BUILDING BETTER MANUFACTURING FACILITIES - PHARMTECH
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APRIL 2020 Volume 32 Number 4
Building Better
Manufacturing Facilities
Development
Accelerating Vaccine Development
Optimizing Drug Delivery
Manufacturing
HPAPI Tabletting Safety
Quality/Regulations
Supplier Oversight
Analytics
Cleaning Validation
Operations
Cold-Chain Packaging
Outsourcing
Continuous Bioprocessing
Peer-Review Research
Identifying Impurity in Topical Gel
9th - 11th September | Philadelphia
April 2020
Pharmaceutical Technology Europe is the authoritative Advancing Development & Manufacturing
source of peer-reviewed research and expert analyses for
scientists, engineers, and managers engaged in process PharmTech.com
development, manufacturing, formulation and drug
delivery, API synthesis, analytical technology and testing,
packaging, IT, outsourcing, and regulatory compliance Cover: nasir1164 - Stock.adobe.com
in the pharmaceutical and biotechnology industries. Art direction: Maria Reyes
36 16 9 26
PharmTech.com
Features OPERATIONS
29 Packaging Preserves the Cold Chain
COVER STORY: MANUFACTURING More sustainable and functional
9 Building Better Manufacturing Facilities cold-chain packaging protects biologics
Whether refitting existing spaces or building and other temperature‑sensitive drugs.
new, the need for quick build times, flexibility,
QUALITY/REGULATIONS
and production efficiency is driving trends
33 Being Vigilant in Supplier Oversight
in bio/pharma facility construction.
Risk assessments, audits, and good
DEVELOPMENT communication between sponsor and
13 Can Vaccine Development supplier are key elements of supplier oversight.
Be Safely Accelerated?
OUTSOURCING
Biopharma companies responding to the
36 Biomanufacturing: Demand
COVID-19 outbreak think accelerating the
for Continuous Bioprocessing Increasing
development of vaccines is safe.
But are innovations sufficient to increase
adoption? CMOs are demanding better
16 Delivering the Goods
continuous bioprocessing options.
The new molecules entering the
development pipeline are bringing forth ANALYTICS
exciting challenges in drug delivery. 39 Alternative Cleaning Validation
Methods for Biologics
MANUFACTURING
Because conventional cleaning methods
26 Understanding Containment for Tabletting
can risk product loss, biopharmaceutical
Risk levels should be considered when
manufacturers are often reluctant to use
designing equipment to enhance operator safety.
PDE/ADE limits to validate cleaning processes.
Peer-Review Research Columns and Regulars
5 Editor’s Comment
20 Identifying the Structure of an Making Every Effort
Unknown Impurity in a Topical Gel 6 European Regulatory Watch
This case study highlights analytical instrumentation Learning Lessons in Crisis Management
and techniques that were used to identify
an unknown impurity detected during routine 41 Ad Index
release testing of a topical gel drug product. 42 Ask the Expert
Critical Knowledge for Preparing Audits
Pharmaceutical Technology Europe APRIL 2020 3
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PharmTech Group PharmTech Europe
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Reinhard Baumfalk Luigi G. Martini
Rita Peters Felicity Thomas
RPeters@mjhlifesciences.com FThomas@mjhlifesciences.com Vice-President, R&D Chair of Pharmaceutical
Senior Editor Publisher Instrumentation & Control Innovation
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Managing Editor Sales Manager
Linda Hewitt Director of Quality Systems Menzel Fluid Solutions AG
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Tel. +44 (0) 151 705 7603 Boehringer Ingelheim GmbH
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LHewitt@mjhlifesciences.com
Manufacturing Editor Phil Borman, DSc Founder and Former President,
Senior Sales Executive
Jennifer Markarian Stephen Cleland Director, PharmSource,
JMarkarian@mjhlifesciences.com Tel. +44 (0) 151 705 7604 Product Development & Supply A Global Data Company
Science Editor SCleland@mjhlifesciences.com Medicinal Science & Technology
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Sales Operations Executive
FMirasol@mjhlifesciences.com Barbara Williams GlaxoSmithKline Senior Director
BWilliams@mjhlifesciences.com Pharmaceutical Sciences
Assistant Editor Evonne Brennan
Lauren Lavelle VP & Managing Director, Shire Pharmaceuticals
LLavelle@mjhlifesciences.com MJH Life SciencesTM International Technical Marketing
Dave Esola Manager, Pharmaceutical Clifford S. Mintz
