Regulatory & Marketplace

Can the Regulators Keep Up with the Emerging

Digitalisation in Laboratories?
The laboratory constitutes an essential
part of any pharmaceutical company
as it is usually where the history of
the company began. Without the
scientific research taking place in
the laboratories, there would be no
medicines to regulate, produce and
distribute.
Over the past years, technology has
rapidly evolved, leading also to a digital
transformation in the laboratory area.
IT has been introduced in almost all
business processes and operations.
Several manual processes have been
replaced by automatic systems,
thus speeding up efficiency and
eliminating the risk of human errors.
Laboratory technicians and chemists
are using IT tools on a daily basis,
e.g. when weighing raw material,
pipetting solutions and documenting
experiments.
The complexity of laboratory
instruments has increasingly evolved
and today many instruments cannot be
operated without software. It is seen
as a crucial component that enables
the user to acquire, process, save and
share data. Software has become an
integrated part of many laboratory
instruments and consequently the
requirements for the intended use
surrounding the instruments have
changed.
Challenges in Laboratories Today
Some of the challenges laboratories
are facing today highlighted in this
article are:
to navigate in new publications
and updates to existing regulatory
requirements and validation
guidelines within the different
GxP regulated environments.
• Impact on laboratories to meet
regulatory expectations: What
does it require for laboratories
to be able to pass an audit and
demonstrate an adequate level of
compliance? What efforts does it
take to meet current expectations?
Laboratory Instrument or
Computerised System? Or Both?
Many types of laboratory instruments
that produce some kind of digital
output are today seen by regulators
as computerised systems and are
expected to be validated accordingly.
But how do you distinguish
between the different instruments
and those that should be considered
to be computerised systems?
To answer this question, it is
necessary to evaluate the complexity
of the laboratory instruments. It can
be useful to visit the ISPE GAMP “A
Risk-Based Approach to GxP Compliant
Laboratory Computerized Systems”1,
which explains how laboratory systems
can be categorised according to
complexity. A summary of the different
categories of complexity is illustrated
in Table 1.
Assessing the complexity of the
different laboratory instruments
provides a solid foundation to begin
with. The outcome of this assessment
is often that instruments of increasing
complexity should be considered to
be computerised systems. Another key
aspect is to understand the regulatory
requirements and validation guidelines
that exist in the GxP regulated environ-
ment that the instruments are
operating in.
Laboratories in Different GxP
Environments
Laboratories exist within different
areas of the pharmaceutical value chain
and are set up differently depending
on the analytical purpose. Examples
of common laboratory functions seen
within a pharmaceutical company are
listed below:
• Research & development (R&D)
carrying out biological target
identification and validation and
discovering lead drug compounds.
This area is not GxP regulated.
• Pre-clinical: Drug candidates are
further developed and the
pharmacokinetic (PK) and
pharmacodynamic (PD) properties
are investigated in animal models.
This area is regulated by Good
Laboratory Practices (GLP).
• Manufacturing: Where production
of the drug takes place. Quality
control (QC) and quality assurance
(QA) laboratories are testing
and verifying that the quality
of the finished drug product is
within the specified acceptable
ranges. This area is regulated by
Good Manufacturing Practices
(GMP).

• Paradigm shift in how regulators Categorization Composition Example

perceive laboratory instruments:
Many types of laboratory instru-
ments controlled by software
are today seen as computerised
systems and are expected to be
validated accordingly.
• Increase in regulatory expectations
to compliance activities: Pharma-
ceutical companies find it challenging
Simple Non-configurable components. Stand-alone balance
Firmware generates a numeric value.
Medium Configurable components. Firmware Fourier Transform Infra-Red
generates a value. Software has (FTIR) Spectroscopy
discrete configuration capabilities.
Complex Multiple configurable or custom made Chromatographic Data System
components based upon network (CDS)
architecture.
Table 1 Categorisation of laboratory instruments based on complexity1

