process Development
Process Documentation
Performance Qualification - "Validation"
Maintenance of Validation - Process and Equipment
Change Control

34
Expectations
??????

Validation is a Program not a Project
Validation Contributes to the Stability of the
Operations
Validation is not Someone Else's Job!

35
Part Four Validation
????????

An Overview

36
Who Validates?
??????
Engineering
Quality Assurance
Validation Staff
Quality Control
Manufacturing
37
Validation
??
Design
Testing
v
Operation
??
38
Validation
??
Vendor
Owner/User
v
Systems Integrator
?????
39
Validation
??
Validation Team Maintenance
Engineering RD
v
Manufacturing Quality Assurance
??????
40
Write Protocols
????
41
Example Data Sheets
?????
42
Conduct Testing
????
Careful Review and Markup of Prints, Specs
Physical Tests (Temp., Press., Flow)
Chemical Tests
Microbiological Tests
Computer Tests
43
Installation Qualification (IQ)
??????

IQ documents that
system is installed in accordance with approved
design, specification and regulatory codes
manufacturers installation recommendation have
been taken into consideration
IQs implemented concurrently with construction of
each system

44
Operational Qualification (OQ)
??/??????

OQ documents that the equipment
can operate as designed and intended
is capable of repeatable operation over the
entire operating range of process variables
OQ executed when equipment can be started up

45
Process Qualification (PQ)
??????

PQ documents
critical systems which can be challenged
test procedures
product quality attributes to be evaluated
acceptance criteria
alert/action levels
system validated under "worst case conditions"
generally 3 consecutive successful runs required

46
Definition of Process Validation

??????
1978

Validation is
Documented evidence that provides a high degree
of assurance that a specific process will
consistently produce a product of a certain
predetermined quality.

47
Definition of Process Validation
??????
1993

In addition to documented evidence that a process
will perform reliably and repeatedly, validation,
in its highest form, provides an understanding of
why.

48
Stages of the Life-Cycle
???????
SOPs/Maintenance
Testing
Change Control
Construction
Design
RD
49
Benefits of Validation
?????

Increased Throughput
Reduction in Rejections and Reworks
Reduction in Utility Costs
Avoidance Of Capital Expenditures
Fewer Complaints About Process Related Failures
Reduced Testing In-process and Finished Goods
More Rapid / Accurate Investigations Into Process
Upsets
More Rapid and Reliable Startup Of New Equipment
Easier Scale-up From Development Work
Easier Maintenance Of The Equipment
Improved Employee Awareness Of Processes
More Rapid Automation

50
Documentation of Validation
????

Master Plan
Protocol
Data Sheets
Report
Procedures

51
Validation Protocols
????

Provide an Outline of the Validation Effort
Include a Clear Definition of What Will Be
Validated
Is Uniquely Identified
Is Dated
Approved By Competent Individuals In Responsible
Areas
Are Suitable For Review By Regulatory Agencies

52
Validation Protocol Essential Elements
?????????

Introduction/Abstract
Description of Process or System
Test Plan
Responsibilities
Acceptance Criteria
Approvals
Append Data Sheets, Etc.

53
Validation Reports Functions
????-??

Restrict to One Task or Subject
Has a Unique Identification
Is Dated
Formally Reviewed and Approved
Identifies Protocol(s) Used in the Study
Is Suitable for Review by FDA

54
Validation Report - Contents
????-??

Abstract Or Summary Conclusion
Plan Of Study
Experimental
Results
Conclusions
Protocol Reference
Diagrams
Any Miscellaneous Information
Approvals

55
Installation Qualification (IQ)
??????

IQ Documents That The
System is Installed in Accordance with Approved
Design, Specifications and Regulatory Codes
Manufacturers Installation Recommendations have
been taken into Consideration
IQ is Implemented Concurrently with Construction
of Each System

56
Design Documentation
????

Design and Procurement Documentation Support of
IQ
PFDs/PIDs
Critical System Installation Drawings (E.G. Water
System Isometrics, Sanitary Duct Drawings)
Purchase and Installation Specifications
Vendor Manuals and Prints
Computer Software Documentation

57
Construction Documentation
????

Construction Documents In Support Of IQ
Slope Checks
Piping Pressure Test Reports
Motor Checkout Reports
Weld Inspection Reports
Cleaning, Passivation and Sanitization Procedures
and Reports
HVAC Test and Balance Reports
Other Appropriate Construction Documentation

