Volume 46 Number 9

SEPTEMBER 2022 Volume 46 Number 9

Advancing Development & Manufacturing

PharmTech.com

Seedling Ideas in
Pharmaceuticals
PHARMACEUTICAL TECHNOLOGY

Development
Delivery Kinetics for Topicals

Manufacturing
Optimizing Cell Line Development
Supply Chain Disruptions

Analytics
Environmental Monitoring Advances

Quality
Approaches to Post-approval Changes

Outsourcing
Robust Bioanalytical Studies
SEPTEMBER 2022

Peer-Review Research
The Value of Primary Working Standards
PharmTech.com
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 September 2022 Volume 46 Number 9

Pharmaceutical Technology is the authoritative source of peer-reviewed research

and expert analyses for scientists, engineers, and managers engaged in process
development, manufacturing, formulation and drug delivery, API synthesis, analytical
technology and testing, packaging, IT, outsourcing, and regulatory compliance in the
pharmaceutical and biotechnology industries.
On the cover

COVER STORY
16 Pfizer’s Idea Orchard
The flow of capital and scientific acuity irrigates this pharm system.

Cover Design by Maria Xelo Images: Елена Бутусова - Stock.adobe.com

FEATURES
DEVELOPMENT ANALYTICS OUTSOURCING

22 Delivery Kinetics 40 Advances in 54 Robust Bioanalytical

for Topical Drugs Environmental Monitoring
API permeation into the skin modulates Cleanroom monitoring may be in
the efficacy of topical treatments. a state of flux after many recent
technological advancements.
MANUFACTURING QUALITY
Studies Can Aid in
Regulatory Submissions
It is important to understand regulatory
requirements and study challenges to
develop and validate the appropriate
methods for a bioanalytical study

28 Exploring Options 44 Industry 1VQ Solutions:

program at the clinical stage.

for Optimizing Cell Change of Lot or Extension of

Line Development
Biopharmaceutical manufacturers
must consider a surprisingly wide range
of factors when deciding where to turn
for assistance with cell line development.
SUPPLY CHAIN
Shelf-life of Reference Standard
Change of lot or extension of reference
standard shelf-life is considered low
risk and should be downgraded from
prior-approval to being managed in the
Pharmaceutical Quality System (PQS) only
based on a science and risk-based approach.

30 Reducing Blind Spots in 48 A Harmonized Approach

the Pharma Supply Chain
Expanded use of data analytics
can help to avoid disruptions, but
the possibilities cannot be realized
without sufficient investment
and direct human involvement.
to Performing a Risk-Based
Audit Trail Review
The IQ Working Group has defined
a pragmatic risk-based approach
to audit trail review, where it is only
required for high impact GxP data.

PEER-REVIEWED RESEARCH
PEER-REVIEW RESEARCH

34 The Value of Primary Working

Standards in Pharmaceutical Quality Control
It is argued that orthogonal quantitative methods can be used to establish primary
working standards. An example details how to calculate the expanded measurement
Continued on page 6
uncertainty (U) for the certified assay value by considering two orthogonal assay methods.

4 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m

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NEWS & ANALYSIS REGULATION & DEPARTMENTS/

FROM THE EDITOR COMPLIANCE PRODUCTS
10 Vaccine REGULATORY WATCH 8 Note from the CEO
Disconnect 14 New Legislation 12 Product Spotlight
Looking ahead, it’s important Overhauls Medicare
to remember our fates are interdependent Drug Pricing
57 Marketplace
no matter what continent you call home. and Benefits 57 Ad Index
Pharma loses battle to block price
negotiations, but implementation
faces many challenges.

ASK THE EXPERT

58 Best Practices Subscribe to Newsletters!

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6 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m

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SALES
Publisher Mike Tracey MTracey@mjhlifesciences.com
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8 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
T
he recent passing of the Inflation Reduction Act expands the Affordable
Care Act and allows Medicare to negotiate for the price of prescription
drugs, in a limited and phased introduction. This introduces direct
government influence on drug prices, albeit in a phased and small-scale
initial deployment. The median launch price of a new drug in the United
States in 2021 was $180,000 for a year’s supply [fewer than 8% of drugs
introduced cost this much in 2008] (1). While drug makers aren’t hiking
prices of existing products quite as aggressively as they did prior to 2019, they
continue to rise approximately 5% a year, according to 46brooklyn Research,
a nonprofit drug pricing research firm (1). Patients’ out-of-pocket costs are
only 13.3% of total costs. But these “are ultimately passed on to members of
the public through the premiums they pay to keep their insurance policies
active (40.4%) and the taxes they pay to the government,” Medicare 31.5%,
Medicaid 9.9%, others 4.8% (1).
On August 17, 2022, bluebird bio’s one-time treatment, Zynteglo, for Be-
ta-thalassemia (liver and heart malfunctions caused by oxygen deprivation)
was approved by FDA and priced at a record $2.8 million (2). Not only sticker
shock, but trendline increases for median prices are hard to ignore. To de-
fend its cost structure, bluebird bio’s Chief Operating Officer Tom Klima
pointed out that traditional transfusion intervention can cost around $6.4
million per patient, and the company will reimburse 80% of the fees if trans-
fusion independence is not achieved after one treatment with Zynteglo. “We
feel the prices we are considering still bring a significant value to patients,”
Klima stated (2).
While it is unclear how the cards will play out for bluebird and Zynte-
glo, it is instructive to look back to what happened to the previous most
expensive drug, Novartis’ Zolgensma, which in 2019 offered discounts and
outcome-based installment payments, after insurers demurred (3).
While high-priced genetic disorder treatments are here to stay, I would
argue the cost of poor diet, lack of pandemic planning, poor general infectious
disease control, and sporadic exercise, are a far higher cost to society, and a
much more obtainable fix, than overreacting to either legislative change or
wildly expensive niche treatment options. The cost of overlooking simple
public health overhauls, and behavior change, is far more expensive.
References
1. R. Langreth, “Why Prescription Drug Prices in the US Are So High,”
Bloomberg, July 19, 2022.
2. M. Roy, “Bluebird’s $2.8 Million Gene Therapy Becomes Most Expensive
Drug after US Approval,” Reuters, August 17, 2022.
3. M. Nuijten, “Pricing Zolgensma–The World’s Most Expensive Drug,
Journal of Market Access Health Policy, 2022. PT
Mike Hennessy Jr
President and CEO
MJH Life Sciences®
 pda.org/annex1palmsprings

2022 PDA
ANNEX 1
WORKSHOP
PALM SPRINGS

Are You Prepared for the Annex 1 Revision?

Get the information you need at the last offering of the 2022 PDA Annex 1 Workshop!
After great success in Dallas, TX, and Dublin, Ireland, you won’t want to miss the last offering of this workshop! Join us in
Palm Springs, CA to prepare for implementation challenges expected from the forthcoming revision.

The program for this interactive workshop was specifically designed to provide you with both presentations of important
aspects of the Annex 1 revision and implementation-focused group discussions.

Sessions will focus on specific sections of Annex 1:

DAY 1 DAY 2 UNIQUE FEATURE:

INTERACTIVE SESSIONS
Overview of and Revision Process Personnel Training, Qualification,
for Annex 1 Gowning, and Assessment You’ll have the opportunity
to participate in breakout
Principles and PQS Production Technologies, Part 1 group sessions, one of our
Premises and Barrier Systems Production Technologies, Part 2 attendees’ favorite features of
this workshop, to ask complex
Equipment, Technology, Aseptic Process Simulation and
questions and take away
and Utilities Environmental Monitoring
solutions for implementation
challenges at your company!
Visit pda.org/annex1palmsprings to learn more and register!

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#PDAannex1
EDITORIAL
Editorial Director Chris Spivey CSpivey@mjhlifesciences.com
Senior Editor Felicity Thomas FThomas@mjhlifesciences.com
Senior Editor Meg Rivers MRivers@mjhlifesciences.com from the editor
Managing Editor Susan Haigney SHaigney@mjhlifesciences.com
Science Editor Feliza Mirasol FMirasol@mjhlifesciences.com
Assistant Editor Grant Playter GPlayter@mjhlifesciences.com
Assistant Editor Alivia Leon ALeon@mjhlifesciences.com
Creative Director, Publishing Melissa Feinen
Senior Art Director Marie Maresco; Senior Graphic Designer Maria Xelo
Vaccine Disconnect
Contributing Editors Jill Wechsler jillwechsler7@gmail.com; Hallie Forcinio, editorhal@cs.com;

W
Susan J. Schniepp, sue.schniepp@mac.com; Cynthia A. Challener, PhD challener@vtlink.net ; hile waiting on a freeze-dried long shelf-
and Jennifer Markarian, Manufacturing Reporter.
life vaccine to be developed, the United
485 Route One South, Building F, Second Floor, Iselin, NJ 08830, USA States let its stockpile of liquid monkeypox
Tel. 732.596.0276, Fax 732.647.1235, PharmTech.com vaccine languish and expire. By 2017, all 27,993,370
doses in the national Jynneos stockpile had expired,
EDITORIAL ADVISORY BOARD although the US still had a huge stockpile of its Chris Spivey is
editorial director of
Pharmaceutical Technology publishes contributed technical articles that undergo a other smallpox vaccines (1). While waste per se is Pharmaceutical Technology.
rigorous, double-blind peer-review process involving members of our distinguished
Editorial Advisory Board. Manuscripts should be sent directly to the managing editor. shameful, it’s akin to Greek tragedy when the rise in monkeypox cases
Below is a partial list of the Pharmaceutical Technology brand editorial advisory members. internationally is associated with lost opportunities to improve millions of
The full board, which includes advisory members from Pharmaceutical Technology Europe, people’s lives in sub-Saharan Africa, where smallpox was eradicated in 1980,
can be found online at PharmTech.com.
and vaccinations halted (2).
Larry L. Augsburger, PhD Jim Miller Many countries now face a growing threat. FDA Commissioner Rob-
Professor Emeritus, President, Advisor on
University of Maryland School of Pharmacy Bio/Pharmaceutical Manufacturing Strategy ert Califf has been quick to revisit strategies discussed in the early days of
Phil Borman, DSc Colin Minchom, PhD COVID-19 vaccine availability, when production scarcities predominated.
Director & Senior Fellow Founder and Prinicpal CMC Consultant
Portfolio & Technology Delivery Cordack CMC Consulting This includes widening the spaces between first and second doses. It also
Medicine Development & Supply includes using an “intradermal injection”—where the vaccine is injected into
Pharma R&D R. Christian Moreton, PhD
Partner
GlaxoSmithKline
FinnBrit Consulting the skin—rather than injecting into the layer of fat underneath the skin.
Evonne Brennan Officials believe this smaller dose is able to produce an equal immunologic
Co-Founder, Fernando J. Muzzio, PhD
Distinguished Professor,
Atam Health Ltd
Chemical and Biochemical Engineering response, which currently seems unclear. But even if true, each vial contains
Rory Budihandojo Rutgers University perhaps enough material for around three times the number of patients, cer-
Independent GMP Consultant
Moheb M. Nasr, PhD tainly not sufficient for the crisis. At least that’s the feedback from front-
Metin Çelik, PhD Principal
President, Nasr Pharma Regulatory Consulting line healthcare workers. “We are definitely in what we’re still calling ‘The
Pharmaceutical Technologies
International (PTI) Wendy Saffell-Clemmer Hunger Games’ phase of this—where there’s nowhere near enough doses for
Sr Director,
Roger Dabbah, PhD Global Pharma Business Operations & BPS R&D the demand,” said Dr Mark Del Beccaro, assistant deputy chief for Public
Principal Consultant , Baxter Healthcare Corporation
Tri-Intersect Solutions Health—Seattle & King County (3).
Gurvinder Singh Rekhi, PhD
Robert Dream Department of Pharmaceutical and Biomedical The new administration route requires using a different syringe and a
Managing Director, Sciences,
HDR Company The University of Georgia College of Pharmacy different needle. This has required tapping into a different supply chain net-
Sanjay Garg, PhD Susan. J. Schniepp work. In addition, administration under the skin requires a new set of onsite
Professor and Director, Distinguished Fellow
Centre for Pharmaceutical Regulatory Compliance Associates training for staff.
Innovation and Development, Looking ahead, it’s important to remember our fates are interdependent
University of South Australia David R. Schoneker
President,
R. Gary Hollenbeck, PhD Black Diamond Regulatory Consulting no matter what continent you call home. It is entirely shortsighted to be
Research Scientist
Aloka Srinivasan disconnected from that simple fact.
University of Maryland
School of Pharmacy Principal and Managing Partner
RAAHA LLC
Ruey-ching (Richard) Hwang, PhD
Read board members’ biographies online at References
Executive Director,
Clinical Supply Operations, PharmTech.com/view/pharmaceutical- 1. M. Kozlov, “Monkeypox in Africa: The Science the World Ignored,”
Pfizer Global R&D technology-editorial-advisory-board.
Pharmaceutical Technology’s Nature, June 23, 2022.
Maik W. Jornitz
President, eNewsletter Team: 2. J. Goldstein, “How the U.S. Let 20 Million Doses of Monkeypox
G-CON Manufacturing Inc. • ePT, Editor Grant Playter,
ptpress@mmhgroup.com Vaccine Expire,” The New York Times, Aug. 1, 2022
Mansoor A. Khan, PhD • In the Lab, Editors Grant Playter and Feliza
Professor & Vice Dean Mirasol, ptpress@mmhgroup.com 3. W. Stone and P. Huang, “The New U.S. Monkeypox Vaccine Strategy
Irma Lerma Rangel College of Pharmacy, Texas • Equipment & Processing Report, Offers More Doses–and Uncertainty, NPR, Aug. 19, 2022. PT
A&M Health Science Center Editor Alivia Leon,
ALeon@mjhlifesciences.com
Heidi M. Mansour, PhD • Send news and product releases to
Regents Professor and Vice Dean, ptpress@mmhgroup.com Send your thoughts and story ideas to:
Presidential Impact Fellow cspivey@mjhlifesciences.com.
Rangel College of Pharmacy
Texas A&M University

10 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m

 pda.org/2022micro

2022 PDA
Pharmaceutical
Microbiology
Conference
Leading through Science:
A Monumental Undertaking

The 2022 PDA Pharmaceutical Microbiology Conference is making its

long-awaited return to a live, in-person format!
This year, the agenda is built around the theme, Leading through Science: A Monumental Undertaking, to
address the many opportunities that will shape the future of the pharmaceutical industry.

This event will feature presentations from global regulatory and industry experts, including the
following plenary sessions:

— Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues
•Martin Blaser, MD, Director, Center for Advanced Biotechnology and Medicine/RWJMS/Rutgers University
— Pharmaceutical Microbiology in Quality of Medicines: Historical Perspectives in Achieving Sustainable
Compliance through Evolving Science
• Rajesh K. Gupta, PhD, President and Principal Consultant, Biologics Quality & Regulatory Consultants, LLC
— Liquid Biopsy: Recent Advances and Future Directions
• Erica L. Carpenter, MBA, PhD, Research Assistant Professor of Medicine,
Perelman School of Medicine
— Ask the Regulators
• Featuring representatives from CBER, CDER, CVM, and ORA

This conference is the best opportunity to learn about current trends in the industry and
to take away practical solutions for common challenges.

Register by 14 August for the most significant savings!

pda.org/2022micro

10-12 OCTOBER | WASHINGTON, DC

EXHIBITION: 10-11 OCTOBER
RAPID MICROBIOLOGICAL METHODS WORKSHOP: 12-13 OCTOBER
TRAINING COURSES: 13 OCTOBER
#PDAmicro
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regulatory watch
New Legislation Overhauls
Medicare Drug Pricing
and Benefits
Jill Wechsler
Pharma loses battle to block price negotiations,
but implementation faces many challenges.
D
espite extensive opposition from
biopharmaceutical manufacturers,
Democrats in Congress pushed
through legislation authorizing Medi-
care to reduce reimbursement for cer-
tain pricey medicines and to limit an-
nual increases in drug prices. The $740
billion Inflation Reduction Act of
2022 (HR 5376), moreover, will lead
to significant changes in the design of
drug benefits for seniors incurring high
costs, shifting much of the liability to
pharma companies.
The drug and health provisions are
part of a broad package of reforms
in energy and tax policy designed
to combat global warming and to
boost taxes on large corporations and
wealthy individuals (1). Republicans
unanimously rejected the entire pack-
age, painting the Democrats’ plan as
inflationary and fiscally irresponsible.
But with all Democrats backing the re-
forms, the Senate was able to approve
the measure in early August, and the
House followed suit a week later to seal
this important political victory for the
Biden administration.
The prescription drug provisions in
the bill will largely affect adults over
age 65, as Senate rules blocked the
application of certain cost controls to
individual pharmaceutical sales and
Jill Wechsler
is Pharmaceutical
Technology’s
Washington editor,
jillwechsler7@gmail.com.
14 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
to health insurance provided through turers to shoulder a much larger por-
the market or employment. Commer- tion of the costs of drugs prescribed for
cial plans will not gain from provisions high-use seniors. Pharma companies
that penalize pharma companies for also would have to pay large “rebates”
raising prices each year higher than or fees to the government if prices on
inflation or from a cap on patients’ in- drugs and biologics increase each year
sulin outlays at $35 a month. beyond the rate of inflation. Insulin
One boon for health plans and con- costs would be capped at $35 a month
sumers, though, is the provision in the for seniors, and free vaccines would be
legislation that extends subsidies for provided for all.
health insurance provided under the Af- Most notable is the provision autho-
fordable Care Act. This extension delays rizing Medicare price negotiations on
for an additional three years premium certain costly medicines, the holy grail
increases for some 13 million individ- in health benefit reform for many Dem-
uals who currently receive discounted ocrats for decades. Starting in 2026, this
coverage for health insurance provided highly contentious provision will permit
through Obamacare state and federal Medicare to negotiate prices on 10 expen-
exchanges. These subsidies were autho- sive and widely used drugs near patent
rized during the COVID-19 pandemic expiration date, expanding to 20 drugs
and are set to expire this year without annually by 2029. If the manufacturer
the added $64 billion authorized here to rejects the Medicare price, it would pay
continue the cost reductions in premi- a hefty fee to the program, a process that
ums for three more years. industry has challenged for being closer
to price controls than to negotiations.
Medicare overhaul One thing for sure is that there will
The changes affecting Medicare drug be considerable jockeying among bio-
benefits, however, are significant and pharma companies over which drugs
calculated to save the government $100 are put on the price negotiation list as
billion over 10 years—but not the $460 the new program shakes out. The process
billion calculated in earlier reform pro- will seek to establish a Maximum Fair
posals. The legislation would cap out- Price for certain expensive single-source
W.SCOTT MCGILL - STOCK.ADOBE.COM
of-pocket drug costs for Medicare ben- drugs seven years after approval and bio-
eficiaries at $2000 a year beginning in logics 11 years on the market. And certain
2025, a provision likely to benefit more therapies from “small” firms and orphan
than 1 million seniors, possibly up to 3 drugs may be exempt, provisions sure to
million as more costly therapies come to affect acquisitions and R&D programs.
market. This measure is part of broader
changes in the design of the Medicare Limiting cures?
Part D program, which also eliminate The Pharmaceutical Research and Man-
the coverage gap and require manufac- ufacturers of America (PhRMA) led

