Computer System Validation– an Integral Part for

Effective Laboratory Automation Service

1. Abstract
Validation Service has now become an integral part of Lab
automation Service, specially in the area of Pharmaceutical
Industry. Objective of this service is to validate whether the defined
purpose for which Lab Automation Project has been undertaken is
met or not. In case of Pharmaceutical Industry, this service often
considers general rules and guidelines as was laid down by United
State’s Food and Drug Administration Act (US FDA). This
whitepaper intends to explore various methodologies used for this
validation service, challenges faced and how HCL uses the expertise
to offer state-of-the-art validation service to industries as a part of
its Lab Automation Service offering.

2. How Computer System Validation

(CSV) Service evolves?
The concept of validation was derived from engineering principles
of validation of mechanical system that has been extended to the
software industry. Software engineering comprises the core
principles consistent in software construction and maintenance:
fundamental software processes and life-cycles, mathematical
foundations of software engineering, requirements analysis,
software engineering methodologies and standard notations,
principles of software architecture and reusability, software quality
frameworks and validation, software development, and
maintenance environments and tools.

To extend it further during mid 1970’s, Ted Byers and Bud Loftus,
two Food and Drug Administration (FDA) officials first proposed
the concept of validation in order to improve the quality of
pharmaceuticals (Agalloco 1995). The first validation activities in
1995 were focused on the processes involved in making these
intended pharmaceuticals product only. However, immediately user
community realized the utility of validation service and did not
hesitate to spread across this concept to associated processes like
environmental control, media fill, equipment sanitization and
purified water production and these days it has extended to
validation of Computer System in the area of Quality Assurance of
desired products.

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Feeling the necessity of Validation, FDA published a guide to the
inspection of Computerized Systems in Pharmaceutical
Processing, also known as the ‘bluebook’ (FDA 1983). In recent
past, American FDA and the UK MHRA have added sections to
this ‘Bluebook’ specifically to address the need of Computer
System Validation. For MHRA this is Annex 11 of the EU GMP
regulations (EMEA 1998), whereas for American FDA, this is 21
CFR Part 11 for rules on the use of electronic records, electronic
signatures (FDA 1997).

According to both American FDA and UK MHRA, computer

system validation is defined as “Confirmation by examination and
provision of objective evidence that software specifications conform to user needs
and intended uses, and that the particular requirements implemented through
software can be consistently fulfilled”

As the demand of this service is increasing consistently,

Information Technology Service Provider companies are also no
exception to realize this need. This results the formation of a
separate Centre of Excellence on this Validation service at these
companies. Most of them are now integrating validation service as a
part of software service offering specially in Life Science and
Healthcare field, more preciously in Laboratory Automation area.
This will be discussed in detail in the next section. Pharmaceutical
Companies on the other hand finds this combined service very
much cost effective. Outsourcing of this validation service to these
companies adds three key benefits to Pharmaceutical Industry
house, namely, neutral 3rd party authorization of implemented
software, ease of availability of regulatory audit documentation and
reduction in dedicated in-house manpower for regulatory
compliance.

3. Lab Automation & Validation Service

Laboratories in an Enterprise today are facing lot of challenges in
order to remain competitive. These challenges are a result of a
combination of market forces, including cost-restraint measures
from the managed care industry, and an overall move toward
containment of national healthcare costs.

As pressures increase for labs to become more productive and cost-

efficient, they are forced to look more closely at their internal

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processes for ways to increase productivity with smaller budgets. In
order to survive in the future, it will be necessary for labs to adopt as
many of the following strategies as possible:
? Run more tests with existing infrastructure.
? Speed in data acquisition from analytical instruments with
accuracy
? Retain lower operating costs.
? Use more automation in a paperless environment.

