Semester-II, PCI syllabus, First Year

1. COMPUTERS AS DATA ANALYSIS IN
PRECLINICAL DEVELOPMENT
PREPARED BY
MRS. MEGHA S SHAH
AISSMS COLLEGE OF PHARMACY, PUNE
1

2. Introduction
In pharmaceutical analysis, computers have active and passive applications.
2
passive
applications
data
handling
processing
file
searching
display
storing

3. eg. when gas-liquid chromatography (GLC) with mass spectrometry (MS) is used
for separation and identification of complex mixtures. GLC separates the
individual component and MS identifies it.
Computer when used for the interpretation of this data, stores these spectra for
some time and then represents it in the graphical form.
For identification by mass spectrometry computer compares the spectrum of the
given sample with the spectrum of pure compound.
3

4. For interpretation of mass spectra efficient computerised library search systems are available.
There are two types of library systems, the large comprehensive ones and small specific ones.
The large library contains around 1,50,000 spectra, whereas the small library contains
maximum few thousand spectra for application to a limited area such as drugs, forensics,
pesticides etc.
For interpretation of IR spectra, commercial software packages are available. Sadtler
Standard Infrared Collection and Sadtler Commerical collection contain over 1,20,000
spectra.
4

5. A diagnostic program helps a physician or researcher use specific patient information to
obtain a diagnosis.
When the physician inputs data, the computer offers a menu of possibilities which narrow
as more information is entered.
SUMEX program allows doctors to enter patient symptoms into the computer and receive
probable diagnoses as well as information about pertinent drugs and their side effects.
MICKIE is another such package MDLS is a package to handle EKG analysis. The
program analyses the EKG and reports parameters like amplitudes, durations and
intervals.
5

6. Data analysis, also known as analysis of data or data analytics, is a process of
inspecting, cleansing, transforming, and modeling data with the goal of discovering
useful information, suggesting conclusions, and supporting decision-making.
Preclinical development, also named preclinical studies and nonclinical studies, is a
stage of research that begins before clinical trials (testing in humans) can begin, and
during which important feasibility, iterative testing and drug safety data are collected.
The main goals of preclinical studies are to determine the safe dose for first-in-man
study and assess a product's safety profile. Products may include new medical devices,
drugs, gene therapy solutions and diagnostic tools.
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7. Initially, all data analysis was performed by using software programs written by each
laboratory. Commercial data analysis software emerged in the late 1970s.
The offerings included programs for statistical, quality, and graphical data analysis.
The variety and quantity of software packages grew as newer data analysis techniques
emerged.
Scientists from many different disciplines participate in pharmaceutical development.
Their research areas may be very different, but they all generate scientific data and text
documents, which are the products of development laboratories.
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8. Literally, truckloads of data and documents are submitted to the regulatory authorities in
support of investigational and marketing authorization filings.
For example, even a typical IND (Investigational New Drug) application requires around
50,000 pages of supporting documents.
One way or another, every single data point has to go through the acquiring, analyzing,
managing, reporting. auditing, and archiving process according to a set of specific rules
and regulations.
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9. The wide use of computers has tremendously increased efficiency and productivity in
pharmaceutical development.
Considering the pervasiveness of computer applications in every scientist's daily
activities, special emphases are put on three widely used computer systems namely,
CDS (Chromatographic Data Systems),
LIMS (Laboratory Information Management Systems)
TIMS (Text Information Management Systems).
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10. It is probably fair to say that these three computer systems handle the majority of the work
in data/document management in the preclinical area, supporting the New Drug
Application (NDA) and Marketing Authorization Application (MAA) filings.
For each of these three types of systems, there are many vendors who provide various
products.
The selection of the right product can be complicated, and a mistake made in the process
can also be costly.
It may also be beneficial to the reader if we define the sources of the scientific data in
10

11. The following are the examples of the
development activities that generate the
majority of the data:
1. Method development, validation, and
transfer.
2. Drug substance/drug product purity,
potency, and other testing.
3. Drug substance/drug product manufacturing
process development, validation transfer.
4. Drug substance/drug product
stability testing.
5. Drug product formulation development.
6 Batch production and control record
keeping.
7. Equipment cleaning testing
8. Master production and control
record keeping
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12. CHROMATOGRAPHIC DATA SYSTEMS (CDS)
•
•
12