a massive assault on the proposal, with
non-stop television and radio ads pre-
dicting long-term harm to patients and
the healthcare system (2). Similarly, the
Biotechnology Innovation Organiza-
tion (BIO) has kept up a steady stream
of warnings that Medicare drug reg-
ulation would limit access to many
important drugs and result in fewer
new cures for patients (3). PhRMA
President Steven Ubl has suggested
that industry may file suit to block ne-
gotiations and will challenge new rules
as Medicare moves to implement the
new policy—and pharma has three
years to mount its opposition.
Less visible were similar objections
from the generic drug industry to the
Medicare price negotiations. The As-
sociation for Accessible Medicines
pointed out that the likely brand can-
didates for spending limits will be
widely used, expensive medicines just
as they become eligible for generic
competition. Consequently, negoti-
ations that lower list prices will leave
ONLINE Visit our website for the latest e-learning
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• Webcasts
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less room for generic-drug makers to
offer lower-priced alternatives that
are profitable, and very little incentive
for multiple copycats to move into the
market. In addition, Medicare drug
plans may have little incentive to give
favorable formulary placement to only
slightly less expensive generics. Bi-
osimilar makers have raised similar
issues, as negotiations to lower prices
on expensive biotech therapies could
make it more difficult for competing
follow-ons to gain market share and
become profitable.
It’s not clear, moreover, how these
new policies will affect state Medic-
aid programs and commercial plans.
Curbs on annual drug price increases
for Medicare could raise prices for
other public and private plans. And
new pricing policies may prompt
higher launch prices for new therapies,
change how formularies cover brand
and generic products, and alter the
design of both Medicare Part D drug
plans and commercial coverage.
Regulatory Watch
Another unknown is the impact of
coverage and pricing policy changes on
investment and innovation in the bio-
pharma industry. Pharma and biotech
manufacturers have loudly predicted
that limits on prescription drug reve-
nue from forced negotiations will curb
incentives to invest in R&D, particu-
larly development programs at new
biotech firms, reducing jobs and the
discovery of many life-saving medi-
cines. Yet many health analysts reject
such dire outcomes, maintaining that
innovation will continue as the new
program spurs competition and ben-
efits Americans more broadly.
References
1. US Senate, H.R. 5376, Amendment,
Title I–Committee on Finance, Subti-
tle A–Deficit Reduction, August 7, 2022.
2. PhRMA, “PhRMA’s Ubl Calls Senate
Passage of Partisan Drug Pricing Plan a
‘Tragic Loss for Patients’,” Press Release,
August 7, 2022.
3. BIO, “Final Reconciliation Package a
‘Disservice to Patients and Researchers’,”
Press Release, August 7, 2022. PT
Pharmaceutical Technology  SEPTEMBER 2022 15
Cover Story: Emerging Therapies
Pfizer’s Idea Orchard
Chris Spivey
The flow of capital and scientific
acuity irrigates this pharm system.
T
rue breakthroughs are never in
plentiful supply. Recognizing
reality, Uwe Schoenbeck, PhD,
senior vice president and chief scientific
officer for Emerging Science & Innova-
tion (ES&I) at Pfizer, has synthesized
and made functional core lessons from
two of the past decade’s best business
books: Creativity, Inc. (1) and Loon-
shots (2). His ES&I group, through
the power of independent invention
and collaboration, applies methods de-
scribed in these books to the tasks of
uncovering, cultivating, and nurturing
novel drugs and therapies. No two
trees in his orchard are exactly alike,
and some bear fruit only when many
seasons of doubt, change, and struggle
have passed by. But as the COVID-19
vaccine and messenger RNA (mRNA)
success stories illustrate, early adop-
tion of new technologies can establish
substantial long-term gains—as well
as provide emergency solutions when
needed. Whatever the season, there
16 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
is always something taking root and
growing at Pfizer.
Each morning, a vast landscape of ac-
tivity and invention to sift confronts the
ES&I team. This team’s X-axis is a chal-
lenge that can be described as identifying
the right partnering opportunity particu-
larly for less known early science develop-
ments and technologies. Pfizer relies on
its Emerging Science Leads (ESLs), a team
of seasoned PhD/MDs to search for and
evaluate opportunities from academia
and the biotech industry for Pfizer’s R&D
organization. According to Schoenbeck,
ESLs are highly experienced in the rele-
vant disease area and embedded within
the respective therapeutic areas, resulting
in high strategic alignment of the oppor-
tunity being sourced and avoiding op-
portunities that are not a strategic fit (1).
Schoenbeck adds, “It’s easier to identify
what’s complementary if you have an un-
derstanding of the therapeutic area and
what’s not on the typical partnering list
that might be cutting edge.”
Each afternoon that same team
takes what they’ve uncovered, turns it
sideways, and overlays this onto their
Y-axis—an $80 billion dollar a year en-
terprise already populated with 80,000
competitive busy staff (3, 4). The ES&I
team, in conjunction with colleagues
working in Business Development, has
stood out for bringing genuinely cre-
ative partnership ideas and innovations
into an already creative and crowded
environment. “They’re not just the typ-
ical corporate venture type of series A,
B, or C,” continues Schoenbeck from a
Pharmaceutical Technology Drug Solu-
tions podcast (5). “Increasingly, we’re
doing more seed investments, new
company formations, really trying to
enable cutting-edge, emerging science
areas that we see on one hand strong
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strategic fit to Pfizer. On the other hand,
[areas] also holding a lot of potential—
but really early, needing more work be-
fore you could fully implement them.” A
long, successful track record has cleared
the decks for Pfizer to go earlier than
most, to uncover exciting advances as
they happen, before first bloom.
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Cover Story: Emerging Therapies
Wet bench assets
To augment integration capability on the
Y-axis, Pfizer brings internal expertise,
capabilities, and resources. Discussing
Pfizer’s Centers for Therapeutic Innova-
tion (CTI), for example—a collaboration
model that helps translate early scientific
concepts into potential drugs—Schoen-
beck says, “We do have a number of wet
bench capabilities, our own labs through
which we run a portfolio of about 25 or so
projects, and these projects are partnered
with academic or very early stage biotech
companies, which focus on cutting edge
new projects.”
Using its many flexible partnering
and collaboration vehicles, Pfizer has
been identifying strong partners in both
the academic world and in the biotech
industry to help its scientific engine and
company at large make changes it needs
in the gene therapy, mRNA, and degrader
spaces. The most recent and most notable
example would be the multi-year part-
nership Pfizer established with German
biotech company, BioNTech, to deliver
the world’s first COVID-19 vaccine in
2020. But before the pandemic arrived,
the two companies had been in discus-
sions since the early 2010s, first about
the use of mRNA for oncology and later editing platform in support of potential
establishing an agreement for influenza. therapies for rare diseases. A collabora-
tion with Acuitas will allow Pfizer to ex-
Early adoption plore the use of their lipid nanoparticles
(LNPs) to deliver a variety of vaccines or
of new therapeutics. Finally, a collaboration with
Codex DNA will potentially streamline
technologies the mRNA production process by facili-
can establish tating synthetic DNA assembly, another
notable fruit of the team’s labor to bring
substantial forth a competitive pipeline in gene ther-
apy. Through gene therapy partnerships,
long-term gains— such as 2019’s deal with Vivet Therapeu-
tics to advance a treatment for Wilson
as well as provide disease, Pfizer now has one of the most
competitive pipelines in gene therapy in
emergency the industry.
solutions when Increasingly, Pfizer’s focus is on a “true
first-in-class mechanism, if not only in
needed. class kind of programs, that would allow
us to bring real breakthroughs to pa-
While COVID has been on the front- tients.” Schoenbeck continues, “So these
lines of the company both in headlines are by definition a higher-risk approach,
and scientific delivery, Schoenbeck’s a higher-risk kind of biology, but they
team has continued to plant and grow its hold a lot of promise and could provide a
roots in other areas. For example, in early very strong fit to the Pfizer R&D organi-
2022 Pfizer announced several collabora- zation, if we can then build a pipeline and
tions designed to augment its leadership portfolio around those areas … So, you
in mRNA. Their agreement with Beam really need to start thinking early and
Therapeutics will leverage Beam’s base clearly about where do you want to focus

Drug Solutions Podcast: How Pfizer Views Partnering and Investing for Emerging Therapies
Pharmaceutical Technology presents the Drug Solutions podcast, where  ow Pfizer Views Partnering
H
the editors chat with industry experts from across the pharmaceutical and and Investing for Emerging Therapies
biopharmaceutical supply chain. Experts share insights into the technologies, September 6, 2022
strategies, and regulations related to the development and manufacture of PharmTech.com/drug-solutions-podcast
drug products.
Premiering on Sept. 6, 2022, Chris Spivey, PharmTech’s editorial director,
interviews Uwe Schoenbeck, senior vice president and chief scientific officer
for emerging science and innovation at Pfizer. Some of the areas discussed
include repeat expansion disorders, senescence, DNA damage response and
nucleic acid sensing, deubiquitinase pathways, and neuroinflammation.
Pfizer feels these hold special promise for new innovative therapies.
Through research collaborations, consortia, licensing, investments, and
acquisitions, the emerging science and innovation team at Pfizer seeks to
harness external, cutting-edge preclinical assets and novel technologies
in emerging therapies. Increasingly, the focus is on true first-in-class
mechanism, if not only in class programs, that would allow us to bring real
breakthroughs to patients.
Visit PharmTech.com/drug-solutions-podcast to learn how Pfizer’s
external-facing research and development scientists uncover the most
promising emerging therapy concepts and ideas in thepharmaceutical
landscape.

18 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m

your search? Where do you want to place
your bets? And what’s important to us is
actually that when we partner, we really
partner in the true sense of doing things
jointly … not just to bring in the intel-
lectual property in-house or anything
like that. It’s really about identifying an
academic or biotech partner, that can
bring something to the table that would
be very complementary … allowing us
to do something to benefit patients that
neither of us could do alone.”
How to manage risk
without risking innovation
Many approaches sound great on paper,
or even anecdotally, so how does ES&I
manage risk? “I think each company
might take a different approach, but the
way we have thought about it is that you
want to have a balance in your portfolio
when it comes to risk. Risk can be defined
as risk in biology, risk in development,
risk in therapeutic modality. If you have
a mature modality, but you go for a new
target, that’s one level of risk. If you go for
a novel target and a new therapeutic mo-
dality and invention in your development
direction, then you’re really multiplying
your risk. Obviously, the COVID-19
vaccine was one of these examples that
fortunately has been quite successful but
really was a high-risk approach. You can
do this where you really see the need for
patients, where you really see the poten-
tial for breakthrough, but you can’t do it
for every single program in your pipeline
obviously. Now on top of that, as I said
earlier, you want to make sure you get a
good feel for the cutting edge for anything
that’s emerging, really promising on the
horizon. And for that we have for exam-
ple this ES&I team here at Pfizer. Some of
the areas that we’re focusing in on include
repeat expansion disorders, senescence,
DNA damage response and nucleic acid
sensing, deubiquitinase pathways, and
neuroinflammation. Pfizer feels these
hold special promise for new innovative
therapies.”
All of the fields mentioned previously
are newly emerging and require technical
bravery and alongside special care. The
book Loonshots mainspring metaphor
borrows from material science concern-
ing phase transition as applied to both
creative (artistic) and execution (soldier)
teams (2). Within that framework, the
author, by examining a multitude of ex-
amples, asserts that structure may matter
more than culture. Transplanting this
to Pfizer’s orchard, Schoenbeck has suc-
cessfully practiced a version of compan-
ion planting, where seedlings of different
crops are carefully placed in proximity
to lower certain technical or resource
barriers, while simultaneously raising
pollination and nutrient availability. Re-
duced footprint along these guidelines is
seen as a feature, not a bug. The concept
itself sprouted within the garden walls of
the Mesopotamian proto palaces, where,
“The oldest written evidence of medicinal
plants’ usage for preparation of drugs has
been found on a Sumerian clay slab from
Nagpur, approximately 5000 years old. It
comprised 12 recipes for drug preparation
referring to over 250 various plants, some
of them alkaloid such as poppy, henbane,
and mandrake” (6). These alkaloid drugs
were far from mild, and great care was
taken not only in their application, but
also in raising their yield, by careful ger-
mination and cultivation techniques.
Pfizer now has
one of the most
competitive
pipelines in gene
therapy in the
industry.
So, the essential oil for the ES&I group
stems from the orchard structure itself,
enabling them to identify and nurture
pharmaceutical creativity well before first
florescence. These orchard rules follow a
pattern laid out in the book Creativity
Inc., by Ed Catmull, who founded Pixar
in 1986 with John Lasseter and Steve
Jobs (1). Their philosophies, or planting
scheme, defied convention and protected
the creative process by institutionalizing
concepts such as “the cost of preventing
errors is often far greater than the cost of
fixing them” and, “It’s not the manager’s
job to prevent risk, it’s the manager’s job
to make it safe for others to take them.”
This is a pragmatic view of what en-
hances the creative process, in line with
that practiced by Schoenbeck. One of
the strongest but subtle suggestions,
being “don’t assume that general agree-
ment will lead to change it takes sub-
stantial energy to move a group, even
when all are on board” (1). This is cer-
tainly a precept worth following up on
when dealing with large organizations
such as big pharmaceutical companies.
Catmull, however, is not above advice
on pruning to promote optimal health.
His sections on recognizing “you
are not your idea” point to the con-
stant need for reality checks, and his
postmortems are as important as any
other section in the book. Pfizer’s ES&I
team, who by their outward facing role
interact with anyone performing in-
teresting material, pharmaceutical, or
manufacturing science, have perhaps
taken to heart the inner core message
of this book, that, “The companies com-
munication structure should not mirror
its organizational structure; everybody
should be able to talk with anybody.”
Last year by any measure was a bumper
crop for the ES&I team, and indeed
they currently top a patient group sur-
vey (7) for best reputation. Even amidst
a widespread drought, Pfizer’s orchard
remains well irrigated.
References
1. E. Catmull and A. Wallace, Creativity, Inc:
Overcoming the Unseen Forces That Stand
in the Way of True Inspiration (Random
House, Apr. 8, 2014).
2. S. Bachall, Loonshots: Nurture the Crazy
Ideas That Win Wars, Cure Diseases, and
and Transform Industries (St. Martin’s
Press, Mar. 19, 2019).
3. Pfizer, “Pfizer Reports Fourth-Quarter
and Full-Year 2021 Results,” Press Release,
Feb. 8, 2022.
4. M. Matej, “Pfizer’s Total Number of Em-
ployees 2006–2021,” Statista, Mar. 2, 2022.
5. C. Spivey, “How Pfizer Views Partnering
and Investing for Emerging Therapies,”
Pharmaceutical Technology Drug Solu-
tions Podcast, Sept. 6, 2022.
6. K. Kelly, History of Medicine (New York:
Facts on file, 2009).
7. Datawrapper, Respondent Cancer Patient
Groups, 2021: Familiarity, and Partner-
ships, witih Pharm Companies. PT
Pharmaceutical Technology  SEPTEMBER 2022 19
DEDICATED DIALOGUE SPONSORED CONTENT

DeltaV ™ Spectral PAT: Achieve Real-Time, Closed-Loop

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Embedding DeltaV ™ Spectral PAT directly into the control

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Bruce Greenwald
compliance with confidence, greater return on investment Business Development Manager
(ROI), and delivery of quality treatments to market faster. DeltaV Distributed Control Systems
Emerson