The answer to this challenge is Laboratory Automation. By

definition “Laboratory Automation is a multi-sphere algorithm to research,
develop, optimize and capitalize on technologies in the laboratory which enable
new and improved processes, generate higher ROI and improve end-user
satisfaction.” It helps in

?
Availability of data on demand for better decision making
?
Enhancing time management,
?
Higher ROI , Productivity and Data quality

Lab Automation indicates appropriate and timely harmonization

of different laboratory centric software to deliver defined service.
These are like LIMS (Laboratory Information Management
System), ELN (Electronic Laboratory Notebook), SDMS
(Scientific Document Management System), CDS
(Chromatographic Data System), ERP (Enterprise Resource
Planning), MES (Manufacturing Execution System) etc.

Registration BioInformatics Reaction

ERP Database Software Database

MES LIMS

Laboratory User
SDMS HTS

Electronic
Inventory Beilstein
CDS Lab
Database
Notebook

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In Pharmaceutical Industry, laboratories like Research &
Development along with Quality Control & Assurance play a key
role to ensure timely delivery of drug moiety to the market and
production of those as per guiding specification & standards.
Needless to say, software plays a key role in managing information
related to these activities. Therefore, it is very important to make
sure software used in Laboratory Automation are adhering to the
International Rules & Regulation as like US FDA or UK MHRA
before those are used for their intended purpose. Following is the
list of some Validation Guiding Specification commonly used in
validating Laboratory Automation System:
? Guidance for Industry: General Principles of Software
Validation; Final Guidance for Industry and FDA Staff
? GAMP (Good Automated Manufacturing Process)
? PDA Technical Report 18, Validation of Computerized Systems
? 21 CFR 11
? 21 CFR 820
? ASTM E2066-00 Standard Guide for Validation of Laboratory
Information Management Systems
? NRC Regulatory Guide 1.170 in compliance to 10 CFR 50
? 1012-2004 IEEE Standard for Software Verification and
Validation

Validation as per FDA allows Pharmaceutical Users (Both Direct

and Indirect) to methodically establish a baseline for control of the
software used in the regulated environment. Whereas as per GAMP,
“In the pharmaceutical and biotechnology industry, Validation
(drug manufacture) refers to establishing documented evidence
that a process or system, when operated within established
parameters, can perform effectively and reproducibly to produce a
medicinal product meeting its pre-determined specifications and
quality attributes” (from European Union Good Manufacturing
Practices Guide, Annex 15). The following diagram explains the
relationship between Laboratory Automation and Validation:

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Depending on situation Software Vendor and Software
Implementer are the same group. Software Validator may be played
by the same group or may be outsourced to Information
Technology Service Provider group.

4. Current Industry Scenario & Market

Trend
As per IDC survey, Regulatory Validation Service will govern
Information Technology spending at Pharmaceutical Industry to a
significant extent. As per their survey, nearly one-third of
individuals expected compliance-related IT spending to increase in
2005, while no one reported any anticipated decreases. This
expectation was supported later in 2006-07 by other research
studies. This trend is due in large part to the increasing number of
regulations and the complexity of regulations such as HIPAA, 21
CFR Part 11, GxP and risk management expansions.

According to industry sources, Lab Automation service market is

estimated to be 1 B$ by end of 2011 and Validation Service is going
to contribute 10% to it. This results lab automation Validation
Service to reach 100 M$ mark by 2011.

Validation Service within Laboratory Automation includes

validation of Analytical Instruments as well. Now all most all
Analytical Instrument makers take care of this validation service.
Respective Instrument software handles Installation Qualification
(IQ), Operational Qualification (OQ) and Performance
Qualification (PQ) internally and there is a little scope of work left
so far as Software Service Organization is concerned.

This leaves Software service companies to offer validation service

only to package software like LIMS, ELN, SDMS and other bio-
informatics software.

5. HCL’c Role in Lab Automation

Validation Service
HCL has a strong validation practice as a part of its Life Science and
Healthcare division. Funded by industry experts in the area of
validation, HCL offers the following services:

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HCL offers Validations, Submission, Consultancy and Audit
services as a part of its Regulatory Compliance Service Offering.