13. Chromatography is an analytical technique used in virtually all sectors of the pharmaceutical
medical device and biotechnology industries to detect or quantify compounds during the
course of product development and manufacture.
The chromatograms generated by these analytical methods are displayed, integrated and
results calculated by a software application called a Chromatography Data System (CDS).
CDS, collects and analyzes chromatographic results delivered by chromatography detectors.
Many chromatography software packages are provided by manufacturers, and many of them
only provide a simple interface to acquire data. They also provide different tools to analyze
this data.
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14. CDS have helped the pharmaceutical industry to increase efficiency and productivity
by automating a large part of pharmaceutical analysis and the main focus of CDS has
been on providing accurate and reliable data.
The current regulatory trend in the pharmaceutical industry is to shift from data-based
filings to information-based filings, meaning that the date must be analyzed and
converted into information.
This implies that enhancements in data searching and trend analysis capabilities will
be desirable in the future.
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15. A CDS can come in one of the following types:
1. Integrator (single user and single instrument data acquisition).
2. Workstation (typically a single user with single instrument data acquisition and control).
3 Client-server (multiple user and multiple instrument data acquisition with an option for
control).
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16. The importance of CDS is directly related to the roles that chromatography, particularly
high-Performance Liquid Chromatography (HPLC) and Gas Chromatography (GC),
use in pharmaceutical analysis.
HPLC and GC are the main workhorses in pharmaceutical analysis.
In day's pharmaceutical companies, development work cannot be done without HPLC
and CDS are also used for several other instrumental analysis technologies such as lon
exchange) Chromatography (IC), Capillary Electrophoresis (CE), and Supercritical
Fluid Chromatography (SFC).
16

17. The essential elements of a CDS and how it can interact with the gas or liquid
chromatograph are shown diagrammatically figure.
Instrument control.
Data acquisition typically via an analogue to digital A/D (Analog to Digital)
converter or direct through a digital interface.
Integration of the data
Calculation and reporting of results
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18. instrumentation
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19. 19

20. Basic Concepts of CDS
In the 1960s and early 1970s, chromatographs were relatively inefficient. Chromato
graphers had to use microsyringes for sample injection and stopwatches for
measurement of times. The chromatograms were collected with a strip chart recorder.
Data analysis was also performed manually.
Peak areas were obtained by drawing a "best fit" triangle manually for each peak and
then using the equation Area = 1/2Base x Height.
At that time the management of chromatographic data was essentially paper based
and very inefficient.
20

21. However, compared with the traditional analytical methods, the adoption of
chromatographic methods represented a significant improvement in pharmaceutical
analysis.
This was because chromatographic methods had the advantages of method specificity, the
ability to separate and detect low-level impurities.
Specificity is especially important for methods intended for early-phase drug development
when the chemical and physical properties of the Active Pharmaceutical Ingredient (API)
are not fully understood and the synthetic processes are not fully developed.
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22. Therefore the assurance of safety in clinical trials of an APS relies heavily on the ability of
analytical methods to detect and quantities unknown impurities that may pose safety concerns.
This task was not easily performed or simply could not be carried out by classic wet chemistry
methods. Therefore, slowly, HPLC and GC established their places as the mainstream
analytical methods in pharmaceutical analysis.
As chromatographic methods became more and more important in the pharmaceutical industry
as well as in other industries, practical needs prompted instrument vendors to come up with
more efficient ways for collecting and processing chromatographic data.
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23. Modern CDS
Use of server-based computing is only one of the important features of the modern
CDS.
Server-based computing uses a multiuser operating system and a method for
distributing the presentation of an application's interface to a client device.
There are no software components installed on the client PC.
The client's PC simply acts as the application server's display.
23