8 INTERNATIONAL PHARMACEUTICAL INDUSTRY Autumn 2018 Volume 10 Issue 3

 Regulatory & Marketplace
Many pharmaceutical companies
find it challenging to navigate the
updates and new publications of
regulatory requirements and validation
guidelines.
Increase in Regulatory Expectations
The pharmaceutical industry has over
the past couple of decades been faced
with an increase in scope of existing
regulatory requirements that they are
expected to comply with.
In 2011, the European Commission
revised and published a new version of
the “EU GMP Annex 11: Computerised
Systems” due to the increased use and
complexity of computerised systems2.
A part of the update concerned an
increase in scope, meaning that Annex
11 would now apply to all laboratory
computerised systems, including
tools developed by the laboratories
themselves such as spreadsheets,
statistical software programs and data-
bases2. The pharmaceutical industry
had to expand their perception of
computerised systems to include
the systems that were previously not
considered within this category and to
ensure they were validated accordingly.
In 1995, the OECD published a series
of documents on the “principles of good
laboratory practice and compliance
monitoring” in collaboration with
pharmaceutical industry experts and
inspectors3. In 2016, document no. 10,
“The Application of the Principles of
GLP to Computerised Systems” was
revised and replaced by document
no. 17, “The Application of GLP
Principles to Computerised Systems”4
to accommodate the advances in
development of computerised systems.
Whereas Annex 11 applies to compu-
terised systems within GMP, the
OECD guidelines apply to laboratories
operating within GLP. Furthermore,
Annex 11 describes computerised
systems from a general point of
view, whereas the OECD guideline
no. 17 contains specific requirements
surrounding the processes of
conducting GLP studies4,5.
Besides the difference in scope, the
core content and approach to computer
system validation seem reasonably
similar. Both Annex 11 and OECD no. 17
address the need for general processes
such as risk management and change
10 INTERNATIONAL PHARMACEUTICAL INDUSTRY
and configuration management, and
lists similar requirements to system
functionality within topics such as
accuracy checks, printouts, electronic
signatures and audit trail4,5.
Data Integrity
In March 2018, the Medicines and
Healthcare products Regulatory
Agency (MHRA) published the guideline
“Guidance on GxP data integrity” to
ensure patient safety and quality of
products6. This was one of the first
attempts to harmonise computer
system validation guidelines across the
different GxP environments, taking into
consideration both OECD no. 17 and
Annex 11, among other guidelines6.
The presented overview of updates
and new publications demonstrate
how the regulators have changed
and updated existing documentation
to accommodate the advances in
technological development and the
increase in use of computerised
systems. But what has changed?
And what is expected from pharma-
ceutical companies today to stay in
compliance?
What Efforts are Required of
Laboratories to Meet Current
Expectations?
The technological development and the
increase in compliance expectations
from the regulators have significantly
impacted laboratories across the
pharmaceutical industry. The bar
has been lifted to a higher level,
meaning that the laboratories need
to invest more time, money and effort
in assessing how the computerised
laboratory instruments can reach
acceptable compliance levels.
A fundamental challenge is that
the paradigm shift in how regulators
perceive laboratory instruments
applies retrospectively. This means
that pharmaceutical companies have
to re-evaluate all their laboratory
instruments, even the ones that were
validated many years ago, in order to
assess if they are considered to be
computerised systems or not.
In reality, this means that laboratories
will have to spend time and resources
on identifying and locating previous
validation documentation. This can be
a challenge in itself if documents are
paper-based and located in physical
archives, either internally or externally.
Once the documentation has been
located, it is necessary to go through
the papers and reports and do a gap
analysis of the compliance state
and potential system functionality
issues.
Case: Missing Audit Trial Functionality
An example of a common system
functionality issue that would be
identified during a gap analysis is the
lack of an audit trail. Regulators expect
to see audit trails on computerised
systems which should include
information about all data runs executed
in the system, as well as changes made
to data. The detailed information should
include who executed the change,
when it was executed (time and date),
the reason for the change, and the old
and new value1.
Many laboratory instruments have
very limited information in the audit
trail, while some instruments do
not have any audit trail functionality
at all. The reason for this could be
Autumn 2018 Volume 10 Issue 3