PHARMTECH: What factors are influencing the current landscape for life sciences manufacturers?
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Molly Firkins
Product Marketing Manager
One of the goals that the FDA first released with their PAT (process analytical technology) guidance
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the science of the process, they’d be able to fast track the approval of those new therapies. The carrot,
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Sponsored by
PHARMTECH: What challenges are life sciences manufacturers facing as a result?
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Emerson, headquartered in St. Louis, Missouri, is a global software and technology company providing innovative solutions for customers in industrial,
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Development
Delivery Kinetics
for Topical Drugs
Cynthia A. Challener
API permeation into the skin modulates
the efficacy of topical treatments.
N
umerous skin diseases and dis-
orders that affect different layers
of the skin can be treated with
topical dermal drug delivery (TDDD)
systems. Topical delivery is advanta-
geous over systemic administration due
to its ability to provide targeted treat-
ment and avoid first-pass metabolism.
Successful topical formulations deliver
the API to the proper layer of the skin at
an appropriate rate so as to maintain the
necessary concentration over a period
of time; in other words, they provide
appropriate permeation kinetics. There
are many factors that determine the
delivery kinetics of TDDD systems, not
the least of which is the need to over-
come the protective barrier function
of the skin. Thoughtful formulation
development is essential to developing
optimal topical drug products.
Cynthia A. Challener, PhD
is contributing editor to
Pharmaceutical Technology.
22 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
A look at topical
delivery mechanisms
Over the years, the skin has become
an accessible and practical site for
the delivery of medicines, accord-
ing to Gayathri Krishnan, associate
director of in vitro sciences with Ter-
gus Pharma. Many different dosage
forms enable delivery of actives to
the skin, such as creams, ointments,
lotions, liquids, suspensions, gels,
hydrogels, pastes, foams, suppositories,
and nail lacquers.
Drugs in topical formulations can
exhibit activity on the superficial layers
of tissues, or via penetration and per-
meation into deeper layers, or through
systemic distribution depending on
the physiochemical qualities, targeted
site of action, and formulation proce-
dures, Krishnan observes. She adds
that there are three main delivery
mechanisms: transcellular, intercellu-
lar, and trans-appendageal.
In the trans-appendageal pathway,
or the shunt route, the API is delivered
through appendages such as hair follicles
and sweat ducts, which provide entry
through the protective stratum corneum.
APIs delivered via the transcellular route
leverage phospholipid membranes and
the cytoplasm in the dead keratinocytes
that make up the stratum corneum to
directly cross the skin. This is the fast-
est route, but APIs must be able to pass
through each cell’s lipophilic membrane,
hydrophilic keratin-containing interior,
and phospholipid bilayer membrane,
repeating this process multiple times to
cross the entire thickness of the stratum
corneum. APIs that can do so effectively
are rare, according to Krishnan.
The intercellular pathway comprises
narrow crevices between skin cells
that APIs can traverse. Despite the
relative thinness (approximately 20 μm)
of the stratum corneum, most APIs
following this pathway must travel
another 400 μm or more as they diffuse
this top skin layer.
Indication and delivery mode
determine ideal delivery kinetics
In addition to these different delivery
mechanisms, there are several possible
modes of action of topical formulations,
according to John M. Newsam, CEO
of Tioga Research. Some are designed
for the API to be active on the exterior
of the skin, and thus operate via a su-
perficial mode. Most are intended for
the API to be active in the epidermis
or dermis, which requires penetration
into the skin. Some are designed for the
API to be delivered through the skin
but remain locally concentrated in an
area adjacent to the site of application,
such as a knee joint. Finally, transder-
mal formulations are engineered for
the API to pass through the skin into
the vasculature or lymphatic system to
PHOTO SESAON - STOCK.ADOBE.COM
achieve systemic delivery.
The kinetics of delivery depend on
which of these four modes is being em-
phasized, Newsam says. For instance,
transdermal delivery has an initial lag
time as the API diffuses through the
layers of the skin and then achieves rel-
atively uniform provision of the active
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Development
into systemic circulation over a period
of time. “The ideal product will have a
short lag time, moving to steady state
delivery as quickly as possible and
then enable sustained delivery for an
extended period of time,” he notes. Ide-
ally, a topical formulation will deliver
the APIs to the right site at the correct
therapeutic level over a few hours.
Delivery kinetics also depend on the
type of skin and the area of the body to
which the product is applied. Some top-
ical drugs are, for instance, applied to
areas of the skin that are compromised.
These drugs are designed to not only treat
the problem, but provide relief as quickly
as possible, according to Newsam. In
other cases, the API could be beneficial
in treating a skin disorder but potentially
give rise to systemic toxicity. Delivery to
the epidermis or dermis with minimal
API reaching the vasculature or use of
an API with a short half-life so that it
is rapidly cleared from the bloodstream
would be important.
The nature of the topical formula-
tion should also be designed to deliver
the active to the appropriate part of the
skin. Treatments of conditions involv-
ing the skin surface and very top layers
should be designed to remain on the
surface. Treatments targeting the epider-
mis should ideally deliver the active in a
sustained-release fashion, while deeper
delivery through the epidermis to the
dermis is needed to treat inflammatory
skin conditions. Options include film-
formers for surface treatments and trans-
dermal patches for deeper delivery.
Patient-related factors important
Topical formulations targeting different
indications and different patient popu-
lations must be designed to address the
specific needs of those patients, accord-
ing to Newsam. The condition of the skin
and the location of application are two
primary factors to consider. Others may
include the age and skin color/pigmen-
tation of the patients receiving the treat-
ment. Blood supply to the skin along with
skin moisture, pH, and temperature are
also important, says Krishnan.
Patients with eczema or psoriasis
might have cracked skin and, therefore,
24 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
a reduced protective barrier. This re-
duced barrier could allow an increased
rate of API delivery. Unlike the hands
and feet where the barrier layer is thick-
est, barrier function is lowest in the
eyelids and scrotum. Skin also tends to
be more permeable for the very young
and the very old.
The presence of structures such as
hair follicles and sweat and apocrine
glands can provide areas of ingress; a
topical formulation applied to the scalp
would likely exhibit different delivery
attributes than the same formulation
applied to the upper torso or thigh.
Sebum, which is a thin, buttery film
exuded from sebum glands located on
the scalp, face, and underarms, has its
own barrier characteristics that differ
from those of the skin itself, leading to
different delivery requirements.
The rate and
degree of drug
absorption can
be affected by
a variety of
illness conditions.
The rate and degree of drug absorption
can also be affected by a variety of illness
conditions, with hepatic, cardiovascular,
and gastrointestinal disorders having the
greatest impact on API bioavailability, ac-
cording to Krishnan. She adds that the
area of absorptive surface, the level of vas-
cularity, and the degree of skin hydration
can impact delivery as well. For instance,
stress reduces blood flow to the gastroin-
testinal tract, leading to less absorption.
“As a result, patient-related factors have a
significant impact on how well medica-
tions can be absorbed via the skin and
thus on the ultimate efficacy of topical
formulations,” she contends.
It is also important to consider the
cosmetics and aesthetics of topical prod-
ucts, because they have a direct impact
on patient compliance. People with acne
want quick-drying products while those
with psoriasis prefer soothing creams or
ointments, for instance.
API properties are crucial
Transdermal absorption is influenced
by an API’s physicochemical character-
istics, such as charge, polarizability, hy-
drogen bonding, shape, and molecular
weight. For delivery into the skin, the
molecular shape of an API can, in fact,
be a key determiner of bioavailability,
according to Krishnan. “The skin acts
as a physical barrier against particles on
a macroscopic level, hence the physical
state of the API has a significant impact
on its permeation,” she says.
Most traditional drug substances cho-
sen as transdermal delivery candidates fall
within a relatively small molecular-weight
range of 100–500 Dalton, Krishnan notes.
“Due to its simplicity, molecular weight is
typically used to approximate molecular
volume with the implicit presumption
that the majority of molecules are essen-
tially spherical,” she explains. In that con-
strained range, the impact of molecular
weight on drug flux seems to be rather
small, Krishnan adds. For larger mole-
cules, factors such as pH and particle size
come into play as well.
A second important characteristic of
APIs that determines their skin permea-
bility is their lipophilicity/hydrophilicity.
That is because the API most likely enters
the stratum corneum through the lipid
bilayers in between desiccated cells, and
this initial partitioning occurs according
to the API’s partition coefficient.
In practical terms, Newsam indi-
cates that optimal skin permeability is
realized for APIs that have logP (octa-
nol-water coefficient) values between
2 and 3. “Lipophilic molecules such as
cannabidiol get stuck in the lipid layers
in the stratum corneum and don’t dif-
fuse much further. Very water-soluble
molecules with negative logP values
also have intrinsically low skin permea-
bility because they are typically charged
or highly polar, which also prevents dif-
fusion through the skin,” he explains.
It is also important to optimize the
concentration or ‘strength’ of API in a
topical formulation as the concentration
gradient drives API diffusion from the
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Development
formulation into the skin. If the API is
poorly-soluble in the formulation, then
the driving force for delivery into the skin
will be low with only modest extents of
delivery. Ideal formulations have the API
concentration approaching, but no more
than approximately 85% of the saturation
limit, according to Newsam.
The potential for APIs to bind to pro-
teins in different layers of the skin must
also be considered because it can con-
tribute to reduced activity. The increas-
ing potency of APIs is also important,
as the percentage of drug candidates in
the pipeline that are highly potent is in-
creasing, and higher potency may allow
for topic formulations containing mole-
cules with properties outside the typically
acceptable ranges.
APIs must also be stable in topical for-
mulations and in the skin. That means,
comments Newsam, they must be resis-
tant to isomerization, oxidation, or hy-
drolysis in the formulation itself and also
to degradation by esterases, proteases,
and other enzymes present in the skin.
Finally, they should not be injurious to
the skin, and therefore not be irritants or
sensitizers, both as is and when exposed
to photo-irradiation.
Excipients play a role
It is important to remember that in top-
ical formulations, excipients comprise
the bulk of the drug product. “Excipients
affect the physicochemical properties of
the API and the drug product, the sen-
sory properties of the formulation, and
the quality features of topical products,”
agrees Krishnan.
The selection of the vehicle is influ-
enced by the physiochemical properties
of the drug, the disease, and the target
patient population. The other excipients
perform a variety of functional roles,
including improving solubility to allow
incorporation of the drug at the target
concentration, controlling or improving
API release and permeation, creating the
desired aesthetics, enhancing API and
formulation stability, and preventing
microbial growth.
By looking at an API’s physicochem-
ical characteristics—molecular weight,
logP, polar surface area, number of
26 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
hydrogen-bonding donors and accep-
tors, melting and boiling points, etc.—
Newsam indicates it is possible to esti-
mate how readily it will diffuse into the
skin. But once an API is put into a real
formulation, “all bets are usually off”. As
a result, excipients play a very important
role in topical formulations.
Excipients that affect the permeabil-
ity of the skin include molecular pen-
etration enhancers such as alcohols,
fatty acids, and fatty esters. However,
Newsam cautions that because of cross
interactions between different diffusion
pathways, the effect of these excipients
is rarely simply additive or subtractive,
making it difficult to predict formula-
tion performance.
APIs must also be
stable in topical
formulations and
in the skin.
Other excipients are used to create
the desired appearance and texture
of topical formulations depending on
the dosage form. Emulsifiers or sur-
factants are needed to stabilize lotions
and creams, which typically comprise
two immiscible phases, while rheology
modifiers are needed to achieve the de-
sired viscosity for products that must
flow. Bioadhesives make it possible for
patches to adhere to the skin even when
wet, but still allow them to be removed
without causing too much pain. Anti-
oxidants and antimicrobials protect
formulations in storage and in use.
Permeability and solubility enhancers
must be compatible with not only the API,
but all of these other excipients and the
carrier, Krishnan comments. They must
adhere to pharmacopeial quality require-
ments, and not irritate, sensitize, or irre-
versibly perturb the stratum corneum
barrier. “Often extensive screening is re-
quired to identify the right combination
of excipients for a given API that affords
the optimum solution with respect to
permeability, applicability, and appear-
ance,” states Newsam.
Formulation success requires
more than achieving the
right level of permeation
Topical formulations are highly com-
plex medicines intended to interact with
the skin, which is designed to serve as
a protective barrier and therefore by its
nature limits the delivery of APIs into
and through it.
“Achieving the appropriate level of de-
livery or permeation is usually the great-
est challenge in topical drug formulation,”
says Newsam. “The number of approved
drugs that actually deliver API through
the skin is few, because even fairly small
molecules can have low skin permeability,
and that permeability tails off exponen-
tially as molecular weight increases above
about 500 Da,” he says. APIs in trans-
dermal products on the market today
were, Newsam adds, initially approved
for another mode of administration and
developed as topical formulation in a
next-generation approach.
Even with the challenge of achiev-
ing appropriate levels of delivery and
permeation, the failure of many top-
ical drug candidates that make it into
clinical development can be attributed
not to efficacy or safety, but actually to
chemistry, manufacturing, and controls
(CMC) issues, according to Newsam.
“To achieve the desired level of perme-
ability, topical formulations are often
complex, which can complicate their
preparation in a robust, reproducible,
and uniform fashion,” he explains.
In addition, the API must be intrin-
sically stable in the formulation and not
react with water or other excipients at the
formulation pH or undergo a structural
conversion such as isomerization. It could
also degrade when coming in contact
with the skin, and the degradants might
be irritating to the skin. “As a conse-
quence, while delivery and permeation
are often the governing concern, there
are many other factors that must be ad-
dressed when developing topical formu-
lations,” Newsam concludes.
Topicals have received a lot of at-
tention recently and are becoming a
greater focus in the pharma industry,
but often, says Krishnan, issues arise
because drug developers do not apply
formulation principles correctly and
safely. “These problems most likely
arise due to a lack of comprehension
of the concepts relating to skin per-
meation mechanisms and kinetics
and the complex requirements for suc-
cessful topical formulations. Effective
development of safe, efficacious, pa-
tient-acceptable, and manufacturable
topical products cannot be realized
unless these concepts are applied and
formulators understand the full range
of characteristics and qualities that im-
pact topical drug delivery and patient
acceptance,” she concludes.
Several potential strategies
for optimizing topical drug delivery
Topical drug formulation development
is a multistep process, according to
Newsam. The first step should be to
understand the physicochemical char-
acteristics of the API using in silico com- of delivery
putational methods to identify the var-
ious challenges that must be overcome.
Analytical method development should
come next so that API quantitation is
possible. Determination of solubility development to be guided towards op-
and compatibility properties follows. timum formulation systems.
With this information it is possible to
narrow down the potential tactics for
achieving required levels of delivery.
Quality by design for topical prod- platforms and proprietary Cascading
uct development with an emphasis on Screening methodology to evaluate
determination of the quality target large numbers of different formulations.
product profile, critical process param- An added benefit of Cascading Screen-
eters, critical quality attributes, and ing, particularly for 505(b)(2) products,
critical material attributes is essential, Newsam points out, is the potential to
Krishman underscores. “Product de- establish a solid basis for composition
velopment at Tergus focuses on quality of matter patentability for the best for-
and compliance in topical formulation mulations. “Screening the entire useful
development, analysis, in vitro release formulation space means that it is un-
and permeation testing, and all the likely that there are other formulations
way through clinical supply manufac- that will perform as well, which makes
turing,” she says it difficult for competitors to circumvent
Tioga Research uses a three-pronged such a patent,” he explains.
approach. First, the company has a set Overall, Newsam stresses that topi-
of established formulation systems de- cal formulation development strategies
signed and built for particular classes should be geared toward the desired dos-
of molecules, such as with logP values age form, and formulation innovation
in a particular range. A new API is in- should focus on the key requirements
troduced into the appropriate starting of the specific product as quickly in the
formulation, potentially with other development process as possible, whether
compatible excipients, and the extent that is a transdermal patch, a film-form-
and permeation measured. ing matrix, a foam, a spray, a gel or a
Second, Tioga’s formulation scientists cream. “At Tioga, we might run some
mine the company’s databases for re- initial screens using simple solutions,
sults with similar molecules over their but as quickly as possible we progress to
20 years of experience in topical drug preparing libraries of prototype formula-
tions and measuring the performance of
each, because, for instance, results with
If these two methods do not yield an simple solutions may be poorly predic-
optimal formulation, Tioga leverages tive of behavior in a practicable patch
its high-throughput experimentation formulation,” he observes. PT

Measuring skin permeation kinetics

Topical drug delivery kinetics are a convolution of two factors: the rate at which
the API is provided to the skin surface from the formulation—the API release—
and the rate at which the drug diffuses into and through the skin.
Older in vivo tests involve applying the product to the skin and then taking
skin biopsies to measure the concentration of the active over time. Microdialysis
and open-flow microperfusion are newer techniques that allow sampling of API
concentrations in the skin without the need for biopsies.
The industry prefers in vitro, or ex vivo, testing. Ex vivo testing using synthetic
polymers or cultured skin is generally not very predictive because these substrates
do not have the same barrier properties as real human skin. Therefore, most ex
vivo testing is performed using real skin. The closest animal model to human
skin is pig skin, and many measurements are made using porcine skin samples
obtained from animals bred and sacrificed for other purposes. When possible,
tests are performed using human skin.
In vitro permeation testing (IVPT) is widely used to investigate the delivery
kinetics of topical drug formulations. Excised human skin obtained from cosmetic
surgeries or donated from cadavers is mounted within diffusion chambers
designed to allow the test to be performed under conditions similar to those
found within the human body.
The skin is prepared and its integrity evaluated to ensure that no defects such as
pinholes exist that could allow excess API to pass through and thus skew the results.
The skin is then placed into a diffusion cell on top of a buffer solution in which
the API is known to have sufficient solubility. The topical formulation is applied
to the surface of the skin and the penetration of the compound is measured by
monitoring its rate of permeation into the receptor solution underneath the skin
samples. This model also allows APIs and metabolites within the different layers
of the skin (i.e., epidermis and/or dermis) to be measured.
IVPT is attractive because it offers a means for controlling the variables that
may influence topical drug performance, including dosing volumes, humidity,
temperature, API stability, skin thickness, and other factors. It also allows for
performance of analyses that are designed with the specific indication in mind,
John Newsam, CEO of Tioga Research says. If the product is intended for use on
a wound, then compromised skin should be simulated by removing some of the
test skin’s barrier function. Some dosage forms can complicate the measurement
process, but it is essential to perform the test using the product as it will be
formulated and used, he says. By taking this approach, IVPT makes it possible
to appropriately examine the behavior of formulations depending on the dosage
form and indication.

