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Chapter Two
The Laboratory
Managers Perspective
Ensuring Efficiency, Data Integrity,
and Compliance

Maribel Rios

Series
2017
B i o P r o c e s s STATE OF THE INDUSTRY

The Laboratory Managers

Perspective
Ensuring Efficiency, Data Integrity, and Compliance

Maribel Rios

L
aboratory managers and
supervisors are responsible for
overseeing analytical methods
and procedures; ensuring
regulatory compliance and personnel
safety; optimizing timelines, budgets,
and workflows; preparing for audits;
and other company- and laboratory-
specific details. Whether their
laboratories focuses on quality
assurance/control (QA/QC), research
and development (R&D), preclinical
or clinical testing, or drug discovery
and screening, forward-thinking
managers have taken advantage of
state-of-the-art innovations in
equipment and automated systems to ADOBE STOCK (HTTP://STOCK.ADOBE.COM)

operate effectively and have made use

of a number of tools to keep their
laboratories running smoothly.
In general, contract laboratories for
the bioprocess industry are keeping
pace with increasing demands, and
large biomanufacturers are expanding
their own laboratories and/or investing
in specialized testing areas. However,
during the past 15 years, managers
have had to face changes in laboratory
policies, instrumentation and
methods, employee turnovers, and
regulations.
Meeting Changes in the Industry
Laboratory managers have seen many
changes take place in the industry
over the past 15 years. One response
we have received from our customers
is increased demand and increased
requirements on documentation
describing laboratory work, from the
research phase to process
developments, says Reinhard
Baumfalk, vice president of R&D
instrumentation and control at
Sartorius. Our customers must
document many more details than
they did just 10 or 15 years ago, he
says. Another change has been the
use of knowledge-driven approaches
in the development of new drugs, new
processes, and new production
strategies. Basically you explore based
on design of experiment (DoE) rules
the available parameters of your
process and generate by that your
knowledge space. Based on these
mathematical tools a robust and
efficient process strategy can be
developed.
Other changes in the laboratory
have been brought from new
regulations. In 1997, 21 CFR Part 11
rules became effective (and would later
be revised). This rule began a
revolution in the processes for
handling quality control laboratory
data, says Nanda Subbarao (senior
consultant at Biologics Consulting
Group and BPI editorial advisor). We
quickly saw chromatography software
vendors release Part 11compliant
versions or patches that made the
software compliant. Many laboratories
started replacing those software
systems that could not be made Part
11 compliant. These new versions
were on the server rather than on
isolated computers. it was no longer
necessary to be physically in the
laboratory to process chromatography
data. Interestingly, this was roughly
the time when email became larger in
number than post office paper mail,
and telecommuting became more and
more common.

