CONVERGENCE of COMPLIANCE

& TECHNOLOGY
How Technology Has Changed Regulatory Compliance in the Past Decade

MATTHEW M. LOWE

ABOUT THE AUTHOR

Matthew M. Lowe, executive vice president at
MasterControl, is a mechanical engineer with
over fifteen years of medical device experience in
product development, product management, and
regulatory compliance. Prior to joining MasterControl
in 2006, he worked in product development and
product management at Ortho Development Corp.
and Bard Access Systems. He has successfully
launched more than a dozen medical devices and
has four patents issued. His regulatory compliance experience includes writing
a 510(k) that was cleared by the FDA and managing a multisite, multiyear postmarket clinical study for orthopedic devices. He received a bachelors degree
in mechanical engineering from University of Utah and an MBA from Indiana
University.
Published by MasterControl Inc.,
6330 S. 3000 E., Suite 200, Salt Lake City UT 84121
Copyright 2016 by MasterControl Inc.
All rights reserved. No part of this book may be reproduced in any
form or by any means without the prior written consent of
the publisher, except for brief quotes in book reviews.
The content of this book is the expression of the authors opinions and
do not necessarily reflect the policy or position of MasterControl.
Publisher: Curt Porritt
Executive Editor: Jason Clegg
Editor: Cindy Fazzi
Art Director: Mike Hansen
Cover Design, Illustrations, and Layout: Deserei Koker
Video: John Johannesmeyer

First edition: September 2016

Published in the United States of America

DEDICATION
To my wife for supporting me in my career these many years and raising our
three beautiful children to be extraordinary young people in spite of the fact that
I am their father. Family is everything.

ACKNOWLEDGMENTS
I want to recognize my editor, Cindy Fazzi, without whom this work would
have never come to fruition. Her vision and encouragement was instrumental
in bringing forth what I think is a very innovative e-book format. I would also
like to thank my many colleagues, past and present, who have shared their
insights and knowledge with me over the past seventeen years. Together we
can continue to shape the future of how technology enables and advances
regulatory compliance.

Contents
01
02
04
10
14
19

VIDEO: CONVERGENCE OF COMPLIANCE AND TECHNOLOGY

PREFACE

CHAPTER 1: THE RECENT PAST REVISITED

The Old Manual Process

The MRR Bottleneck
Murphys Law
Other Life Science Companies
CHAPTER 2: THE MOVEMENT TOWARD AUTOMATION

The Heart of 21 CFR Part 11

How Part 11 Became a Big Deal
Early Days of Automation
When Compliance is Adversarial
CHAPTER 3: REGULATIONS THAT HELPED SPUR TECHNOLOGY USE

Compliance and Technology: Important Milestones

CHAPTER 4: NO TIME LIKE THE PRESENT

Approval of Novel Drugs

Approval of Medical Devices
Greater Onus
Software Industrys Response
Evolution of Quality Software
Manual Process as Part of Obstacle Course

25

CHAPTER 5: THE FUTURE STARTS NOW

31

CHAPTER 6: PREPARE TO SUCCEED

34

CHAPTER 7: CONCLUSION

36

REFERENCES

Prediction versus Observation

Part of the Tech Movement
Future Collaboration

How Best to Prepare

Positive Regulatory Relations

Software Providers as Part of Collaboration
Right Place, Right Time

01

Preface
We live in a time of rapid change and information overload. It helps to pause
and ponder the state of things once in a while. In the software industry, the
Agile principles call for regular evaluation to sustain constant development
work. In the quality field, the concept of continuous improvement is embedded
in the quality management system (QMS) as a never-ending cycle of changes
based on reviews and audits.
My background in both medical device and software technology has instilled
in me the value of the Agile and quality approaches to contemplation. Whether
it was implementing a rework due to a nonconformance back when I was a
product development engineer at a med tech firm or helping a pharmaceutical
company automate its quality system in my current role, the need for
assessment is the same. Reflection is necessary in order to learn, adapt, and
improve.

In terms of pharmaceuticals, the drug called Ivacaftor (brand name: Kayledeco)

is the first medicine to treat the causeinstead of symptomsof cystic fibrosis
in patients with the G551D mutation.2 Not the stuff that Hollywood films are
made of, but incredibly important for patients suffering from the potentially fatal
disease.
Breakthroughs such as these happen, thanks in large part to faster and more
efficient, technology-driven clinical trials, regulatory submissions, and approval
process. I feel very fortunate to be part of this movement that advances
societys ability to deliver life-changing products to market. If you work in the
life science industry or a regulated environment or the compliance technology
sector, then youre part of this movement.
I hope this book helps increase awareness and understanding of this common
path we share. This is not a history book, but just the same, its an opportunity
to look back at the most important developments in the recent past that have
shaped regulatory compliance for life science companies.

Writing this book is an opportunity for me to do exactly thatto reflect not just
on the medical device sector but the life science industry in general, as well as
the software development business.
If our society were a city, then writing this book is a chance for me to offer you
a snapshot of the highway where life science and technology merge in order to
deliver medical solutions to the rest of the world. That on-ramp where the two
merge is regulatory compliance.
Without compliance, there can be no product approval, which means no matter
how cutting-edge your device or how innovative your medicine, it will not
reach the people who need them. In this metaphor, the individual life science
companies are the different vehicles on the highway of compliance that deliver
life-changing products to the global market.
This book will explore how the use of technology in the past decade or so has
helped both regulated companies and regulatory agencies in easing the pains
of delivering those products to patients and consumers worldwide. Regulatory
milestones enforced by the FDA helped define the books scope.
In the past decade, we have seen numerous breakthroughs in the life science
industry. For example, the BrainGate2 Neural Interface System is in the
early stage of clinical trial to test the ability of paralyzed patients to control
assistive devices with their thoughts.1 While telekinesis makes for great fiction,
technology-driven telekinesis by implanting a sensor in the brain might just be a
reality soon.
02

The cochlear implant worn by this woman alleviates certain types of

hearing loss, one of the many med device breakthroughs.

03

01
THE RECENT PAST REVISITED

Life science companies face enormous scientific, economic, and regulatory

challenges during development of medical products. While the growth of R&D
has always been intertwined with technological advances, it has not been the
case for regulatory compliance.
The watershed regulation, 21 CFR Part 11, established the criteria for the
use of electronic records and electronic signatures by organizations under
the jurisdiction of the U.S. Food and Drug Administration (FDA). Part 11 was
controversial from the start. Critics complained it was too broad and confusing.
Companies said it was too costly to implement.
Part 11 went into effect in August 1997, but it took the FDA two guidances
(in 2001 and 2003) to explain the regulations scope and application. The
2003 guidance signaled that, at last, the FDA had embraced technology for
compliance purposes. It served as a catalyst for software companies to develop
compliance solutions tailored to Part 11 and for the industry to automate quality
processes.
Its no coincidence that in 2004, the Pharmaceutical Research and
Manufacturers of America (PhRMA) issued the SAFE (Signatures and
Authentication for Everyone) digital signature standard.