58
The PID
(Piping Instrumentation Diagram, Engineering
Flow Diagram)
??????

Process Equipment
Support Vessels
Interconnecting Lines
Utility Lines
Instruments/Instrument Functions
Schematic
No Scale - Not Spatially Precise
Shows Relationships and Relative Position

59
Operational Qualification (OQ)
??????

OQ Documents That The Equipment
Can Operate as Designed and Intended
Is Capable of Repeatable Operation Over the
Entire Operating Range of Process Variables
OQ Implemented After Equipment has been Started
Up or Commissioned

60
Process Qualification (PQ)
??????

PQ Documents That
Processes Operate as Required at the Normal
Operating Limits of Critical Parameters
Systems Operate Consistently and Reliably
Appropriate Challenges Are Employed

61
Review and Approvals
?????

Design Drawings and Specifications
Master Plan
Protocols
Reports
Procedures

62
Part Five Validation Master Planning
?????????
63
Planning
??

If you dont know where you are going, you are
likely to end up someplace else! - Lewis Carroll
Like any other important activity in a complex
organization validation must be managed. This is
especially true given the multi-disciplined
nature of many validation activities.

64
Existing Plants
????

The same level of management is necessary for the
validation of an existing facility, whether fully
validated or not.
Validation is easier when it is an integral part
of the day-to-day operation of the facility.

65
Master Plan
???

Defines and Establishes the Validation Approach
and the Acceptance Criteria

and more!
66
Facilities, Processes or Products
??,?????

What needs to be done?
Who will do it?
How will they do it?
How long will it take?
How much will it cost?

67
Master Plan - General
?????

Introduction to Facility Purpose and Design
Intent
Facility/Process Description
Process Control Considerations
System Definitions
Planning/Scheduling

68
Master Plan - Why
?????????

Project Familiarization/Training
Management Introduction
FDA Introduction/Familiarization
Validation Program Foundation
Basic Procedures
Protocol Outlines/Bases
Resource Planning/Scheduling
Contract Execution Interaction

Codifies Prior Decisions
Structures Validation Activities
Facilitates Regulatory Compliance
Useful in Regulatory and Client Interactions
Use With 3rd Parties
Convertible Into Drug Master File
Internal Audit Preparation

69
Master Plan - What
???????

Introduction
Facility / Process / Product Description
Process Control Considerations
System Definition
Protocol Outlines/Acceptance Criteria
Formats
SOPs
Planning/Scheduling

70
Master Plan - Getting Started
??????

Facility Layout
Process Description(s)
Product Description(s)
Equipment List
Utility List
Controlled Environment Requirements
Control Philosophy
Schedule

71
Master Plan Facility Description
?????????

Layout/Equipment Arrangement
People/Material/Component Flow
Controlled Environments
Materials of Construction
Sketches

72
Master Plan - Process Description
?????????

Major Process Steps
Block Diagram
Process Flow Diagram(s)
Utilities (WFI, DI, CIP, Etc.)
Major Support Equipment
(Autoclaves, Ovens, Etc.)

73
Master Plan - Process Control
?????????

General Architecture
Central/Distributed Control System
PLCs/Individual Control Systems
Building Automation System
Higher Level Systems (LIMS, EBR, Etc.)
Integrate into other Sections if Minimal

74
Master Plan - Validated Systems
??????????

Lists Of Systems To Be Validated
General Acceptance Criteria
Specific Acceptance Criteria
Basic Protocol Outlines

75
Master Plan - Procedures and Formats
?????????

Protocol Format
SOP Format
Basic Procedures
Validation Program
Responsibilities
Calibration
Change Control
List Of SOPs

76
Master Plan - Planning and Scheduling
?????????

Manpower Resources
Document Preparation
Field Execution
Calibration
Lab Support
Test Balance/Filter Certification
Start-Up/Commissioning

77
Master Plan - Focus
???????

Sterile Products Facility
Emphasis On Facility and Environment
People, Component, Product Flows
Automation May Or May Not Be Central
Support Systems Critical (Autoclaves, Ovens, WFI,
Etc.)