HCL uses traditional “V” model while offering Validation service to

packaged laboratory automation software. This model can be used
for both Software Development Validation and Software
Configuration Validation. HCL, through its Validation Centre of
Excellence, offers services to both these area. For both these cases,
HCL performs Requirement Study and generate certain planning
documents, whereas during validation exercise, some documentary
evidences are generated. The following figures explain activities and
output of both the phases.

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As an example, for any COTS LIMS systems validation, HCL
performs the following activities and generate the following
outputs:

?
Requirements Specification Review and GAP Analysis: We
review the requirement specification as is laid down by the user
community or LIMS Implementation Vendor. We also perform
an AS-IS study to understand if there is any GAP with respect to
requirement at present and which has been documented
previously. If a GAP is identified, we document the same and
validate it with respect to regulatory framework. Under some
cases, these GAPs are also assessed based on merit and
submitted in the form of Change Request to customer.
?
System/software specifications: We also review the
System/Software Specification to understand and document if
there is any GAP with respect to Requirement Specification and
System Design Document (SDD). This creates a Traceability
Matrix to establish the link between the requirement
specification and SDD
?
Risk Assessment: This is a crucial stage as during this phase, we
analyze process and procedure vis-à-vis COTS LIMS
application to identify RISKs. While identifying, we also
consider different guiding FDA / GAMP4 specification. This
Risk Assessment document will later generate different Change
Requests to the product Vendor or to internal Quality Assurance
Team.
?
Validation Plans (VP) : This often refers as Master Validation
Plan and it documents Requirement / Plan under the following
heads
  Purpose
  Concept of Operation

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  Risk Analysis
 Environment
 Functional Requirement
 Software Design/Configuration
 Test Plan / Scope with indication of Exclusion Criteria
 Test Specification and Cases
Test Result Recording
©
Test Exception Handling
©
Test
©
Test Data
©
Test Result Analysis & Reporting
©

 Resources
Personnel
©
Facility
©
Schedule
©

 Version Description Information

 Operations/Maintenance/Training/User Instructions
?
Installation Verification/Qualification (IQ) : This step also has
further sub activities like
  Development of Installation Qualification Protocol
  Development of Installation Qualification Test Cases
  Execution of Installation Qualification
  Reporting Installation Qualification (IQR)
? Operational Verification/Qualification (OQ) & Performance
Verification/Qualification (PQ) : Like Installation Qualification,
these two steps also follow the similar process like creation of
Protocol, Validation Test Cases, Execution of Validation and
Reporting of Validation Results (OQR and PQR). However, in
case of Performance Qualification, HCL prefers to have a
Operational LIMS systems for a length of minimum 15 days.
? Validation Summary Reports (VSR): This report is a summary
of finding of all individual qualification reports like IQR, OQR
and PQR. This is considered as final deliverable to the requesting
organization.
? Maintenance logs and change control requests: As was pointed
out earlier, HCL validation engineer adds value to the validation
exercise by not limiting themselves to submission of Validation
Summary Report. They always try to find the deviation from
regulatory perspective and maintain an Issue Log. This issue log
generates Change Control Requests if requesting organization
desires so.
This process may be different in case any GxP COTS system is
intended for validation. However, before we discuss this aspect, let
us understand what the core principle behind this validation

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exercise is. A frequently overlooked element for COTS use is the
end user validation requirements. We will now discuss the validation
requirements for COTS software, provide points to consider during
the product selection phase, some of the common pitfalls and
misconceptions associated with COTS applications, and how to
define the documentation and quality systems necessary to achieve
and maintain an adequate validation status for a COTS system.

As we have discussed earlier, Validation of computerized systems

used in producing, managing, and reporting data for
pharmaceutical activities is required by the US Code of Federal
Regulations, Title 21, parts 210 and 211, as well as in other related
pharmaceutical areas. A recognized problem area in this software
validation includes the end user validation requirements for COTS
applications.