Part 11 confirmed the

dire need for improvement
of processes.
04

Before the advent of laws regulating the life science industry, leeches* and snake oil were sold as medicine.

THE OLD MANUAL PROCESS

To understand how technology revolutionized the compliance process, its
important to put this story in the right context. Let me describe what a paperbased process was like when I worked in the med tech industry.
In my first job in a med device firm, I was a product development engineer
(PDE). The process for getting a new drawing through the system required a
lot of time and effort. Bear with me and imagine the process we endured back
then.

Imagine standing before a long table with an array of stamps and different
colors of ink pads with your piles of documents. Perhaps you would need a
blue stamp for proposed documents, a green stamp for approved and black
for released. Talk about watermarking! You would stamp each copy with the
appropriate stamp. You would then attach your documents to the CO form and
submit everything to doc control, cross your fingers, and hope you didnt miss
anything.
If doc control took issue with anything, it would involve re-printing, revisiting the
table for re-stamping, and re-submitting the change packet. Are you tired yet?
Wait, were not yet finished.

First, you would start with an informal redline of the paper drawing among your
peers (e.g., other PDEs and the manager). Once done with that, you would
incorporate the changes and print a new copy. You would have to print an old
copy and manually go through the drawing and redline it to reflect the changes
in the new proposed copy.

Once the doc control team members were satisfied, they would then consult
the signature matrix and ensure the CO form had the right signatories. The list
was often bloatedby designas there would be several individuals on the list
included only as a safeguard

Prior to all of this, you would get a change order (CO) number from the
Document Control Department, so you could include it on your new drawing.
You would then fill out the Excel spreadsheet that served as the CO form and
print it out. Then you would take all of that to the doc control area with a copy
of the original, the proposed redlines, and the new drawing.

The packet would then start to go through the signatories. Typically there would
be a round of questions and/or redlines with each of the signatories, which
would require changes to be made, new copies to be printed, and re-routing
to any signatories who signed off prior to the change. The packet might sit on
someones desk for several days, if not weeks. It might mysteriously disappear
for several days at a time. You just never knew.
Once you were lucky enough to get everything signed off, you might then have
to hold a training for impacted parties to go over the changes and have them
sign off to prove that they have been trained. Heaven forbid someone were
traveling or out sick because you might have had to chase that person for
several more days before the drawing could be released.

When the drawing was ready for release, doc control would keep the official
copy and would then start replacing all of the controlled copies spread
throughout the plant, including the manufacturing floor, quality control, and
engineering.
The Procurement Department may also have had to send out new copies
to contract manufacturers and pray that the vendor would indeed receive
them and would actually build the next lot of parts, and in some cases the lot
currently in process, to the new spec.

Dr. lie Metchnikoff, shown in his lab, embodied the challenges of the old manual process.
He won the 1908 Nobel Prize for his research in immunology.

05

We used to have great filing cabinets with very long drawers. The Engineering,
Purchasing, and Manufacturing Departments each maintained its filing cabinet.
For Engineering, we kept a controlled copy there with little labels (e.g., Parts
x, y, z). The person who needed a document would thumb through all fifty
drawings and look for the right document, if it was there at all.

06

Doc Control had a document room where the final, controlled documents
resided. The team held the master copy and it was responsible for changing
any documents that had been revised.
This meant the other departments kept uncontrolled copies on electronic
servers with directory structures. Uncontrolled copies did not have the
necessary signatures, unlike the master copy. For example, Purchasing might
send an uncontrolled copy to show a vendor, but it was strictly for review only.

THE MRR BOTTLENECK

If you think the abovementioned process is cumbersome, let me remind you
there were other hurdles along the way. Another onerous process involved the
material review report (MRR). Its also known as the nonconforming material
review (NCMR) process.
The process would typically involve a material review board (MRB) meeting
at least once a week (scheduled) and potentially several times a week
(unscheduled). Representatives from Quality Assurance (QA) and Quality
Control (QC), an R&D engineer, manufacturing engineer, and quality engineer
would attend the meeting. You can just imagine the hourly cost of these weekly
meetings.

MURPHY'S LAW
The problem with a manual process is Murphys law itselfany number of
things can go wrong and they will go wrong. I recall being in the midst of
an FDA audit. The field investigator asked for a document that could not be
found. We could find the electronic copy stored in the FileShare, but the hard
copy with the wet signatures that should have been filed with doc control was
missing. It could have been filed improperly, lost in the process, accidentally
discardedthe perils go on and on.
As bad as that experience was, there are worse things that could happen. What
if someone accidentally puts a nonconforming product on the shelf? If the
defective item gets out in the marketplace, you could injure a patient and face a
recall.
I remember a case in my previous life, in which customer complaints on a
device were not dispositioned properly and an MDR was not filed. It was
a common problem with a manual process. The slip-up resulted in an FDA
warning letter for not filing reportable events.

If some of the parties fail to attend, you can bet that a chase would follow to get
the reviewed MRRs signed by those people. What if you have MRB members
who are dispersed geographically? Perish the thought! Often an MRR would
result in a rework instruction, supplier deviation, change request, supplier
corrective action request (SCAR), or some other activity that would also be
initiated and chased on paper.
On top of this, the folks in the Materials Department would have to be notified,
so they could update the enterprise resource planning (ERP) system and
quarantine the product in question. The quarantine would last until the nonconforming product could be corrected for shipment to customers. When
something like this happened, Procurement and Product Management
would not be able to forecast the number of units the company needed to
manufacture in order to keep up with the demandand any delays in the
communication or updates could result in back orders (read: lost revenue).
Now that youve had a glimpse of my experience enduring the manual process,
how does it compare to your experience? Perhaps you and your colleagues
share a few battlefield stories similar to mine, or worse.

07

Regulatory compliance has come a very long way from the days when heroin was sold over the counter.

08

The problem with a manual

process is Murphy's law....
OTHER LIFE SCIENCE COMPANIES
My story is just one example confined to a med tech firm. Pharmaceutical
companies, blood centers, and other regulated companies have similar
experiences with paper-based processes.
The Institute for Transfusion Medicine (ITxM) used to have a hybrid qualitymanagement system (part paper and part electronic), which required the
different departments to manually route their documents for review and
approval. Those documents were stored on electronic servers, printed
on hard copy, and compiled in more than 250 binders. Using a modified
National Committee for Clinical Laboratory Standards (NCCLS) nomenclature,
documents were tracked by their number, type, and revision number.3
Teva Pharmaceuticals, the top developer and manufacturer of generic drugs
in the United States, used to conduct early-morning meetings affectionately
dubbed by employees as document signature parties. At one point, the
company had 3,500 SOPs under its manual process.4

02
THE MOVEMENT TOWARD AUTOMATION

Which came first, the chicken or the egg? This dilemma applies to automation
and regulatory compliance. Did the FDA issue 21 CFR Part 11 to encourage
technology use? Or did life science companies use technology first, which in
turn prompted the FDA to develop corresponding regulations?
Its the latter, according to an article published in ISSA Journal. In the days of
old, pharmaceutical companies would literally ship truckloads of data to the
FDA, wrote Ben Rothke. There clearly had to be a better, faster, cheaper, and
easier way to move data. And indeed there wasvia electronic networks.
A group of pharmaceutical companies met with the FDA in the early 1990s
to find out how they could submit voluminous documents electronically. This
eventually led to the development of 21 CFR Part 11.7
Its true that regulatory requirements impose a heavy documentation burden
on life science companiesa compelling reason to automate quality and
compliance processes and regulatory submissions.