78
Master Plan - Focus
???????

Solids Facility
In-process Controls
Tests
Examinations to be Conducted on Appropriate
Samples of In-process Materials of Each Batch

79
Master Plan - Focus
???????

API Facility
Emphasis On Chemical Process
Identify API Step
Cross-contamination Control, if Appropriate
Automation Critical
Cleaning Critical In Multi-product Facilities

80
Master Plan - Focus
???????

CIM Systems
Emphasis on Functional Requirements
System Structure
Communication Routing

81
Master Plan - Focus
???????

Anything Unusual
Areas that are Unique to Your Process
Emphases on the Philosophy for Controls
(Procedural and Automation)

82
Part SixMethods of Performing Validation

Including Document Requirements,
Formats and Approvals

??????????? ??????,??,???
83
Qualification
????

Combine I/OQ into Single Document
Add PQ for Smaller Projects
I/OQ is Sometimes 90 of the Overall Effort, but
Receives Only 10 of the Investigators Attention
Review Contractor Proposals Closely

84
Design Qualification
??????

Useful on Larger Projects
Critiques Design from an Operability Validation
Perspective
Reduces Costs of Correcting Errors
Required in Device Regulations

85
Installation/Operational Qualification
??/??????

Checklist Format Preferred
Avoid Arbitrary Criteria
Convey Requirements to Suppliers in
Specifications
Check at Vendor and Reconfirm on Site
Focus on Accuracy of Collected Documentation
Test to Manufacturers Specifications if the
Detailed Process Needs are Vague

86
Performance Qualification
??????

Use Generic Protocols Terminal Sterilization
rather than Sterilization of xxxxx Vials,
Autoclave 6, Building 4
Use Quantitative Criteria RSD Maximum of 4.5
Rather Than Must Demonstrate a Uniform Mix
Use Meaningful Criteria 3 Log Reduction in
Endotoxin Rather Than 8 Minutes At 300 C

87
Validation as discussed in Q7A
Q7A?????

Should extend to those operations determined to
be critical to the quality and purity of the API
Critical parameters/attributes are normally
identified during the development stage or from
historical data, along with ranges necessary for
reproducible operations

88
Prospective Validation Q7A
?Q7A?????

Normally performed for all API processes
Validation of API process should be completed
before commercial distribution of the final drug
product manufactured from that API

89
Concurrent Validation Q7A
Q7A??????

Conducted when data from replicate production
runs are unavailable
Limited number of API batches produced
API batches produced infrequently
API batches produced by a validated process that
has been modified

90
Concurrent Validation Q7A
Q7A??????

Batches can be released and used in production of
drug products for commercial distribution based
on thorough monitoring and testing of the API
batches

91
Retrospective Validation Q7A
Q7A???????

Exception for well established processes used
without significant changes to API quality due to
changes in
Raw materials
Equipment
Systems
Facilities
Production Process

92
Retrospective Validation Q7A
Q7A???????

May be used where
Critical quality attributes and critical process
parameters have been identified
Appropriate in-process acceptance criteria and
controls have been established

93
Retrospective Validation Q7A
Q7A???????

May be used where (Continued)
Process/product failures attributed mostly to
operator error or sporadic equipment failures
unrelated to equipment suitability
Impurity profiles have been established for
existing API

94
Validation Q7A
Q7A??????

Validation is NOT for exploration to design a
process. It is for showing that an already
established process does what it is supposed to
do.
Validation approaches, protocols, execution, and
reports are fully described.
Different from drug manufacturing Only critical
processes are usually validated, e.g.. at the
following points of the processing -
significant impurities may be introduced or
removed - no significant impurities will be
removed - all essential structural elements
of the API are present

95
New Equipment/System Milestones
???/????
96
Commissioning/Qualification Transformation
??/???????
Commissioning
Mechanical Completion
Qualification
97
Qualification Program
??????
98
Qualification Program Attributes
?????????

Completion Of Commissioning.
Test Protocol(s) With Pre-determined Acceptance
Criteria Covering Installation and Operation.
Execution Under Pre-approved Procedures For
Protocol and Report Development
Documentation Practices
Change Control (Pre-approval Of Changes)
Investigations (Deviations)
Approvals

99
Commissioning Program Attributes
???????

Ability to Fix Equipment/System as Required
(Design Intent).
Documented Activities.
Tests That Have Pre-determined Expectations.
Execution Under Pre-approved Procedures For
Test Plan Development
Test Execution
Documentation Practices
Change Management (Documented Audit Trail for
Changes, including Approvals)
Approvals

100
Proposed Qualification Program
?????????
101
Test Documentation
????
102
PROJECT RESPONSIBILITIES THE RESPONSIBILITIES OF
THE VALIDATION TEAM
???????