2 BioProcess International 15(6)e C hapter 2 of 11 State of the I ndustry 2017

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Lab Compliance Requirements
Equipment qualification and computer
validation
Validation of analytical methods and
procedures
Quality assurance of (certified) reference
material
Staff qualification and training
Corrective and preventive actions
Recording, archiving, and retrieval of
data
Laboratory audits
Source: Huber L. Regulations in
Pharmaceutical Laboratories. Agilent,
February 2004.
With these changes came the
expanded use of electronic laboratory
notebooks (ELNs) and other devices
that started the move from paper-
based data recording to digital
technologies. As the cost of memory
in servers decreases, we are seeing
larger amounts of electronic data
being generated in the QC laboratory,
says Subbarao. Other changes that
have changed the laboratory
environment includ the increase in
microfluidics-based methods and mass
spectrometry methods.
Technologies
Laboratory managers are
incorporating advances in laboratory
equipment and automation to replace
routine, repetitive manual procedures
and boost productivity and efficiency.
Automation allows greater control of
reactions and conditions and reduces
operational costs and variability. Full-
or semiautomated improvements have
been made in high-throughput
screening, liquid handling, automated
workstations, microarrays, robotics,
microfluidics, a number of scientific
software, and automated data capture
(1). The most state-of-the art
instruments combine one or more
tasks with the use of robotics (2). In
the past, laboratory processes were
mostly manual and paper-based tasks
from bench to desk, including the
definition and decision about the right
clone or media. says Baumfalk. Now
we see an increased need to optimize
these steps by using new hardware
such as multiparallel screening
4 BioProcess International
OOS Investigations
The FDA outlined the role of laboratory
managers in its guidance on OOS
investigations (15). As part of the
assessment, a laboratory manager
should do the following:
Discuss test methods with analysts,
confirm analyst knowledge of and
performance of correct procedure
Examine raw data obtained in the
analysis and identify anomalous or
suspect information
Verify that calculations used to convert
raw data values into final test results are
scientifically sound, appropriate, and
correct and determine whether
unauthorized or unvalidated changes
were made to automated calculation
methods
Confirm instrument performance
Determine that appropriate reference
standards, solvents, reagents, and other
solutions were used and that they met
quality control specifications
Evaluate test-method performance to
ensure it is performing according to
standard according to method
validation data and historical data
Fully document and preserve records
on the laboratory assessment.
systems or software such as DoE and
MVDA [multivariate data analysis]
packages.
Many of those changes were made
to address the need for improved
product quality and reduced procedure
errors. R&D analysts, for example,
rely on high-throughput screening
because it allows rapid testing of
multiple drug candidates. And some
laboratory instrument suppliers have
developed flexible, configurable
automated liquid-handling systems
and workstations to address specific
laboratory needs (e.g., Beckman
Coulter and Hamilton). Such systems
can include multiple configurable
pipetting workstations with disposable
tips, and a model from Hamilton
Robotics can be used with an
extension module to increase capacity.
Analytical instrument suppliers
typically develop software platforms to
control their instruments as well as
collect, display, and store the data
acquired with their instruments. To
optimize laboratory managers
15(6)e C hapter 2 of 11 State of the I ndustry 2017
budgets, some software suppliers are
now offering single-sourced platforms.
The goal is to simplify laboratory
equipment selection, minimize
training costs for laboratory managers,
increase employee efficiency, and
reduce overall service costs.
The use of electronic data capture
systems instead of paper notebooks
has been a major change in
laboratories. Automated systems such
as electronic notebooks, laboratory
informatics systems, and laboratory
information management systems
(LIMS) are used for data capture,
transfer (e.g., to batch-scale operations
and data historian systems), and data
management. They also help
laboratory managers prepare for
regulatory audits because LIMS
provide records of workflows,
preparation methods, procedures,
analytical test data, metadata, and
changes made. Early problems with
automated systems included the need
for extensive amounts of time for
implementation and training, and
managers had difficulties with project
and hardware selection and budget
justification (3). Today LIMS and
similar systems are available off the
shelf or customized through suppliers,