SynCardia, manufacturer of the worlds first and most widely used Total Artificial
Heart, had a hybrid process that generated documents in different formats
and were all hand-stamped, numbered, and hand-delivered to approvers. The
companys servers stored 1,200 files at one point, but paper documents were
kept in different filing cabinets. As business grew, the companys quality system
challenges also increased, culminating in an FDA audit that compelled the
organization to improve its processes through automation.5
For many years, companies endured the pains of their labor-intensive processes
while trying to maintain compliance and stay competitive in the global market.
The situation changed for the better by the time the second Part 11 guidance
was issued in 2003.
The movement toward automation of such tedious manual quality processes
began in earnest at that time. Part 11 confirmed the dire need for improvement
of those processes and justified corporate spending on electronic systems.
It showed executives of life science and other regulated companies that
investing in automation was a wise option. Indeed software companies such as
MasterControl tailored their software solutions to Part 11 requirements.6

(Left) The first X-ray shows the handwith a ringof Wilhelm Roentgens wife. He accidentally discovered
X-ray in 1895. (Right) Modernization as exemplified by X-rays preceded automation in medicine.

09

10

THE HEART OF 21 CFR PART 11

The FDA issued the rule to establish criteria for the use of electronic records
and electronic signatures by organizations that comply with the Food,
Drug, and Cosmetic Act, the Public Health Service Act, and other FDA
regulations. It applies to organizations under the agencys jurisdiction, such as
pharmaceutical, medical device, biotech, blood, and biologics companies, and
contract research organizations. It took effect on August 20, 1997.8
Part 11s overall goal is to allow the use of electronic records as much as
possible and at the same time ensure public safety. In complying with Part
11, its important to remember the essence of the regulationFDAs main
concern is to safeguard record integrity in order to ensure product quality. The
FDA cares whether all electronic records in support of regulated activities are
accurate and valid.
The FDA felt that the risks of falsification, misinterpretation, and change
without leaving evidence are higher with electronic records than paper records
and therefore specific controls are required, wrote Rothke. The journal dubbed
Part 11 as both a security and a trust regulation, in the sense that Part 11
builds on security toward trust. While security controls rights and access so as
to maintain confidentiality and integrity, trust aims to control the basis of denial
and ensure accountability of individuals responsible for certain acts within the
electronic system.9
I would add that on top of those concerns, both the FDA and the industry
wanted to reduce the tremendous time and effort, plus the high cost involved in
regulatory submissions and compliance.

HOW PART 11 BECAME A BIG DEAL

Part 11 is voluntary in the sense that it applies to an organization only if it
chooses to adopt electronic systems for compliance purposes. In the 1990s,
many companies still operated with paper-based processes and sent paper
submissions to the FDA, so those organizations were excluded from Part 11
requirements.
However, it became clear that the huge amounts of artifacts required to
prove compliance necessitated automation and drove companies to switch
to electronic systems. Many organizations combined paper and electronic
processes, making hybrid systems widespread and are still so today.
Although the FDAs Part 11 guidance clearly states that the agencys
recommendations are nonbinding, it is not a license to ignore the regulation.

Maurice Wilkins is shown with a model of the double helixthe basis of all DNA researchwhich he helped develop.
Similarly, Part 11 provides a foundation for the use of electronic records in life sciences.

Does Part 11 have any teeth? Yes, judging by the hefty fines Abbott
Laboratories and Schering-Plough paid due to a host of Current Good
Manufacturing Practice (CGMP) violations, including requirements related to
Part 11. Over a decade ago, the two companies entered into a consent decree
with the FDA, in which Abbott agreed to pay $100 million, and Schering-Plough,
$500 million in fines. 10

11

The FDA made its expectations of industry compliance very clear after Part
11 took effect. Referring to the consent decree, an FDA official told a news
publication, Manufacturers who choose to wait until FDA investigators find
violations rather than policing themselves will find that they have made a very
poor and costly decision.11

EARLY DAYS OF AUTOMATION

I have to admit that back when I worked in an R&D Department of a med
tech company, my colleagues and I were not familiar with Part 11. The first
time I heard about it, I learned we were required to validate software as part
of our testing regimen. Validation is something we dealt with all the time in
manufacturing and design, but with the introduction of Part 11, there was an
added requirement of software validation.
We struggled with how to deal with Part 11 and what it meant. Like most in the
industry, we used the GAMP V model, which is about risk management. GAMP
(Good Automated Manufacturing Process) does not prescribe a method, but
it offers a pragmatic framework of good practice to ensure that your computer
systems are compliant.12
GAMP was meant to be used along with other industry guidelines, standards,
and best practices to determine the best approach for validation. So, to comply
with Part 11, we took those principles and applied them in software validation.

talk them through it. We presented all the data they needed. They could have
made everyones life easier if only they told us how they needed such data to be
presented.
I understood the need for regulation, but often felt that I jumped through a lot of
hoops just for the sake of jumping, not because those requirements made my
product safer or better.
Since then, the industry and regulators have matured and our understanding of
Part 11 and other quality regulations has grown with experience. More and more
companies have adopted technology and automated their quality processes
and quality management systems.
Now I look back at those days with a lot more appreciation, a feeling similar to
graduating from college or graduate school. Once I received that hard-earned
diploma, all the struggles melted away. Ive survived the hardest part, and more
importantly, Ive learned and succeeded.

FDA's main concern is to

safeguard record integrity.

WHEN COMPLIANCE IS ADVERSARIAL

Given the laborious manual process Ive described in the previous chapter and
the advent of Part 11, which we barely understood back then, it was easy to
develop a negative attitude toward compliance.
I became interested in bioengineering as a grade school pupil, back when the
field was in its infancy. Its novelty made it seem almost magical to a child in
second grade. To think that the body could be healed through engineering and
science fascinated me, and still does today.
So when I worked as a development engineerpursuing my longtime passion
for science and devicesit was disappointing to see the development process
blocked with many hindrances. My relationship with regulators back then was
somewhat adversarial.
My departments internal relationships with QA and RA personnel greatly
affected my views. There were times when all I could see were the obstacles to
getting my products to market. We were bombarded with demands that were
tedious at best and often whimsical.
It seemed as if the other departments always moved the target on my team,
showing little understanding of what presented risks and what didnt. I often
felt it was easier for me to just complete a regulatory task instead of trying to

12

The FDA protects consumers and enhances public health. These old posters fall under
the same banner of safeguarding the public from contagious diseases.

13

03

Since 2000, we have benefited from a technologydriven era in regulatory compliance. Ours is a time of
faster and more effective regulatory submissions and
adverse-event reporting. I would like to think that
things will get even more efficient in the future.

