Overview of Validation

1
QUALITY CONTROL FOR REGULATED ENVIRONMENTS

UNIVERSITY OF HOUSTON

Validation Overview
2

Definition
History
Building Blocks
Elements
Documentation
Components
Validation Process
Project Validation The big picture

Fact:
We are working in a cGMP environment
3

Does not stand for continually Generate Mounds of

Paper
We are bound by Federal Regulations:

21CFR Part 210, 211 (Drugs)

21CFR Part 600 (Biologics)
21CFR Part 820 (Medical Devices)
21CFR Part 11 (Electronic Records and Signatures)

Its the Law

Fact:
We are working in a cGMP environment
4

Current Good Manufacturing Practices

A set of current, scientifically sound methods, practices or

principles that are implemented and documented during
product development and production to ensure consistent
manufacture of safe, pure, and potent products

cGMP Overall Summary

5

cGMP needs to be in place for products used in

clinical IND studies

cGMP reflects and are consistent with good product
development
Follow general approaches and principles that are
broadly applicable
Tailor cGMP application to product, process, and
facility

Assess risks and take appropriate actions

Emphasize Product Quality

What is Validation?
6

Establishing documented evidence which provides a

high degree of assurance that a specific process

consistently products a product meeting predetermined specifications and quality attributes

-FDA 1987

State of Control

Key Words
7

Documented
Consistently
Pre-determined
High Degree of Assurance

What is Validation Simple Definition

8

Prove that each process involved in producing the

product can be shown to be both doing the right job

and doing the job right

Goal of Validation
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Ensure that quality is built into the system at every

step, and not just tested for at the end

Interesting side-note hypothetical

IF we were able to test every single product for all of its

important attributes before sending it off to the customer,
validation would not be required

Think of it another way

10

It is documented evidence of something you already

know!

Building Blocks
11

Quality Assurance
Quality Control Microbiology
Quality Control Analytical
Engineering
Process Development
Manufacturing
Information Technology
Calibration
Facilities/Maintenance
Validation

Lifecycle Timeline
12

Step-wise Approach to Application of

Regulatory Requirements
100
Percent

Product Characterization & GMP

75

50

25

13

The Flow from Controls to Quality

14

Man, Materials, Methods, Machine, Environment

Historical Basis for Validation

15

Assumptions concerning virus inactivation resulted

in ten deaths and 200 children becoming paralyzed,

from a supposedly inactivated polio vaccine.
Assumptions about sterilization caused severe
infections among burn victims given supposedly
sterile solutions.
Validation eliminates assumptions and relies on

experimental proof!

History
16

1906 The Jungle, Upton Sinclair, FD Act

1937/1938 107 death Elixir / FD&C Act
1962 Thalidomide, Frances Kelsey
1978 GMP Validation Rule 211.110,..165
1987 Aseptic Processing Guideline (2004)
1987 Process Validation Guideline (2004)
1993 Guideline on Cleaning Validation

History
17

1993 Guide to Inspection of High Purity Water

Systems
1994 ICH Quality Guidelines
1997 Computer Systems, 21CFR Part 11 (rescinded in
2003)
2005 Biotechnology Guidelines on Process
Validation
2006 FDA withdraws 7 regulations
2006 FDA formally adopts ICH Q7A

Validation Elements
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DQ Design Qualification

Does the design satisfy requirements?

IQ Installation Qualification

Are all systems properly installed?

OQ Operational Qualification

Does everything work when switched on?

PQ Performance Qualification

Qualifying Performance leads to Validation

PV Process Validation

Sum total

Design Qualification
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Documents that the needs of the end user are met

with the functional characteristics of the piece of

equipment

Functional
Specifications
User
Requirements

FDA Definitions
20

Installation Qualification (IQ)

Establishing confidence that the process equipment and

ancillary systems are compliant with appropriate codes and
approved design intentions and that the manufacturers
recommendations are suitably considered

FDA Definitions
21

Operational Qualification (OQ)

Establishing confidence that the process equipment and subsystems are capable of consistently operating within
established limits and tolerances

IQ, OQ, PQ ?
22
Installation Qualification (IQ)

A process used to document that the piece of equipment was supplied and
installed properly and that appropriate utilities, i.e., electrical, steam, gas, etc.
are available to operate the equipment according to the manufacturers
specifications.