Pharmaceutical Technology  SEPTEMBER 2022 27

Manufacturing
Exploring Options for
Optimizing Cell Line
Development
Jason Martin
Biopharmaceutical manufacturers
must consider a surprisingly wide range
of factors when deciding where to turn
for assistance with cell line development.
B
iopharmaceuticals are revolutioniz-
ing the way the industry prevents
and treats a broad spectrum of dis-
eases. Therapeutic recombinant proteins,
including monoclonal antibodies (mAbs),
bispecifics, and biosimilar molecules, are
among the most common biologics de-
veloped for therapeutic applications (1).
Although versatile and powerful, the living
organisms required for the production of
therapeutic proteins can be more difficult
to control and optimize in a manufactur-
ing setting than chemical compounds.
First, a lead candidate is identified, and,
once this happens, an appropriate produc-
tion cell line is developed before upstream
and downstream processes are established
and optimized. Although under constant
Jason Martin is regional product
manager of Cell Line, Media & Testing
Solutions at Sartorius.
28 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
opment vendors using optimized protein
expression platforms that include the host
Chinese hamster ovary (CHO) produc-
tion cell line, optimized gene expression
vectors, cell culture medium, and feed for-
mulations. However, manufacturers may
not realize the extent of their options when
it comes to developing clonal production
cell lines. This article discusses key factors
to consider when planning how to accom-
plish this bioprocessing step.
Outsourcing cell-line
development activities
To develop and maintain cell lines at scale
throughout a product’s life cycle, man-
ufacturers need to invest in a significant
amount of expansion, including increas-
ing facility footprint, equipment, instru-
ments, and personnel hiring and training.
Companies must determine whether they
have the necessary skills, capacity, and re-
sources to complete cell line development
from start to finish or whether they need
to outsource some, or all of, the process to
save time and costs.
As part of this decision, biopharma-
ceutical developers also need to consider
how many molecules they intend to have
in production and carry out a cost/benefit
analysis. For a large manufacturer plan-
ning to create a multi-product facility, it
may be worthwhile to build in-house capa-
bilities as a long-term investment. On the
pressure, it is critical that biotherapeu- other hand, virtual, small, and mid-sized
tic developers spend time and resources companies with one or more molecules
getting the cell line development process in their pipeline may lack the necessary
cell-line development expertise and in-
right. Without a robust production cell line
ternal resources and choose to outsource
that yields sufficient titers of a high-quality
these activities to an experienced vendor.
product, the facility will eventually reach a
point where scalability becomes limiting, Nonetheless, some large biopharmaceu-
and commercialization is untenable. Cell tical companies still choose to outsource
line development also offers the opportu- cell-line development requirements based
nity to perform a number of physicochem- on internal capacity and business objec-
ical analyses and functional assays directly
tives. Even after cell line development is
on the therapeutic protein, which will helpcomplete, companies have the option to
GIOVANNI CANCEMI - STOCK.ADOBE.COM
improve the chances of clinical- and com- scale up and accomplish manufacturing
mercial-phase success. with the help of a contract manufacturing
Since cell line development is such a organization (CMO) or other third parties.
critical part of the drug development pro-
cess, biomanufacturers should leverage a Top priorities when selecting
wide range of solutions to fill the gaps in a cell line development partner
their internal capacities and capabilities. Success in the biopharmaceutical industry
It is possible to reap new benefits by part- always involves achieving a balance be-
nering with experienced cell-line devel- tween factors, such as speed, cost, techno-
logical advancement, and scale. Whether a
developer is outsourcing just a few steps or
the entire cell-line development process, it
is essential to know which factors to weigh
most heavily when comparing options for
products and services.
Scientific expertise. Cell line development
is a lengthy and complex multi-step pro-
cess. To produce high-quality molecules
on the most efficient timelines, the man-
ufacturer or vendor that performs cell line
development needs to gather a team with
deep and broad scientific bioprocess exper-
tise. Many stages along the path to produce
a new production cell line often require
subject matter expertise, including the final
transfer step that will bring the cell lines
from an external vendor to the intended
manufacturing facilities.
Time to clinic is a central concern for all
biopharmaceutical developers. To achieve
production goals as quickly as possible, sci-
entific operations teams must be intimately
familiar with workflows that are both ef-
ficient and error-free. This often means
avoiding the use of outdated, cumber-
some processes (i.e., limited dilution clon-
ing) and eliminating unnecessary stages,
such as pool generation. Eliminating pool
generation from the cell-line development
workflow allows a much shorter timeline
from DNA to research cell bank (RCB)
generation, often by four to five weeks.
Manufacturers also need an analytical
team capable of accurately characterizing
the protein product during cell line devel-
opment stages, particularly at the clone
selection stage. Achieving high titers is
pointless if the new production cell line
produces a deficient molecule incapable of
achieving its desired function or mecha-
nism of action. Discovering that the mol-
ecule has a sub-par quality target prod-
uct profile (QTPP) after the cell line has
been developed is costly and will cause
significant delays in getting the molecule
to the clinic. To prevent these risks, the
cell-line development operations team
must measure certain key characteristics
of the protein, beginning with function-
ality, in a biological assay or binding assay
(depending on the protein’s mechanism
of action) that determines purity, aggre-
gation potential, product related impuri-
ties, and the protein’s likely glycosylation
profile. The team must be familiar with tem (2) rather than a system that in-
high-resolution analytical methods using volves toxic selection agents, such as
ultra-high-performance liquid chroma- methotrexate (MTX) and antibiotics.
tography (UHPLC), liquid chromatogra- Such metabolic selection-based systems
phy-mass spectrometry (LC-MS), capil- allow for improved robustness in cell
lary electrophoresis, and other methods, growth and viability properties, reduced
all of which should be incorporated into risk of genetic instability, and ability to
the cell-line development workflow. With enable high titer production.
this knowledge, teams can select clones Expression vector. After choosing the
that produce a molecule that achieves the appropriate host cell line, a good vendor
desired product quality attributes. Picking should provide an optimized expression
the right clones upfront removes the need vector capable of expressing high prod-
to optimize the critical quality attributes uct titers after transfection. Developers
post-cell line development. need optimized expression vectors to
Regulatory expertise. Because many bio- ensure stable expression with minimal
logics are relatively new modalities, regu- secondary effects on the otherwise op-
latory agencies demand rigorous quality timized host cells. Ideally, a single ex-
control. Deviations from biosafety stan- pression vector should show utility for
dards can put developers at risk of denied any type of molecule: mAbs, bispecifics,
regulatory applications or significant de- and biosimilars, among others.
lays resulting from directives to generate Media. A cell line development part-
new data, which can be laborious. ner should be able to provide cell culture
Scientific and regulatory expertise often media and feed that is highly compatible
overlap because regulatory requirements with the host cell line. A secure supply of
inform scientific workflows. For example, that same media and feed supplements
one dimension unique to biopharmaceuti- should be readily commercially available
cal manufacturing is a manufacturer’s abil- to purchase and use for any further pro-
ity to prove that a protein-based biologic cess optimization and development and
was derived from a single clone. Strategies for good manufacturing practice (GMP)
to demonstrate and assure monoclonality requirements. It is also important to con-
could include isolating single clones and sider the future availability of the cell cul-
capturing photographic images as the cells ture media because assurance of supply is
divides. Tracing the direct path from clone critical as production is scaled up.
to the final product is essential to cell line Process design. The facility and op-
development, along with rigorous quality erations must be configured to enable
control and risk management. efficient and easy scale-up of the new
production cell line. Streamlined pro-
Four components for a successful cess design involves implementing intel-
cell line development project ligent, scalable technologies and software
Host cell line. Cell line development begins to monitor, control, and analyze critical
with choosing the right host cell line. Un- process parameters and product quality
suitable cells can produce low titers or a attributes. End-to-end solutions with in-
low-quality product, ultimately causing tegrated sensors and analytical software
delays and inefficiencies. CHO cell lines can reveal new process insights that can
are most frequently used as hosts because be used to gather information about host
they have an established, decades-long cell performance and optimize the cell
track record, are easy to grow in suspension line development process.
at large scales (2000+ L), and possess the
cellular machinery required to carry out Flexibility and control
appropriate post-translational modifica- Living organisms, fluctuating supply
tions, which can be critical to the function chains, and shifting consumer markets all
and quality profile of the protein. add variability to the production of bio-
Biopharmaceutical developers should logics. As a result, maintaining flexibility
look for a vendor whose starting cell
lines employ a metabolic selection sys- Contin. on page 56
Pharmaceutical Technology  SEPTEMBER 2022 29
Supply Chain
Reducing Blind Spots in
the Pharma Supply Chain
Suzanne Shelley
Expanded use of data analytics can help to
avoid disruptions, but the possibilities cannot
be realized without sufficient investment
and direct human involvement.
I
t has become painfully clear in
recent years that potential supply
chain disruptions across all in-
dustries have become more the rule
than the exception. Such disruptions
arise when manufacturers experience
short-term or prolonged shortages
in raw materials, packaging materi-
als, and/or critical components and
are then unable to produce a reli-
able output of finished products or
deliver them on time to their own
downstream customers.
For pharma manufacturers, such is-
sues increase business risk, create un-
necessary costs and product losses, and
increase the likelihood of drug short-
ages. Today, a range of parallel efforts
are underway to address them. These
Suzanne Shelley is a contributing editor
at Pharmaceutical Technology.
30 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
include the expanded use of affordable
monitoring solutions, increased over-
all digital connectivity among a larger
number of players up and down a given
supply chain, and advanced modeling
capabilities to make sense of the re-
al-time data. Such efforts aim to an-
alyze and model large data sets using
machine learning and artificial in-
telligence (AI) techniques and other
modeling modalities.
“The goal is to develop advanced in-
sights and predictions under changing
scenarios to enable earlier, data-driven
interventions that can help to avoid
supply chain interruptions—before
they occur,” says Emanuel Schapper,
term leader, key account management,
Elpro Global.
“The effort to improve supply chain
visibility is essentially an inventory
-management strategy that involves
using advanced techniques to im-
prove the allocation and orchestration
of products and shipments to achieve
better outcomes,” says Vivian Berni,
director of product management and
strategic marketing, Sonoco Thermo-
Safe. “Improved visibility allows you
to see what inventory is with your sup-
pliers in your distribution center and
in your warehouse at any moment—
and understand what’s going on with
your suppliers and your customers—
so you can take the necessary steps
to accelerate order fulfillment and
exceed customer expectations while
keeping operating costs low,” she adds.
Efforts aim to
analyze and model
large data sets
using machine
learning and AI
techniques and
other modeling
modalities.
“The idea of transparency carries
more weight than it did years ago,”
Berni continues, adding that such
efforts are especially important in
the pharma industry, as pharma-
ceutical companies routinely out-
source key segments of the process—
such as packaging, logistics, distri-
bution, and more—to third-party
partners, amplifying the potential risk
of disruption.
“It is essential to map the supply chain
BLUE PLANET STUDIO - STOCK.ADOBE.COM
both upstream and downstream and to
perform a proper risk assessment,” says
Ben VanderPlas, director of engineering
and R&D, Sonoco ThermoSafe. Mean-
while, VanderPlas notes that establishing
regular audits, quality agreements, and
standard operating procedures with all
suppliers is also essential to reduce risk
and eliminate supply chain blind spots.
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Supply Chain
“As audits uncover issues, each find-
ing should be categorized according to
risk (major, minor, recommendation)
and an action plan must be developed
with the supplier to address each con-
cern,” VanderPlas adds.
“We have all these islands of infor-
mation and all these people working
in the supply chain, but we just don’t
share the right information as effec-
tively as we could,” says John Bermu-
dez, vice president, product marketing,
TraceLink. “Increased visibility among
all upstream and downstream supply
chain helps pharma manufacturers
detect issues sooner, inform decision
making, and enable data-driven inter-
ventions to prevent more costly and
disruptive problems.”
Potential supply
chain disruptions
across all
industries have
become more
the rule than
the exception.
“[During the COVID-19 pandemic,]
the pharma industry got a very rude
awakening that the way that compa-
nies run their supply chains was not
very good,” Bermudez continues. “His-
torically, many pharma companies
used a very basic approach, saying, ‘If
we maintain two years of inventory,
we’ll always be able to ship on time.’
But during the early months of the
COVID pandemic, products for which
they had held a two-year inventory ran
out in two months. That’s not a very
agile supply chain.”
Turning insights into action
“As the level of global interconnectivity
continues to grow among supply chain
partners, technical and compliance
challenges must also be addressed to
ensure data integrity and enable trace-
32 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
ability and audit trails,” says Schapper.
“More work needs to be done to figure
out how we can validate distributed sys-
tems, software, and databases, as well
as critical supply routes, and whether
the current regulations and guidance
are still applicable for the possible dig-
itized systems of the future.”
Similarly, increasing end-to-end
visibility within a supply chain “[i]s an
ever-changing process because new
technologies and opportunities are
introduced every day to improve
operations and results,” says Berni.
“This is not an area of business where
you can simply integrate solutions and
consider it done.”
“As a packaging manufacturer and
service provider that takes possession
of critical pharma products while en
route, our role is to reduce [the] risk
for our pharma customers as time- and
temperature-sensitive pharma prod-
ucts are moving through city streets,
interstate highways, and international
airspace,” Berni continues, adding that
today’s innovative packaging options
are designed to both secure pharma
deliveries and support improved sup-
ply chain visibility. The options range
from lightweight insulated recyclable
shippers to plug-and-play rental ser-
vices to high-tech air freight containers
and containers for bulk transportation.
Real-time monitoring capabilities
integrated into cold chain packaging
yield insights into what’s potentially
going on right now along the route.
“Intervention can be further en-
hanced by being able to predict the
performance over a given route or
shipping lane using existing data sets,
ultimately mitigating the risk of po-
tential product spoilage,” says Alyssa
Roberts, director of global product
management, CSafe Global.
State-of-the-art containers are
equipped with an integrated telemetry
system to provide critical real-time,
cloud-based data on both payload and
ambient temperature and key environ-
mental factors, precisely synchronized
with GPS location while maintaining
the payload at the required refrigerated
or frozen temperatures, adds Berni.
Increased digitalization
helps to connect the dots
Increased investment in supply chain
digitalization is essential and can yield
many dividends, according to Bermu-
dez. These include improvements in:
• Transparency. Improving prod-
uct availability, change man-
agement, a nd t he ha nd li ng
of recalls.
• Traceabilit y. Suppor ting an-
ti-counterfeiting and product di-
version effort.
• Visibility. Reducing upstream
material shortages and down-
stream shipping delays and help
capture key performance trends
for ongoing process improvement.
• Collaboration. Integrating sup-
pliers more effectively and enable
greater operational flexibility.
• Sustainability. Safeguarding the
business and clinical objectives of
both pharma manufacturers and
patients over time.
Increased
investment in
supply chain
digitalization
is essential
and can yield
many dividends.
“If—despite precautionary measures
being taken—shipping delays still
occur, the ultimate consequences
will depend on how much data is avail-
able to demonstrate relevant product
quality,” says Schapper. “For instance,
when shipping temperature-sensitive
pharma products, access to [real-time]
monitoring data related to the tem-
perature, humidity, duration of travel,
open-door events, and other factors
that could imperil product integrity
can help stakeholders to prove that de-
spite the delays, the product stability
and quality were not corrupted, which
allows the products to still be released
for patient use.”
Prewave, a company that specializes
in supply chain visibility, has pioneered
a data-gathering process to yield timely
alerts for stakeholders.
“We analyze the direct suppliers of
our clients and map out their supply
chain down to the raw material. The
data allows us to screen suppliers and
generate a risk score,” says Miriam
Jonas, industry specialist for pharma-
ceuticals, Prewave. Specifically, the
company’s monitoring system gath-
ers publicly available information
about the client’s suppliers, which
may range from posts on social media
about human rights issues to local
newspaper reporting to a regional risk
of COVID infection due to a supplier’s
particular location.
“We generate risk alerts for these
events, which are displayed in the Pre-
wave system,” Jonas continues. “Our
customers can then track the types
of factors impacting their suppliers
and get alerts in real-time to factors
that could interrupt upstream sup-
plies—many of which have not been
announced by the company.”
“If pharma manufacturers are not
aware of, say, multiple fires at a given
raw material supplier’s site, the impact
on the availability for that commodity
could impact the entire supply capac-
ity, and even if the news eventually rip-
ples through the supply chain, having
more time to react to it—and pivot to
an alternative source for that strategic
material—can provide a significant
advantage in the long run,” says Jonas.
“We’ve been working with a con-
sortium of pharma companies, and
one thing they’ve consistently asked
for is the improved capability to use
TraceLink data to predict shortages,”
says Bermudez.
Toward that end, TraceLink has
developed AI-based “collective intelli-
gence capabilities” to analyze just the
shipments from pharma companies
and the receipts of drug dispensers.
“We’re looking at the mismatch using
machine learning capabilities to pre-
dict shortages even more accurately
to allow for preventive measures to be
taken before the crisis,” says Bermudez.
Bermudez emphasizes that, no mat-
ter how effective the technology-based
elements are, the human element can-
not be overlooked.
“The system must alert the right
people when things change so [that]
they can collaborate with their peers
to make decisions that cannot be made
with data alone,” says Bermudez.
No matter how
effective the
technology-
based elements
are, the human
element cannot
be overlooked.
Consider, for example, the pro-
longed shipping bottlenecks that
occurred in 2021 in the Ports of Los
Angeles and Long Beach in Califor-
nia, which created weeks of delays
when cargo ships piled up without
the resources needed to unload and
reload them or the prolonged cargo
shipping crisis that resulted after a
2021 shipping accident jammed up
the Suez Canal.
“This past spring, supply chain
professiona ls continued to send
cargo through these pinch points
despite the known extended delays
we were all experiencing,” says Ber-
mudez. “We know it can only take
30 to 40 days for a cargo ship from
China to reach the US; so, it made no
sense to put cargo on ships headed
to ports with a 40-70 day backup…
Either they didn’t have the required
visibility, or they didn’t understand
the implications.”
By contrast, freight forwarders
with the right visibility could have
redirected many cargo ships that
normally go through the Port of Long
Beach to Jacksonville, Savannah,
Charleston or Oakland, Bermudez
adds, which would help to reduce
the glut in that port and prevent-
ing losses (in terms of missed sales
and spoiled products) that resulted
when shipments ended up being 40 to
70 days late. But companies can’t be
that nimble if they don’t have full in-
sight into what’s going on up and down
the supply chain.
Initially introduced to reduce drug
counterfeiting and improve track-
and-trace capabilities, serialization
also plays a growing role in expanding
supply chain visibility today, says Ber-
mudez, helping pharma companies to:
• Verif y product identit y and
products as they move through
supply channels
• Develop and deploy rules-based
ser ia l i z ed produc t ident it y
profiles based on business and
market needs
• Track and manage products
across internal packaging and
other external partners
• Create a single source of truth
for critical product, copay, and
partner master data across the
supply chain
• Manage serialized inventory,
events, and operational work-
flows to connect the physical sup-
ply chain with the digital network.
“Ongoing barriers are not really re-
lated to the available system or tech-
nological capabilities,” says Bermudez.
“Such systems are coming along, and we
are already able to connect tens of thou-
sands of entities to improve overall sup-
ply chain visibility.” Instead, Bermudez
says that greater commitment is needed
across the entire industry.