REGULATIONS
THAT HELPED SPUR
TECHNOLOGY USE

The following laws and initiatives have helped shape

the rapid modernization of regulatory compliance like
never before.

2010
The Physician Payments
Sunshine Act was
passed requiring drug
and medical device
manufacturers that
participate in U.S. federal
health care programs
to report payments and
items of value they give
to doctors and providers.
The reporting is done
electronically through the
Open Payments Program.

2008
The FDA launched the
Sentinel Initiative, a national
electronic system designed
to track the safety of drugs,
medical devices, and
biologics once they reach
the market. The project will
be implemented in stages.
As of 2016, the FDA has
implemented a mini-Sentinel.

2003
The FDA issued the second
guidance for 21 CFR Part 11, the
regulation on electronic records and
standards. Part 11 is meant to allow
the widest possible use of electronic
technology for FDA submissions and
compliance purposes.

2007
Congress passed the FDA
Amendments Act expanding
ClinicalTrials.gov submission
requirements.

2000

2004

2007

The National Institutes of Health's

National Library of Medicine
(NLM) launched ClinicalTrials.
gov, a database that provides
easy public access to information
about clinical trials. Its an
offshoot of a federal law that
required a registry of clinical trials
for medicines.

PhRMA (Pharmaceutical
Research and Manufacturers of
America) issued SAFE (Signatures
and Authentication for Everyone)
digital signature standard for the
global pharmaceutical, biotech,
and health care industries
worldwide. It is intended to
encourage the use of digital
signatures as part of an electronic
environment within the industry.

The FDA enforced SPL (structured

product labeling), a Health
Level 7 international standard
that defines the content of drug
prescriptions in XML format to
make the information accessible
and readable.

14

2008
In the pharmaceutical industry,
the electronic common technical
document (eCTD) became the
standard for electronic submission
to the FDAs Center for Drug
Evaluation and Research (CDER)
and the Center for Biologics
Evaluation and Research (CBER).
Drafted under the auspices of
the International Conference
for Harmonisation (ICH), the
eCTD specifies how electronic
submissions should be created,
reviewed, and archived.

15

2012
Congress created a new category
of breakthrough therapy in the
FDA Safety and Innovation Act,
which became law in July 2012.
The breakthrough pathway is an
expedited process of review and
approval of new drugs for lifethreatening illnesses. This pathway is
in addition to three other expedited
approval processes already in place:
priority review designation (1992),
fast track designation (1997), and
accelerated approval (1997).

2015
2014
The FDA required device
manufacturers and importers
to submit mandatory reports of
adverse events electronically
(known as eMDR).

2015

The FDA finalized its guidance

that required most eCTD
submissions to be submitted
electronically, including new
drug applications (NDAs),
biologic license applications
(BLAs), and investigational
new drug applications (INDs).

The FDAs Adverse

Reporting System/
MedWatch required that
applicants electronically
submit all MDRs, MDR
attachments, and periodic
safety reports.

2011

2013

2014

2015

The FDA introduced the

Innovation Pathway pilot, a
priority review program for
pioneering medical devices.
Under this program, the FDA
could conduct premarket reviews
within 150 days of submission,
about half the time of approval
for non-priority products.

The FDA released a final rule

establishing a unique device
identification (UDI) system that will
identify medical devices through
distribution and use. A UDI is a unique
numeric or alphanumeric code.

The FDAs 510(k) eSubmissions

Pilot Program offers a pathway for
the construction and submission
of a pre-market notification
application electronically without
the requirement of a hard copy or
a compact disk. Its sometimes
called turbo 510(k) because
its similar to the Turbo Tax
electronic process for taxpayers.

The FDAs Center for Devices

and Radiological Health (CDRH),
Offices of Device Evaluation
(ODE) and In Vitro Diagnostics
and Radiation (OIR) participated
in the International Medical
Device Regulators Forum's
(IMDRF) Regulated Product
Submission (RPS) Pilot Program.
The FDAs goal is to implement a
standards-based fully electronic
receipt, review, dissemination,
and archival environment. The
RPS is meant to harmonize
electronic submission methods
for pharmaceutical and medical
device industries.

16

17

04
NO TIME LIKE THE PRESENT

The days of manually stamping piles of documents with different colors of ink
are long gone. Most life science companies have automated their QMS to some
extent, though a recent report by LNS Research shows that the majority use
disparate systems.
Out of more than 900 regulated manufacturers surveyed, 78 percent relied
on fragmented data sources and systems that were not connected. Todays
prevalence of disparate solutions and strategies is not providing the visibility or
level of interaction across the value chain required to maintain competitiveness
in the global market, according to the report.13
Companies using connected or closed-loop electronic QMS (EQMS) performed
better in terms of these key indicators: overall equipment effectiveness, on-time
and complete shipments, and successful new product launches.14
From the perspective of the industry, there has been marked progress from the
old manual processes, but the use of technology for quality and compliance still
has a long way to go.

APPROVAL OF NOVEL DRUGS

How has technology use in submissions and compliance affected regulators?
Recent reports indicate that the FDA has approved more products in less time.
While the Center for Drug Evaluation and Research (CDER) approves hundreds
of new medications every year, public attention is mostly focused on novel
drugs, which are few and far between. These are the truly groundbreaking
medicines that advance clinical care to a new level.
On the average, CDER has approved twenty-eight novel drugs annually since
2006. The figures have improved to forty-one approvals of novel drugs in 2014
and forty-five approvals in 2015. Out of the forty-five approved in 2015, thirtynine (87 percent) were approved during the first cycle of reviewmeaning the
FDA didnt request additional information, which would have delayed approval.
Twenty-nine of those drugs were approved in the United States before receiving
approval in another country.15

The FDA cleared more than 15,000 devices between 2011 and 2015. The compliance process
makes it possible to bring technology such as MRI to the marketplace.

18

Also noteworthy is the efficiency with which most of these drugs were
reviewed and approved. CDER used a variety of expedited development and
regulatory tools in an effort to speed these drugs to market, according to the
divisions annual report, Novel Drugs Summary 2015.16

19

APPROVAL OF MEDICAL DEVICES

The statistics for the FDAs approval time for medical devices were neither
impressive nor alarming. In 510(k) submissions, the FDA cleared 3,025 devices
in 2015lower than the number of devices cleared in 2014 (3,203), and in 2013
(3,054), according to the Emergo Group, a consulting firm for the industry.17
In 2015, 22 percent of pre-market notification applications were cleared within
three months of submission (compared with 21 percent in 2014); 61 percent
were cleared within six months (compared with 60 percent in 2014). The
consulting firm also said only 65 percent of the 510(k) submissions in 2015
came from American med tech firms, down from 78 percent in 2014.18

The initiatives of IMDRF20, a voluntary group of regulators, to harmonize

international regulations pertaining to medical devices point toward global
cooperation that could be aided by technology. Greater expansion of global
adverse-events reporting is another area ripe for automation. As tax dollars
become more and more stretched, regulatory entities will be expected to do
more with less. One of the easiest ways to achieve this is through automation
and technology solutions.

