Postapproval CMC Changes

Increasingly a Fact of Biopharmaceutical Life

by Angelo DePalma

Series
Series
2017
2018
Postapproval CMC Changes
Increasingly a Fact of Biopharmaceutical Life
by Angelo DePalma

Introduction page 2

Why Go Through the Trouble? page 3

Global Conundra page 5

Safety Signals paGe 6

Raw Materials paGe 7

Not So Fast paGe 8

Changes That Aren’t Really Changes page 9

References page 10

Further Reading page 10

About the Author page 11

1 BioProcess International 16(1)e January 2018 E-Book

T
he manufacture of vaccines and therapeutic proteins has suffered Back to Contents
from a reputation of being part art and part science, with heavy
doses of regulatory uncertainty thrown in. Postapproval changes
(PACs) to chemistry, manufacturing, and controls (CMC) were
initiated reluctantly and carefully in the era of “the process is the
product.” Today, CMC PACs are a normal part of the biopharmaceutical
industry business.
Emma Ramnarine (head of global biologics quality control at
Hoffmann-La Roche in South San Francisco, CA) notes that “reasons
for PAC improvements can be varied: staying current with industry
trends and regulatory expectations, driving optimization of processes or
methods, innovation in technology, addressing aging facilities and
equipment, improvements in efficiency, and addressing manufacturing/
quality issues that can impact cost of goods (CoG).” Speaking at a PDA
event in April, 2017, Ramnarine reported some interesting statistics:
• Fully one-third of all pharmaceutical PACs are filed by biotech
companies.
• PAC-related activity is widespread, with sponsors initiating a
significant multiple of PACs relative to marketed products.
• Respondents assessed about 60% of all changes as “major” and
85% of those as reportable to regulators.
• Technology transfer or testing changes were cited as justification
for 69% of PACs.
• The highest percentages of PACs (71–89%) arose in response to
equipment and plant changes — compared with just 60% from
technological innovation.
• Nearly two-thirds (64%) of survey respondents cited raw-material
replacement, the “unknown unknown” of ingredient procurement, as a
cause for initiating a PAC.
Those are the core drivers behind big-picture rationalization for
PACs such as “continuous improvement,” “patient access,” “quality,” and
others. Although it would seem to be the most obvious reason for
initiating changes, CoG turns out to be relatively insignificant.
The US Regulatory Approach: After a deluge of PAC applications
beginning in the early 2000s, the US Food and Drug Administration
began, around 2010, to streamline its process for manufacturers to
notify the agency of CMC changes. Relevant FDA guidelines are
general in nature without being vague. From a top-level view, the
agency designates PACs as major, moderate, and minor, assigning to
each a recommended level of agency notification.
If a change is considered to be major, an applicant must submit and
receive FDA approval of a supplemental application to its associated new
drug application (NDA) or biologics license application (BLA) before
the product made with the manufacturing change is distributed. This is
known as a prior approval supplement (PAS).
For moderate changes a sponsor must submit a CBE-30 supplement
to its NDA or BLA at least 30 days before distribution. In some cases,
sponsors submit a CBE-0 supplement at the time of distribution. A
sponsor may proceed with minor changes without prior approval but
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must notify the FDA in an annual report. All companies must assess the
effects of changes on product quality through appropriate studies.
The minutiae of PAC regulation are beyond the scope of this
publication. The References sidebar points to other publications that
detail which situations induce process changes, their extent and
complexity, and how regulatory specialists might handle those situations.
The BPOG Approach: PACs for biologics often involve process
changes to lower CoG, intellectual property considerations, and
product/process improvement. Strategies for handling CMC changes
balance the perceived value and risk of such changes, global market
penetration, and regulations within different jurisdictions. The
BioPhorum Operations Group (BPOG) defines postapproval strategies
as “approaches companies take to meet the needs of regulators around
the world, when improving manufacturing processes, increasing capacity
and responding to changes in regulations, after a product has been
approved initially and launched in the marketplace.” BPOG’s efforts
related to CMC changes focus on attempting to understand the issues
associated with such changes for biologics, then influencing and
establishing best practices for current good manufacturing practice
(CGMP) compliance.