“One of the biggest barriers to better
supply chain visibility is that the in-
dustry as a whole has not yet invested
the time, resources, or effort that is
needed to move to the next level in
terms of predictive modeling,” adds
Roberts. “Interaction and integration
with all the stakeholders in the sup-
ply chain are key to be able to use re-
al-time data to inform efforts to avoid
disruption and increase overall supply
chain integrity and reliability.” PT
Pharmaceutical Technology  SEPTEMBER 2022 33
 Peer-Review Research
The Value of Primary
Working Standards in
Pharmaceutical Quality Control
Moritz Perscheid
The use of primary API quantitation standards as
working standards has clear advantages over the
widely established use of secondary standards.
According to United States Pharmacopeia in 2021,
secondary standards carry a higher measurement
uncertainty than the primary standard upon which
they depend. This may lead to out-of-specification
(OOS) results, which are not realized by the user. It
is argued that orthogonal quantitative methods,
as recommended by FDA for API standards, can be
used to establish primary working standards, which
can then be used in multiple analytical methods.
An example is provided in this article, which details
how to calculate the expanded measurement
uncertainty (U) for the certified assay value by
considering two orthogonal assay methods. Key
concepts used include the root sum of squares
of the uncertainties to reflect uncorrected
method bias in the expanded measurement
uncertainty U of a reference standard, rules for
treating measurement uncertainty as described
by Eurachem’s guide on quantifying uncertainty
in analytical measurement, and the introduction
of guard bands to protect acceptance zones. It
is argued that commercially well-available
reference materials produced under the scope of
an ISO 17034 accreditation can be used as assay
standards for frequent testing within compendial
and non-compendial analytical methods.
Submitted: June 3, 2022
Accepted: July 20, 2022
34 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
A
PI standards have multiple applications in pharma-
ceutical quality control (QC). Where they are used
for identification purposes—for example, in impurity
methods or system suitability checks—they do not
necessarily require an accurate assay value. Where API stan-
dards are used to assess the potency of drug substances or drug
products, their accuracy is crucial because it will directly influ-
ence the assigned potency of the drug. These quantitative API
standards are sometimes referred to as “assay standards,” or
API quantitation standards. Their demand in routine analytical
testing is often met by the establishment of secondary standards
by assay against a primary standard. By this, the use of the pri-
mary standard can be reduced to an economically advantageous
degree. Historically, this was often necessary because a primary
API standard required—and still requires—raw material of the
highest quality, extensive characterization, and scientific evalu-
ation that go beyond the normal QC routine. Therefore, the pri-
mary standard was often of limited availability and expensive
to manufacture. For this reason, the European Pharmacopoeia
endorses the establishment of secondary standards (1) while the
United States Pharmacopeia (USP) argued in 2021 that the use
of secondary standards may lead to out-of-specification (OOS)
results that might not be recognized (2).
Today, a primary standard can either be manufactured in-
house, sourced from an accredited reference material (RM)
producer, or obtained from other official sources (e.g., from
national pharmacopeias or national measurement institutes).
Key characteristics of such a primary standard are, as defined
by the World Health Organization (WHO), that the “assigned
content when used as an assay standard is accepted without
requiring comparison to another chemical substance,” and that
it has “appropriate qualities within a specified context” (3).
Over time, some of the cost drivers for primary standards
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have changed significantly. The availability of analytical tech-
niques has increased. With the ISO norm 17034 (4), the prin-
ciples of how to establish a reliable RM have been made more
transparent and accessible to a broader audience.
An important aspect to consider when establishing API
assay standards is that one quantitative analytical method
alone might not be capable of assessing the true assay of a the compendial procedure because they have been qualified
material, as it might be biased. To better understand these for specific methods defined in the documentary standard.
potentially present systematic effects, FDA’s industry guid- Zeine and colleagues (USP) (2) therefore argued that:
ance (5) recommends the use of orthogonal assay methods. It “The assay value and related measurement uncertainty
can be challenging to find appropriate orthogonal techniques, should be determined independently for the secondary RS,
but the emergence of quantitative nuclear magnetic resonance using mass balance calculation instead of assay against
(qNMR) spectroscopy during the past few years has helped the pharmacopeial RS” (2).
ease the production of primary standards. Malz and Jancke
(6) described parameters for recording quantitative nuclear Primarily in relation to the use of secondary standards
magnetic resonances (qNMRs) in 2005, which enable the use within compendial procedures, but more widely applicable to
of the technique as a sensitive and highly specific orthogonal primary assay standards, Zeine et al. (2) also recommended
method. In practice, however, qNMR results can be biased (e.g., the introduction of guard bands around specification limits
because of impurity interferences with signals). to ensure that no OOS result is obtained without realizing it.
In addition, the ISO norm 17034 (4) lays down the principles of
The authors (2) further recommended using an independent
how to establish reliable reference materials. The norm contains mass balance calculation and the associated measurement un-
valuable and clear guidance on how to ensure that the RM is certainty of the mass balance result, alongside the standard
reliable and that metrological traceability is not only established
deviation of the method used for substance testing, to calculate
but also maintained throughout the production process and over the values of the guard bands.
time. The norm further contains operational guidance on pro- Figure 1 shows how guard bands, a concept endorsed by Rozet
duction planning (§7.2), assignment of property values and their et al. (10), can be introduced to protect the lower and upper
uncertainties (§7.13), and representative analytical sampling. In limits, leading to a narrowing of the acceptance zone of Y% on
addition, ISO guide 35 (7) provides guidance on technical is- both sides. This proposal is helpful in practice because the asso-
sues and further explains how to assess homogeneity (§7) and ciated standard deviations of measurement results used for the
stability of reference materials (§8), and how to summarize the characterization of the reference standard, and of the analytical
analytical results in an assay value accompanied by a measure for method used for substance testing, are usually readily available.
its reliability, the expanded measurement uncertainty (U) (§10). The proposal also marks a more fundamental change. The
assay values which are supposed to be used within compendial
From secondary working standards procedures are primary values in nature. Following USP’s rec-
to primary working standards ommendation, a working standard’s content is to be established
With these changes and based on good drug substance avail- without comparison against the official compendial standard.
ability for most pharmaceuticals, assay standards appeared Therefore, the working standard fulfills an important criterion
in the market, which have been qualified with two assay of a primary standard according to the definition of WHO.
methods. These standards were created in alignment with
the relevant ISO norms and guides and made available at Methods
price points that allow for frequent use as working standards. Appropriate qualities of a working standard. Another key question
Some reference standard manufacturers originally com- to consider is whether the working standard or, in a slightly
pared these assay standards against quantitative compendial wider context, the assay standard has “appropriate qualities”
standards, implying that the assay value was “traceable” to a within the application for which it is used. These qualities of
specific compendial standard. However, Hauck et al. (8) ques- the material will be determined by the way the material has been
tioned whether such a secondary standard leads to the same characterized and manufactured, and how it is continuously
results and decisions as the original compendial primary stan- controlled for stability.
dard. The assay value that is established by comparison against What complicates the situation is that the working standard
a primary reference standard unavoidably carries a higher mea- will not only be used for compendial procedures but also for in-
surement uncertainty than the primary standard. As such, it house application or, generally, for multiple, chromatographic
is unclear whether the standard leads to the same decisions methods. In contrast, compendial reference standards lead to
regarding acceptance/rejection. Zeine et al. (2) concluded in correct results when used within specified compendial proce-
2021 that, when using such a secondary standard within a com- dures; but they do not necessarily lead to a result of comparable
pendial procedure, the acceptance zone should be tightened to accuracy when used within non-compendial procedures. The
ensure that specification limits are not unwittingly infringed. reason is that these standards have been established for specific
In principle, when exchanging any standard in a compen- use within well-defined procedures where the method itself is
dial or other validated procedure in pharmaceutical QC, as in- the essential part of the traceability chain and where the un-
dicated by USP’s expert committee in 2009 (9), the equivalence certainty of results and standards are factored into the accep-
of pass/failure decisions needs to be ensured. In a similar vein, tance criteria. Therefore, USP states that its physical standards
and as explained later in this article, caution is necessary when are traceable to a specific analytical method (11) and that for a
using reference standards from any pharmacopoeia outside specific reference standard “it is the responsibility of the user
Pharmaceutical Technology  SEPTEMBER 2022 35
Peer-Review Research
Figure 1. Illustration showing how guard bands can be introduced to protect lower and upper limits (1).
to determine the suitability of the USP Reference Standard for
non-compendial uses” (12).
An approach is needed for working standards, therefore, that
overcomes the dependence on a specific analytical procedure
and leads to reliable reference materials that can be used as an
economically feasible working horse in all the relevant (usually
chromatographic) analytical methods.
Accounting for uncorrected method bias by means of measurement
uncertainty. Enabling such use of assay standards in multiple
pharmaceutical analytical methods can be achieved by a com-
bination of reflecting the difference between the two orthogonal
assay values in the measurement uncertainty of the reference
standard and by introducing guard bands that account for the
measurement uncertainty of the RM and the method used.
These guard bands will then protect the specification limits
and increase confidence in product compliance.
The application of the concept of measurement uncertainty
plays a crucial role in pharmaceutical QC, as also argued by
Weitzel and Meija (13), because “without quantitative assess-
ments of uncertainty, it is impossible to decide whether observed
differences between results reflect more than experimental
variability, whether test items comply with specifications, or
whether laws based on limits have been broken” (14). As argued
by Jackson and Borman (15,16), the combined uncertainties of
analytical procedures should be considered in the analytical
target profile (ATP), which defines critical quality attributes
and acceptance criteria for the reportable result. Further, USP’s
general chapter <1220> (17) describes how measurement un-
certainty considerations can be summarized in the target mea-
surement uncertainty (TMU), which states the quality of the
reportable value.
36 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
As described in ISO guide 35 (7), the measurement uncer-
tainty of a RM should reflect uncertainty contributions from the
analytical characterization, heterogeneity, and stability effects
(§10). In the following example, the contributions from hetero-
geneity and stability are neglected, and the discussion focuses on
the uncertainty contribution, which stems from the analytical
characterization itself.
The reference standard will be qualified with two quan-
titative, independent, appropriately specific, and validated
methods. However, it will remain unknown which of the two
assay values is closer to the true assay value of the material.
In pharmaceutical QC, a customer would usually expect that
the certified assay value of a reference standard can clearly
be traced back to a specific measurement. In most cases, a
mass balance approach will be preferred for pharmaceuti-
cal assay standards. A combination of the two assay values
is, therefore, unfavorable. As both results are equally valid,
however, it would be misleading to state only one single result
with its associated standard measurement uncertainty because
the difference between the two assay values can be seen as a
proxy for underlying systematic effects (18,19), also referred
to as method bias. Where both assay values come together
closely and agree within their measurement uncertainties, the
FIGURE COURTESY OF THE AUTHOR.
probability is high that they are close to the true value of the
material. However, where the second assay value is a result
of a measurement of higher metrological order—for example,
a result of an absolute method—and does not lie within the
interval of the U of the first assay value, but is still sufficiently
close to it, the method bias should be reflected in the U. This
modified U will then define a widened interval in which the
true value can be expected to lie with a certain probability.
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as proposed in this article has clear advantages over the use of sec-
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[Eq. 8] ondary standards. While it remains necessary to narrow the com-
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* % % % !"
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&
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assumed 'to+,.075! be & ( 3'#(&)%
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# !#! ./45.67
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similar '
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ratio(8 (8can 9:;92<(8=
R be approximated
9:;92<3=
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' 4 2 3by assuming that the
3 9:;92<(8= (& * $
9:;92<3= uncertainty A..
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( $
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tested >?9:;92<(8=@ and of the primary
9:;92<3=
stan- %% %
A..
advantage
A..
in that the produced secondary standard depends, as
( )%%3 #&%dard
'9:;92<(8= * ( :is% #the % 9:;92<3=
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9:;92<(8=
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3 9:;92<3= strictly as the compendial reference standard, on the compendial
#! 9:;92<3= !#!'! (TXDWLRQ! ./0#$+,-!6!
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documentary
( $( A.. &% !O!(C((FI!
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standard. Also in this case,
;!#!
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9:;92<(8=
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!#!'!
0.2%, this results in uR ≈ 0.0028. See Equation 11:
&& : +,++.3
specification * (
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need +,.07to be tightened. In contrast to an ISO
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38 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
K0&$%3#!1( 2(8 #$% & '%.( %2 +,-;5 % % ' +,;05!%
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is that the provided U for the certified assay value contains at
least a contribution that reflects the homogeneity of the RM. In
the case of certified reference materials (CRMs), it also contains
a contribution for the stability of the material over its lifetime. In
sum, the end user is empowered to use the ISO 17034 accredited
primary standard, whether used as the working standard or for
singular occasions, in multiple analytical methods.
Acknowledgments
The author gratefully thanks Guenter Funk, global technical
director, LGC, Thomas Linsinger, scientific offical, European
Commission, and Bernhard Geisel, principal scientist Quality
and Release, LGC, for their immensely valuable input and the
inspiring discussions.
References
1. EDQM, EurPh, General Text 5.12, Ph.Eur. 10.2 online version
(EDQM, Strasbourg, France, 2020).
2. C. Zeine, et al., Pharmaceutical Technology 45 (2) 36-42 (2021).
3. WHO, WHO Technical Report 943: WHO Expert Committee on
Specifications for Pharmaceutical Preparations, p. 62 (WHO, Ge-
neva, Switzerland, 2007).
4. ISO, ISO 17034:2016, General Requirements for the Competence of
Reference Material Producers, 2016.
5. FDA, Guidance for Industry, Analytical Procedures and Methods
Validation for Drugs and Biologics (CDER, July 2015).
6. F. Malz and H. Jancke, Journal of Pharmaceutical and Biomedical
Analysis 38, 813–823, 2005.
7. ISO, ISO 35:2017, Reference materials—Guidance for Characterization
and Assessment of Homogeneity and Stability (2017).
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8. W.W. Hauck and USP Reference Standards Committee, Pharm.
Res. 29 (4) 922–931 (2012).
9. W.W. Hauck, et al., “Stimuli to the Revision Process: Acceptable,
Equivalent, or Better, Approaches for Alternatives to Official
Compendial Procedures,” Pharmacopeial Forum 35 (3) (2009).
10. E. Rozet, et al., Anal. Chem. 84, 106–112 (2012).
11. R. Reddy, “Reference Standards and Traceability (to documentary
standards and secondary standards),” presentation at the 13th In-
ternational Symposium on Pharmaceutical Reference Standards
(Strasbourg, France, March 13–14, 2019).
12. USP, “Certificate Ibuprofen,” www.static.usp.org, June 18, 2020.
13. M.L.J. Weitzel, et al., “Stimuli to the Revision Process: Measure-
ment Uncertainty for the Pharmaceutical Industry,” Pharmaco-
peial Forum 44 (1) (2017).
14. ISO, ISO 21748:2010, Guidance for the Use of Repeatability, Repro-
ducibility and Trueness Estimates in Measurement Uncertainty
Estimates (2010).
15. P. Jackson, et al., Anal. Chem. 91 (4) 2577–2585 (2019).
16. P. Borman, et al., Anal. Chem. 94 (2) 559–570 (2022).
17. M.P. Gregory, et al., “Stimuli to the Revision Process: Proposed
New USP General Chapter: The Analytical Procedure Lifecycle
<1220>,” Pharmacopeial Forum 43 (1) (2016).
18. M.S. Levenson, et al., J. Res. Natl. Inst. Stand. Technol. 105, 571 (2000).
19. S.L.R. Ellison and B. Magnusson, Anal Bioanal Chem 390,
201–213 (2008).
20. V.J. Barwick and S.L.R. Ellison, Analyst 124, 981–990 (1999).
21. Eurachem/CITAC, Guide Quantifying Uncertainty in Analytical
Measurement, S.L.R. Ellison and A. Williams, Eds., (Eurachem,
Gembloux, Belgium, 3rd ed., 2012). PT
Moritz Perscheid, PhD, moritz.perscheid@lgcgroup.com,
is a pharmaceutical chemist at LGC.
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Analytics
Advances in
Environmental Monitoring
Grant Playter
Cleanroom monitoring may be in a state of flux
after many recent technological advancements.
C embrace a more
leanroom monitoring is an indus-
try that some reports estimate will
be valued at as much as $7.1 billion
by 2028 (1). In spite of that massive pro-
jected value proposition, however, many
questions remain regarding the current
(and future) state of the industry. How
are recent advances affecting the field?
What upcoming changes should we be
aware of? Is the industry stable or in flux?
To learn more about the current state
of cleanroom monitoring, recent ad-
vances in the field, and potential upcom-
ing changes that might impact the indus-
try, Pharmaceutical Technology spoke
with the Alex McDaniel, Environmental
Monitoring Program manager, Element;
Joe Mundell, chief research officer, Son-
icu; and Stephen Tierney, president, Xil-
triX North America.
When taken together their perspec-
tives provide insight not only into the
current state of cleanroom monitoring,
but also into changes that may be crest-
40 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
ing over the horizon. Topics of discus-
sion include the current state of clean-
room monitoring, recent advances in the
industry, upcoming changes, and more.
The state of cleanroom monitoring
PharmTech: Broadly speaking, can you
share your thoughts on the current state
of cleanroom monitoring? Would you say
it is in flux, or a relative state of stability?
McDaniel (Element): Over the course of
the past six years, it has been apparent
the current state of cleanroom monitor-
ing is always seemingly in flux. As the
industry works to align the methodology,
frequency, and validation of a formal en-
vironmental monitoring (EM) program,
many applicable guidance documents
and standards are undergoing revision.
This includes USP [United States Phar-
macopeia] General Chapter <797> (2),
which is (hopefully) nearing the finish
line of its long overdue revision. An in-
creased frequency of surface sampling
within the cleanroom suite is anticipated
in the USP <797> revision, in addition
to changing the organism identification
requirements to be more pragmatic to
delivering patient care.
In the current good manufacturing
practices sector, the EU Annex 1 revision
will emphasize the increasing need for a
contamination control strategy, whereas
the current version lacks specificity on
this. A more consistent and patient-fo-
cused approach to EM will be embraced
by the industry, as the Annex 1 revisions
will impact cleanroom monitoring, espe-
cially as it relates to an enhanced focus
on conducting a risk assessment of the
activities within the facility.
Mundell (Sonicu): Cleanroom technol-
ogy is rapidly evolving as more health-
care and life science customers migrate
to the cloud and demand mobile-first
solutions that are always on and can be
accessed from anywhere. Moreover, cli-
ents are looking for monitoring solutions
that both integrate with and serve as a
multiplier for their BMS/BAS [building
management system/building automa-
tion system] systems.
The industry will
consistent and
patient-focused
approach to EM.
Recent advances
PharmTech: Can you discuss some of
the most recent advances in cleanroom
monitoring? What makes these tech-
nologies fundamentally different from
those that came before?
Tierney (XiltriX): Some of the recent ad-
vances in cleanroom monitoring would
be continuous particle counting and
measurements, such as volatile organic
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compounds (VOCs), becoming more
and more ‘the norm’. Technologies
never fundamentally change because
it’s evolution, not revolution. Legisla-
tion and regulation would not be able
to keep up if it were the latter.
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and other applications requiring CO monitoring refrigerators, or (clean)rooms