SOFTWARE INDUSTRY'S RESPONSE

More than 15,000 medical devices were cleared by the FDA between 2011 and
2015 through the FDAs Pre-Market Notification Program, also known as 510(k).
The figure does not include medical devices subject to Pre-Market Approval
(PMA).19

In response to an increased demand for quality and compliance software

solutions, providers have tailored their offerings to specific requirements and
standards. If you can identify a standard or a regulationfrom CFR rules
enforced by the FDA to ISO standards series and various regional and statebased requirementsthere is likely to be a niche software solution for it.

GREATER ONUS

I joined the software industry in 2006 as a product manager at MasterControl. It

was among the first companies to provide Part 11 capabilities. From the second
I walked in the door, change control was a hot button.

Given the wider use of electronic systems in life science companies today,
regulators and standards bodies increasingly expect automationat least to
some degreein a QMS.
In some cases, like with the eMDR and eCTD, it is even mandated. So, while
quality requirements remain the same, the onus to comply better and faster with
the help of automation is much greater today.
If your company is just getting started, now is a better time than ever to start
right and automate from the get-go. It is much easier to do this than to develop
a manual process and adapt it into software later.
Companies recognize that a streamlined QMS is crucial to remaining
competitive in the marketplace and staying out of trouble with regulators.
They should expect new regulations to come out with a specific technological
interface going forward. There may not even be a paper solution from day one
of a new regulation.
Increased automation also means software validation will become more
important in terms of business risk. Understanding what your software does
and ensuring that your system performs exactly as expected is pivotal.
I expect to see many established regulations to turn to technology to improve
efficiency at government agencies and regulating bodies. The RPS Program,
meant to harmonize electronic submissions, is pushing regulators toward this
direction.
The Investigational Device Exemption (IDE) submission process is an area
where the right electronic tools could help accelerate approval.When the
FDA and institutional review board (IRB) approve an IDE for use in clinical
research, the sponsor faces a new round of requirements, including collection
of informed consent from patients, monitoring of the protocols, and appropriate
recording and reporting throughout the study. These are activities that could be
streamlined with the help of software solutions.
20

The company had established itself as a leader in the document control space
by the time I arrived, but it still had not developed a good functionality for
managing change resulting from a document change. Being able to manage
and bring together all of the documentation and activities for a change in one
place and selectively trigger training was a huge problem I had faced while
working in the med tech sector. Our customers at MasterControl faced the
same problem in 2006.
Other challenging quality areas for life science companies back then were
quality event management (the term QEM was not yet invented at the time) and
corrective action and preventive action (CAPA).
I was involved in a number of initiatives to advance the companys presence in
the product lifecycle management (PLM) realm, as well as in the development
of solutions for management of bill of materials (BOMs), parts, suppliers, and
computer-aided design (CAD) files.
Back then, life science companies found it challenging to integrate their
enterprise applications like ERP, learning management systems (LMS), and
manufacturing execution systems (MES) with an EQMS. During this time,
MasterControl developed its capability to connect those information systems
and synchronize data. It also developed connections with submissions
publishing tools and its own capability for eMDR submissions.

Quality is increasingly becoming

everyone's concern.
21

EVOLUTION OF QUALITY SOFTWARE

Using MasterControl as a yardstick, the software industry continues to adapt.
Software products are evolving to connect more and more business processes and
remain current with changing regulations.
Today the concept of quality has become pervasive, in the sense that the burden
of compliance no longer rests solely on quality and regulatory personnel. Quality is
increasingly becoming everyones concern and compliance efforts are implemented
throughout the enterprise. As a result, software providers have also expanded their
products to provide functionality for a broader range of users.
At MasterControl, we constantly strive to simplify the user experience and make
it easier for our customers to roll out and validate our products as our user base
expands to non-quality areas. Our goal is to permit regulated companies with
software validation restrictions to adopt software like non-regulated businesses do.

From my vantage point today, I understand better the motivations of my QA

and RA colleagues. I believe that putting the right processes in place in an
automated fashion can satisfy the demands of both compliance and speed to
market.
Today its easier to establish a cross-functional team approach that will allow
you to bridge the gaps that exist among the quality, regulatory, and product
development silos. With the right software solution, departments with seemingly
opposing interests need not be adversarial. The right tools will allow each team
to apply its expertise and at the same time cooperate with each other and attain
common goals together.

We dont want our customers sitting on a system that is three years old because
they are unable to secure the resources or monies required for re-validation. Cloud
software vendors release new versions of their solution multiple times a year and
often do not give their clients the option to not take the new version. This means that
clients must be nimble enough to accept and validate new versions of software on a
near continuous basis.
Software vendors like MasterControl can greatly help in this pursuit by providing
the necessary tools and documentation to make this a reality for their clients.
MasterControl has been a pioneer in this regard since the introduction of its Transfer
Operational Qualification package in 2006 called MasterControl Transfer OQ. Our
delivery model continues to evolve. Today our customers can have our products
on their own premises, hosted in our private cloud, or delivered through one of the
mainstream public cloud vendors. This array of choices didnt exist a decade ago.

MANUAL PROCESS AS PART OF OBSTACLE COURSE

Let me circle back to what I said in the second chapter about the seemingly
adversarial compliance process. During my time as a product development engineer,
the development process resembled an obstacle course, which I had to undergo
even if those obstacles (otherwise known as regulations) did not help improve my
product.
In hindsight, I can attribute my resentment to the laborious manual processes I
had to endure, especially those that kept the different teams at my company stuck
in their little silos. Paper-based processes were a big part of the obstacle course
during product development. If there had been technology that facilitated my teams
interaction with other teams and with regulators, maybe the process would have
been less bumpy. Technology also greatly facilitates the re-use of information. It
could have reduced the burden I faced in recreating documents in a specific format
for one regulatory body versus another.

22

CT scans are highly accurate images that help doctors make better diagnoses.
Regulatory compliance is meant to ensure such complex devices are safe.

23

05
THE FUTURE STARTS NOW

In life sciences, time is of essence. Product development requires tremendous

investment in time, money, and effort. You simply cant afford any delays.
On the average, it takes more than a decade to develop a new medicine and get
it approved at a cost of about $2.558 billion, according to the latest research
from the Tufts Center for the Study of Drug Development. When post-approval
R&D costs of $312 million are included, the full, product lifecycle cost per
approved drug, on average, rises to $2.870 billion, according to the center.21
The cost of medical device development is harder to nail down. There are no
research figures similar to the Tufts annual study. However, a book by Elaine
Whitmore estimated that development of a medium-risk medical device that
has received clearance through the Pre-Market Notification Program requires
$31 million on the average, while a high-risk device subject to the Pre-Market
Approval process requires about $94 million.22 In my experience, development of
a new medical device takes anywhere from eighteen months for a 510(k) product
to five years for a device requiring a PMA.
The entry of Googles Verily and Apple into medical-device development is
bound to disrupt the industry and increase the already intense pressure to go
to market sooner. Among other things, Verily is developing smart contact lens
with glucose sensor for diabetics. The lens will measure the amount of sugar in
a patients tears. Meanwhile, Apple is exploring ways to detect a heart attack
through the sound blood makes as it flows through the arteries. Amazon might
jump on the bandwagon too. Its meeting with the FDA has fueled speculation
about the online-retail giants interest in the regulated space.23
These tech giants are accustomed to very short product lifecycles and could put
slower-moving incumbents under the gun to launch their products faster. What
does this mean for you and everyone else in life science product development?
It means every day you fall behind your product-launch schedule is another day
of additional cost and unrealized market potential. It also means you are giving
your competition a chance to beat you in the marketplace.