and data capture software applications
are typically embedded within a
companys standard operating
procedures (SOPs) or test methods (4,
5). Secure platform software solutions
for data capture, storage, and review
must comply with FDAs 21 CFR Part
11 regulations for electronic records
and signatures and be compatible with
audit trail systems.
Most improvements in laboratory
instrumentation have taken place in
larger companies. However, many
smaller or start-up companies are
working on small-volume processes or
emerging therapies such as cell, gene,
or tissue innovations. Those processes
are typically conducted using
laboratory-scale instruments. Cell
therapy manufacturing in academic
laboratories, for example, are still
mainly manual processes (6). For a
laboratory-scale process (e.g., process
development), suppliers have
developed bench-scale units such as
microbioreactors, laboratory-scale
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chromatography and purification
systems, and single-use systems. In
the past 15 years, we have seen a
growing trend toward more single-use
solutions such as bioreactors for
laboratories, in addition to traditional
equipment such as single-use pipette
tips. These systems offer incredible
benefits and significant increases in
efficiency and safety in lab
environments, says Baumfalk.
Contract Laboratories
Managers of contract laboratories face
the same issues as those in sponsor
companies, but they have the added
responsibilities of collaborating with
clients and ensuring that client-specific
needs are met. As BPI authors Nims
and Meyers point out, The laboratory
to which a pharmaceutical company
outsources QC testing in effect
becomes an extension of that companys
own QC organization. Its compliance
requirements must therefore be
matched by those of the contractor.
Managers of contract testing
laboratories must ensure that their
facilities meet the expectation of clients
by defining quality systems, including
sample chain of custody, organization
and personnel, buildings and facilities,
equipment, control of components,
laboratory controls, change control, and
records and reports (7).
As the number of different classes
of biotherapeutics increases, some
laboratories are expanding their
expertise by adding niche
specializations. These can include
testing within a specific process/
product phase (e.g., chemistry,
manufacturing, and controls (CMC)
testing, early development), or class of
therapeutic (e.g., testing of biosimilars
and other emerging therapies) as well
as offering a traditional range of
services such as method development,
characterization, and extractables/
leachables testing for single-use
components and films.
Efficiency Goals
A large part of a laboratory managers
job involves working with staff to meet
shrinking timelines and the demands
of increasing workflows. One driver
we have seen as a request from our
6 BioProcess International
customers is the increasing level of
regulatory requirements for
documentation for what is done in the
laboratory, from early research phases
to process development says Baumfalk.
To fulfill data integrity requirements
our customers are required to
document in much more detail than
they had to do about 15 years ago.
Todays laboratories use
optimization tools such as factorial-
based design of experiments (DoE)
strategies, lean manufacturing, and six
sigma, Kaizen, and 5S (8).
Commercially available workflow
management software also can help
increase efficiency by organizing and
streamlining process tasks. Other
approaches can be as simple as keeping
up to date with instrumentation,
designing a supportive workspace,
investing in training and innovation,
defining storage space, and
maintaining inventory regularly (911).
Regulatory Compliance
Quality laboratories (both in-house and
outsourced) must comply with current
good manufacturing practices
(CGMPs), including document control
for audit/inspection preparation and
personnel qualification. Within a QC
laboratory, CGMP requirements include
validation of analytical methods,
sampling, product testing, and approval
of test reports (1213). A number of
guidelines from the International
Council of Harmonisation (ICH), (e.g.,
ICH Q6B, Q5C, Q5D, and S6) are
specific to biopharmaceutical testing.
As in all laboratories, bioprocess
managers are responsible for ensuring
compliance with occupational safety
and health administration (OSHA)
regulations and safety training to
minimize risk, especially when the
laboratory works with highly potent
materials. Several presentations and
articles have been dedicated to details
about GMP inspections for laboratories
and how to avoid pitfalls. Some areas
to watch include equipment
(calibration, validation, maintenance),
SOPs (data records), out-of-
specification (OOS)investigations and
documentation, training, and analytical
method validation documentation and
records (1416).
15(6)e C hapter 2 of 11 State of the I ndustry 2017
Some FDA guidances discuss