Why Go Through the Trouble? Back to Contents

An Outsourcing Perspective: John Foy (vice president of business
management at Patheon in Durham, NC) classifies the justifications for
postapproval CMC changes into four categories: CoG improvements,
regulatory issues (e.g., arising from product stability or quality), business
drivers that include the materials and ingredient availability, and
changes in materials of construction for critical components (e.g., single-
use containers). He speaks from the perspective of a contract development
and management organization (CDMO). “CMC changes are effected
through notifications by the owner of the product license. A CDMO’s
job is to provide data to support such changes and to institute a change
control system that covers anticipated and actual changes.”
Initiation of postapproval changes occurs through what Foy describes
as a “mutual introduction of opportunity.” For CDMOs, an obvious
(but not entirely sufficient) goal is CoGS improvement. “But in the
end, customers must justify changes on the basis of regulatory and
business factors. They alone can determine if a change is worth the
investment.”
Because so much development and production is outsourced, CDMOs
feature prominently in both pre- and postapproval process changes. A
contractor’s work on process performance qualification (PPQ ) batches
serves as the reference for postapproval changes as well as regulatory
applications arising from the sponsor’s need for process changes as
dictated by circumstances.
Although economics is the bottom line, and CoG a significant
component of profitability, unit cost is less likely to drive postapproval
changes than would seem obvious. According to Foy, “Improving CoGS
is of tremendous benefit, but it must be weighed against the cost of
making a change, the time involved, and how changes affect supply.
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That is why change drivers can be more likely to arise from business or
operational factors.”
PPQ is conducted at the assumed commercial scale, which is selected
specifically to facilitate first approval and early market supply. Process
improvement does not cease during the product approval stage, however.
“Even as a product is on the verge of commercialization, we routinely
identify improvement opportunities.”
Justifications for PACs that positively affect CoGS but might arise
from issues unrelated to cost include the ability (or need) to scale up a
process or some portion of it and the need to reduce manufacturing cycle
times. Operational and equipment changes that affect scale and cycle
time will improve CoGS, even though their original goal might have
been related to a more general operational efficiency.
A Sponsor Perspective: Kavita Ramalingam Iyer is associate director
of global regulatory affairs and clinical safety for vaccines CMC at Manufacturers
Merck Sharp & Dohme in West Point, PA. She explains that although LAUNCH with the
many factors drive CMC changes, speed-to-launch immediately upon knowledge that changes
demonstration of clinical efficacy almost necessitates initiating them are forthcoming related
post-licensure. “Manufacturers launch with the knowledge that changes to increasing batch sizes
are forthcoming, for example, to increase batch sizes and/or construct and/or construction of
new facilities to expand patient access.” Changes sometimes arise from
new facilities to expand
the need or desire to improve product quality or process robustness. “As
patient access.
companies gain experience in commercial manufacture, they also
institute changes to exploit new or emerging manufacturing technologies
that enhance process efficiencies.” Changes also may be initiated to
comply with new regulations.
Because regulatory review of CMC changes is critical to safeguarding
patient safety, health agencies take all proposed changes seriously.
“Their approval can take significant time due to the complexity of the
review and approval process,” Iyer adds.
A lack of regulatory (or operational) harmonization among global
regulators makes international applications for significant CMC changes
arduous for many product sponsors. Iyer notes that for a global
submission the same core data can be submitted to some 140 countries.
“Although guidelines and requirements exist for many of these countries,
some do not have a mature regulatory apparatus.” Diverse agency
expectations and change reporting thus may necessitate multiple rounds
of reviews of same core information — all of which adversely affects
approval timelines.
Postapproval filing complexity is increased further by regulators’
demands for ancillary documents, real-time stability data, and shipping-
validation requirements. “Variability in review and approval timelines
for the same change across markets could range from six to eighteen
months,” Iyer says. From a sponsor’s perspective, those complications do
nothing to improve product safety, quality, efficacy, or supply but lead
only to higher costs, a more complex supply chain, and a need for ever
more sophisticated systems for maintaining regulatory compliance.
Maintaining multiple versions of a CMC dossier increases the potential
for errors, which in turn adversely affects regulatory compliance,
inventory management, and manufacturing costs. “The absence of
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international harmonization is a significant burden with little upside for
manufacturers or patients.”