Smart drugs, which use nanotechnology for effective delivery and

control of side effects, behoove smarter compliance.

25

PREDICTION VERSUS OBSERVATION

Prediction is one of the things the brain naturally does, according to Jeff
Hawkins, a neuroscience buff and founder of Palm Computing, which introduced
the first handheld computer. He said prediction is the primary function of the
neocortex.24 Even so, Im not inclined to make any predictions, so I will share my
observations instead.
I feel very fortunate to have been a part of the life science industry and now, the
software industry serving it. Based on what I have seen from both sides of the
fence, I expect the following things to happen because they are, in fact, already
beginning to happen:
Regulators will introduce more and more technology-facilitated
standards and regulations.
As a result, we will see greater interaction among industry, regulators,
and technology vendors.
The importance placed on software quality and validation will increase
as compliance becomes more dependent on these solutions.
Security concerns will continue to rise, both from a piracy and hacking
perspective and intentional misrepresentation of data and/or users.
Biometrics will be used more broadly in helping secure the data and
quell concerns of misrepresentation.

THE NEED FOR SMARTER COMPLIANCE

As technology grows to be more pervasive in regulatory compliance, there are
bound to be missteps. Firms are likely to be saddled with some unnecessary
regulations because technology makes it easy to comply with them, but I
think these cases will be short-lived. Todays global economy and widespread
media coverage shine a light quickly on unnecessary government bureaucracy.
Regulators are also more collaborative with industry, resulting in rapid feedback
cycles that help adjust interactions that are not functioning or dont make sense.
I believe that in the future, we will see compliance get smarter as technology
takes a greater role. Given how fast things change in the industry, any
discussion about the future implies you need to get a head start now.
Even with the abundance of software solutions in the market today, many life
science companies still fail to realize all the benefits of technology. Its not
so much turning a blind eye to the latest technology but refusing to adopt it
properly. Even when organizations automate their QMS, many of them fail to
optimize their usage because of their unwillingness to put control in the hands of
those who can most effect change. Deputizing colleagues outside of the quality
department to create and execute compliance-related processes can accelerate
the speed with which companies are able to get their products to market and

26

The future of medical technology includes more applications of 3-D printing in the
manufacture of cell and tissue products and orthopedic, dental, and other implants.

27

improve compliance simultaneously. Involving the people who are going to be

working within the processes is also much more likely to improve buy-in and
compliance.

certain devices, such as a wheelchair or a blood pressure monitor, adding a UDI

marking would be simple. A tag could be etched directly on the device without
affecting patient safety.

Rather than take advantage of what technology has to offer, many companies
shackle themselves with outmoded processes in a digital world. Going back to
the LNS Research mentioned in Chapter 4, the majority of survey participants
using disparate systems used a combination of spreadsheets, email, and some
form of enterprise content management system (CMS) to connect their quality
activities across the value chain.25

What about more complex devices such as a heart pacemaker or artificial hips
or other implantable devices? How would a UDI marking affect their safety?
Under an FDA draft guidance, any direct marking that would interfere with the
safety or effectiveness of a device that has already been approved will require a
new 510(k) submission.27

When an organization first switches from paper to electronic documents, there is

a tendency to replicate its paper-based processes instead of adopting fully the
new electronic system and automating all processes and workflows. Such was
the case when ITxM first used an automated QMS in 2005.
Patrick Farley, application administrator, said, When we first moved from
paper to electronic documents, we tried to mimic exactly what we did on paper
instead of allowing the system to assist in the automation process. Ten years
later, we are using every tool we can to automate as much as possible.26
Replicating your manual processes may bring some advantages, such as user
acceptance because employees are familiar with the old ways, but you lose out
on the quantum jumps in productivity that technology can afford your company
if you look at things through new lenses.
If this sounds familiar, take a closer look at your compliance program and
individual quality processes. Perhaps there is opportunity there to trim some of
the fat from outdated processes and for you to get to the heart of what actually
brings value.
The need for smarter compliance may be sooner than you think. To succeed in
a fiercely competitive global market, any projection for the future ought to start
now. This is the best time for you to get smarter with your technology use.

This is an example of how innovation can bring both good news and bad news
for the industry, but it should be seen as inherently good over the long haul.
There is much at stake for the regulated companies and their technology providers in the ongoing movement toward innovation, which makes smarter compliance and stronger partnership all the more necessary.

FUTURE COLLABORATION
Life science companies today face largely the same compliance challenges as
in 2006. The big difference is the tendency for regulators to turn to an electronic
solution rather than manual or paper processes. We saw this in the changes in
the MDR regulation domestically and abroad. Today, the FDA will only accept
MDRs electronically. There is no longer a paper option. This is also evident, as I
mentioned earlier, in the UDI regulation, whose implementation and enforcement
requires a technologically facilitated solution from the get-go.
If life science companies have learned their lessons from Part 11 compliance,
they should have a smoother experience in any new technology-enabled
regulation. It is imperative, however, that regulatory bodies show willingness to
collaborate with technology vendors and the firms they are trying to regulate.
If implemented correctly, technology should give regulators greater insight into
the businesses they are regulating and allow them to enforce regulations more
efficiently with fewer personnel.

PART OF THE TECH MOVEMENT

Being part of the life science industry or the compliance technology sector
means we are instruments of the technology movement, which has resulted in
a dramatic transformation in health care and regulatory landscape. However,
with medical advances and new applications in pharma, med tech, and
biotechnology come new safety and regulatory concerns.
For example, the FDAs release of its UDI (unique device identification) rule in
2013 was heralded as a regulatory breakthrough. The UDI system is designed to
help reduce medical errors and allow the agency and the med tech industry to
address adverse events faster, including more rapid corrective actions.

Being part of the life science

industry means we are instruments
of the technology movement....