Operational Qualification (OQ)

A process designed to supply the documented evidence that a piece of

equipment operates as it is intended through all anticipated operational ranges.

Performance (Process) Qualification (PQ)

Verifies that a process / piece of equipment performs as it is intended to in

the manufacturing process and produces product (in process or final) meeting
predetermined specifications.

Example of a protocol for the

IQ component of validating a
pH meter

As with all other SOPs this

document will contain an
Objective, scope, and responsibility
Section.

23

Typical information in an IQ protocol

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Name and description of equipment, including model

numbers
Identification, including model and serial numbers
Location of the equipment
Any utility requirements, i.e. electrical voltage, steam or
water pressure, etc.
Any safety features of the equipment, including alarms,
interlocks, or relief valves.
That all documentation, including manufacturers contact
information, spare parts inventory, operational manual,
and installation drawings are available on site.

OQ Protocol
Example of a protocol for the
OQ component of validating a
pH meter

As with all other SOPs this

document will contain an
Objective, scope, and responsibility
Section.

25

OQ Protocol
Example of a protocol for the
OQ component of validating an
autoclave

As with all other SOPs this

document will contain an
Objective, scope, and responsibility
Section.

26

Typical OQ Protocol Components

27

Objective
Responsibility
Equipment required (Calibration verification &

Traceability)
SOP(s) used
Equipment Identification
Parameters measured (Specifications)
Documentation

FDA Definitions
28

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 meets all
release requirements for functionality and safety

The PQ is documented evidence that the product or

output of the equipment or process meets all predetermined criteria

Unbreakable Rule
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The scope of the Validation Project PLUS

The criteria for the Acceptance of the Validation

Data
Must be set BEFORE Validation starts

The OQ and PQ Confusion

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Having an OQ and a PQ is not required for all

systems
The OQ verifies operation
The PQ verifies output
Example:

An OQ for an incubator used for media plates in QC-Micro

verifies the temperature mapping characteristics of a unit
The PQ is actually verification that the media can support
growth at that temperature

Validation Documentation
31

Validation Master Plan

Basis of Design
SOPs specific for validation equipment
Policies General Corporate Philosophy
Protocols DQ/IQ/OQ/PQ
Final Reports DQ/IQ/OQ/PW
Change Control Equipment, Systems, and

Software
Re-validation

Validation Components
32

Upper Managements Support

Re-validation
Change Control
Computer / Software Validation
Calibration
Preventive Maintenance
$$$$ and Time

Utility Validation
33

Purified Water
WFI
Clean Steam
CCA
Nitrogen
Vacuum
HVAC
Back-up Generator

Equipment / Systems
34

Autoclaves
Dry Heat Ovens
Stopper / Vial Washers
Glassware Washers
Bioreactors
Process Equipment
QC Equipment
Analytical Equipment

Specialty Studies
35

Cleaning Validation
Computer / Software
Container Closure Integrity
Steam-in-Place (SIP)
Clean-in-Place (CIP)
Shipping Validation
Stability Studies

Analytical Method Validation

36

We need to be certain that the measurements were

making are giving us meaningful, accurate, precise,

and quality information about whatever were
measuring
AMV ensures that our measurements, assays, and
tests performed on raw materials, in-process
materials, final product, stability samples, or
microbiological samples is performing as it should
(i.e. to our stated expectations/specifications)

Process Validation
37

Establishing documented evidence

Provides a high degree of assurance
Specific Process
Consistently produces
Product meets pre-determined specifications
Process Qualification
Product Qualification