specifically the responsibilities of
laboratory managers. For example,
the agencys guidance on OOS
investigations (part 3) includes a
section on laboratory investigation,
the responsibility of analysts, and
laboratory supervisors (see box OOS
Investigations). Other FDA and ICH
documents detail the laboratory role in
pharmaceutical quality systems,
analytical method validation, stability
programs, and audits and inspections.
Effective this year, the FDAs data
integrity guidance is changing the way
analysts must record and store data
(e.g., data must be contemporaneously
recorded) to comply with CGMPs
(see Regulatory Affairs article in this
issue) (17).
Subbarao offers the following tips
to consider when preparing for a
laboratory audit:
Have a clear picture of the
regulations with which you need to
comply, will you need to comply with
US GMPs, good laboratory practices
(GLPs), and local OSHA rules?
Do a thorough gap analysis,
preferably by a third party that was
not involved in the laboratory process
design or the quality assurance (QA)
team that routinely monitors the
laboratory. Address gaps based on risk
or be prepared to defend the gaps that
remain.
Assign roles such as host, scribe,
and so on. Prepare and train the audit
team and all personnel on the audit
procedure.
One of the things that I do when I
go into laboratories is ask whether
they are subject to GMPs or the
GLPs, says Subbarao. Often, the
laboratory personnel think theyre
subjected to the GMPs, but they find
out that there is one assay or one
sample or something else to which the
GLPs apply. Now theres a lot of
commonalities between the two, but
theyre not identical.
Opportunities Ahead
Some forward-thinking laboratories
have begun incorporating green/
sustainable chemistry practices by
watching energy consumption,
reducing footprint, minimizing the
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use of volatile organic compounds
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bioprocessing laboratories, however,
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have embraced sustainable concepts.
References
1 Gwynne P, Heebner G. Laboratory
Automation: Smaller, Cheaper, Faster. Science.
January 2006; www.sciencemag.org/site/
products/labauto_011306.xhtml#Full.
2 Scott C. Robots in the Laboratory.
BioProcess Int. 11(10) 2013: 2225. WRsz-a35_bQ.
3 Rutherford ML. Managing Laboratory
Automation in a Changing Pharmaceutical
Industry. J. Auto. Chem. 17(2) 1995: 5963.
4 Helfrich JP. Compliance-Bsed
Operational Excellence in Pharmaceutical
GMP Laboratory Operations. Lab Manager 31
December 2006.
5 Rios M. Analytics for Modern
Bioprocess Development. BioProcess Int. 12(3)
2014: S1S8.
6 Harris IR, Meacle F, Powers D.
Automation in Cell Therapy Manufacturing.
BioProcess Int. 14(4) 2016: S18S21.
7 Nims RW, Meyers E. Contractor
Responsibilities in Outsourced Pharmaceutical
Quality Control Testing. BioProcess Int. 8(6)
2010: 1620.
8 BioProcess International
8 Harte A. Improving Lab Performance
with Six Sigma. iSix Sigma; www.isixsigma.
com/implementation/case-studies/improving-
lab-performance-six-sigma.
9 Thomas S. 10 Top Tips for Life
Science Laboratory Efficiency. SelectScience 3
February 2017; ww.selectscience.net/top-
lists/10-top-tips-for-life-science-laboratory-
efficiency/ ?artID=37745.
10 Reynolds T, Scharton-Kerston T.
Designing Labs for Lean Operation. Lab
Manager 6 December 2013; www.labmanager.
com/lab-design-and-furnishings/2013/12/
designing-labs-for-lean-operation#.
11 Filosa A. The New Normal in
Laboratory Efficiency: Leaner, Faster,
Smarter. GEN September 2014; www.
genengnews.com/bioperspectives/the-new-
normal-in-laboratory-efficiency-leaner-faster-
smarter/5298.
12 Sceppa M. CGMP Pitfalls in the QC
Laboratory: Preparing the QC Laboratory and
Staff for an FDA Inspection. MSceppa
Consulting; www.pda.org/docs/default-source/
website-document-library/chapters/
presentations/new-england/cgmp-pitfalls-in-
the-qc-laboratory-preparing-the-qc-
laboratory-and-staff-for-an-fda-inspection.
pdf?sfvrsn=6.
13 Compliance for Biopharmaceutical
Laboratories Primer. Agilent Technologies:
15(6)e C hapter 2 of 11 State of the I ndustry 2017
2015; www.agilent.com/cs/library/primers/
Public/5991-5700EN.pdf.
14 Huber L. Compliance by Design for
Pharmaceutical Quality Control Laboratories:
Insight from FDA Warning Letters. ; http://
www.agilent.com/cs/library/primers/
Public/5991-5456EN.pdf.
15 Center for Drug Evaluation and
Research. Guidance for Industry: Investigating
OOS Test Results for Pharmaceutical Production.
FDA: Rockville, MD, October 2006.
16 FDA 483s in the Lab; Compliance
Insight, Inc., 2013; https://www.slideshare.
net/complianceinsight/fda-483-observations-
in-the-lab.
17 FDA Guidance for Industry (draft):
April 2016. Rockville, MD. c
Data Integrity and Compliance with CGMP.
Maribel Rios is managing editor of
BioProcess International; mrios@
bioprocessintl.com.
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