Global Conundra Back to Contents

As part of a global business, biopharmaceuticals marketing authorization
holders must stay abreast with evolving requirements in each country
where their products are sold, which demands constant application of
resources. Sponsors must maintain country-specific dossiers and may
need to support manufacturing and testing of the same product in
multiple ways to ensure global availability. “From a supply perspective,”
Iyer notes, “the industry is pressed to design a flexible and dynamic
strategy to cope with varying review timelines and processes approved
in each country as a result of those timelines.” Yet such activities don’t
necessarily provide benefits of improved analytical methods or even
process robustness, particularly in markets that are slow to approve
changes or have unclear target approval times.
Sponsors base CMC change submissions on guidelines from the
International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH,) with the aid of country-specific
databases built on historical experience and input from regional affiliates
and agency guidances. According to Iyer, companies use templates for
building documentation and bundle changes when possible into single
submission to reduce the number of separate documents to be reviewed
and approved. “At the same time, they maintain specific dossiers for
countries or regions to accommodate specific market requirements.”
Such strategies may be effective as stopgap measures, but Iyer believes
that they are inefficient. “Considering the growing complexity, time,
and resources required for obtaining global CMC change approvals,”
she says, “it would be in the interests of all stakeholders to educate and
advocate for harmonizing regulatory requirements according to ICH
guidelines.” She suggests as a constructive step toward the ideal state of
a single global submission that industry and health authorities engage in
candid conversations. They need to “understand each other’s perspectives,
identify common interest and objectives, and work together toward this
common goal, which is ensuring that patients continue to receive quality
medicine.”
Europe: Predicting the level of regulatory review for PACs is fairly
straightforward for US, EU, and Japanese markets. Europe is similar to
the United States except for being more conservative with biologics: By
default most PACs for biologics in the European Union fall under the
type 2 designation. Type 2 is roughly equivalent to an FDA prior-
approval application, with an upper time limit of four months. The
European Medicines Agency (EMA) also has a type 1B process similar
to FDA’s CB-30 (through which regulators have 30 days to respond to
an approval application) and a type 1A, which resembles annual-report
notifications in the United States, but such protocols are rarely allowed
for biologics in Europe.
EU Type 2 postapproval changes require GMP plant certification,
which FDA approvals do not. Manufacturers must request an inspection

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specific to a given change, maintain the resulting certification for
several years, and obtain a “qualified person” release for subsequently
manufactured products — all of which adds an additional layer of
complexity.
Acceptance of the final ICH Q12 guidance (1), which specifies
changes that are of higher or lower risk, may bring Europe more into
line with US regulatory practice. EMA adoption of ICH Q12 would
probably broaden the category of changes requiring minimal or no prior
approval. But for now, manufacturers operating in Europe must dance
to EMA’s tune.
Japan’s CMC-change regulatory apparatus most closely resembles
where Q12 is heading. This nation’s approval structure reflects more
reasonably the low-, medium-, and high-risk changes encountered in the
real world. Where Japan differs is that all changes and related assays are
preassigned to specific risk categories that are similar to those followed
by the FDA and (theoretically) EMA. Japan also has a unique way of
approaching change-approval timelines. A review period may be
advertised as 12 months, but that does not include time for responding
to regulator questions, during which the clock stops.
Elsewhere: Things get more complicated in second-tier markets such
as Brazil, Russia, China, South Africa, and Mexico, where common
approval times are at least 18 months. Handling supply in the face of
long approval timelines demands planning and resources that may be
unavailable to mid-sized biomanufacturers. Depending on the situation,
companies may stockpile product to supply their markets during the
approval process — or they may maintain two separate processes or
facilities. Because so many markets are characterized by protracted
approval times, such supply chain work-arounds are fairly common.

Safety Signals Back to Contents

Most drugs and biologics approved by FDA undergo postmarketing
surveillance, which may include phase 4 postapproval clinical studies
and/or mandated pharmacovigilance. These activities emphasize patient
safety as part of the FDA’s implicit agreement with the biopharmaceutical
industry to follow a risk-based protocol for approving medicines.
CMC changes rarely are spurred by postapproval safety signals, but
related incidents can have dire consequences. Problems can arise from
using a new lot of an ingredient that behaves differently than it has in
the past. Safety signals also can be linked to observed changes in
product quality attributes over time, e.g., from the emergence of a new
degradant or impurity.
Assessing the need to submit postapproval change reports to address
such deviations depends on their safety implications. “If a product falls
outside the approved scope for safety and efficacy,” says Earl Dye
(director of regulatory policy at Genentech/Roche in Washington, DC),
“that would be a high-priority case that could lead to recall and require
submission of a high-priority postapproval change to address an
unanticipated safety signal.”
Safety signals fall into a hierarchy of gravity, but all safety signals
reported to biomanufacturers must be investigated, to determine their
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relationship to product quality. If a problem is limited to a single vial,
then storage or handling will be the most likely cause; process-related
issues are more likely to affect entire lots.
As part of routine lot release, manufacturers monitor the quality of
each drug lot and assess trends in quality over time. Product attributes
trending toward the upper or lower range of approved acceptance criteria
usually require minor process tweaks. “In that case,” Dye says, “where
approved specifications have not actually been exceeded, the manufacturer
might make relatively minor adjustments and describe them in a low-
priority annual report. But if product attributes trend out of approved
ranges, the company must go back to its process and adjust that to bring
product attributes within the narrower range of historical precedent.
Such changes are more significant and would require higher priority
submissions.”

