With the FDA’s increasing focus on
modernizing regulation of pharmaceutical manufacturing and product quality,
companies are being forced to
reexamine whether traditional development
and commercialization processes
are sufficient. A major goal of
the new current Good Manufacturing
Practices (cGMPs) initiative and Process
Analytical Technologies (PATs) is
encouraging the adoption of new technological
advances to enable high-quality
and efficient manufacturing.
Pharmaceutical development and
manufacturing has not changed its
fundamental paper-based infrastructure
in decades. The principal reason is
that regulatory requirements resist
change. Until recently, industry and
the FDA were not aligned with respect
to utilizing innovation and technology
to bring manufacturing processes into
the twenty-first century. Leading companies
are adopting a new approach to
automating compliance by utilizing
innovative technologies and building
quality into the compliance infrastructure
(e.g., standard operating procedures,
work instructions, analytical
methods, data sheets, and batch
records). Many of these internal programs
are sometimes called “Right the
First Time” programs. Their key conclusion
is that compliance activities
can be automated, creating a new,
more compliant paradigm; reducing
risk; and providing higher productivity
and improved quality.
This paper discusses the current situation
in laboratory operations relative to
compliance initiatives and manufacturing
challenges, and profiles a “method-centric”
software platform, designed for
the analyst, to electronically execute
and manage QC testing protocols,
yielding significant reductions in overall
product release cycle times. This
technology can be defined as PAT (process
analytical technology) for QC and
process laboratory processes.
Today, the U.S. pharmaceutical industry
spends approx. $90 billion on manufacturing.
By improving manufacturing
efficiency by only 5%, the industry
could yield over $4.5 billion annually.1
Leading pharmaceutical companies,
generics, and contract research organizations
have prioritized programs
designed to eliminate the routine, nonvalue-added tasks through automation.
Research conducted at VelQuest Corp.
(Hopkinton, MA) confirms that in
most regulated companies, approx. 70%
of laboratory-based resources are
focused on compliance-related functions.2 Within the quality operations,
the initiative to “go paperless” is
expected to create operational benefits
resulting in millions of dollars in efficiency
gains. This e-manufacturing
environment will enable immediate
communication between the many disparate
data sources, ranging from product
and process development, pilot
operations, incoming raw materials
inspection, in-process monitoring, and
process analytical technologies to final
quality control laboratory results. Interfacing
these data sources and higher-order
information management technologies
provides a platform for
enterprise-wide decision-making to significantly
improve batch release cycle
times. Going paperless can allow one to
manage the data across the entire enterprise—within the plant, plant to plant,
or across the entire global operation.
Industry operational
challenges
The pharmaceutical and biotechnology
industries are challenged to
improve product quality, productivity,
return on investments, and compliance
while at the same time generating
an annual 10–15% growth for
their stakeholders. This is becoming
increasingly difficult due to the large
number of branded products coming
off patent over the next three years
and vulnerable new product pipelines.
This means that these companies
must roughly double the number of
new lead candidates entering the clinical
trial phases of the drug approval
process, shorten overall time to market,
and decrease overall costs. The
entire product life cycle (research,
development, and manufacturing)
must be streamlined. Within this
environment, large amounts of data
are being generated across the entire
enterprise. Today, most laboratory
operations rely on the ubiquitous use
of paper-based systems that are fraught
with potential human-generated
errors and require constant checking
and manual verification procedures. These processes add no value
to the operations and significantly
contribute to the costs.
Also, complying with cGMP
requirements is another challenge
for the life science industry,
further adding costs stemming
from manual activities
centered on compliance.
21 CFR Part 11 emerged as a
demanding regulation for the
pharmaceutical and biotechnology
industries. Regulations
that affect the overall management
of electronic records
have added new priorities for
the industry. Part 11 has
recently been modified to
lessen the total scope and provide
a more rational framework
for implementation;
however, the rule still applies
if the electronic record is in a
high-risk area as defined by
impacts on human health.
The QA/QC functions within
the pharmaceutical production
arena clearly fall into this
high-risk definition. Systems
that generate electronic
records required by a predicate
rule must be examined,
including analytical instruments
(chromatography data
systems, balances, and spectrophotometers,
etc.), office
applications (Microsoft®
Word™ and Excel™, Redmond,
WA) used for documentation,
and LIMS. From
each QC laboratory across the
enterprise, Part 11 significantly
impacts good electronic
record-management practices.
Opening the door to the
paperless laboratory
The automation initiatives in production
over the last decade were driven by
the need to precisely control production
processes and cut costs. That environment
is now being further modified
by reviewing the costs associated with
nonvalue-added tasks. An identified
area is the large amount of paper processes
used in manufacturing, particularly
quality control and quality assurance
functions. These e-manufacturing
initiatives have received attention as
one of a small number of critical path
issues that, if solved, will provide significant
cost savings for decades. Some key
insights obtained from a research survey
conducted by VelQuest Corp. in 20022
are revealing: “Our company has a priority
initiative to delegate decision-making,
enrich jobs and create
accountability for delegated decisions.