Process Validation
38

Cell culture parameters

Mixing Studies
Hold Studies
Bioburden/Endotoxin Control
Qualification lots
Purification Studies

Impurity removal
Contaminant removal
Viral safety

Change Control
39

System to Ensure State of Control

Validated Equipment and Systems
Emergency Changes
SOP document changes and approval

Revalidation
40

Key to maintaining State of Control

Change Control component
Routine timing depends on System/Equipment
Scaled-down validation
Frequency

Preventive Maintenance Program

41

Scheduled maintenance program to maintain

validated State of Control

Documentation
Rationale
Trained Personnel

Validation Costs
42

Validation is expensive
Saves time and money in the long run

Throughput is increased due to a reduction in rejects and reworks

Lower utility and raw material costs
Fewer complaints
Quality

Upper Managements support

Validation
Line between too much and not enough
Use Quality Vendors

Type of Pharma/Biotech Projects

43

Quality Attributes
A refresher
44

Identity

Safety

21 CFR 600.3 (r) relative freedom from extraneous matters in the finished product, whether or not harmful to the recipient or deleterious
to the product.

Cleaning Procedures

Stability

21 CFR 600.3 (s) specific ability or capacity of the product, as indicated by its appropriate laboratory tests or by adequately controlled
clinical data obtained through the administration of the product in the manner indicated to effect the given result.

Purity

Effectiveness of the product in achieving its medicinal purpose (therapeutic, prophylactic, diagnostic). Gathered at phase II and Phase III
trials.

Potency

21 CFR 600.3 (p) safety as the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently
administered, taking into consideration the character of the product in relationship to the condition of the recipient at the time.

Activity of active ingredients

Activity of the excipients or additives

Activity of process related impurities

Efficacy

21 CFR 211.84 (d) at least one test shall be conducted to verify the identity of each component of a drug product.
Chemical, biological, Immunological
Raw materials, In-process intermediates, final products.

21 CFR 211.137 (a) to assure that a drug product meets applicable standards of identity, quality, and purity at the time of use; it shall bear
an expiration date determined by stability testing. Drugs may use accelerated time studies, biologics must use real time studies.

Consistency

The ability of the product and/or process to reliably possess specified quality attributes on an ongoing basis. 3 consecutive batches of
product meeting predetermined specifications is accepted as proof that a process is consistent. However, in NDA data from up to twenty
batches may be submitted.

CASE STUDY
An example of a facility / process validation
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Remicade (infliximab) is a chimeric mAb* directed

against TNF-.
Approved in 1998 (US) and 1999 (EU) to treat
Crohns disease, and RA.
Produced by Centocor, Inc. in Malvern, PA

* Contains mouse variable domains and human constant

domains (IgG1)

Antibodies
46

Proteins

2 heavy Chains
2 Light Chains
Disulfide Bonds

Variable region

Recognizes antigen

Constant region

Effecter function
Classes & subclasses

Ig G class

Production of Remicade
47
BLA

approved in August 1998 (FDA), 1999 (EMEA).

First site for bulk manufacture was Leiden, The Netherlands.

Process was transferred to Malvern,

PA in April 2002*.

Process changes,

including larger bioreactors, external spin filters, and a change in media components were
introduced to meet increased demand.

Not only did a new facility have to be validated, but also the changes to the manufacturing process had to be validated.

Necessary to demonstrate that product produced under these new conditions had same quality attributes as product produced in Leiden.

An

unanticipated consequence of increased product yield was a change in chromatography conditions due to
product breakthrough under old conditions.

Minor changes can have unanticipated consequences on product quality!

A new facility for production

2007

of remicade is being constructed in the Republic of Ireland and should be on line in

Changes in Production Process in Malvern, PA

48

49

Example of a 1000 L Bioreactor with an external spin filter used in the production of Remicade
in Malvern, PA

Remicade Production
50

51

These tanks are used for the holding of material from the bioreactors prior to
product capture and initial chromatography.
What performance aspects of these tanks do you think need to be validated?
How does cleaning of these tanks between use affect validation?