that there were no requirements for
audit trail from the regulators when
the instruments were developed and
taken into use. In order to address
the magnitude of this issue, it is
necessary for laboratories to create an
overview of how many computerised
instruments affected by audit trail
functionalities are not able to meet
the requirements.
A way to address missing audit
trail functionality is to perform a risk
assessment in order to mitigate the
risks. It could also be an option to test
the audit trail functionality as part of
a user requirements verification. If the
audit trail functionality is tested, this
opens up further questions related to
compliance: Are you able to quickly
demonstrate this test to an auditor?
If yes – How do you know that you
have tested the audit trail functionality
sufficiently and that it will meet the
auditor’s expectations?
Approach to Closing Compliance Gaps
The outcome of the gap analysis
should provide an indication of which
remediation approach to embark
on. Potential gaps can relate to the
technical and functional aspects of a
system, such as the lack of an audit
trail. Issues can also relate to the
compliance state of the validation
documentation. Based on the findings
in the initial gap analysis, there are
different possible outcomes. If a
technical and/or functional change is
needed, a decision should be made
on whether the existing validation
documentation should be updated to
reflect the change. Or is it better to
www.ipimediaworld.com
Regulatory & Marketplace
discard the existing documentation
and create new documents from
scratch that reflect the pharmaceutical
companies’ current policies and
standard operating procedures (SOPs)?
A third option could be to replace the
instrument with a new system that
fulfills the business and compliance
needs.
In order to spend time and efforts
efficiently, there are several aspects to
consider when evaluating the different
options. Questions that laboratories
should ask themselves could be:
• Is it more expensive to fix the gaps
than it is to buy a new system and
validate it from scratch?
• Is the system customised to meet
specific business needs, meaning
that it cannot easily be replaced?
• Has the use of the instrument
changed over the years?
• Is it more time-consuming to go
through the existing validation
documentation than it is to start
over from scratch?
• Does the old validation
documentation reflect current
company policies and SOPs or is
an update needed?
Future Outlook on Digitalisation in
Laboratories
Even though instrument validation
documentation was accepted by the
regulators 10 or 20 years ago, it might
not be accepted today. The underlying
cause could be that the regulators
have not been able to keep up with
the rapid technological development
over the years. Consequently, the
pharmaceutical companies have openly
embraced new technology options and
taken laboratory instruments into use
before the regulators had any clear
view on how to regulate them. It will
be interesting to see when and how
regulators will respond to Internet of
Things (IoT) and other new technologies
that are beginning to emerge within
laboratories today.
REFERENCE
1. ISPE GAMP “A Risk-Based Approach to
GxP Compliant Laboratory Computerized
Systems”, second edition (2012).
2. https://www.gmp-compliance.org/
gmp-news/the-new-gmp-annex-11-
and-chapter-4-is-europes-answer-to-
part-11, visited on 07 July 2010.
3. http://www.oecd.org/chemicalsafety/
testing/oecdseriesonprinciples-
ofgoodlaboratorypracticeglpand-
compliancemonitoring.htm,
visited on 07 July 2010.
4. Organisation for Economic Co-operation
and Development (OECD) Series on
Princicples of Good Laboratory Practice
and Compliance Monitoring, Number
17, The Application of GLP principles to
Computerised Systems, Paris, France (2016).
5. European Commission Health and
Consumers Directorate-General,
EudraLex: The Rules Governing Medicinal
Products in the European Union.
Volume 4, Good Manufacturing Practice
Medicinal Products for Human and
Veterinary Use. Annex 11: Computerised
Systems, Brussels, Belgium (2011).
6. https://mhrainspectorate.blog.gov.
uk/2018/03/09/mhras-gxp-data-
integrity-guide-published/, visited on
07 July 2018.
Nadia Sara
Adjal
Nadia Sara Adjal is a Business
Consultant within Life Sciences
Professional Services in NNIT. She
has a background in pharmaceutical
design and engineering, and has
for the past three years worked
with bridging the gap between life
sciences and IT, with a focus on
laboratory processes and scientific
data management. She has hands-on
experience working in laboratories
and has carried out projects related
to validation of laboratory instrument
software in different GxP regulated
environments.
Email: nsra@nnit.com
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