24. The other two important features of modern CDS are the use of
1. embedded data structure
2.direct instrument control.
The earlier generations of CDS used a directory file structure, meaning that the raw
data and other files such as the instrument method and data processing method were
stored at separate locations which is problematic and causes data redundancy.
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25. 1. Embedded Data Structures
The embedded relational database has been widely used for LIMS and a much better file
structure.
Can be used to manage not only chromatographic data, but also all aspects of the CDS,
including system security and user privileges.
Maintains all information and changes by date and time stamping them to prevent accidental
overwriting of raw data and method files.
Controls versions of all processed result files, acquisition methods, processing methods, and
reporting methods to provide full audit trails.
All of the metadata (acquisition, process, and reporting methods) related to a specific result are tied together.
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26. 2. Direct Instrument Control
It was an important issue for the earlier version of CDS.
The scheme of connecting the detector channels through A/Ds to CDS worked well in
analytical laboratories across the pharmaceutical industry.
The scheme provided enough flexibility so that the CDS could collect data from a
variety of instruments, including GC, HPLC, IC, SFC, and CE.
It was equally important that the CDS could be connected to instruments that were
manufactured by different vendors.
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27. Major CDS Vendors and their Products
Sr. No. Product Vendor Name URL
1 Atlas Thermo Electron Co. www.thermolabsystems.com
2 Cerity Agilent Technologies, Inc. www.agilent.com
3 Chromeleon Dionex Co. www.dionex.com
4 Class VP Shimadzu Scientific Inst. www.shimadzu.com
5 Empower Waters Co. www.waters.com
6 EZChrom Elite Scientific Software, Inc. www.scisw.com
7 Galaxie Varian Inc. www.varianinc.com
8 TotalChrom Perkin-Elmer, Inc. www.perkinelmer.com
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28. LABORATORY INFORMATION
MANAGEMENT SYSTEMS (LIMS)
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29. Introduction
Laboratory Information Management System (LIMS), is a software-based laboratory
and information management system that offers a set of key features that support a
modern laboratory's operations.
Key features include workflow and data tracking support, flexible architecture, and
smart data exchange interfaces and more.
The features and uses of a LIMS have evolved over the years from simple sample
tracking to an enterprise resource planning tool that manages multiple aspects of
laboratory informatics.
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30. The development of LIS (Laboratory Information System) or LIMS (Laboratory
Information Management System) has been a new specialty focusing on using
computer software for data management of various laboratory operations.
An LIS is defined as, "the functions built into a class of software for a laboratory
to manage patient data and issue results".
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31. 31
A comprehensive LIS specifically designed for a cytogenetic laboratory may
include the ability to collect and store data, analyze and report results, interface
with lab instrumentation and outside clinical facilities, organize workflow, evaluate
personnel performance, monitor Quality Assurance (QA) and Quality
Improvement (QI) parameters, and ensure accurate billing practice.
LIS applications exist on a variety of database platforms such as dBase Oracle,
Meditech and Microsoft Access in addition to proprietary systems.
LIS have been widely used, for many cytogenetic laboratories a manual system
using a simple notebook or logbook is still valuable as a direct daily reviewing
method and a supplemental hardcopy backup.

32. LIMS is a software-based laboratory and information management system that offers
a set of key features that support a modern laboratory's operations.
Necessary to track all aspects of the workflow in a laboratory, including instruments,
samples, personnel and quality assurance and quality control procedures.
Emerged to address needs for managing the totality of the laboratory's analytical
testing data and information.
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33. LIMS represent an integral part of the data management systems used in preclinical
development.
LIMS are needed partly because CDS cannot provide enough data management
capability.
For example, CDS cannot handle data from non-chromatographic tests.
Another important use of LIMS is for sample management in preclinical development,
more specifically in drug substance and drug product stability studies.
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34. Stability studies are very labor intensive, and the results have an important impact on
regulatory filings.
LIMS are designed to automate a large part of these stability studies including sample
tracking, sample distribution, work assignment, results capturing, data processing, data
review and approval, report generation, and data archiving, retrieving, and sharing.
LIMS is a complex system and requires significant capital and manpower investment.
Selection of the right LIMS product is a daunting task, and the outcome can have a
significant impact on the business.
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35. Components of LIMS
Compared with CDS, LIMS has more core functionalities in managing laboratory
data and other electronic information.
It also has much stronger search and reporting capabilities.
Components of a LIMS include both computer hardware and software.
The system's physical hardware components include its computer processor, peripheral
devices such as terminals, primers, disc drives etc., and elements such as cables and
switches that connect the various parts.
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36. Software is the set of instructions to be carried out by the physical hardware components.
They are the means by which the computer system accomplishes its work.
Software programs dictate how and which information is stored in the database, how
calculations are performed, the format of reports, and how information is displayed on a
terminal, and can even restrict selected individuals from carrying out specific functions.
Cables hold the physical components of the computer system together.
They provide the pathway for movement of data and control signals to and from various
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37. Networking hardware ties several computer systems together.
They include specialized high-speed switches, protocol translators, and multiplexors.
Networks require a sophisticated and tightly integrated web of specialized hardware,
operating systems, network management software, and communications lines.
A interfacing hardware establishes data connectivity between laboratory instruments
and the LIMS computer included are devices such as digitizers, signal filters, and
instrument controllers.
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38. Interfacing hardware, in some cases, may be accompanied by specialized software for
the acquisition and processing of data from instruments.
The operating system provides detailed instructions that control most basic functions
of the computer system.
It provides the fundamental coordination of all physical hardware components such as
terminals, printers, etc.
The database consists of Laboratory data stored on the computer in a format and
structure determined by the DBMS.
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39. The DBMS is a series of sophisticated programs and utilities that controls how data is
stored and retrieved.
It is the electronic equivalent of file cabinets with pre-designated locations for various
items of information.
The development utilities software packages are available for the development of
applications to improve the efficiency and quality of the time-consuming software
development process.
LIMS vendors frequently use some of these tools for development and maintenance of
their products.
39

