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Chapter Five
The Regulatory Affairs
Perspective
Addressing Compliance in
a Changing Industry

Maribel Rios

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

The Regulatory Affairs Perspective

Addressing Compliance for a Changing Industry

Maribel Rios

B
ioprocessing remains a highly
regulated industry, and full
compliance is vital to ensuring
the high quality, safety, and
efficacy of biopharmaceuticals.
Working collaboratively with the
FDA early in a process can help
manufacturers meet comprehensive
regulatory expectations and address
regulatory concerns when working
with new technologies or therapeutic
classes. Over the past 15 years,
regulatory agencies have released or
revised many industry guidances and ADOBE STOCK (HTTP://STOCK.ADOBE.COM)

requirements. Most of them have

come about because of increased in
process knowledge, improvements in
the precision of laboratory instruments
and methods, and the need for flexible
process systems.
For an industry under stringent
regulations, ensuring compliance is
the biggest factor for success.
Participants of BPIs state of the
industry survey were asked about the
effect of regulatory changes on their
work ranked 1 (least influential) to
5 (most influential). Below are the
percentages of respondents that
ranked the specific regulation as a
four or five:
implementation of quality by
design and other risk-based
approaches, 59%
FDA draft guidance for
biosimilars, demonstrating
comparability, 49%
FDA and EMA revised process
validation guidance, 55%
21 CFR Part 11, 44%.
Changes in GMP Training
Fifteen years ago, the FDA released
its good manufacturing practice
(GMP) for the 21st Century that
encouraged manufacturers to apply
new technologies, risk-based and
science-based approaches, and quality
management systems in processing.
Since then, FDA working groups have
released related guidances on 21 CFR
Part 11 Electronic Records and
Electronic Signatures, PAT: A
Framework for Innovative
Pharmaceutical Manufacturing and
Quality Assurance, and others.
Those and other revisions in the
regulations have prompted a change in
the way training is conducted. In the
past, GMP training consisted
primarily of reading standard
operating procedures (SOPs) as they
were written or revised and attending
annual GMP training conducted by a
GMP expert from the companys
quality group, says Gary Gilleskie,
director of operations and teaching
associate professor at
Biomanufacturing Training and
Education Center (BTEC) at North
Carolina State University (with his
colleagues Rick Lawless and John
Balchunas). As agency inspections
revealed that this mode of training
was not always effective, training
courses focusing on GMP
fundamentals, agency expectations,
and application of new learning
became more popular.
A number of online education
offerings (e.g., webinars) also provide
professionals with more options.
Gilleskie says online GMP/
compliance training offers the
following benefits: accessibility to
trainees, access to subject-matter
experts, and ability to address current
topics of interest in a timely way. A
key driving force behind this change is
simply the advancement of technology
that enables delivery of online
learning (in addition to the need to
dive deeper into GMP topics).