Writing and approving the Master Plan.
Writing protocols
Providing validation engineers
Providing supervisory assistance
Generation of summary reports
Preparation of designated Standard Operating
Procedures (SOP).
Training to construction and operation personnel
as needed for the validation activities.
Review, assistance and support as outlined in the
project approach section of this Master Plan for
the Engineering/Construction/Validation interface.

103
PROJECT RESPONSIBILITIES THE RESPONSIBILITIES OF
THE GENERAL CONTRACTOR
??????

Reviewing and approving the Master Plan and
appropriate protocols.
Review, approval and implementation of
Validations checklists.
Establish and maintain the document control
procedures and administration for this project.
Transmission of all design drawings,
specifications, purchase documents and vendor
literature
Execution of the Protocols as defined.
Assembly of the turn-over and construction
support documentation.
Coordination of Calibration, certification
activities and supervision of the subcontractors
execution of validation activities.
Support activities as outlined in the project
approach section of the Master Plan for the
Engineering/Construction/Validation interface.

104
PROJECT RESPONSIBILITIES THE RESPONSIBILITIES OF
ENGINEERING CONTRACTOR
???????

Write up the Basis of Design for all systems and
sections of the facility and have them approved
by the responsible operations personnel.
Preparation of all design drawings and
specifications necessary for the completion of
the scope of work by Validation.
Support activities as outlined in the project
approach section of the Master Plan for the
Engineering/Construction/Validation interface.
Reviewing and approving the Master Plan.

105
PROJECT RESPONSIBILITIES THE RESPONSIBILITIES OF
OPERATIONS
?????

Providing personnel, when necessary, to assist in
the sampling and operating of equipment and
equipment systems during the execution of
qualification studies.
Coordination of all other Validation Team
requirements and responsibilities.
Providing Validation personnel with adequate
office and specified Quality Control laboratory
support and test methods as required for the
execution of the scope of work.
Support activities as outlined in the project
approach Section of the Master Plan for the
Engineering/Construction/Validation interface.

Supplying all procedures and documentation
necessary for the generation of the Master Plan
and execution of the protocols.
Reviewing and approving the Basis of Design and
the Master Plan and all other documentation such
as protocols, the executed protocol data packages
and the final reports produced by Validation.
Preparation of designated Operation, Calibration,
and Maintenance Standard Operating Procedures
(SOP).

106
List and Compare
?????

Break Down of Scope
Categorize the Packages
Keep Like Items Together
Define Boundaries

107
Integrated E,P,C,V,SI Timeline
???????
Research Development
Start-up/ Validation
Basic Engineering
Detailed Engineering
Conceptual Design
Operation
Construction
GMP Design Audits
FDA Meeting
Automated System Planning
Protocol Development
User Reqs Analysis
Construction / Installation Review
System Definition
Selection / System Specifications
Installation Qualification
Operational Qualification
Software Development Configuration
Integration Testing / PQ
Software Testing
Summary Reports
FDA Review
Change Control
CHANGE CONTROL
108
Integrated Validation
????

The purpose of integrated validation is to
provide assurance and documented evidence that a
facility will consistently produce pharmaceutical
substances which meet the owners specifications
that are their interpretation of the regulatory
requirements for the products they are going to
manufacture. Integrated validation will assure
that the equipment and facilities are installed,
constructed and operate per the manufacturing
requirements and that they provide an
environmentally and physically safe work area for
employees.
Integrated validation requires all vendors and
suppliers of equipment, contractors and sub
contractors responsible for construction and
installation of plant systems and equipment, all
departments and disciplines which are confronted
with cGMP requirements to participate and
understand their role in the implementation of
the regulatory requirements of the operation.
Integrated validation incorporates the use of the
expertise and documentation of skilled personnel
hired to perform functions in a project and to
transfer the necessary technology to the on going
operations.
The integrated validation will be organized
following the modular or system approach,
mimicking the design methods used, when
performing Installation Qualification (IQ) and
Operational Qualification (OQ).
What follows is an outline of a methodology using
integrated validation at an inspected and
qualified facility. The methodology developed in
the project is the methodology still in place for
both on-going operations and new projects.