Senior Art Director
Marie Maresco
C.A.S.T. Data and List Information Division, President and Founder
Michael Kushner
IMCD Ireland BioInsights
Graphic Designer MKushner@mjhlifesciences.com
Maria Reyes Rory Budihandojo Tim Peterson
Director, Quality and EHS Audit Transdermal Product
Boehringer-Ingelheim Development Leader, Drug
MJH Life SciencesTM Vice President, Human Resources Christopher Burgess Delivery Systems Division, 3M
Chairman and Founder & Administration
Managing Director John Pritchard
Mike Hennessy, Sr Shari Lundenberg
Burgess Analytical Consultancy Technical Director
Vice Chairman Vice President, Business
Jack Lepping Intelligence Ryan F. Donnelly Philips Respironics
President and CEO Chris Hennessy Professor Thomas Rades
Mike Hennessy, Jr Vice President, Marketing Queens University Belfast Professor,
Amy Erdman
Chief Financial Officer Tim Freeman Research Chair in Formulation
Neil Glasser, CPA/CFE Executive Creative Director, Design and Drug Delivery,
Creative Services
Managing Director
Executive Vice President, University of Copenhagen
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Enterprise Systems Siegfried Schmitt
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John Moricone
Ch65 9HQ, United Kingdom Vice‑President Technical
Senior Vice President, Audience Tel. +44 151 705 7601 Anne Marie Healy
Generation & Product Fulfillment
PAREXEL
Professor in Pharmaceutics and
Joy Puzzo Stane Srcic
Pharmaceutical Technology
Trinity College Dublin, Ireland Professor
University of Ljubljana, Slovenia
Deirdre Hurley
Senior Director, Plant Griet Van Vaerenbergh
Helsinn Birex GEA Process Engineering
Pharmaceuticals Ltd. Benoît Verjans
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4 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com
EDITOR’S COMMENT
Making Every Effort
W hile the majority
of the world is in
isolation to try to slow
Regulatory response
The global pandemic of COVID-19
has been pushing the boundaries of
that are not yet proven to be effective in
the treatment of COVID-19. As reported
by The Guardian people suffering from
the spread of the virus regulatory possibilities both within lupus are now facing empty pharmacy
responsible for COVID- Europe and around the rest of the world. shelves that would normally contain a
19, companies and Guidance on how to best manage clinical vital medicine used for their treatment,
regulatory bodies in the trials in the current situation, deferral of hydroxychloroquine (3). The emptying of
bio/pharma industry non-essential inspections, prioritization the shelves can be attributed to the, as
are facing numerous of COVID-19 treatment applications, of yet unproven, link with the drug having
challenges and committing significant expediting applications, and funding efficacy in the treatment of COVID-19.
efforts to support the development of novel are some of the measures being taken Therefore, in this current climate, it
therapeutics and monitor supply chains. by European authorities to support the is imperative that pertinent scientific
industry. information that can be of reassurance
Drug and vaccine development These practical measures being and informative be disseminated
According to the European Federation of implemented by European regulatory with due diligence and care. So, in
Pharmaceutical Industries and Associations enforcers have undoubtedly been more addition to thanking all those working
(EFPIA), its members are actively engaged in easily formulated as a result of lessons tirelessly to develop potential vaccines
the development of collaborative research learned from previous outbreaks. In this and treatments, the Pharmaceutical
programmes that will assist in accelerating issue’s European Regulatory Watch (pages Technology Europe team invites you to
the advancement of therapeutics for 6–8), Sean Milmo delves into this topic in keep up-to-date with industry efforts via
COVID-19 (1). Some examples of work being more detail, looking at specific examples our website, www.PharmTech.com where
performed by EFPIA member companies from past outbreaks and how closer there will be regular COVID-19 coverage
in tackling the COVID-19 outbreak relationships built up by agencies in spanning drug development, research,
include: companies, such as Bayer and Europe with companies and researchers supplier news, and regulatory updates.
GlaxoSmithKline, joining the COVID-19 is advantageous for the current situation. Stay safe and healthy.