Raw Materials Back to Contents

PACs involving raw ingredients can initiate internally or externally (e.g.,
by the raw material supplier itself). The latter is common, says Yuval
Shimoni (principal quality assurance specialist at Bayer Healthcare in
Berkeley, CA). In line with a generally conservative approach to process
changes, he advises sponsors to determine whether a change actually is
necessary and also to consider possible alternatives.
“For self-initiated changes, the complexity depends on a company’s
experience,” Shimoni explains. Because they are postapproval changes,
sponsors should have already a broad range of history and onsite
knowledge regarding both product and process and thus an
understanding of how raw-material changes might affect them. A
process may be mature or new or a platform process for which
knowledge from other similar products and PACs could apply. If it’s a
new class of biotherapeutic or modality, however, less information will
be available, so the associated risk would be higher. Continuous improvement
Supplier-originated changes may occur for various reasons, such as to raw-materials
issues of supply availability with secondary suppliers. Vendors are under production processes —
great pressure to stay competitive and reduce costs. Continuous
based on advanced
improvement to their raw-materials production processes — based on
technologies or a desire
advanced technologies or a desire to improve quality or safety — also
can drive these changes. to improve quality or
The risk involved in a raw-materials change depends partly on a drug safety — can drive
sponsor’s own capabilities and experience. Smaller companies that use SUPPLIER-originated
off-the-shelf compounded culture media are probably unfamiliar with changes.
every ingredient or its appropriate batch-to-batch concentration range.
A change in media supplier, however, should raise questions about the
composition of such products because it might be reportable. Companies
with their own proprietary media formulae — production of which is
often outsourced — are in a better position to understand the significance
of associated changes and exercise a higher degree of control over them.
If a drug sponsor deems such a PAC to be of low risk, then subsequent
work required could be minimal. For example, a simple technical
assessment of a certificate of analysis (CoA) could justify a change,
essentially a paper exercise that entails examining requested or supplied
7 BioProcess International 16(1)e January 2018 E-Book
change information and evaluating it. Of particular concern is whether
such changes must be reported to regulators (see ICH Q12 for
established conditions and reporting requirements). And once again, the
answer is conditional.
“If an ingredient is in the license, it must be reported,” Shimoni says.
“Although many raw materials are not listed, a developer’s own standard Scaled-down process
operating procedures (SOPs) might call for some level of evaluation,
including validation, to justify approval for use. And you have to MODELS must be
qualified, approved, and
consider not just what’s in the license, but also current regulatory agency
expectations such as described in pertinent ICH guidelines.” current representatives of
To reduce the validation burden in support of raw-materials changes, manufacturing-scale
Shimoni stresses the importance of having a qualified, approved, and processes.
current scale-down process model. “The scaled-down process must be
representative of the manufacturing-scale process. Having been qualified
at one point long ago is insufficient.” For companies that lack production-
scale capacity sufficient for at-scale validation, having a currently valid
small-scale model in place “is well worth the cost and time involved in
qualifying it.”
Sponsors should be prepared to align the tests they perform with the
nature of a given change, as well. For example, changing a sugar or
source of it in a medium or feed could affect glycosylation, which is
typically a critical product quality attribute. The resulting
biopharmaceutical product might be different from the earlier product
even if it meets all release specifications. “That’s when you might wish
to go beyond release assays and perform ‘extended characterization’ to
assure that a change has not affected product quality,” Shimoni says.
(Disclaimer: Dr. Shimoni’s views reflect his own personal opinion and
do not necessarily reflect the views of Bayer.)