Two widely recognized references for computerized system

validation, the PDA Technical Report No.18, Validation of
Computer-Related Systems and the GAMP (Good Automated
Manufacturing Practice) Guide for Validation of Automated
Systems in Pharmaceutical Manufacture, present widely accepted
and recognized validation concepts and procedures. These reports
draw from the essential steps in the life-cycle validation approach,
all of which should be evaluated and interpreted in any
computerized-system qualification project. Much of the
development, design, and test requirements are completed by the
vendor; however, it is the end user’s responsibility to verify that the
vendor has provided the application in accordance with these
defined procedures.

That is the reason while we carry out one such exercise; we put our
primary focus to validation of End Users. HCL, with the help of
Industry Expert take care this part with ease. As per GAMP4,
approach to be followed during such as assignment will be

“The user should define validation procedures and requirements prior to

performing qualification activities. These documents are the cornerstone
documents in any validation effort, and they should be developed in clear, concise
terms. Establishment of these documents will result in the development of
concise qualification tests and verifications to demonstrate the proper
functionality of all defined user requirements, business practices, and functional
requirements for the computerized system.

Establishing policies and procedures to define responsibilities and requirements

for any type of computerized systems implementation and ongoing support are
essential. COTS applications range in complexity from the basic "one person"
development/test/management systems to integration/implementation teams
involving multiple departments, locations, third-party system integrators, and

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defined cross-functional implementation teams. Implementing adequate quality
systems and procedures for all levels of computerized system validation efforts
should be completed to maintain the validation status of the computerized
system.”

For this reason, we take a facilitator approach during GxP

Validation assignment. We look for documentation, evidence of
Internal Audit system, evidence of appropriate certification of
Internal Auditor from the performing organization etc.

6. Conclusion
Validation Exercise in the area of Laboratory Automation is an
important step before the COTS software are used in the
laboratory. Computer-related system validation, as defined in the
PDA Technical Report No. 18, is "establishing documented
evidence which provides a high degree of assurance that a specific
computer-related system will consistently operate in accordance
with pre-determined specifications." To accurately assess the
validation status of a system, the validation requirements must be
clearly defined and documented. Therefore, appropriate
documentation of end-user requirement is a must for
Implementation Vendor. Currently it has been noticed, vendors are
not paying adequate attention to this step and this causes failure of
COTS or MOTS (Modified off the Shelf) software implementation
in the laboratory. Performing Validation is a retrospective analysis
only, and we recommended this exercise to be performed during the
period of Implementation only. In case, Validation is performed
much after the implementation, robust Change Management
System is a must to bring back operational system to normalcy,
which is according to International guideline like FDA, GAMP etc.

7. Reference

Wikipedia
?
Worldwide Regulatory Compliance Issues in Life Science (IDC
?
#32690,December 2004)
1Q05 Leading
? Indicators in Life Science s IT Spending
Survey, an IDC Report
History of the FDA, John P. Swann, Ph.D., FDA History Office
?
http://www.fda.gov/oc/history/historyoffda/default.htm
A Historical Guide to the U.S. Government, George Kurian, ed.,
?
New York: Oxford University Press, 1998
F
? DA Budget Proposal for FY 2003

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http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS011
35.html
The Story Of The Laws Behind The Labels Part I 1906 Food
?
and Drugs Act ,
Ja n n s e n , Wa l l a c e, F ; F DA H i s t o r i a n
?
http://www.cfsan.fda.gov/~lrd/history1.html

8. About the Author

Somnath Mukherjee is head of L IMS P r a c t i c

e a t HC L Technologies Ltd. He has over 18
years of experience in the development of
LIMS, its implementation and support services.
Somnath has worked in almost all areas of
LIMS, and he specializes in the area of
interfacing LIMS with other software in an
enterprise. Prior to joining HCL Technologies,
he worked with LabVantage Solutions.
Somnath has a post graduation degree in Chemical Technology and
has written in multiple research publications on system automation

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