109
Develop Standard IQ Protocol
?????????????

Write One IQ Protocol that is General and has a
Method of Being Uniquely Identified so Specific
Attachments for Qualification can be Attached
Develop Appropriate Checkout Sheets
Accept Vendor Documentation
Accept Contractor Verification

EXAMPLE
110
Documentation
????

Clear, Concise Prose
Tables and Drawings, Rather than Words
Summaries not Narratives
Plagiarism Should Be Encouraged
Put Repetitive Elements in Procedures
Dont Rewrite War and Peace

EXAMPLE
111
Approvals
????

Minimize the Number of Approvers
Maximum of 4-6
Must Include the Quality Control Unit
Approvers Must Have Technical Understanding

EXAMPLE
112
Approach to IQ Verification
??????????

The Appropriate Engineer to Walk Down and Red
Line the PIDs
Validation Personnel to Develop Checkout Sheets
from Engineering Drawings and Specifications
Vendor Documentation for Their Specific Required
Specifications of Their System or Equipment
Contactor Verification of Installation per Vendor
Requirements or Drawings

EXAMPLE
113
Approach to IQ Verification
??????????

Terminations and Connections Verified per
Contractor Verification Forms or Checkout Sheets
CM to Verifies the System was Checked and No
Blind Flanges, Start Up Strainers or other
Temporary Items were Found or were Identified as
Necessary For OQ.

EXAMPLE
114
Approach to IQ Verification
??????????

CM verifies that all extraneous tags are removed
- electrical and mechanical
CM verifies that the identification of all items
is correct and completed
Proper safety and caution notices are placed on
pressurized lines and rotating equipment.
Restriction notices for the module or System are
in place.

EXAMPLE
115
Approach to IQ Verification
??????????

Overall installation was found correct
Correct Ordering
Inlet/Outlet Damping Distances (if applicable)
Accessibility for Operation
Accessibility for Maintenance
Dead Ends / Insertion Depth
Freedom for Expansion (No Stress)
All Internal Equipment Components Installed where
Required
All Manual Equipment is Functional

EXAMPLE
116
Develop Standard OQ Protocol
???????????

Write One OQ Protocol for Each Type of Package
that is General and Has a Method of being
Uniquely Identified so Specific Attachments for
Qualification can be Attached
Develop Appropriate Checkout Sheets
Follow the FAT Model
Define Test to Assure Operational Requirements
are Met

EXAMPLE
117
Transition IQ to OQ
?????????????

Verification by Validation of the Completion of
IQ or Authority to Proceed with OQ
Pre-OQ Verifications
Calibration
Start-Up/Commissioning
Documentation Complete
Vendor Start-Up
Procedures Identified
Qualified Personnel Identified
Exceptions/Deviations Noted and Approved

EXAMPLE
118
Pre-OQ Verification
??????????

Report For Completion of the Building and/or Area
and the Required Support Areas or Systems are
Attached or Referenced in PRE-OQ Checkout Sheet.
Required Package Start-Up Preparation is
Performed (If Applicable).
Cleaning of Area / Room and Equipment Externals
is Completed.
Inspection of Equipment Internals is Completed
(If Applicable).
An Appropriate Safety Inspection has been
Performed and Found Acceptable for OQ Activities.
The Device Calibrations are Complete and the
Calibration Data Documented in the Appropriate
System.

EXAMPLE
119
Pre-OQ Verification
??????????

Confirmation of Availability of the Tag Checkout
Forms, Loop Tuning Checkout Sheets and 72 Hour
Motor Runs and Checkout Sheets.
BOPs To Be Tested are Identified, Downloaded and
Ready to be Started.
BOP Requirement Specifications and Test Matrices
are Available.
Sequence of BOPs to be Tested are Identified.
BOP Test Procedures are Available for Each
"Typical" Package.
Partial Recipes - Water are Identified,
Downloaded and Ready to be Started.
Synthetic Recipes - Water are Identified,
Downloaded and Ready to be Started

EXAMPLE
120
Calibration
??