Not So Fast Back to Contents

Industry consultant and BPI editorial advisor Peter Calcott warns
against common assumptions regarding the regulatory complexity of
PACs. “Too many experts believe there is a formula for determining the
significance of a change. But when you ask them about the category into
which specific changes might fall, you get a range of answers — from
annual reportable to prior approval and everything in between. We’d
love to have a software program that provided the answers, but that
program doesn’t exist and never will. In the end, experience and your
risk appetite provide the final answer.”
How companies treat changes depends on the conservatism or
aggressiveness of their regulatory specialists and how they manage
change with regulators. The “conservatives” predominate, in Calcott’s
view, always noting the difficulties and risks. “Their pronouncements
become self-fulfilling prophecies.”
Much rarer are specialists who, to use his example, would risk
applying for a CBE-30 whereas conservatives would go for a prior
approval. “The agencies educate us through guidances. They try their
best, but sometimes we’re our own worst enemies. The agency is trying
to tell you how complex or easy a change is, but sometimes we don’t
listen. We make our lives harder than they need to be.”
8 BioProcess International 16(1)e January 2018 E-Book
 One company Calcott worked with designated 90% of its postapproval
changes as prior approvals. “I suggested picking a few lower risk projects
to push through as CBE-30s, and it worked. Then we picked a few
more, and they also got approved as CBE-30s. Everyone was shocked,
and I got a reputation. But the regulators took me aside and complimented
us on our changed approach. Remember that the agency will never
downgrade a submission from prior approval to CBE if you recommend Regulators will never
the more conservative approach.” DOWNGRADE a
Regulatory affairs specialists almost always hold a science degree, but submission from prior
many paths lead to such jobs. People who get there through clinical approval to CBE if you
regulatory writing often are not knowledgeable about CMC issues. recommend the more
“They learn on the job,” Calcott says. “All they ever hear is ‘this is conservative approach.
incredibly hard,’ and after a while they believe it. They are the
conservatives.” Another group enters regulatory affairs from the CMC
side, often from quality jobs. And according to Calcott, they tend to be
more progressive. He credits his own background in research, production,
process development, quality, and then regulatory consulting with
membership in the latter group.
One manifestation of the conservative approach with a direct effect
on the complexity of an approval is the level of detail in submissions.
Calcott says this presents an interesting paradox. “One goal of these
submissions is to trigger the minimum number of queries. If you include
everything in the application, you cover all bases, but agencies have
more to question.” Therefore, he recommends taking a fluid, science-
based approach to CMC change submissions. Sometimes that means
doing more than regulations ask; sometimes it means stepping outside
of comfort zones. “Even when no regulation requires something, the
added time to do it makes your life easier. If you design a process that
makes good scientific and business sense, you just might impress
regulators.”

Unofficial Changes Back to Contents

Although CMC changes are common and often justifiable, some
biomanufacturers avoid making PACs for reasons that are well known.
“CMC changes are out of the question for many of our clients looking
to boost productivity,” says Charles Siletti (director of planning
applications at Intelligen in Scotch Plains, NJ). For such companies, the
most effective approach may include scheduling changes — essentially
reorganizing the timing and organization of batch unit operations.
“When considering scheduling changes,” Foy of Patheon says, “the
first question that arises is whether it constitutes a process change that
is substantial enough to require regulatory oversight. That, he points
out, “when you come down to it, is the basis for all postapproval change
applications.”
The exercise begins with identifying scheduling bottlenecks. Several
usually are present, typically in operations that are heavily used or long
in duration. Reusable equipment that is cleaned in place, for example,
involves a period between use and cleaning usually specified and known
as “dirty hold time.” “You want that hold time to be as short as possible,”

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Siletti says. “It’s possible to achieve this without changing the cleaning
process, by instead altering the order in which equipment is cleaned. If
there’s a queue, you clean the bottleneck equipment first to increase its
total availability time. That’s what we mean by improving processes
without changing them.”
Disposables: Single-use equipment presents its own challenges.
“Cleaning is not an issue, but there are setup and turnaround times,”
Siletti says. “Biobags need to be prepared, and when a run is over you
have to swap them out. These activities are also scheduled. So even
though you don’t have a cleaning operation, you need to schedule
turnaround.” The critical resource for disposables may be the staff
required to implement and replace disposable equipment. “You don’t
want a bioreactor waiting to be deployed because staff are working on
something else. In that case, you either need more staff or to prioritize
them so that they work first on time-critical processes.”
Siletti goes on: “When we examine a process, we set the constraints
so that nothing process-critical will vary. But clean and dirty hold times
and process durations are fair game. Scheduling may have unanticipated
effects, but that’s unusual.” For example, scheduling one step at a
particular time of day when cooling-water temperature is lower could Without postlaunch
make certain steps take or more less time. “But those are secondary CMC changes, such
effects. You might consider them, but all things being equal, scheduling
should have a significant impact only when a step that was not BENEFITS as
continuous improvement,
considered to be time-variant turns out to be.”
Efforts to maximize the potential of a new biologic do not end with novel dosage forms, and
its market approval. But of all postlaunch lifecycle-enhancing strategies, broadened patient access
CMC changes are arguably the most fundamental. Without them, such would not be possible.
benefits as continuous improvement, novel dosage forms, and broadened
patient access would not be possible. Think of CMC PACs as the “phase
four” of manufacturing. Given the industry’s increasing emphasis on
speed to market and risk-based manufacturing, they are nearly inevitable.