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ambient pressure monitoring incubator or freezer is left open, and see trends of recovery

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Analytics
[Increasingly] sensors [are being
seen] in a single system. For example,
analog magnehelic differential pressure
sensors can now be digitally integrated
into an [environmental monitoring sys-
tem] alongside a room’s conditions and
particle counters, as well as the equip-
ment stored inside.
McDaniel (Element): Rapid microbiol-
ogy has garnered a great deal of inter-
est, yet it remains an unknown quantity
and certainly does not look to unseat
conventional microbiological testing
methods in the near future. The turn-
around time for traditional incubation
of viable media is its primary pain point,
as it takes a minimum of (roughly) a
week to 10 days, depending on duration
of media dual incubation conditions.
This does not include the time micro-
bial identification and reporting takes.
Rapid test methods allow for quicker
batch release and insight into the state
of microbial control, as firms can re-
ceive insight into potential growth of
bioburden much sooner (some within
minutes or hours).
Fundamentally, the validation process
for this is not necessarily as straightfor-
ward as traditional methods. Guidance
documents like USP <1223> Alternative
Microbiological Methods (3) are a good
starting point to consult when consider-
ing validation of this system. The data
comparison is not ‘apples to apples’, as
the rapid method employs the use of
technologies like ATP [adenosine tri-
phosphate] bioluminescence and via-
bility staining to detect the presence of
More on analytics
Visit PharmTech.com to read more articles on analytics:
• Inspecting Finished Products with Precision
www.PharmTech.com/view/inspecting-finished-
products-with-precision
• An Integrated Approach to
the Data Lifecycle in BioPharma
www.PharmTech.com/view/an-integrated-
approach-to-the-data-lifecycle-in-biopharma
• Ensuring Patient Safety Through Elemental
Impurity Analysis
www.pharmtech.com/view/ensuring-patient-
safety-through-elemental-impurity-analysis
42 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
viable organisms. Rapid forms can cover Including secondary points, such line
a wide range of assays, from bioburden drops within the building that are not
of raw materials to sterility confirma- routinely monitored, can provide a ho-
tion, water monitoring, and active air listic diagnosis of how the entire system
sampling. However, it is important to is performing versus a fragmented ap-
ensure that rapid methods are of equal proach of selecting only certain locations.
or better quality than traditional testing. [It is expected that there will be a] sig-
nificant increase in this [request] moving
Industry changes forward, especially in terms of validating
PharmTech: Has there been any recent a previously installed system.
changes in what customers want in their Within the next several years, the mo-
environmental monitoring systems? If so, mentum will likely swing towards sys-
how has the industry changed to accom- tems that can provide continuous and
modate it? automated sample collection during a pro-
Tierney (XiltriX): Data security is contin- duction run. Some processes are still per-
uously becoming more stringent every formed in a very manual way and require
year. Since the pandemic, life science a great deal of human intervention, from
facilities have been in greater need of differential pressure monitoring, tem-
remote accessibility; to have full insight perature, and humidity data, or non-via-
into everything going on in a facility, no bles. Some manufacturers of monitoring
matter where the staff are located. [Fa- devices are also developing viable particle
cilities’ operators] want their electronic counting units to provide real-time data of
management systems more integrated colony forming unit (cfu) counts with the
with other critical systems like LIMS use of laser technology similarly used for
[laboratory information management non-viable particle count testing.
system], building management systems,
electronic lab notebooks, batch records, Annex 1’s approach
asset management, [and so on]. PharmTech: As the EU GMP Annex 1 re-
McDaniel (Element): Along with automa- visions edge closer to publication, what
tion, clients are asking for trended data changes, if any, will this make to environ-
from their monitoring projects. While mental monitoring specifically? If we’re
trending is a wide-ranging regulatory anticipating significant change, what
requirement, it is currently performed future-proofing (if any) are you seeing in
via a very manual process. To produce customer orders?
better reports that feature trended data McDaniel (Element): There is an increased
as a standard inclusion, [Element imple- onus on manufacturers to implement and
ments and uses] LIMS. document a contamination control strat-
Compressed gas testing is also more egy and a vigorous risk assessment within
frequently requested in the industry. the pharmaceutical quality system. Man-
• When Is It Appropriate to
Outsource Bioanalysis Work to a CRO?
www.PharmTech.com/view/when-is-it-appropriate-
to-outsource-bioanalysis-work-to-a-cro-
• Material Management and the
Impact on Extractables and Leachables
https://www.PharmTech.com/view/material-
management-and-the-impact-on-extractables-
and-leachables
• Advances in Dissolution Testing
www.PharmTech.com/view/advances-in-
dissolution-testing
ufacturers may need to completely over-
haul their program to include additional
sampling locations if a formal monitor-
ing program was not previously estab-
lished, or the original program was not
updated to reflect current processes or
was based upon previous facility designs.
An increase in EM performance qualifi-
cations conducted on existing cleanroom
areas to align with an updated and more
modern approach to the documented risk
assessment [is expected].
Given the push to take a comprehen-
sive look at processes to identify failure
points and consequences of those failures
in the upcoming Annex 1, using the fail-
ure mode and effects analysis (FMEA)
tool has worked out well for clients look-
ing to future-proof their risk assessments.
Final thoughts
PharmTech: Do you have any final
thoughts on the topic that you can share
with our readers?
Mundell (Sonicu): [A] greater attention
from larger healthcare systems to include
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air pressure differential and humidity
as well as O2, CO2, and VOCs [is being
witnessed]. Infection control experts are
driving the conversation as part of their
risk management focus while construc-
tion firms are being consulted on both
new build and retrofit projects to work
collaboratively on these projects. [Addi-
tionally, a] significant demand relative to
pre-COVID [is being seen] and [this is]
expected to continue accelerating.
McDaniel (Element): [From personal ex-
perience, it is apparent that] critical gaps
within an operation may not be identi-
fied until it is too late. Downtime can be
eliminated, back-end costs reduced, and
production lines will stay in operation
if those within the industry tasked with
maintaining compliance to these stan-
dards establish documented protocols
in partnership with a subject matter ex-
pert (SME) and team of microbiologists.
As professionals, [there is] a respon-
sibility to seek out continual education,
as well as educate others in the industry.
Establishing a partnership with a col-
laborative organization with a consul-
tative team invested in teaching others
is vital to staying on top of these dy-
namic requirements—and that is only
the beginning. Selecting a firm that
has a robust scope of service offerings
and quality procedures that can look at
processes, provide a gap analysis, estab-
lish methods to help mitigate contami-
nation control before it becomes prob-
lematic, and even assist in validating a
cleaning and disinfection program is
a gamechanger when the FDA walks
through the door.
References
1. Market Research Future, Cleanroom Tech-
nology Market (August 2022).
2. USP, General Chapter <797>, “Pharmaceu-
tical Compounding—Sterile Preparations,”
USP 21-NF 26 (Rockville, MD, 2008).
3. USP, General Chapter <1223>, “Alternative
Microbiological Methods,” USP 32-NF 27
(Rockville, MD, 2006). PT
Editor’s Note: This article has been
updated from the original version.
Pharmaceutical Technology  SEPTEMBER 2022 43
Quality: Industry 1VQ Solutions
Q10, will allow companies to overcome
barriers to continual improvement and
innovation. Additionally, it will help
mitigate drug shortages in the global
pharmaceutical supply chain by allow-
ing faster implementation of PACs and
reduce the burden on both industry and
regulators.
This specific PAC example of changing
a lot or extending the shelf-life of a Ref-
erence Standard (RS) has demonstrated

Industry 1VQ Solutions:

the application of the principles outlined
in ICH Q9, Q10, and Q12 (3) irrespective
of current national or regional reporting

Change of Lot or category and concluded that it could be

managed in the PQS only, rather than
as a prior-approval change submission

Extension of Shelf-life when meeting pre-determined criteria.

This position paper is part of a series
of industry case studies intended to

of Reference Standard demonstrate the standard application

of the principles outlined in “Effective
Management of Post-Approval Changes
in the Pharmaceutical Quality System
Marie-Claire Beckers, Delphine Collete, (PQS)—Through Enhanced Science and
Julie Barthuet, and Thierry Gastineau
Risk-Based Approaches: Industry One-
Voice-of-Quality (1VQ) Solutions” (4).
Change of lot or extension of reference This PAC example and the 1VQ for
PAC Initiative are sponsored by the
standard shelf-life is considered low chief quality officers from more than
risk and should be downgraded from 20 pharmaceutical companies (5).

prior-approval to being managed in the Current state for a change of lot

or the extension of shelf-life of RS
Pharmaceutical Quality System (PQS) only A RS is a material used as a quantitative
based on a science and risk-based approach. or qualitative comparator in the release
or stability testing of APIs, drug prod-

T
he International Council for Har- mechanisms and guidance for PACs do ucts (pharmaceuticals/biologicals), or
monisation’s (ICH’s) Q10, Pharma- not consider the company’s latest product intermediate products. A RS can be a
ceutical Quality System, Annex 1 and process knowledge when determin- certified reference material (e.g., United
describes potential opportunities to en- ing the type of filing required to imple- States Pharmacopeia [USP] or European
hance science and risk-based regulatory ment the change. Further, the application Pharmacopoeia [Ph.Eur.]), a commer-
approaches to post-approval changes of ICH Q9, Quality Risk Management cially supplied material, or a material
(PACs) as follows: when a company can (2), or the effectiveness of the company’s prepared in-house. Both chemical and
“demonstrate effective PQS and product pharmaceutical quality system (PQS) to biological standards (termed as primary
and process understanding”, this is an manage PACs, is not considered during reference standard or a working stan-
opportunity to “optimize science and the assessment of individual PACs, or dard) can be used as RS.
WLADIMIR1804 - STOCK.ADOBE.COM

risk-based PAC processes to maximize during inspections. Demonstrating a Regulatory authority prior-approval
benefits from innovation and continual detailed understanding, effective im- is required in several countries for
improvement” (1). Current regulatory plementation, and compliance with ICH changes associated with introduction of
a new lot of RS or with shelf-life exten-
Marie-Claire Beckers is global subject matter expert for QC Materials and Samples sions for the RS even when there are no
Management, and Delphine Collete is global subject matter expert for QC Materials
Management; both at GSK Vaccines. Julie Barthuet is head Regulatory CMC&D changes to the product quality, patient
Vaccines, and Thierry Gastineau is global head quality innovation, Culture & safety, or drug product efficacy, or to
Engagement; both at Sanofi Vaccines. the manufacture of the RS.
44 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
 Table I. Regulatory reporting category in different countries. CQA is critical quality attributes.
CPP is critical process parameters.
Registration of new batch of working standard used for quantitative or semi-
quantitative test (e.g., in-house lot to in-house lot)
(The new lot is declared with its shelf life when applicable) Shelf-life extension for an
Countries/Region Methodology already registered working
Is there an approved qualification protocol/information? standard batch

NO YES
Without comparability data:
Type II
European Union No reporting Type IB
With comparability data:
Type IB
Annual notification:
Annual notification if protocol registered
notifiable change: if the test is a Notifiable change: if no
Canada Notifiable change
potency test, or concerns a test protocol registered or if the
related to a CQA or CPP RS is for a key quality control
or in process control assay
If protocol registered:
annual report
United States Prior-approval submission Annual report
If no protocol registered:
prior-approval submission
International variation International notification International variation
Australia
(self-assessable change) (self-assessable change) (self-assessable change)
International variation (if impact on
batch release protocol)
China International variation International variation
No reporting (if no impact on
batch release protocol)
Ghana, Gulf Cooperation
Council (GCC), India, Israël,
International variation International variation International variation
Peru, Philippines, Russia,
Switzerland, Turkey, Vietnam
International notification—
MIV-2 C14
No reporting in case of “a change
of a reference Standard that is
International variation qualified as per an approved
Singapore International variation
(MiV1 – B14) calibration/qualification protocol”
with no impact on Module 3 /
no commitment of submission
made in the approved protocol: no
submission required
Annual report Annual report Annual report
WHO
Change type R Change type R Change type R

*International variation must be understood as a variation that needs to receive approval before the change can be implemented.

Differences in regulatory require-
ments between countries are observed
and range from no requirement to sub-
mit the PAC to regulatory authorities, to
major variation as type II in the Euro-
pean Union, or prior-approval passing
through annual reportable, notification,
and minor variations.
The use of approved qualification
protocol to downgrade the level of sub-
mission is accepted by some regulatory
authorities but not all.
Differences in regulatory require-
ments between countries is shown
below in Table I. Note: Only some coun-
tries are included in this table. Visit
PharmTech.com for a more complete list.
Drug shortage situations, in partic-
ular for vaccines, caused by stock-out
of a RS lot, either because it reached its
expiry date, or it was fully consumed,
could in many cases be avoided by ex-
tending shelf-life using sound scientific
and risk-based assessment principles
or introducing a new RS lot in a timely
fashion. However, for countries requir-
ing regulatory authority approval prior
to implementation of such a change, the
approval process usually varies between
18 to 24 months from submission at an
international level, until the last national
regulatory authority has approved the
change. This lengthy approval timeline
can lead to drug shortages. Although
companies are carefully planning the
supply and use of each RS lot, they are
Pharmaceutical Technology  SEPTEMBER 2022 45
Quality: Industry 1VQ Solutions
not always in full control of the rate of lot or extension of shelf-life of a RS with- be assessed by using the following risk
consumption particularly when drug out the need to submit documentation questions: What might go wrong with
product demand suddenly changes or for each specific PAC. the new RS or with the extended shelf-
if regulatory authorities make a sudden The industry 1VQ for PAC position is life? Why and how could this happen?
increase in their request for RS samples that information about the lot reference This initial impact assessment should
for their own testing. number or expiry date should not be re- consider an absence of:
This PAC example demonstrates how quired in the marketing authorization • QSE impact for:
applying a science- and risk-based ap- dossiers. If, for historical reasons, the o RS used for qualitative tests
proach using laboratory control strat- reference standard lot number or ex- intended to give a pass/fail re-
egies including qualification protocol, piry date is mentioned in the dossier for sult, or for all quantitative tests
comprehensive implementation planning, those RSs, this information should not not considered as biological or
and bundling of changes, can support a be considered as an “Established Condi- potency tests, as these RSs do
faster implementation of this type of PAC. tion” (per ICH Q12 definition) but only not need an extensive qualifi-
This position paper describes how ICH informative, and the reference number cation as a RS used for quan-
Q9, ICH Q10, and Q12 can provide the can be removed in the context of any fu- titative biological or potency
basis for regulatory relief for the change ture variation application impacting the tests. Standards used in quan-
of lot or the extension of shelf-life of RS concerned Common Technical Docu- titative tests not considered as
when it presents no additional risk to ment (CTD) sections. biological or potency tests have
product quality and/or patient safety and This will allow faster implementation a well-defined composition and
minimal regulatory risk. of this type of change and optimize the structure. They are highly char-
testing network for timely and efficient acterized and controlled.
Example: scope testing and disposition of product. In o RS used for potency or bio-
This practical PAC example applies sci- addition, it will contribute toward meet- logical assays if the change is
ence- and risk-based concepts from ICH ing the ICH Q10 objectives of achieving performed according to quali-
Q9, Q10, and Q12 to the change of lot or product realization, establishing and fication/extension strategy and
extension of the shelf-life of a RS used maintaining a state of control, and con- met the acceptance criteria de-
in a test already registered, so that such tinual improvement. scribed in a submitted and ap-
changes can be implemented timely uti- As part of a company’s change con- proved protocol as established
lizing the framework of an effective PQS trol process, a science- and risk-based condition (EC). The approach
and without extensive regulatory burden. approach with appropriate justification and level of detail given in jus-
The scope covers RS used in qualitative will be documented in the PQS for each tifying ECs for qualification/
assays or quantitative assays. change of lot or the extension of shelf- extension of a RS is a company
Industry 1VQ for PAC position for change life of RS. decision, and may depend upon
of lot or extension of shelf-life of reference other elements associated with
standard. ICH Q12, Technical and Regu- Standard risk-based approach the overall control of the prod-
latory Considerations for Pharmaceutical Figure 1 (4) describes the standard risk- uct. The approach must be
Product Lifecycle Management, provides based approach that can be used for adapted to ensure the absence
regulatory flexibility for post-approval assessment of a PAC to change a lot or of QSE impact.
changes to the product or its manufac- to extend shelf-life of RS. Application • Legal/regulatory impact in the
turing process based on latest product of this risk-based assessment should above-mentioned situations. There
and process knowledge, sound scientific demonstrate that the change does not is an absence of any legal or regu-
and risk-based approaches (3). increase the risk to product quality and/ latory obligations which would
The industry 1VQ for PAC position is or patient safety. require reporting to regulatory au-
that the change of a lot or extension of The following steps are completed thorities. If there is a regulatory im-
the shelf-life of a RS can be managed in to assess the impact and risks associ- pact per local/regional regulation,
the PQS only, without prior regulatory ated with a change of lot or extension a more detailed risk assessment
authority approval, provided pre-reg- of shelf-life of RS as described in the should be performed to define the
istered acceptance criteria are met. It scope section. reporting category of the change.
is recommended for each PAC that the Step 1: change proposal. When a PAC Step 2: change evaluation. When the
company shares its testing and accep- to change a lot or to extend shelf-life initial impact assessment indicates that
tance criteria for introducing a new lot of RS is proposed, the potential quality, there is no additional potential QSE risk
or extending the shelf-life of a RS with safety, efficacy (QSE), and legal/regula- and no legal/regulatory impact, no addi-
regulatory authorities in the form of a tory impact of the change needs to be tional risk assessments are needed. The
qualification protocol/plan. This docu- considered during the initial high-level change is managed directly in the com-
ment would be the basis for changes of impact assessment. This impact can pany’s PQS only.
46 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
 Figure 1. Risk-based assessment of post-approval changes (PACs) and determination of
regulatory reporting category (4). QRM is quality risk management. PQS is pharmaceutical
quality
Figure 1. Risk-based assessment of post-approval system.
changes (PACs) and determination of regulatory reporting
category (4). QRM is quality risk management. PQS is pharmaceutical quality system.
Step 1 – Change Proposal
Change Mgmt.(CM)
PAC System
Step 2 – Change Evaluation
Assessment of risks to QSE
Q9
(based on current knowledge & Control Strategy)
Assignment of regulatory reporting category :
Q12 • What is the legal / regulatory impact (e.g. to ECs )?
• Document justification for proposed reporting category
Step 3 – Change Implementation
Step 4 – Change Review & Closure
1
per local regulations
Steps 3 and 4: change implementation, re-
view, and closure. Change implementation,
review, and closure should be performed
according to the change management
process. The outcomes of the impact
and risk assessments (if needed) will be
integrated into the change implementa-
tion plan. After implementation of the
change, residual risks should be assessed
and managed to acceptable levels prior
to change closure; any unintended con-
sequences or risks introduced as a result
of the change should be evaluated, docu-
mented, and handled adequately through
effectiveness verification mechanisms. In
case several changes are introduced at the
same time or related to each other, the
company should assess the cumulative
effect of the changes.
If ECs are not met (strategy and/or
FIGURE COURTESY OF THE AUTHORS
acceptance criteria) or if there is no EC
registered, the initial impact assessment
should consider a potential QSE and
legal/regulatory impact for these changes
as well as all the other changes related to
RS not included in the scope of the doc-
ument and managed through a prior-ap-
proval submission.
High Level Impact Assessment of Change
NO No impact on QSE AND
• Is there a potential impact to Quality, Safety no legal / regulatory impact
Efficacy (QSE) ? Q9,
• What might go wrong that may affect Q12
QSE?
• Is there a potential legal / regulatory impact ?1
YES or MAYBE
(likely impact to ECs)
Risk Assessment of
Change
(QRM tool/extent may vary)
HIGH MODERATE / LOW
High risk Low/Moderate risk No submission/reporting required
Prior-Approval Notification1 Document with rationale within the
CM system and implement change
Change Implementation plan
(including risk controls identified)
Q9
Change Review & Closure Q9, Q10 Ongoing Review/Monitoring
June 2019
(incl. Risk Review & Change Effectiveness) (through PQS post change closure)
Demonstrating effective The Pharmaceutical Inspection and
management of a change of lot or Co-operation Scheme (PIC/S) Recom-
extension of shelf-life of reference mendation Paper on How to Evaluate and
standard within the PQS Demonstrate the Effectiveness of a Pharma-
The following risk control elements ceutical Quality System in Relation to Risk-
have been considered for ensuring based Change Management (6) provides a
effective management of the change practical checklist tool that can be used
of lot or extension of shelf-life of RS by the company to evaluate the effective-
within the PQS: ness of its risk-based change management
• It is not triggered by any out-of- process.
trend results or out-of-specifica-
tion results. Conclusion
• Statistical analysis (e.g., extrap- This position paper provides a standard
olation linear regression) shows and enhanced risk-based approach
the RS parameters and/or values within the framework of an effective PQS
of control(s) generated with the that can be utilized by any company to
RS remain within acceptance gain regulatory flexibility, reduce the
range throughout the proposed burden and global complexity, and en-
shelf-life extension. able faster implementation of a PAC for a
The completion of qualification activi- new lot of RS or extension of its shelf-life,
ties and the implementation of this change without increasing risk to the patient and/
will be documented and tracked within or product quality, safety, and efficacy.
Page 3 of 3
the change management PQS element. The benefits of practical application of
This change should be included in the the principles of ICH Q9, Q10, and Q12
annual product quality review and re- as described in this document are contin-
ported to concerned regulatory authorities ual improvement with timely (weeks or
through the annual or periodic regulatory
reporting mechanism as appropriate. Contin. on page 53
Pharmaceutical Technology  SEPTEMBER 2022 47
Quality/Regulations
In 2018, the United Kingdom’s Med-
icines & Healthcare products Regula-
tory Agency (MHRA) and the US FDA
issued guidance documents on the topic.
MHRA’s ‘GXP’ Data Integrity Guidance
and Definitions was issued in March
2018. FDA’s Data Integrity and Compli-
ance with Drug CGMP—Questions and
Answers was issued in December 2018.
These documents join guidance issued
by the World Health Organization
(Guideline on Data Integrity) and the
Pharmaceutical Inspection Convention