Calibration of all Instruments which Require
Calibration will be Performed.
A List by Module or System of all Instruments
that Must be Calibrated which belong to the
Package will be Prepared and Attached to the
Package OQ Protocol.
This List will Identify the Instruments which
Require Calibration as well as the Applicable
Calibration SOPs.
Confirmed on Package Pre-OQ

EXAMPLE
121
Start-Up/Commissioning
??/????

All Systems and Equipment in a Package to be
Started Up will be Identified.
Procedures to Perform Start-Up/Commissioning will
be Written and Approved
Adjustments and/or Modifications will be Allowed
And Documented Appropriately

EXAMPLE
122
Vendor Start-Up
?????

Vendor Start-Up Procedures and Requirements will
be Met and Verified by CM
Documentation will be Part of the Protocol

EXAMPLE
123
Procedures
??

Written Procedures for all Operational Functions
will be in Place in at Least Draft Form before OQ
Begins
Approved Procedures for Support Packages will be
in Place Before Operational or Follow on Packages
Proceed with OQ

EXAMPLE
124
Qualified personnel
????

Personnel Performing the Required Functions will
have Verification of Their Ability to do the
Qualification Work.
Training Records
Education
Resumes
Contractor Certifications
Etc.

EXAMPLE
125
Tag Checkout
????

The main objective of tag checkout is to test the
communication and correctness of an input signal
from a calibrated field device to the computer
console and an output signal from the computer
console to a calibrated field device.
Specific procedures are developed for Tag
Checking of Instruments which are DCS or FMS
controlled. Depending on the Instrument type, one
of the following forms will be completed for each
of the Instrument Tags
- "VFD controlled motors"
- "Analog Inputs"
- "Analog Outputs"
- "Digital Inputs"
- "Digital Outputs"
- "One Speed Motor"
- "Two speed Motor".
The appropriate procedure to follow when
performing Tag Checkouts, is described on the
forms mentioned above.
A list of instruments to be tag checked will be
attached to the package OQ Protocol.
The completion of Instrument tag checkout for a
specific package is confirmed on package OQ
Checkout Sheet.

EXAMPLE
126
Construction Cleaning - Process Facility
????????????

A reference to the construction cleaning -
process and facility (external equipment, pipe
lines, vessel internals, miscellaneous
construction equipment removed, etc...)
applicable to the proposed package will be
confirmed on the OQ Checkout Sheet.
The cleaning will be completed by the responsible
contractors and verified by Construction
Management/Start up.

EXAMPLE
127
Loop Tuning
????

The objective of loop tuning is to adjust a
controller in order to make it able to maintain
process variable stability under any combination
of internal or external disturbances which may
reasonably occur to the process.
The control loops will be tuned according to a
SOP and may be performed more than once and at
several stages of OQ in order to fine tune the
controller.
A list of the controllers to be tuned will be
attached to the package OQ Protocol.

EXAMPLE
128
Execution
??

Use Appropriately Trained Operational Personnel
Use Validation Teams for Larger Tasks
Maintain Some Internal Expertise
Use Contractors for Peak Demand and Special Tasks
Use Prepared Forms For Data Gathering

EXAMPLE
129
BOP Testing
BOP ??

Each BOP for each typical package will be
operated and tested for proper performance within
the package.
Where possible, the performance of the individual
components of the package or module will be
tested using water as the process media.
Documentation of performance will be recorded,
where possible, via the DCS and acceptance
provided by a sign off, on hard copy, by the
performer and the user, if required.
Additional testing results will also be recorded
directly on the testing procedure being part of
the OQ Protocol for that package.
The package specific OQ Protocol will list the
BOPs that are applicable to the package.
The documentation of testing compliance is
reported on OQ Checkout Sheet and confirmed on OQ
Summary

EXAMPLE
130
72 Hour Test
72 ????

The 72 hour run in of rotating equipment will be
performed per a specific SOP.
Results will be documented on the appropriate
checkout sheet performed for recording 72 hour
test.
The documentation of testing compliance is
reported on OQ Checkout Sheet and confirmed on OQ
Summary

EXAMPLE
131
Partial Recipe Testing - Water
???????