This is, undoubtedly, an important milestone, but one that affects requirements
for med tech companies, their suppliers, CROs, and technology providers. For

28

29

06
PREPARE TO SUCCEED

If success depends on preparation, then it behooves life science companies to

prepare for an even more technology-driven regulatory landscape in the future.
Global health care spending is expected to increase by 4.3 percent until 2019,
according to Deloittes 2016 Global Life Sciences Outlook. Biotech drug sales
are expected to grow from $289 billion in 2014 to $445 billion in 2019, while the
market share of generic drugs is likely to jump from 27 percent ($261 billion) in
2012 to 36 percent ($421 billion) in 2017. Meanwhile, medical device revenues
are expected to increase from $369 billion in 2015 to $454 billion in 2019.28
In spite of this kind of growth, many life science companies are still using
outdated IT infrastructure and spending significant money to fix issues because
of it, according to the Deloitte report. For example, an infrastructure designed
around an impermeable core may hamper external collaboration, an important
element of open innovation in R&D, according to the document. From a
compliance perspective, outdated IT systems may stymie efforts to meet
mandatory FDA GxP requirements for pharma manufacturing and product
quality.29
One of the problems is the industrys predilection for the tried and tested at the
expense of better options. Pharma has tended to customize IT to fit its old
process/organization/installed technology base; in the process, compromising
benefits realization, the report said.

HOW BEST TO PREPARE

For all of the modernization and innovation we have seen in the past decade,
speeding up the delivery of medicines, med devices, and therapies from
laboratories to the marketplace remains a crucial goal for the industry today.
The key to improved time to market is streamlined and standardized processes,
which are best achieved through automation.
Here are some recommendations for leveraging the latest technology and
developing a forward-looking orientation within your organization:

Collaboration through a cross-functional approach, bridging the gap among silos, and taking
advantage of the latest technology are all necessary to speed up time to market.

30

#1 Develop a cross-functional approach. A silo mentality directly affects your

organizations efficiency, not to mention morale. Remember how I felt as a PDE
working with QA and RA teams? In hindsight, I can attribute the adversarial
undercurrents in our relations to a silo mentality. The right software solution can
help you overcome silos by facilitating a cross-functional team approach.

31

Weigh the pros and cons of buying a point solution versus an enterprise
platform, factoring in your specific needs and your budget for the project. If
you have a pressing concern (e.g., CAPA or audit) that can be separated from
other QMS needs, then consider using a point solution, which will address
the problem right away at a relatively low cost. A better option is to choose an
enterprise platform that will allow you to implement a point solution and at the
same time enable you to add solutions in the future as your needs evolve.
#2 Bridge the gap between the quality team and the rest of your
organization. Your quality team exists primarily to ensure product quality
and compliance, a daunting responsibility that the rest of the company might
perceive as a police role. The ability of the team to elicit awe and anger in
equal parts stems from non-quality personnels FUDfear, uncertainty, and
doubtwhen faced with quality issues. Empower your quality team with the
right tools, namely a robust QMS that will make it easier for other departments
to cooperate and participate in compliance.

To overcome the valley of death, you must focus on your core competency and
devote your energy and resources to developing and manufacturing the best
vaccine or heart pump or active pharmaceutical ingredient or whatever product
your organization is committed to delivering to patients and consumers. Dont
overburden your employees with routine tasks associated with a manual
system. If you have a dozen employees whose sole responsibility is to
control documents, switch to an electronic system so you can manage your
documents with fewer people and redeploy the extra manpower to other areas.
If budget is a concern, you can automate your paper-based or homegrown
electronic quality system without the upfront cost of a traditional on-premise
system. Pick a cloud or hosted service that offers access to the same
robust, compliant, and secure EQMS without the capital expenditure and IT
overhead. This type of service provides rapid deployment of electronic QMS
over the Internet. It usually includes dedicated support that covers security,
maintenance, backup, and upgrades.

#3 Make your processes transparent. Transparency is not just a buzzword in

politics and business. As applied to life sciences, the concept plays a key role
in compliance, in the sense of creating processes that are easily assessed and
audited by regulators and customers alike. Its impossible to be transparent with
a paper-based process that requires physically digging into piles of documents.
An electronic system provides a single, centralized repository of all compliancerelated documents, forms, and records. It means your employees and auditors
will go to only one place for all compliance-related documents they need.
#4 Increase your inspection readiness. There is a lot of wisdom in the motto,
Be prepared or Always prepared, which has been adopted by many groups,
from the Boy Scouts to the U.S. Coast Guard. For heavily regulated companies,
what could be a more relevant admonition? It is agonizing to sit with an FDA
investigator or an assessor conducting an ISO certification audit when a certain
document requested is incomplete, unsigned, or worse, missing. There is no
better way to make preparedness a habit than through automation.
In the most practical sense, compliance boils down to passing an audit or
inspection. An FDA inspection certainly prompted SynCardias switch from a
hybrid system to a fully automated QMS. The company has said it now moves
at light speed to meet FDA requirements, thanks to its electronic system. In
addition to complying with FDA regulations, the company also complies with
the European Unions Active Implantable Devices Directive and the Canadian
Medical Devices Conformity Assessment System.30
#5 Increase your competitiveness by focusing on your core competency
instead of routine. Up to 90 percent of medical products being developed fail
before they ever get tested on people, according to the National Institutes of
Health. Such failure-prone development period is known as the valley of death.
It stands as a wide gap between scientific discoveries and the actual translation
of those discoveries into medical treatments.31

32

Life science companies should focus on their core competency to

avoid the valley of death in product development.

33

07

Technology will continue to

play a pivotal role in the future.

CONCLUSION
SOFTWARE PROVIDERS AS PART OF COLLABORATION
Change is inevitable, so is technological advancement. As technology evolves,
the regulatory landscape will also change. This books basic premise is that
technology has been good for compliance and will continue to play a pivotal role
in the future.
The only disadvantage that could manifest along the way is the introduction of
regulations for the sake of introducing them. They may not provide value, but
because technology facilitates their implementation, then why not?
The tendency to ask for needless data simply because its there can increase
undue burden on the regulated and regulators alike. A good question to ask
yourself when you ask for a new piece of data or a new view of the data is:
What question are you trying to answer? If you cant formulate the question in
a way that makes sense and provides value, you are likely wasting your effort in
collecting the data.

POSITIVE REGULATORY RELATIONS

Judging by a recent report, life science companies and regulators (the FDA in
particular) maintain a positive relationship.
A report by PricewaterhouseCoopers Health Research Institute (HRI) shows that
78 percent of life science executives surveyed said their communication with the
FDA has improved; 76 percent said the agency provides actionable feedback;
and 70 percent said it offers more applicable guidance, rules, and regulations.

I would like to add that software providers are more than willing to participate
in the collaborative process. Indeed current developments point us in that
direction. For example, at MasterControl, we have increased our dialogue with
customers to address their evolving regulatory needs as soon as they are able
to identify those needs instead of waiting for the effects of those regulations,
namely problems. As I alluded to earlier, we want life science companies to be
able to adopt cloud software methodologies in spite of the Part 11 validation
challenges they face. The key to this is close collaboration with and reliance on
your solution providers and taking advantage of what they can provide in terms
of toolsets and artifacts to ease your validation burden.
If your company has yet to make a switch from a legacy system to an FDAcompliant automated system, now is the best time to do it. We (life science
industry, regulators, and technology providers) have arrived at a place wherein
our desire and commitment to improve and speed up the process of approving
and delivering medical products are aligned.