A Harmonized Approach to
Pharmaceutical Inspection Co-opera-
tion Scheme (PIC/S, Good Practices for
Data Management and Integrity in Reg-

Performing a Risk-Based ulated GMP/GDP Environments) (1–4).

The publication of these guidance doc-
uments is associated with enforcement ac-

Audit Trail Review tions with an emphasis on data integrity

that stem from a failure to follow current
good manufacturing practices (CGMPs)
predicate rules and existing regulations in
Julie Lippke, Joseph Mongillo, Thomas Cullen, 21 Code of Federal Regulations (CFR) 211
Christian Metz, Katria Harasewych, and Fouad Benamira for electronic systems (5).
PIC/S Good Practices For Data Man-
agement And Integrity In Regulated GMP/
The IQ Working Group has defined a pragmatic GDP Environments—July 2021  (6)—
gives an indication of the key elements
risk-based approach to audit trail review, where to consider for an effective risk-based
it is only required for high impact GxP data. approach: “Data criticality (impact to de-
cision making and product quality) and

A
udit trail review (ATR) is a mech-
anism to detect potential critical
changes to data/system security
settings and to ensure the quality and
integrity of reported data. The authors
have defined a risk-based approach to
ATR where ATR is only required for high
impact GxP (good manufacturing prac-
tices [GMP] and good laboratory prac-
tices [GLP] for the purposes of this paper)
analytical data and possible system se-
curity changes. This approach requires
a fully documented risk assessment that
encompasses the technical controls and
identification of data impact. Note that
while analytical data are the focus of
this paper, the principles outlined may
be applied to other activities.
Regulatory expectations
Data integrity, particularly electronic
data integrity, has become an area of
increased regulatory focus. Per FDA,
“For purposes of this guidance, audit
trail means a secure, computer-gener-
ated, time-stamped electronic record
that allows for reconstruction of the
course of events relating to the cre-
ation, modification, or deletion of an
electronic record” (1).
data risk (opportunity for data alteration
and deletion, and likelihood of detection/
visibility of changes by the manufactur-
er’s routine review processes).”
Therefore, regulatory expectations for
audit trail review have become an estab-
lished part of the GxP data lifecycle.
Scope and intended use
This article introduces a harmonized
approach to performing a risk-based
ATR developed by a working group of
the International Consortium for Inno-
vation and Quality in Pharmaceutical
Development (IQ).
It should be noted that the scope of this
PARRADEE - STOCK.ADOBE.COM

Julie Lippke* and Joseph Mongillo both work in Analytical Research and article includes electronic instrument an-
Development at Pfizer Inc. (Groton, CT); Thomas Cullen and Christian Metz both alytical data where raw data are stored in
work in Analytical Research and Development at AbbVie Inc. (North Chicago, IL and
Ludwigshafen, Germany, respectively); Katria Harasewych works in Computer non-volatile memory (i.e., can be recalled
System Validation Quality, CoE at Merck & Co., Inc., (West Point, PA); Fouad Benamira later). Both enterprise and standalone
works in Analytical Development Sciences for Biologicals at UCB S.A. Belgium. All data acquisition systems are in scope.
contributors are part of the IQ Working Group. Systems that do not generate data
*To whom all correspondence should be addressed. are out of scope.
48 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
• Formulation
Development Delivering
for Poorly
Soluble Drugs
sophisticated
• cGMP formulations.
Manufacture
for Clinical
Materials
• CR, Parenteral
& Topical
Dosage Forms

O U R T E C H N O LO G I E S

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732-638-4028
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Quality/Regulations
The following terms are defined (5):
• technica l control—comput-
erized features like audit trail,
backup mechanism, user man-
agement and security, electronic
signatures and/or digital signa-
tures to assist or enforce admin-
istrative and procedural controls
• procedural control—standard
operating procedures (SOPs) and
work instructions for operation
and administration, system user
controls, computer system valida-
tion, calibration, network quali-
fication, awareness training, etc.
• system controls—combination
of procedural and technical con-
trols for a system.
Risk-based approach
Recent regulatory guidance such
as t hose f rom FDA a nd MHR A
emphasize the implementation of risk-
based approaches to ensuring data
integrity. The FDA guidance reminds
us that, “CGMP regulations and guid-
ance allow for flexible and risk-based
strategies to prevent and detect data
integrity issues” (1).
Similarly, the MHRA guidance de-
scribes “a risk-based approach to data
management that includes data risk,
criticality and lifecycle” (2).
The concept of performing a data in-
tegrity risk assessment specific to a par-
ticular data acquisition and processing
system is laid out in the MHRA guidance:
“An example of a suitable approach
is to perform a data integrity risk as-
sessment (DIRA) where the processes
that produce data or where data are
obtained are mapped out and each
of the formats and their controls are
identified and the data criticality and
inherent risks documented” (2).
The data integrity risk assessment is
seen as a driver of compliance and pri-
oritization of any necessary remediation
activities. While audit trail review is often
considered an essential part of ensuring
data integrity, the same guidance clarifies
that routine data review should include
a documented audit trail review where
this is determined by a risk assessment
(emphasis added) (2).
50 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
The appropriateness of any mitigation
of a data integrity risk should be assessed
in the context of the criticality of the gap.
MHRA defines critical risks as those that
impact the potential of data or metadata
“to be deleted, amended, or excluded
without authorization.” FDA states that,
“Data integrity is critical throughout
the CGMP data lifecycle, including in
the creation, modification, processing,
maintenance, archival, retrieval, trans-
mission, and disposition of data after the
record’s retention period ends” (1).
It should be noted that archival and
retrieval are out of scope for this paper
on ATR.
A decision tree has been developed
(Figure 1) where data types were catego-
rized and the need for audit trail review
considered. This serves as a risk assess-
ment that can be used to determine the
need for procedural controls, and the
controls should be documented within
the qualification package for new equip-
ment or in change management system
for equipment updates. A risk assess-
ment, for instance the one described
in Assessing Data Integrity Risks in an
R&D Environment (7), may be used
to define data integrity elements for a
system where audit trail review is the
chosen mitigation. Figure 1 is specific to
ATR and does not include data review.
For GLP, data review and ATR need
to happen at the same time, for GMP
there may be opportunity to separate
and streamline some activities with a
documented risk-based approach.
Determining the need
for and frequency of ATR
Data risk. ATR should be considered for
electronic GxP relevant data when a
technical control does not remove the
need to review the audit trail. A risk-
based approach should be applied to ATR,
and this general approach is described
in Figure 2. Tools such as the risk filtering
tool in International Council for Har-
monisation (ICH) Q9 (8) may be used.
When possible, there is a preference
to implement technical controls to re-
duce/eliminate the need for ATR. It is
preferred to prevent an undesirable ac-
tion from occurring if this is technically
feasible. In cases where prevention is not
possible, detection of the undesirable
action through data review (includ-
ing ATR) is required. In rare (limited)
cases where an action may be neither
prevented nor detected, discuss with ad-
ditional business/IT/quality assurance
(QA) support to risk assess whether the
system may be used for GxP work or
if alternate controls need to be put in
place such as a procedural control.
It is preferred that a technical control
be employed to prevent data deletion.
If deletion cannot be prevented, the
ATR process should be designed to de-
tect that specific activity. It should be
noted that, in many cases, ATR is most
logically performed concurrent with
other data review activities. The sever-
ity of any residual risk should be as-
sessed. The frequency for ATR should
be commensurate with the probability
of the risk occurrence. The frequency
may be adjusted based on documented
historical performance.
Intended use of the data. The intended
use of the data should also have an
impact on the need for and frequency
of ATR. The data’s potential risk
impact on patient safety and product
quality should be considered, and
GxP-relevant data are determined by
regulatory requirements.
High risk impact data are defined as
data with potential for direct impact to
product quality and patient safety. In-
dividual companies may identify other
activities as high impact but at a min-
imum would include release, clinical
stability, and cleaning verification.
While it is acknowledged that com-
panies may assign slightly different
levels of impact to the same data types,
some useful guidance may be obtained
from an informal poll conducted of IQ
member companies. Data arising from
activities such as GLP studies, cleaning
verification, clinical product release, and
stability were considered greater impact
and may trigger ATR. Activities such as
method validation may have an indirect
effect on product quality and patient
safety and may be less impactful and
have a medium/low impact dependent
on a company’s risk considerations.
 Figure 1. Risk assessment tool for determining audit trail review requirements. Where ALCOA+ is attributable, legible,
contemporaneous, original, and accurate, plus the data needs to be complete, consistent, enduring, and available.

GxP Data

High Impact
data?
See Fig 2

Yes

Are electronic No Audit Trail available to review; there is

records No no electronic data.
generated? Note: Ensure processes / practices for managing paper records CAT#1
are ALCOA+ compliant.

Yes

Document that
Can critical parameters are locked, data cannot
parameters / be changed, reviewing the displayed/
No
data / metadata printed parameters is all that is necessary,
be modified? Note: Includes parameters and metadata both during and after a no additional audit trail review is needed.
run such as: CAT#2
• Time • Acquisition parameters
Yes • Date • Processing parameters
• Who • Methods

Document those changes that can be made

Can changes in
and although changes can be made, these
the parameters
No changes don’t have an impact on the
affect the
results/data.
results /data? Note: If the business process already includes a review of the CAT#3
parameters and metadata there may not be a need for an
additional electronic audit trail review.
Yes

Are changes
tracked in a
reviewable audit
trail?
Are changes
inherently
No
reviewed in the STOP and discuss with
process? No
Can these parameters additional business/IT/QA
be checked by a 2nd support to risk assess
person prior to No whether system may be
acquisition/processing used for GxP work or if
and locked? alternate controls need to
be put in place.

Identify specific
Document the
changes that can be Document that
FIGURES ARE COURTESY OF THE AUTHORS

parameters that
Yes made. parameters are
Yes require review and the
checked on entry,
process to look for
Review audit trail for Yes critical parameters are
these changes each
these specific changes locked, data cannot be
time, and state that no
changed, no audit trail
additional audit trail
Develop a list of items review is needed.
review is necessary.
to be checked? CAT#6
CAT#5
CAT#4

Categories 1, 2 and 3 are preferred, the acceptability of categories 4, 5 and 6 are

Categories 1, 2 and 3 are preferred, the acceptability of categories 4, 5 and 6 are dependent on the risk tolerance of a company as well as the
availability of alternative compliant instruments (1).

dependent on the risk tolerance of a company as well Pharmaceutical

as the availability
Technology  of alternativ
51 SEPTEMBER 2022

compliant instruments
Quality/Regulations
Defining appropriate ATR effort/frequency.
Figure 2. Determining the rigor of audit trail review (ATR) as a function of data
Together, the assessments of the system Figure 2: Determining
risk and data impact. the rigor of audit trail review (ATR) as a function of data
characteristics and limitations and the risk and data impact.
impact of the data’s intended use will
facilitate identification of records, steps, H 2 3 3
and changes, and enable risk classifica-
tion (low to high) and a tiered audit trail
M 1 2 3
review effort.