40. Computer networks connect separate computer systems to one another.
A network benefits the organization by allowing it to share data and hardware resources.
A network consists of a series of highways through which data can move from one
computer system to another.
Specialized networking hardware and software coordinate the movement of data between
the numerous hardware components.
Networking software defines contact points for each hardware device and coordinates the
transfer of data between the various points.
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41. The LIMS application provides general laboratory functions.
This includes common laboratory tasks such as sample log in, sample tracking; test
scheduling, test data entry, test approval, and reporting.
The exact functions provided and approach taken can differ significantly from one LIMS
application to another.
A wide variety of other applications software can be on the system. This includes
laboratory software packages for statistics, structural data management, word processing,
spreadsheets, textual data management, image management and document control.
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42. An LIMS, consisting of specifically
designed software and properly
installed hardware and peripherals,
could be customized to facilitate a wide
variety of laboratory activities.
The most advanced LIMS utilize
server-based architecture to ensure
system security and control.
42

43. There are four main types of architectural options when implementing LIMS as explained below
1. The LAN (Local Area Network) Installation: In a multiple-site situation and through the
standard client/server setup, the application would be hosted separately on a server at each site
connected to PC clients. In this setup, the LIMS are installed on both the clients and the server.
System administration is required at each facility.
2. The WAN (Wide Area Network) Installation: In this setup the LIMS take advantage of
telecommunication technology to cover a great distance. The setup can also be used to connect
disparate LANs together. In this configuration, the LIMS are installed on both the clients and a
central server.
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44. 3. The Centrally Hosted Thin Client Installation: For this setup, system administration is
managed at a corporate center, where the LIMS are hosted and distributed via a WAN or the
Internet with a Virtual Private Networks (VPN).
4. The ASP (Application Service Provision Provider) Hosted Installation: In this setup, the
LIMS are hosted on a centrally managed server form and maintained by third-party specialists.
Users access the LIMS with any Internet-connected PC with a standard Web browser.
There are large numbers of established vendors that provide commercial LIMS with a similar range
of core functionality, but few of them are dedicated to the pharmaceutical industry because of the
market size as shown in Table.
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45. LIMS Vendors specialized in Pharmaceutical Industry
Sr. No. Product Vendor Name URL
1 Debra LabLogic Systems Ltd. www.lablogic.com
2 Q-DIS/QM Waters www.waters.com
3 QC Client Agilent www.agilent.com
4 WinLIMS QSI www.lims-software.com
5 ACD/SLIMS Advanced Chemistry Development www.acdlabs.com
6 V-LIMS Advanced Technology Corp. www.vetstar.com
7 VET/HEX HEX Laboratory Systems www.hexlab.com
8 BioLIMS PE Informatics www.pebiosystems.com
9 LabCat Innovative Programming Assoc. www.labcat.com
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46. Advantages of LIMS
1. Efficiency: LIMS streamlines data entry by automating the process. This results in less
downtime, faster access to data, accurate up-to-date data and the ability for the LIMS
to grow with the increasing needs of the lab.
2. Cost Reduction: Total costs of operations such as labor, resources etc. are reduced by
using LIMS.
3. Compliance: LIMS can assist in real-time monitoring and quality control. Workflows
can be managed, samples logged, and tests can be checked against protocols and
procedures to ensure compliance.
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47. TEXT INFORMATION MANAGEMENT
SYSTEMS (TIMS)
47

48. Introduction
A TIMS is essential for in preclinical development because huge number of text documents
and other related information such as images, photographs etc., in the area and requires
protection and easy access.
TIMS has helped the pharmaceutical industry to improve efficiency in managing business-
critical text documents.
However, TIMS is still a time-consuming process to write, review, audit, approve, and
publish text documents for submission. The pharmaceutical industry is working toward
making submissions electronically.
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49. 49
However, this may take time, and the industry may need many changes in business
practices to reach the goal.
The objective of an information retrieval system is to organize and store large amounts
of text so that information can be retrieved from the repositories in response to users
information requests.
A text document management system is essential in preclinical development because
huge numbers of text documents and other related information such as images, drawings,
photographs and so on are generated in the area.
All these documents and data information are considered intellectual property and
require protection and easy access.