RIGHT PLACE, RIGHT TIME

There was a time when I entertained the idea of going to medical school. After I
completed my undergraduate degree, I mentioned it to my wife. She promptly
responded, If I wanted to marry a doctor, I would have married one who was
already a doctor! My wife is an ER nurse, so we have shared our love of health
care and the life sciences throughout our careers.

The study is based on a 2014 survey conducted among 100 executives from
a cross-section of life science companies. The survey focused on their views
about the industrys relationship with the FDA. HRI also surveyed 1,000
consumers on their attitudes toward the industry and the FDA as part of the
study.

Her reaction helped me focus on mechanical engineering. As it turned out,

the field offered the perfect combination of studying science and applying
technology to improve patient outcomes. When I landed a product development
job at an orthopedic company shortly after graduation, it strengthened my belief
that I was in the right place at the right time. I could not think of a better way to
apply my skills and promote the betterment of the human condition. The rest, as
they say, is history.

The report recommended enriching the ongoing dialogue. Skilled at utilizing

the latest in science and technology to develop breakthrough therapies,
pharmaceutical and life science companies will need to deploy new techniques
to strengthen their relationships with the FDA and consumer. A closer, more
collaborative bond among all stakeholders may create a more efficient
development and regulatory process that leads to the next generation of
treatments and cures, according to the report.32

What I said at the beginning of this book bears repeating. Life science
companies, regulatory bodies, and technology providers share a common path.
We are instruments in producing and delivering life-changing products to the
world. We are very fortunate to be part of this movement where life sciences,
compliance, and technology have converged to bring positive change. As the
industry continues to evolve, we would do well to strengthen our collaboration.

34

35

SE
TR: 3
TE: 9
EC: 1

Change is inevitable, so is
technological advancement.

HEAD
FOV:2
5,0th
20/02:27
256x192/2
NT/VB/ED

P
1
2
7

EX: 3382
SE: 4
IM: 12
OSAG: L6.5

References
*Photo credit for leech jar, chapter 1, page 4: A leech jar; Essex type by Wellcome Images,
CC BY 4.0. Slightly modified from original.
1

For more information about the BrainGate2 clinical trial, visit its clinical trial website.

The FDA approved Kalydeco for the treatment of CF in patients age six years and older who
have the specific G551D mutation in the cystic fibrosis transmembrane regulator (CFTR)
gene. In patients with the G551D mutation, Kalydeco helps the protein made by the CFTR
gene function better and, as a result, improves lung function and other aspects of CF such as
increasing weight gain. Visit the FDA website for more information.

ITxM Marks 10-Year Milestone of MasterControl Usage, a case study, published by

MasterControl. ITxM, based in Pittsburgh, provides blood collection services and distributes
more than one million blood components across the country and overseas.

Supra, Closed-Loop Quality Management and the Cost of Inaction, GxP

Lifeline blog.

14

15

From CDERs report, Novel Drugs Summary 2015.

16

Supra, CDERs report, Novel Drugs Summary 2015.

Emergo Analysis: Fewer 510(k) Submissions from U.S. Medical Device Firms in 2015,
from Emergo Groups website.

17

18

Supra, Emergo Analysis.

From Emergo Groups website, How Long it has Historically Taken the FDA to Clear 510(k)
Submissions.

19

International Medical Device Regulators Forum (IMDRF) was launched in 2012 as the
successor to the Global Harmonization Task Force, which disbanded in the same year. For
more information, visit the IMDRFs website.

20

Teva Pharmaceuticals automated its manual process in 2001. A case study about Tevas
experience is available here.

Tufts CSDD at Tufts University, based in Boston, Mass., provides strategic information to
support drug developers, policy makers, and regulators. The statistics came from a Tufts
press release, March 10, 2016.

21

SynCardias Total Artificial Heart is an implantable system designed to assume the function
of a failed human heart in patients suffering from advanced heart failure.
A case study about SynCardias switch from a hybrid to a fully automated QMS is available
here.

MasterControl, founded in 1993, was among the first to provide Part 11-compliant software
solutions for life science companies.

Development of FDA-Regulated Medical Products: A Translational Approach

(Second Edition) by Elaine Whitmore, pages 6-7, ASQ Press, Milwaukee, Wis., 2012.
The book attributed the figures to this article: FDA Impact on Medical Technology, by J.
Makower, A Meer, and L. Denend, www.nvca.org, 2010.

22

5 Trends Medical Device Companies Cant Afford to Ignore in 2016, a white paper by Lisa
Weeks, May 2016, published by MasterControl.

23

21 CFR Part 11The Biggest Security Regulation Youve Never Heard of by Ben Rothke,
page 16, ISSA Journal, March 2004 edition, published by the Information Systems Security
Association.

How Brain Science will Change Computing, Jeff Hawkins, TED speech,
February 2003.

24

Guidance for Industry: Part 11 Electronic Records; SignaturesScope and Application,

from FDA website.

Closed-Loop Quality Management: Connecting the Value Chain, page 17, published by
LNS Research, 2014.

25

26

Supra, note 3, ITxM Marks 10-Year Milestone of MasterControl Usage.

Unique Device Identification: Direct Marking of DevicesDraft Guidance for Industry and
Food and Drug Administration Staff, June 26, 2015, from FDAs website.

27

Supra, note 7, 21 CFR Part 11The Biggest Security Regulation Youve Never
Heard of.

21 CFR Part 11: How and Why to Comply, Medical Device and Diagnostic Industry, Sept.
1, 2002.

28

Deloittes 2016 Global Life Sciences Outlook, page 4.

29

Supra, page 12.

10

11

FDA Deputy Commissioner Lester M. Crawford was quoted in an article titled, ScheringPlough Pays Fine, by Anne Thayer, Chemical & Engineering News, May 27, 2002.

30

12

Learn more about GAMP. View this free webinar: GAMP 5 - A Risk-based Approach to
Compliant GxP Computerized Systems

31

Closed-Loop Quality Management and the Cost of Inaction, by David R. Butcher, GxP
Lifeline blog, which cited the book, Closed-Loop Quality Management: Connecting the Value
Chain, by LNS Research.

32

13

36

Supra, note 5, from a case study about SynCardias switch from a hybrid to a fully
automated QMS.
Supra, note 22, Development of FDA-Regulated Medical Products: A Translational
Approach, pages 29-30.
The FDA and Industry: A Recipe for Collaborating in the New Health Economy, published
by PwC Health Research Institute, January 2015.

37

ABOUT MASTERCONTROL
MasterControl is a committed team of quality, regulatory and software experts
who work to empower regulated companies to get their products to market
faster. MasterControls enterprise quality management software solutions
(EQMS) reduce overall costs, increase efficiency and accelerate compliance,
creating a significant competitive advantage for customers. Drawing upon
unparalleled industry experience, MasterControl offers a suite of seamlessly
integrated and scalable software solutions for quality management, document
control, training management, corrective and preventive actions (CAPA),
supplier management, audit management, clinical management and much more.
MasterControls complete EQMS is designed for easy implementation, validation
and use, continually improving on the promise of Compliance Accelerated. For
more information, or to contact MasterControl, visit www.mastercontrol.com.

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