We see paperless labs as a tool to
empower analysts to fulfill this charter.
We also want to reduce the time lab
supervision spends on review and investigations,
so they can work on process
improvement. . . . We believe [that
through paperless labs] real-time
feedback enables analysts
to reduce errors, minimize
rework loops and correct
ambiguous results immediately.”
The main issues mentioned
here are decreased review
times, reduced operator error,
minimization of rework and
investigations, and ultimately
enhancement of the work
experience for well-trained
analysts and operators. All of
these issues contribute to costs
and product release cycle times
and, if minimized, will significantly
affect an operation’s
bottom line.
The patented SmartLab™
software was developed to
embed an automated data
capture software application
within a company’s existing
standard operating procedures
(SOPs) or test methods
(VelQuest Corp.). In doing
this, the software presents
only the approved method to
the analyst and captures all
the critical data and metadata
created during the process of
implementing a method on
the laboratory or process
floor. Data elements include
method preparation data
(reagent information, weighing
operations, metrology,
etc.), analytical instrument
data (chromatography and spectroscopy), and analyst or
operator observations (color,
texture, shape, etc.).
Figure 1 - A digital version of a standard operating procedure (or
method) is presented to an analyst with automatic capture of critical
method-based data. This process eliminates transcription errors associated
with paper-based notebooks.
Figure 2 - After a method is completed, all data are presented to
reviewers with visual flags for all specifications and materials expiration
requirements along with instrument calibration dates, audit trails,
annotations, e-signatures, and direct “drill-down” links to the raw
data sources at the click of a mouse.
The software takes existing written
protocols (methods or SOPs) and
presents them in an electronic version
with embedded data capture
technology. Analysts and operators
interact with the digitized SOP
through PCs or handheld tablet PCs
that force data entry and capture
either manually or automatically
(directly from instruments). The
technology can be thought of as a
QA/QC Operation e-Notebook. At
the end of the process all of the data
are aggregated in a reviewer screen
(see Figures 1 and 2) with all data flagged for specifications and a
direct link to the original data
source. Review times are typically
reduced by a factor of 50% or more.
Raw data files are automatically captured
and organized in a secure
repository for future needs.
Access to the SmartLab platform is
controlled via a secure privilege grid
with full audit trail and electronic
signature capability providing compliance
with the FDA’s 21 CFR Part
11 regulations. The resulting data
are accessible to any authorized
member of the QA review or management
team. Customized reports,
including certificates of analysis for
batch release documents, can then
be automatically created and
approved. Data and trending reports
can also be exported to other inhouse
IT infrastructure requirements
such as a LIMS or Enterprise
Resource Planning/Manufacturing
Resource Planning (ERP/MRP) system.
In many respects, this technology
represents the process analytical
technology applied to the QC laboratory
processes. Just like physical
manufacturing processes, the laboratory
environment utilizes method
processes conducted by analysts, and
through embedded method-centric
software (SmartLab), the PAT philosophy
can be applied to the laboratory
with equivalent productivity
improvements and significant
returns on investment.
Conclusion
The pharmaceutical industry is seeking
to control costs as a result of questionable
new product pipelines and
the erosion of business due to the large
number of products coming off patent
over the next few years. For decades,
most of the data management processes
in QA/QC have been paper
based, requiring numerous nonvalue-added
manual checks to ensure that
data integrity and product quality
standards have been met. In today’s
modern computer-based environments,
technology can be adapted to
totally eliminate these paper systems
and replace them with a fully all-electronic
method execution and data
capture and review system. An example
of such a system is the SmartLab
platform, which is designed to present
approved SOPs in a digital form and
embed software to automatically
prompt analysts and operators to follow
the procedure as written and automatically
capture and catalog all the
method data and outcomes in a secure
repository. This process eliminates
operator method error or transcription
issues in working with a paper-based
notebook process. The data are automatically
grouped and presented to a
QA reviewer with color-coded flags
for specification verification, e-signatures,
and full audit trail of activity.
This process can typically reduce
review times by over 50% and reduce
rework and internal investigation processes,
resulting in overall operational
QA/QC laboratory cost improvements
of over 20%. This technology
can be viewed as PAT technology for
the laboratory environment.
References
-
Pharmaceutical Processing Dec
2003:20.
- Laboratory IT-Enabled Solutions
Research Report. VelQuest Corp., Nov
2002.
Mr. Helfrich is Director, Laboratory Automation
Programs, VelQuest Corp., 25 South St.,
Hopkinton, MA 01748, U.S.A.; tel.: 508-497-0128; fax: 508-497-2396; e-mail:
[email protected].