2 BioProcess International 15(6)e C hapter 5 of 11 State of the I ndustry 2017

 Another change in GMP training
is the large increase in the number of
community colleges, colleges,
universities, and education centers
offering GMP. Some of these
programs, such as courses offered at
BTEC, offer hands-on learning in a
CGMP-like environment, says
Gilleskie. These programs were
largely nonexistent 1520 years ago.
He says one reason for this increase is
that state and local governments are
realizing that a skilled workforce helps
attract and retain biopharmaceutical
companies.
Gilleskie says that one common
misunderstanding is that only
production operators and quality
professionals need to know about
GMP. However, regulatory agencies
recently have expanded their
expectations of process development,
process control, and manufacturing
science, so a thorough understanding
of GMP is needed throughout
biopharmaceutical organizations.
Students seeing GMP implemented
for the first time, including our
university students, are surprised at
the number of documents and
procedures associated with CGMP
operations and unaware of their
importance to ensuring that
operations are carried out correctly
and reproducibly, says Gilleskie. The
concept of addressing deviations and
the need to minimize them is a new
concept for many university students.
Introducing basic GMP principles to
our university students gives them a
leg up when they go to industry.
A training center such as BTEC
can provide hands-on GMP training.
The BTEC facility has a simulated
GMP manufacturing area dedicated to
training and educations. Not only do
course attendees learn what GMP
regulations say, but they learn how
GMP is implemented in a
manufacturing environment through
practice. For example, students can
learn to write batch records and execute
them on industry-relevant equipment,
they can qualify a production-scale
chromatography system, or they learn
about cleaning validation by actually
swabbing cleaned process vessels, says
Gilleskie.
3 BioProcess International
The BTEC facility is dedicated to
training and education but is not used
to produce human-use products, so the
environment is low risk. Instructors
can allow real-time failures to occur,
which offers a great learning
opportunity, without risk to the
facilitys GMP status or product. It is
difficult for biopharmaceutical
companies to offer this kind of
training in-house, because company
equipment and facilities are dedicated
to GMP use and typically tied up in
production
Gilleskie also sees an increased
need for GMP training for those
working with automation and digital
technology in bioprocesses. Using such
systems (such as electronic batch
records) can reduce the number of
process and analytical errors and help
manufacturers analyze process data
and increase process understanding.
But he says they also bring a need for
understanding GMP related to system
qualification and validation as well as
demonstrating compliance with 21
CFR Part 11. There is significant
and unique expertise required to
implement these technologies, and the
need for GMP expertise is required
from the engineers and scientists
implementing these systems, not just
the production operator.
Data Integrity
Advances in analytical instrumentation
have led to the increased sensitivity and
precision of analytical techniques. BPIs
State of the Industry survey asked
participants to comment on the
changes in analytical instrumentation.
Nearly two-thirds (64%) said that the
sensitivity/specificity of analytical
instruments had an impact on their
work.
When asked about the types of
analytical methods that have
undergone the most change in the
past 15 years, most survey respondents
pointed to quantitative methods,
especially quantitative polymerase
chain reaction, qPCR. The sensitivity
of PCR-based assays has resulted in
partial replacement of less sensitive or
more time-consuming assays. There
has also been some adoption of PCR-
based assays in virus testing.
15(6)e C hapter 5 of 11 State of the I ndustry 2017
Infectivity-based assays can take a
week to complete, so being able to
determine the presence of a virus with
a quick turnaround time is a big
advantage, says Susan Woodard
(Texas A&M University, an analytical
chemist working on analytical assays
in downstream bioprocessing and
purification process development).
The emphasis on quantitative
measurements has been one driver for
recent discussions on the importance of
storing, securing, and managing data
and ensuring data integrity. For
example, last year the World Health
Organization (WHO) published its
final version of Good Data and
Records Management Practices
guidance document; the European
Medicines Agency (EMA) added data
integrity to its good manufacturing
practice (GMP); and the US FDA
issued its draft guidance on data
integrity and compliance with current
good manufacturing practice (CGMP)
document (13). According to FDA
draft guidance, data integrity refers to
the completeness, consistency, and
accuracy of data. Complete consistent,
and accurate data should be
attributable, legible, contemporaneously
recorded, original or a true copy, and
accurate (ALCOA).
Data integrity is a hot topic with
auditors at the moment, says Darren
Barrington-Light (product marketing
specialist, Informatics and
Chromatography Software, at Thermo
Fisher Scientific). When they walk
into laboratories, they are always alert
to people who are not following data
integrity guidelines. Data integrity is
all about being able to prove that you
followed your documented procedures
and that you are in control of your data
and that it is maintained and available
to auditors in the future for the lifetime
of your product, however long may be.
Its about making sure that you have
that computer data audit trail and that
you can defend your result.
The guidance states that all data
become a CGMP record when
generated to satisfy a GMP
requirement. An analyst, for example,
must document or save data at the
time of performance to create a record
in compliance with CGMP