50. Need of TIMS
Text retrieval systems are often referred to as textual information management systems
(TIMS) in literature.
These systems deal with various kinds of documents which are textual in nature.
The scientists in preclinical development spend quite a large percentage of their
working time writing compound documents (reports).
The report generation, review, approval, filing, and retrieval process can be very
inefficient and time consuming or even bureaucratic in a pharmaceutical company,
partly because of the strict regulations.
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When TIMS is used in today's workflow, the scientist can use a report template to
facilitate report writing.
Conventionally, text retrieval systems deal with bibliographic documents/materials
characterized by various keys like author, title, keywords, publication details, abstract .
Such systems enable users to search the bibliographic records through any of the keys
like author name, title, assigned keywords, or by one or more words occurring in the
abstract field.
In such a situation, the text retrieval system acts as a bibliographic or reference
retrieval system because the search retrieves one or more bibliographic records, and
the users have to consult the hard copies of the documents to get the required
Information.
This is the most conventional use of text retrieval systems in libraries. A number of
software packages are available worldwide to serve this function.

52. However, text retrieval systems may also contain full texts of any kind of documents like
letters, correspondences, office memos, legal documents, patient records and case histories.
complete texts of articles and books, and so on.
Users of such systems expect to retrieve the complete text or parts of it in response to a query
and can go through it to get the desired information.
Such systems, because they store the complete text of documents rather than mere
bibliographic information of the same, take much disk space and the retrieval mechanism
needs to be sophisticated to provide fast access to the records.
These text retrieval systems are known as full text or free text retrieval systems
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53. Documentation Requirements in Preclinical Development
1. The Standard Operating Procedures (SOPs) are controlled in a way similar to that of
specification documents and analytical methods.
 It must be ensured that the correct versions of the SOPS are accessed and used by the
scientists.
 After use, the hard copies should be destroyed and disposed of properly.
 An added requirement is that the SOPS should be accessible during working hours
without interruption.
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54.  Hard copies should be available at a manageable location so that the SOPs are
available when the electronic system is down.
2. Research Reports such as stability reports, method validation and transfer reports,
and pharmaceutical development reports are key documents used for NDA/MAA
filings.
 These documents are strictly version controlled.
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55. 3. Laboratory Notebooks may be debatable to consider laboratory notebooks as text documents, but
they should be mentioned here because of their importance in preclinical development.
 Laboratory notebooks are used to record experimental procedures, observations, raw data, and
other important information.
 Currently, most of the major pharmaceutical companies still use paper-based laboratory
notebooks.
 Electronic-based notebook systems are being developed. An Electronic Laboratory Notebook
(ELN) is defined by the Collaborative Electronic Notebook Systems Association (CENSA) as, "a
system to create, store, retrieve and share fully electronic records in ways that meet all legal,
regulatory, technical and scientific requirements".
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56. 4. In preclinical development, Product Specification Documents and Analytical Test
Methods are important documents and they evolve along with the development phases.
 Drug substances and products for clinical trials are tested based on these documents, and
so are the stability samples.
 It is critical to ensure that the analyst will perform the right tests against the right
specifications with the correct version of the test method.
 Therefore, a mechanism must be in place to control these documents. This can be done
manually or with TIMS.
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57. 57
Sr. No. Product Vendor Name URL
1 Documentum Web Publisher Documentum www.documentum.com
2 P8 WCM FileNet www.filenet.com
3 TeamSite Interwoven www.interwoven.com
4 Stellent Content Management Suite Stellant www.stellent.com
5 V7 Content Management Suite Vignette www.vignette.com
6 Communique Day Software www.day.com
7 Content Server FatWire www.fatwire.com
8 Workplace WCM IBM www.ibm.com
9 Mediasurface Mediasurface www.mediasurface.com
10 Ingeniux CMS Ingeniux www.ingeniux.com
11 CommonSpot PaperThin www.paperthin.com
12 RedDot CMS RedDotSolutions www.reddot.com
TIMS Vendors and their Products

58. QUESTION BANK
1. What is data analysis?
2. Explain preclinical development in detail.
3. Define the following terms: (i) LMIS (ii)TIMS (iii)CDS
4. Laboratory Notebooks
5. Explain the need of TIMS.
6. Describe LIMS in detail.
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59. QUESTION BANK
1. Write short note on: Modern CDS.
2. Enlist the products of following: (i) LIMS (ii) TIMS (iii) CDS.
3. What are the uses of LIMS?
4. Enlist uses of TIMS.
5. Compare LIMS and TIMS.
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