Each Partial Recipe for the package will be
operated and tuned for proper performance within
the package.
The capacity of the components of the package
will be tested for the ranges outlined in the
specifications.
These ranges will be listed in the package OQ
Protocol.
Documentation of performance will be recorded,
where possible, via the DCS and acceptance
provided by a sign off, on hard copy, by the
qualification team , if required.
The documentation of testing compliance is
reported on OQ Checkout Sheet and confirmed on OQ
Summary.
Additional testing results will also be recorded
directly on the testing procedure being part of
the OQ Protocol for that package.

EXAMPLE
132
OQ Checkout and Summary
????????

Complete the Package OQ Checkout Sheet which
documents the hand over of the package from the
qualification team to the user in order to
certify
The required package preparation for operational
condition runs is performed.
Equipment calibration is complete and calibration
data documented.
Tag checkout is completed and documented
Loop tuning is completed and documented
72 hour run test is completed and documented.
Water batch testing is completed and documented.
Safety inspection has been performed and found
acceptable for operational runs.
Passivation procedure is available (if
applicable).
Availability of instrument calibration SOPs is
noted and referenced within the system.
Availability of maintenance SOPs is noted and
referenced within the system.
Availability of the operating procedures is
noted.
Specific sequence of BOPs to be tested for
operational runs is identified.
Partial recipes for operational runs are
identified, downloaded and ready to be started.
Availability of approved cleaning SOPs are noted
for rooms and equipment which are not cleaned
through automated controlled cleaning procedures
and that the cleaning is performed.

EXAMPLE
133
Methods of Performing Validation
???????

The above methodology was followed in detail to
achieve an efficiency that allowed the facility
to quickly start production and to expand the
operations under controlled procedures.

EXAMPLE
134
Part SevenTechnical Content Requirements
??????????
135
Process Parameters Diagram
?????
136
Validation Protocol
????

Provide an outline of the validation effort
Include a clear definition of what will be
validated
Is uniquely identified
Is dated
Approved by competent individuals in responsible
areas
Are suitable for review by regulatory agencies

Introduction/abstract
Description of process or system
Responsibilities
Challenge criteria
Acceptance criteria
Append data sheets, etc.

137
Operational Qualification (OQ)
??????

OQ documents that the equipment
Can operate as designed and intended
Is capable of repeatable operation over the
entire operating range of process variables
OQ implemented after equipment has been started
up or commissioned

138
PAR Approach To Process Validation
????? PAR ??
low
high
lower limit normal range

upper limit normal range
NORMAL OPERATING RANGE
upper limit PAR
lower limit PAR
lower edge of failure
PROVEN ACCEPTABLE RANGE (PAR)
upper edge of
failure
EDGE OF FAILURE
139
Process Qualification (PQ)
??????

PQ documents that
Processes operate as required at the normal
operating limits of critical parameters
Systems operate consistently and reliably
Appropriate challenges are employed

140
Automation / System Integration
????/????
Administration
Utilities Instrumentation
Process Instrumentation
141
HVAC Qualification
HVAC ????

IQ Verification
Engineering Documentation
Engineering Drawings
Equipment and Filter List
Instrument List and Calibration
Construction Completion
SOPs Review
Room Finishes (optional)
Lubricant List
Trainings
Preventive Maintenance Program
Variance Summary Report

OQ Verification
Control System Checkouts
Room Air Changes
Power Failure
Air Flow Direction
Air Make-up
HEPA Filter Integrity Test Report
Air Balance Report
Monitoring of Environmental Conditions
Qualification Test Equipment and Instruments
Variance Summary Report

142
Dust Control Qualification
????????

IQ Verification
Engineering Documentation
Engineering Drawings
Utilities List
Dust Collectors Inspection
Spare Parts List
SOPs Reviews
Preventive Maintenance Program
Instruments Calibration / Certification Records
Variance Summary Report

OQ Verification
Alarm System Verification
Dust Collectors Motors Checkout
Back Flow Prevention
Dust Collection Capture Velocity at Use Point
Variance Summary Report

143
Room Facilities Qualification
????????

IQ Verification
Engineering Drawings
Engineering Specifications
Room Design Verification
Utilities List
Preventive Maintenance Program
Variance Summary Report

OQ Verification
Checkout Drawings, Specification, Instrument,
Equipment and Utilities
Room Layout is effective for material and
personnel flow
Room Surfaces meet the specifications and
designed to be easily sanitized and clean
Floor,Walls and Ceiling finish meet
specifications
Variance Summary Report

144
Room Cleaning Qualification
????????