Data Risk
Performing data ATR L 1 1 2

A decision tree describing the perfor-

mance of ATR is provided in Figure 1. L M H
Additional explanatory comments about
Data Impact
the decision tree are given as follows.
Where it is possible for changes to be
made to the experimental conditions,
LEVEL AUDIT TRAIL REVIEW EFFORT LEVELS
metadata, or other parameters that have No ATR is required, as supported by a documented risk assessment.
1
the potential to affect the results/data, ATR is performed on a “for cause” basis only.
one control strategy to ensure detection ATR may be performed on an ad-hoc basis or periodically at a pre-
2
defined interval.
is to perform ATR. In these cases, the ATR must be performed as part of the broader data review prior to the
3
following should be considered as critical release of the data.
changes (and potentially included in a list
of elements to be checked):
• changes to test parameters Figure 3. Decision tree for determining minimum system level audit trail
• changes to data processing param- review requirements.
eters (analytical method)
• deletion of data System and Data security elements include:

System Security Data Security

• repeated analysis or reprocessing
without justification
Evaluation of the need for
system level audit trail • Create/modify user accounts/
roles including admin privileges
• Audit Trail security settings (such
as deactivation
review • Ability to modify data paths/
• System configuration settings/
files folder structures

• change histor y of f inished • System policies • Ability to modify data back-up

location/structure

product test results

• changes to sample sequences
• changes to sample identification Can system/data
security elements be
Yes
Lock down system/data security elements
from modification.
• changes to critica l process locked down from
modification?
No system audit trail review necessary.

parameters.
The requirements for ATR (and data
verification in general) should be pro- No

ceduralized and should define require-

ments on a software-by-software basis Identify the system/data
Evaluate these system/ Document risk assessment
security elements that are Mitigate high-risk system/data security
dependent on the assessed data risk and not locked down from
modification.
data security elements
based on risk assessment .
for each of these system/
7
data security elements
elements by conducting audit trail review.

impact. The frequency and responsi-

bility for ATR should be defined in the
procedure. Evidence of audit trail review (7) J. Lippke, J. Lippke,et. al.,
et. al., “Assessing
Assessing 7
Data
Data Integrity Risks Integrity
in an R&D Risks
Environment, PharmTechin 44(8),
an R&D Environment,”
pp. 51-53, 2020. Pharm. Technol. 44 (8)
should be documented, in most cases by 51–53 (2020).

defining the meaning of the overall re- changes to system security settings) also • changes to reports or calculations
view signature. be reviewed at least periodically. This pe- • data security management (life-
riodic review will ensure the system has cycle including archival, resto-
System level ATR remained configured as it was during val- ration, etc.)
The purpose of a system level ATR is to idation/qualification. Based on the type • audit trail review may be used to
ensure key configurations and settings of the system and corresponding data, the verify appropriate access privileges
have not been changed (either inten- following items might be considered: have been used. Other processes
tionally or unintentionally). It is recom- • system policies may be employed to satisfy this re-
mended that the system audit trail (which • deactivation of audit trail quirement such as user access re-
contains, for example, system adminis- • changes to data paths or folder views (including admin privileges)
trator actions such as deletion of data or structure • configuration files
52 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
 • library files (where applicable) Conclusion or searching capabilities, these abilities
where the technical controls of the ATR is a mechanism to detect potential may be leveraged to streamline ATR.
library would drive the need and critical changes to data and one means
frequency for review. to ensure the quality and integrity of re- References
A decision tree has been developed ported data. The authors have defined 1. FDA, Data Integrity and Compliance with
(Figure 3) for system-level ATR where data a pragmatic risk-based approach to Drug CGMP—Questions and Answers
(Rockville, MD, December 2018).
types were categorized with examples and ATR where ATR is only needed for high 2. MHRA,‘GXP’ Data Integrity Guidance and
the need for audit trail review considered. impact GxP data and that ATR can be Definitions (London, UK, March 2018).
targeted to focus specifically on critical 3. World Health Organization, Guideline on
Appropriate audit trail comments changes that may be possible. This ap- Data Integrity (Geneva, Switzerland, Oc-
Manually entered audit trail comments proach requires a fully documented data tober 2019).
4. PIC/S, Good Practices for Data Manage-
should be suitable for an auditor/in- risk assessment that encompasses the ment and Integrity in Regulated GMP/
spector to read and should include the technical controls, identification of rel- GDP Environments (Geneva, Switzerland,
scientific rationale for why the change evant high-risk impact data, which may November 2018).
was made. GAMP 5 (9) provides audit vary on a per-organization basis. The 5. US CFR, Title 21, Food and Drugs (Gov-
trail requirements for an audit trail entry. preferred approach is to utilize technical ernment Printing Office, Washington,
DC), Part 211.
Note: There may be character limitations, controls wherever possible. 6. PIC/S Guidance PI 041-1: Good Prac-
so it may be necessary to document ATR inherently remains a manual tices for Data Management and Integrity
justification outside of the electronic process that is resource intensive, and in Regulated GMP/GDP Environments
system and include a cross-reference. opportunities for automated data trans- (July 2021).
Manually entered comments will also fer/digitalization removes opportunity 7. J. Lippke et al., Pharm. Technol., 44 (8)
(51–53) (2020).
require review and should be contempo- for critical changes negating the need for 8. ICH, Q9 Quality Risk Management (ICH,
raneous (within a reasonable experiment/ ATR where utilized. In addition, when a Geneva, 2005).
review time frame). If time has elapsed, system has been configured to provide 9. ISPE, GAMP 5: A Risk-Based Approach
then the time gap should be supported visual flags for undesirable actions/states, to Compliant GxP Computerized Systems
with a justification. or when the audit trail provides filtering (February 2008). PT

Quality:
Industry 1VQ Solutions —
Contin. from page 47
months vs. years) implementation of such
PACs, enhancing product availability and
mitigating potential drug shortages, fo-
cusing regulatory resources on PACs that
may have a potential to impact product
quality as it relates to safety and efficacy,
reducing the regulatory review and ap-
proval burden for medium- and low-risk
changes, and faster implementation of
new knowledge and innovative technol-
ogies (if applicable).
About the 1VQ for PAC Initiative
Many PACs require regulatory agency
approval by individual countries before
implementation. Because of the global
regulatory complexity, individual PACs
usually take years for full worldwide
approval even when they reduce patient
risk, improve compliance, or enhance the
manufacturing process or test methods.
Senior quality leaders (chief quality
officers and heads of quality) from more
than 20 global pharmaceutical com-
panies are speaking with “One-Voice-
Of-Quality” (1VQ) to advocate for an
effective management of specific PACs
that currently are handled as a prior-ap-
proval change in some countries, but
where a standard science and risk-based
approach concludes that these should be
downgraded to a notification or handled
only in the PQS. This benefit would be a
reduction of the implementation timeline
from years to months with no increased
risk to patient safety.
Acknowledgements
The authors would like to thank the fol-
lowing chief quality officers (CQOs) for
their endorsement of this example and for
their continued sponsorship of the 1VQ
for PAC Initiative: Kunihiko Kokubo
(Astellas, CQO at time of completion of
example), Jackie Elbonne (Amgen), An-
thony Mire-Sluis (AstraZeneca), Oliver
Brehm (Bayer), Melissa Seymour (Bio-
gen), Lothar Halmer (Boehringer Ingel-
heim), Kerstin Koenig (Bristol-Myers
Squibb), Laura O’Brien (CSL Behring),
Valerie Brown (Gilead), Paul Daly (GSK),
Anil Sawant (Merck Sharp & Dohme
Corp.), Dirk Bissinger (Merck Healthcare
KGaA), Maria Soler (Novartis, CQO at
time of completion of example), Chris-
tine Møller-Jensen (Novo Nordisk), Andi
Goddard (Roche), Philippe Germanaud
(Sanofi), and Scott Gunther (Catalent).
The authors also wish to acknowledge
Joanna Baszczuk (Global System Owner
Change Control, GSK at the initiation of
this document) and members of the 1VQ
for PAC team who contributed to the de-
velopment of this manuscript.
References
1. ICH Q9, Quality Risk Management
(ICH, 2005).
2. ICH Q10, Pharmaceutical Quality Sys-
tem (ICH, 2008).
3. ICH Q12, Technical and Regulatory Con-
siderations for Pharmaceutical Product
Lifecycle Management (ICH, 2019).
4. E. Ramnarine, et al., PDA Journal of
Pharmaceutical Science and Technology
74 (4) 456–467 (2020).
5. E. Ramnarine and A. Vinther, PDA Jour-
nal of Pharmaceutical Science and Tech-
nology 73 (5) 517–521 (2019).
6. PIC/S, Recommendation: How to Eval-
uate and Demonstrate the Effectiveness
of a Pharmaceutical Quality System in
Relation to Risk-based Change Manage-
ment, 2021. PT

Pharmaceutical Technology  SEPTEMBER 2022 53

Outsourcing
Robust Bioanalytical
Studies Can Aid in
Regulatory Submissions
Susan Haigney
It is important to understand regulatory
requirements and study challenges to develop
and validate the appropriate methods for a
bioanalytical study program at the clinical stage.
P
harmaceutical Technology spoke
with Amy Lavelle, associate direc-
tor, Bioanalytical Lab, PPD Clin-
ical Research, Thermo Fisher Scientific,
about the challenges of performing bioan-
alytical studies and how contract research
organizations (CROs) can help mitigate
possible regulatory submission problems.
Challenges in bioanalytical studies
PharmTech: What are the challenges in per-
forming bioanalytical studies?
Lavelle: Common challenges include
supply chain issues and the availability of
proper quality reagents. As science contin-
ues to find new modalities for therapeu-
tics, complex molecular structures and
delivery systems pose challenges for the
development of specific and robust assays.
For example, in the cell and gene therapy
space, use of adeno-associated virus (AAV)
54 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m
vectors for drug delivery creates complica-
tions for immunogenicity assessment due
to the fact that pre-existing antibodies to
the viral vector make finding negative con-
trols and appropriate cut points difficult.
When evaluating low-level biomarkers,
highly sensitive assays are required, as the
assay range needs to be relative to expected
biological concentrations, which requires
appropriate reagents and equipment.
PharmTech: What are some mistakes
companies make in performing bioana-
lytical studies and/or a bioanalytical study
program?
Lavelle: The best way to avoid mistakes
is to fully understand regulatory require-
ments and the appropriate guidance to fol-
low when performing bioanalytical studies.
It’s also important to allow sufficient time
for the laboratory to develop a robust and
validated method intended for sample
analysis at the clinical stage. The type of lab
compliance and assay validation parame-
ters are key factors in ensuring the data are
fully supported for the appropriate regu-
latory submission. Utilizing a CRO that is
experienced with and knowledgeable of
agency requirements will help prevent the
sponsor from facing any submission issues.
Following regulations
PharmTech: What kind of data from bio-
analytical studies are included in regu-
latory filings?
Lavelle: This is dependent on the drug
and its mechanism of action, the proposed
indication, and the phase of the trial. Ad-
ditionally, it depends upon the history of
the data already available on the drug and
similar compounds or if the need for the
drug allows for alternatives, as is the case
with orphan status.
An investigational new drug (IND)
filing application to start human clinical
trials is used to determine if the proposed
drug is reasonably safe to administer to
humans. Regulatory agencies will review
preclinical data, such as pharmacology and
toxicology information, genotoxicity, drug
absorption and metabolism, and toxicity of
metabolites. The proposed clinical protocol
for the trial as well as manufacturing infor-
mation for the drug is discussed.
Phase I, II, and III clinical trials are per-
formed based on FDA-approved protocols.
In order to manufacture and sell the drug,
clinical test data and analysis from Phase
I–III are used in a new drug application
(NDA) to determine if the drug is safe and
effective for its context of use and if there
are any risks associated with the drug,
and if so, that the benefits outweigh any
risks. An abbreviated new drug applica-
tion (ANDA) also may be filed for generic
drugs. These data must demonstrate bio-
equivalency to the original drug.
PharmTech: How are these data compiled
SODEL VLADYSLAV - STOCK.ADOBE.COM
and presented to regulators? Is the process
different for FDA versus the European
Medicines Agency (EMA)?
Lavelle: For an FDA IND filing, data
from animal and in-vitro toxicology and
pharmacology studies are compiled with
drug manufacturing information and
clinical protocols proposed. In addition,
available clinical testing or data from for-
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Outsourcing
eign countries may be included. A pre-IND
meeting with FDA may be conducted to
ensure compliance moving forward.
Animal pharmacology/toxicology in-
formation includes a summary on phar-
macology and drug disposition, phar-
macokinetic (PK) bioanalytical data, and
mechanism of action (MOA) of the drug; a
toxicology summary, including toxicology
study design, findings, and data from toxi-
cology and toxicokinetic studies; a full toxi-
cology data tabulation; and toxicology GLP
[good laboratory practice] certification.
For an FDA NDA filing, clinical data
from human studies (Phase I–III), which
include safety and efficacy results, are
compiled and also include drug product
control, manufacturing, and stability data.
For an ANDA, bioequivalence results also
are required.
While the United States has one main
body governing drug approval, Europe
has multiple agencies, including the EMA,
the Committee for Medicinal Products
for Human Use (CHMP), and various
national health agencies. There are also
multiple registration processes in Europe,
including centralized, decentralized, mu-
tual recognition, and national. There is a ogy, expertise, and experience; regulatory
two-step process similar to the US, which knowledge; end-to-end support from trial
includes the clinical trial application, ap- design to analysis to regulatory submission;
proved at the member state level, and dedicated support groups such as quality
the marketing authorization application, control, quality assurance, data manage-
which is approved at the member state and/ ment, report writing, and statistical anal-
or centralized level. ysis; and time/cost savings. Outsourcing
PharmTech: Are data from bioanalytical frees up internal resources for alternative
studies a factor in post-marketing of ap- needs and enables sponsors to work with
proved drugs? limited dedicated internal personnel. Ca-
Lavelle: Yes, post-marketing studies are pacity and capabilities are often drivers for
often important for optimizing the drug’s outsourcing.
use. For instance, drug-drug interactions, PharmTech: How can sponsor companies
dose response, or safety studies and mor- and CROs work together to gather and
tality/morbidity studies. Other post-mar- present these data to regulators?
keting studies may be requirements set Lavelle: CROs can work with spon-
by FDA (post-marketing commitments) sors to ensure appropriate regula-
to further monitor and characterize the tory guidance and testing are being
drug’s effects and safety, such as in sub- followed for data submission, as well as to
populations. help to ensure data and reports are com-
piled in an appropriate format for submis-
Outsourcing bioanalytical studies sion. CRO labs are subject to audits by FDA,
PharmTech: What are the benefits of out- and they often have experience in their
sourcing bioanalytical studies? interactions with regulatory agencies that
Lavelle: The benefits depend on the can benefit the sponsor. Some CROs have
needs and resources of the sponsor. These regulatory compliance staff to work with
benefits can include, but are not limited to, the sponsor as they design and execute
laboratory resources including technol- their trials. PT

Manufacturing — house processes. Through technology is key to delivering life-saving medi-

Contin. from page 29
is even more critical to biopharmaceu-
tical experts than to manufacturers in
other industries.
In-house manufacturing gives the
highest amount of control and over-
sight for end-to-end bioprocesses, but
some vendors offer options that allow
for significant freedom while still
providing technical assistance. For
example, developers often have the
flexibility to choose which CMO to work
with for production after completing cell
line development and optimization and
further GMP cell banking (for master and
working cell bank production). Some ven-
dors also present multiple options for how
each project can be accomplished, which
adds transparency and gives developers
more control over which strategies and
technologies are applied.
Selected vendors also offer technol-
ogy licensing options to create a middle
ground between outsourcing and in-
licensing, biopharmaceutical organiza-
tions can access expert-designed pro-
tocols, advanced technology platforms,
and optimized materials from a vendor
for use within their own facilities with
their own team.
It is important to note that some
vendors charge licensing fees or mile-
stone payments for using their cell-line
development technology. These fees are
often based on the molecule’s success as
it progresses through the various clini-
cal phases. Other licensing agreements
may include royalty fees in which the
vendor receives a percentage of the
molecule’s annual revenues. Biophar-
maceutical developers should consider
reliable vendors that operate on a simple
fee-for-service model to maximize cost
efficiency and retain complete control
and ownership of their molecule.
Better cell lines for better therapies
Optimizing bioprocesses at every
step, including cell line development,
cines to patients with maximum speed
and quality at an accessible cost.
Biopharmaceutical companies should
answer questions about their biopro-
cess development plans as early as pos-
sible, including how they will generate
their new production cell lines, rather
than devising sub-optimal strategies
to solve problems that will undoubt-
edly arise as a result of poor plan-
ning. By dedicating time to taking
stock of their own internal capabilities,
exploring options for outsourcing,
and weighing the right priorities,
biopharmaceutical developers can give
their therapeutic molecules the best
chance of remaining viable through
every phase of development process,
manufacturing stages, regulatory
approval, and commercialization.
References
1. R.M. Lu, et al., Journal of Biomedical Science
7, 1–30 (2020).
2. B. Tihanyi and L. Nyitray, Drug Discovery
Today: Technologies 38, 25–34 (2020). PT

56 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m

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ask the expert — Contin. from page 58 Step 1
Company quality and operational management identify the
need for an audit and request the company audit cadre to
Regarding the question,how much or how little text is
prepare for the audit.
required—there is no simple answer. It depends on many
Open the request in the audit management application
factors, such as the size of your organization, how you following WI eyfds.
structure your qualit y system, or the expertise of your The audit preparation by the company audit cadre follows
personnel. A company with a staff count of five requires a WI xyzzy.
different level of detail and amount of text than a company Note: Typically, the need is identified as part of a supplier
with thousands of staff in multiple locations. assessment or as part of a deviation
Note: The right to perform an audit should be documented

A company with a staff in the quality/technical agreement with the third party
Note: The audit can be an on-site or a remote (virtual or

count of five requires a paper) audit

Then go to Step 2

different level of detail If, however, you pack the “what to do” and the “how to do”
all into one document, then this will become a large and more
and amount of text cumbersome-to-use document.
It is quite easy to change the structure of your current SOPs
than a company with into this best practice one, every time you need to revise an
existing SOP. This allows your staff to become continually
thousands of staff in more familiar with the new design and layout. And it should,
iteratively, help achieve consensus between your departments
multiple locations. as to the amount of detail required. PT

If you structure your quality system such that the SOPs Your opinion matters.
contain the “what to do” and the Work Instructions (WI) the Have a common regulatory or compliance question?
Send it to shaigney@mjhlifesciences.com, and
“how to do” information, then the description for step 1 in
it may appear in a future column.
the SOP can be as short as:

Pharmaceutical Technology  SEPTEMBER 2022 57

ask the expert

Best Practices for Developing

a Third-Party Auditing SOP
A process flow diagram can help create an agreed-upon process flow for a
third-party standard operating procedure, says Siegfried Schmitt, VP Technical at Parexel.

Q. During the periodic review of our ‘Third-Party

Auditing’ standard operating procedure (SOP),
the quality and the operational teams could not agree on the
contents. Some wanted more detail, others less. What best
practices can you recommend?
Best practices take this into account. Thus, a SOP shall
be based on an agreed process flow. Unfortunately, all too
often process flows are an afterthought when the SOP has
already been written. It is rarely easy or even possible to
create a process diagram based on existing text. The opposite,

A. Quality systems evolve, and this evolution brings changes to

the contents of the documents, such as SOPs. The regula-
tions do not demand effective and efficient systems and instruc-
tions, but this of course is in the interest of any company. They do,
however, require that activities that must comply with the laws
and regulations are documented. Before starting to write any text,
please remember:
• All activities that form part of a quality system can be
described as processes.
• All processes can be described in a process flow diagram.
• The description of the activities, roles and responsibilities,
and associated data and documents are associated with
specific process steps.
however, is straightforward.
Let us therefore look at the example of your third-party
auditing SOP. First, you need to prepare a process flow
diagram. A generic example is given in Figure 1.
Based on this process flow, you can now start writing,
detailing the activities. As you can see, the steps are
numb ere d. T his numb ering e s t ablishe s a c onnec tion
bet ween the text and the graphic; allowing anyone to
quickly find the information either in the process diagram
or the instructions.
Contin. on page 57

Figure 1. Process flow diagram for a third-party auditing standard operating procedure.

Prepare for audit Confirm & communicate

1 critical finding
4

yes

Potential critical Prepare & issue

Conduct audit no Follow-up on audit
observation noted audit report
2 6
during audit? 5
3

Escalate overdue or inadequate

responses, corrective & preventive Responses
no
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action (CAPA) plans & acceptable?

FIGURE COURTESY OF THE AUTHOR

Effectiveness checks 7
8

yes

Audit process complete

& documents archived
9

58 Pharmaceutical Technology  SEPTEMBER 2022 P h a r mTe c h . c o m

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