Therapeutics Accelerator Initiative and
opening up compound libraries; the Supply chain concerns References
donation of supplies, such as Merck’s Another important aspect being looked 1. EFPIA, “European Pharmaceutical Industry
donation of interferon beta-1a, to be used at by regulatory bodies and industry Response to COVID-19,” efpia.eu, Press
in clinical trials; provision of expertise associations, which has the potential Release, 25 Feb. 2020.
and advice to relevant stakeholders; and to be detrimentally impacted by the 2. Pharmaceutical Technology Editors, “Indian
leveraging previous vaccine development COVID-19 pandemic, is that of supply Government Restricts Export of APIs and
work to potentially enable a more rapid chain. For example, industry concerns Formulations Due to COVID-19,” PharmTech.
development of a COVID-19 vaccine, such were raised when the Indian government com, 6 March 2020.
as work being done by Sanofi (1). revealed it would be restricting the export 3. The Guardian, “Vital Drug for People with
Some notable drugs and vaccines for of 26 APIs and formulations, including Lupus Running Out After Unproven COVID-19
COVID-19 in development are: paracetamol, progesterone, and vitamin Link,” theguardian.com, 27 March 2020. PTE
• Messenger RNA vaccines, from CureVac B12, as a result of COVID-19 early in
and BioNTech, are in preclinical stages. March 2020 (2).
• Remdesivir, from Gilead Sciences, And, it isn’t just trepidations around Felicity Thomas
originally developed to treat Ebola, is in the availability of ingredients, there is Editor of Pharmaceutical Technology Europe
Phase III clinical trials. also the added issue of hoarding drugs FThomas@mjhlifesciences.com
• SNG001, from Synairgen Research, is an
inhaled formulation of interferon-beta-1a
that is entering Phase II clinical trials.
Join PTE’s community
Join the Pharmaceutical Technology Europe group on LinkedIn™* and start discussing the issues
• Chloroquine and hydroxychloroquine are that matter to you with your peers.
currently being investigated in clinical Go to PharmTech.com/linkedin
trials and are being donated by various
companies for evaluation. *The linkedIn logo is a registered trademark of LinkedIn Corporation and its affiliates in the United States and/or
other countries
Pharmaceutical Technology Europe APRIL 2020 5
EUROPEAN REGULATORY WATCH
Learning Lessons
in Crisis Management
Regulatory emergency planning has been put to the test with the COVID-19 pandemic.
E uropean medicine regulators have, over the
past few decades, been drawing up a series of
detailed plans for the emergency development and
Disease Prevention and Control commented in a bulletin
on 12 March 2020 (3). “In addition, there is presumably
no pre-existing immunity in the population against the
mass‑scale production of vaccines, antivirals, and other new coronavirus and everyone in the population is
medicines, as well as diagnostics to combat epidemics assumed to be susceptible.”
or pandemics. Regulatory bodies have been confronted Fortunately, regulators had learned a lot from other,
by a range of diseases from outside Europe, such as smaller-scale, outbreaks, particularly those of swine flu
severe acute respiratory syndrome (SARS) in 2002, in 2009 and the 2014–2016 wave of the Ebola virus. The
H5N1 and H7N9 bird flues in 2003 and 2013, Middle East European Medicines Agency (EMA), responsible for the
Sean Milmo is a
respiratory syndrome (MERS), and H1N1 swine flu in EU’s central medicines authorization process and for
freelance writer based in
2009. Among the most dangerous has been the Ebola coordinating the EU’s medicines licensing network down
Essex, UK, seanmilmo@
virus, which first appeared in 1976 and still has not been to national level, performed “lessons to be learned”
btconnect.com.
completely eradicated (1). exercises after the swine flu and Ebola episodes.
Most of these infectious diseases have high death Swine flu highlighted the importance of providing a
rates—from 10% for SARS to 53% for H5N1 flu—but scientific platform for quick research into new vaccines
have a relatively low transmission level. Although posing and medicines, working closely with partners such as
major threats to the health of the region, they have not public health agencies, and improved collaboration
had a major impact on Europe. with international organizations active both inside and
However, the novel coronavirus disease, COVID-19, outside Europe.
which emerged in China in late December to become a The regulatory effectiveness of the current response
pandemic with over 600,000 cases and close to 30,000 to COVID-19 has been helped by closer relationships
deaths globally by 29 March 2020 (2), has been an built up by medicines agencies in Europe with
entirely different matter. With a high transmission rate researchers and drug companies working on new
and a relatively low death rate, it has changed the whole medicines. Regulators now frequently become involved
regulatory process of dealing with sudden pandemics. at an early stage in the development of new drugs to
speed up time-to-market.