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requirements. The guidance requires
contemporaneous recording of data.
That means that laboratory analysts
cannot record data on paper that will
be thrown away after transferring that
data to electronic format, for example.
Contemporaneously recording
basically means that as data are
created, it should immediately be put
into long-term storage where you can
control and maintain that data. A
scientific data management system
(SDMS) helps you with that because it
can take a raw file from any
instrument and put it into secure long-
term storage. With a laboratory
information management system
(LIMS), you can also extract results
from that data and put them directly
into the sample record with a link to
the raw data, says Barrington-Light.
Electronic data that are
automatically saved into temporary
memory do not meet CGMP
documentation or retention
requirements. However, analysts can
save data automatically after each
entry on a computer system LIMS) or
electronic batch record (EBR) to
satisfy CGMP requirements (4).
The requirement is asking us to
secure electronically captured data that
can track the lifecycle of a sample from
receipt to whenever those data are
needed again, such as for a regulatory
audit or a recall, says Patty
McDermott (senior marketing
manager, Informatics and
Chromatography Software at Thermo
Fisher Scientific). Over the past years,
weve seen companies with strong
electronic data management, including
sophisticated LIMS and
chromatography systems in place and
with all of the lab interconnected. But
weve seen other companies where
theres still a paper notebook at the
front of the laboratory. And the trend
in industry in terms of software is to
get to the point where all of our
customers are fully integrating all of
their instruments and bench
equipment, so that their data, no
matter where from, are captured
instantaneously in the LIMS, stored in
the SDMS in an original raw format,
and then made available at any point
in the future for archiving and review.
4 BioProcess International
Thermo Fisher recently developed
its Chromeleon CDS system for
helping its customers in response to
customer demand for help with data
integrity requirements. One of the
changes weve seen recently is that
now our customers are asking us
What do we need? when in the past
they would say We need this, says
Barrington-Light.
In Q&A format, the FDA draft
guidance also explains audit trail
review, computer workflow validation,
metadata, GMP records, electronic
signatures, and other GMP-
laboratory-relevant issues. Warning
letters already have been issued for
noncompliance, and those are available
for viewing as well.
Electronic Submissions
The bioindustry is an innovative
industry, and the number of document
files needed for novel therapies such as
new drug applications (NDAs),
abbreviated new drug applications
(ANDAs), and biologics license
applications (BLAs) for FDA review
have increased over the past 15 years.
The agency has been under pressure to
process such documents more rapidly.
Last month, the FDAs electronic
submission requirement took effect (5).
Section 745A(a) of the Federal Food,
Drug, and Cosmetic Act requires that
submissions under section 505(b), (i), or
(j) of the FD&C Act and submissions
under section 351(a) or (k) of the Public
Health Service Act be submitted in
electronic format specified by the
FDA. According to the Center for
Drug Evaluation and Research
(CDER) Electronic Submission Team
and FDA spokesperson Jeremy Khan
(trade press officer), the guidance
applies to all NDA, ANDA, and BLA
products, with certain exemptions for
BLA products that are addressed in
the guidance.
The FDA team pointed out that
drivers for developing the guidance are
to fully implement an electronic
submission and review environment
based on standardized electronic
submission formats and data. Issuing
the guidance also was a performance
goal of Prescription User Fee Act
(PDUFA) V (www.fda.gov/
15(6)e C hapter 5 of 11 State of the I ndustry 2017
forindustry/userfees/prescription
druguserfee/ucm272170.htm).
In 2003, the FDA began accepting
electronic common technical
document (eCTD) submissions, and
since 2008 eCTDs have been the only
electronic submission format for the
Center for Drug Evaluation and
Research. The agency issued two draft
guidance documents (January 2013
and July 2014) that announced the
electronic submissions requirement
and requested public comments, before
finalizing the guidance in May 2015.
The final guidance was issued May
2015 and provided a 24-month grace
period for NDA, BLA, and ANDA
submissions. It also has a 36-month
grace period for commercial INDs and
drug master files (DMFs).
The FDA has provided support on
the implementation of the eCTD
through presentations and training at
DIA conferences, webinars, and
through CDERs and CBERs
electronic eCTD email accounts, says
Khan. In addition, the FDA issued
letters about the guidance requirement
to all sponsors who submitted non-
eCTD submissions within the last 90
days (between January 2017 and March
2017). All ESG portal (Webtrader)
users also received two communications
from the FDA regarding the upcoming
change. The FDA has also published
an eCTD Technical Conformance
Guide and supporting documentation
on our eCTD website (www.fda.gov/
ectd). There are exemptions (e.g.,
noncommercial INDs) included in the
eCTD guidance.
To lessen the chance of improper
submissions, the agency developed the
guidance for industry on Providing
Regulatory Submissions in Electronic
Format Certain Human
Pharmaceutical Product Applications and
Related Submissions Using the eCTD
Specifications. Its important to read
the guidance because it does include
additional requirements. For example,
use of FDAs Electronic Submissions
Gateway for submissions 10 GB and
less and the requirement to submit
fillable forms, says Khan.
Most large companies already have
been submitting files electronically to
the FDA, so they should face a
seamless transition. But smaller or
start-up companies might face some
difficulties. It requires a fair amount