Some Questions
52
A valve used to transfer material from a holding tank to the purification suite jams

closed. You have a spare valve that is an identical model. Can you change this valve
with the spare and continue operations? What if the valve is from a different
manufacturer?
You notice that your autoclave loading plan leaves room for additional material.

Realizing that increasing that amount of material in the autoclave will shorten the
turn around time for the production line you contemplate increasing the amount of
material loaded into the autoclave then specified by the loading plan. What should
you do? What will be required to implement this change?
An SOP for calibration of a pH meter calls for a two point calibration at pH 4 and pH

7. You notice that a single point calibration at pH 7 produces the same result from pH
measurements of your buffer solutions and allows you to take a longer break. Is it Ok
to do the one point calibration when the SOP calls for a two point calibration? How
would you go about changing the SOP to allow for a one point calibration?

53

What documents would provide information concerning

the make and model of a particular valve used to

regulate the transfer of material from a holding tank to
the purification suite?

Your supervisor is concerned that the fermentation

vessel is not providing sufficient aeration of the culture

to get optimal growth and suggests installing a different
kind of baffle in the vessel. How would you demonstrate
that this change has no effect on product quality?

References
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Pharmaceutical Manufacturers Associations (Pharmaceutical Research and Manufacturers of America) Validation Advisory Committee

Process Validation Concepts for Drug Products Pharmaceutical Technology, September 1985 p 82.
Bismuth, G. Cleaning Validation: A Practical Approach. CRC Press, 2000. ISBN 1574911082.
Pharmaceutical Process Validation, 3rd Ed. Edited by Robert Nash and Alfred Wachter, Marcel Decker, 2003. ISBN 082470838-5
Validation of Pharmaceutical Processes: Sterile Products. 1998. 2nd Edition. Edited by Frederick J. Carlton and James Agalloco. Marcel

Decker, 1998. ISBN 0824793846.

Validation Standard Operating Procedures: A step by Step Guide for Achieving Compliance in the Pharmaceutical, Medical Device, and

Biotech Industries, Syed Imtiaz Haider, St. Lucie Press, 2002. ISBN 1574443313.
Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control From Manufacturer to Consumer, Sidney J. Willig.

Marcel Decker, 2000. ISBN 0824704258.

Voss, J. Cleaning and Cleaning Validation: A Biotechnology Perspective. CRC Press, 1995. ISBN 0939459507.
LeBlanc, D.A. 2000. Validated Cleaning Technologies for Pharmaceutical Manufacturing. CRC Press. ISBN 1574911163.
Cloud, P. 1998. Pharmaceutical Equipment Validation: The Ultimate Qualification Guidebook. CRC Press. ISBN 1574910795.
Juran, Quality Control Handbook, 4th Edition., McGraw-Hill, 1988.
DeSain C, Sutton C. (1995). Process development that supports process validation. Pharmaceutical Technology 19 (Oct.): 130-136, 1995.
Garcia T, Wilkinson S, Scott J. The development of a blend-sampling technique to assess the uniformity of a powder mixture.

Drug Development and Industrial Pharmacy 27(4): 297-307, 2001.

Chaloner-Larsson, G., Anderson, R., Egan, A. 1997. A WHO guide to good manufacturing practice (GMP) requirements Part 2: Validation .

World Health Organization, Geneva. www.who.int/vaccines-documents/DocsPDF/www9666.pdf Accessed on October 2nd, 2006.

Brown, F. 1993. Review of accidents caused by incomplete inactivation of viruses. Dev. Biol. Stand. 81: 103-7
Nathanson, N. and Langmuir, A.D. 1995. The Cutter incident. Poliomyelitis following formaldehyde-inactivated poliovirus vaccination in the

United States during the Spring of 1955. II. Relationship of poliomyelitis to Cutter vaccine. 1963. Am. J. Epidemiol. 142:109-40.