Reference
1 ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product
Lifecycle Management. International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use: Geneva, Switzerland, 28 July
2014; www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/
Quality/Q12/Q12_Final_Concept_Paper_July_2014.pdf.

Further Reading Back to Contents

Calcott P. How QbD and the FDA Process Validation Guidance Affect Product
Development and Operations, Part 1. BioProcess Int. 9(10) 2011: 12–19; www.
bioprocessintl.com/analytical/downstream-validation/how-qbd-and-the-fda-
process-validation-guidance-affect-product-development-and-operations-
part-1-323457.
Calcott P. How QbD and the FDA Process Validation Guidance Affect Product
Development and Operations, Part 2. BioProcess Int. 9(11) 2011: 14–19; www.
bioprocessintl.com/analytical/qa-qc/how-qbd-and-the-fda-process-validation-
guidance-affect-product-development-and-operations-part-2-324819.
Dobbins JR, et al. Evolution of Biopharmaceutical Control Strategy Through
Continued Process Verification. BioProcess Int. 15(1) 2017: 10–19; www.bioprocessintl.
10 BioProcess International 16(1)e January 2018 E-Book
com/business/cmc-forums/continued-process-verification-evolution-
biopharmaceutical-control-strategy-cmc-forum.
Hoath C, et al. Postapproval Changes for Biopharmaceutical Drug-Substance and
Drug-Product Manufacture: Regulatory Complexity and Impact. BioProcess Int.
14(11) 2016: 38–43; www.bioprocessintl.com/business/regulatory-affairs/
postapproval-changes-biopharmaceutical-drug-substance-drug-product-
manufacture-regulatory-complexity-impact.
Kennett S, et al. CMC Strategy Forum on Combination Products for
Biopharmaceuticals: Emerging Trends in Development, GMPs, and Regulatory
Expectations. BioProcess Int. 15(3) 2017: 20–29, 37; www.bioprocessintl.com/
business/cmc-forums/cmc-strategy-forum-combination-products-
biopharmaceuticals-emerging-trends-development-gmps-regulatory-expectations.
Kutza J, et al. Change Happens: Technical and Regulatory Considerations for
Pharmaceutical Product Lifecycle Management (CMC Forum). BioProcess Int. 15(8)
2017: 24–35, 47; www.bioprocessintl.com/business/cmc-forums/change-happens-
technical-and-regulatory-considerations-for-pharmaceutical-product-lifecycle-
management-cmc-forum.
Mire-Sluis A, et al. Combination Products for Biopharmaceuticals: Emerging
Trends in Development, GMPs, and Regulatory Expectations. BioProcess Int. 11(9)
2013: 28–39; www.bioprocessintl.com/analytical/cell-line-development/new-
paradigms-for-process-validation-347349.
Shimoni Y, Moehrle V, Srinivasan V. Process Improvements Increase Production
Capacity of a Legacy Product. BioProcess Int. 11(10) 2013: 26–31; www.bioprocessintl.
com/upstream-processing/cell-culture-media/process-improvements-increase-
production-capacity-of-a-legacy-product-347985.
Towns J, Webber K. Demonstrating Comparability for Well-Characterized
Biotechnology Products: Early Phase, Late Phase, and Post Approval. BioProcess Int.
6(2) 2008: 32–43; www.bioprocessintl.com/analytical/product-characterization/
demonstrating-comparability-for-well-characterized-biotechnology-
products-182256. c

About the Author Back to Contents

With a PhD in organic chemistry from the State University of New York at Stony Brook, freelance
writer Angelo DePalma ([email protected]) was a chemist first at Brookhaven National
Laboratory and then at Schering-Plough. For over 25 years, he has written for dozens of
technical online and print publications, as well as product and service companies in
biotechnology, bioprocessing, pharmaceutical chemistry, pharmaceutical development, drug
discovery, and laboratory instrumentation.

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