of work to get it right, says Ken
Hughes (president of Roker
Biotechnologies). The trouble is that
getting everybody to read from the
same sheet of music requires some
pain upfront. There are people who
are saying Look at the work Ive just
been loaded with! But I think in time,
when everybodys doing it that way,
everybodys life will be easier. I think
most people understand what those
requirements are trying to achieve. Its
just one of those short-term pain for
long-term gain scenarios. Well see
how implementation goes.
Approval of Biosimilars
Biosimilars present new market
opportunities and are already
increasing market competition. The
common belief in the industry is that
if a manufacturer is not already
thinking about competing against the
biosimilar of its innovative product,
then its already too late. Regulatory
agencies are under immense pressures
to create abbreviated pathways for the
approval of biosimilars to reduce
consumer healthcare costs.
Europe was the first region to
provide regulatory steps toward
approval for biosimilars. In 2003 the
European Union (EU) established a
legal framework for the approval of
biosimilars through the European
Medicines Agency (EMA). In 2006
Europe became the first region to
establish biosimilar guidelines with an
abbreviated registration process.
Sandoz obtained the first
authorization to market Omnitrope
(somatropin), a biosimilar to Pfizers
Genotropin that same year. In 2015
(effective September 1), the EMA
issued a new guideline on nonclinical
and clinical development of
biosimilars containing recombinant
human insulin and insulin (6). And on
March 2016, the EMA updated its
draft guidance on human clinical
trials for cancer drugs.
So far, the EMA has established
product-specific guidelines. As part
of these requirements, biosimilar
applicants are expected to conduct a
6 BioProcess International
productbyproduct analysis using
stateof-theart bioanalytics and
manufacturing along with clinical and
regulatory experiences to support
biosimilarity, says Miriam Monge
(director of marketing for integrated
solutions at Sartorius Stedim Biotech).
The FDA has not developed
productspecific guidances but instead
has issued general guidances related to
a productspecific development
approach. Each biosimilar has its
own approval requirements, developed
in a stepwise approach, following
multiple comparisons of the proposed
biosimilar product to the reference
product, says Monge. Required
clinical studies and other study
requirements are determined by how
similar the products are as well as the
observed bioanalytical differences.
Compared with the EMA, the
FDA is more cautious with its
biosimilar approvals, says Monge. For
example, the FDAs publicly announced
decision, rejecting Hospiras application
for a biosimilar version of Amgens
Epogen (EPO), suggests that the
agency is taking a cautious approach
and will not approve a proposed
biosimilar even if it is already marketed
in the European Union. It remains to
be seen to what extent the US
regulatory pathway follows the
contours of the EU model.
Other emerging markets such as
China, India, Brazil and Mexico also
have developed regulatory pathways
toward biosimilars approval. Monge
says they generally set a lower barrier
in terms of clinical trial requirements
and regulatory control, which enables
local manufacturers to enter the
emerging markets on a more level
playing field, but that also potentially
provides a lower cost entry point for
international players. Such a looser
structure has already fueled the launch
of modified biologics within the
oncology and EPO markets in key
countries such as China.
Regulation Is a Team Effort
Establishing new and revising existing
regulations also has been the result of
cooperation between regulatory
agencies and the industry, especially
through collaboration and input from
15(6)e C hapter 5 of 11 State of the I ndustry 2017
specialty groups. In addition to the
issues discussed here, the industry has
benefitted from many other regulations
in the past 15 years, including revisions
to the FDAs and the EMAs process
validation guidelines and the
International Council for
Harmonisation of Technical
Requirements for Pharmaceuticals for
Human Use (ICH) quality guidelines
Q8, Q9, Q10, and Q11. With the
number of emerging therapies
increasing in the pipeline and the
expanded adoption of automated/
digital systems, collaboration between
regulators and industry will need to
continue for the benefit of all.
References
1 Guidance on Good Data and Record
Management Practices. WHO Technical Report
Series, No. 996, 2016, Annex 5; World Health
Organization: September 2016; http://apps.
who.int/medicinedocs/en/m/abstract/
Js22402en.
2 Good Manufacturing Practices to Ensure
Data Integrity. European Medicines Agency:
London, UK; August 2016.
3 Guidance for Industry (draft): Data
Integrity and Compliance with CGMP; Food and
Drug Administration: Rockville, MD: April
2016; www.fda.gov/downloads/drugs/
guidances/ucm495891.pdf.
4 What the FDA Guidance on Data
Integrity Means for Your Lab. Astrix Technology
Group Blog 11 May 2017; https://astrixinc.com/
fda-guidance-for-data-integrity.
5 Guidance for Industry: Providing
Regulatory Submissions in Electronic Format:
Certain Human Pharmaceutical Product
Applications and Related Submissions Using the
eCTD Specifications. Food and Drug
Administration: Rockville, MD, April 2107;
https://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-drugs-gen/documents/
document/ucm333969.pdf.
6 Guideline on Nonclinical and Clinical
Development of Similar Biological Medicinal
Products Containing Recombinant Human Insulin
and Insulin Analogues. European Medicines
Agency: 26 February 2016; www.ema.europa.
guideline/2015/03/WC500184161.pdf. c
eu/docs/en_GB/document_library/Scientific_
Maribel Rios is managing editor at
BioProcess International; mrios@
bioprocessintl.com.
To share this article in a PDF or professionally
printed format, contact Rhonda Brown,
rhondab@fosterprinting.com, 1-866-879-9144
x194.
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