A massive challenge As a result, many of the companies submitting
In Europe, COVID-19 has been a massive challenge to candidates for anti-COVID-19 vaccines and medicines
national healthcare services, public health policies, and for approval are already known to regulators, who have
scientists striving to develop vaccines and medicines often been acquainted with the technologies behind
to fight the virus as rapidly as possible. The carefully them as well.
worked out emergency-response plans of the regulators
to help bring new vaccines and medicines to the market An international dimension to research
has been severely tested. Regulators are having to cope with a growing
By late March 2020, Europe had become the global international dimension to the emergency research
epicentre of the outbreak when growth in infections into new vaccines and therapeutics, whose ultimate
in China started to slow and cases in the World Health objective is to bring to the market as quickly as possible
Organization’s (WHO’s) European Region rose to more products with a potential for global application. National
beugdesign - Stock.adobe.com
than 360,000 with over 20,000 deaths (2). agencies are tending to play a limited role amid this
“There are no vaccines available (for COVID-19), and drive to globalize anti-COVID-19 vaccines and medicines
there is little evidence on the effectiveness of potential with availability across Europe being only the first move
therapeutic agents,” the EU’s European Centre for to a worldwide market.
6 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com
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European Regulatory Watch
CureVac, a German biotech company based at Tuebingen, large-scale GMP production in Europe, we plan to seek
which is developing a messenger RNA (mRNA) vaccine MHRA and then EMA approvals.”
against COVID-19, is already known to German and EMA However, similar to a lot of other European companies
regulators because of its progress with work on a rabies developing vaccines and COVID-19 therapeutics, Stabilitech is
vaccine, company officials said in a phone press conference looking to China as a fast-track option for global distribution.
on 17 March 2020 (4). After the COVID-19 outbreak, It has already established links with the Chinese Academy of
CureVac’s mRNA technology quickly made it a frontrunner Sciences, the country’s leading research institute.
for the development of a global coronavirus vaccine, a role in
which it is competing with BioNTech, another German mRNA An alternative distribution route
specialist. Another route to global distribution is being provided by
The attraction of the CureVac and other mRNA WHO, which has been playing a major role in controlling
technologies is that its production can be scaled up without the pandemic. WHO quickly published an updated
difficulty to good manufacturing practice (GMP) standards version of its Emergency Use Listing (EUL) procedure for
to produce low-cost vaccines that can be relatively easily emergency distribution of unlicensed products two days
stored and distributed without the need for refrigeration. after the Chinese announced the genome sequence for
Messenger RNA vaccines have the added advantage of the COVID-19 virus in early January 2020. The new version
being effective in small doses, and they can be modified simplified the EUL application process for manufacturers
fairly quickly to counter new strains of a virus. after it resulted in no new vaccines or therapeutics being
With vaccines based on more traditional technologies listed in the 2014–2016 Ebola outbreak (7).
necessitating refrigeration, European regulators have pointed Unlicensed vaccines, medicines, and in-vitro diagnostic
to the problem of storing and administering investigational devices on the list can be made available throughout
products to clinical trial participants who have had to self- the world. Under the scheme, which is part of the 2005
isolate. With the early backing of regulators, CureVac’s International Health Regulations backed by all 194 WHO
COVID-19 vaccine seems destined to reach the market member countries, dossiers on products submitted for
quickly. Clinical trials are due to start in the summer 2020 (4). listing are thoroughly assessed by an expert committee,
Senior company executives met Ursula van der Leyen, with the first endorsements likely to be made in March or
the European Commission’s (EC’s) president, in March 2020. April 2020 (7).
This was followed by the commission offering an €80 million The EUL is seen by WHO as a process running parallel with
(US$97 million) grant for the building at Tuebingen of a mass those operating in individual countries or regional entities,
production plant for the vaccine (5). Also in March 2020, such as the EU, and as a result should not interfere with
company executives met in Washington, DC with President ongoing clinical trials (7). Additionally, WHO stresses that EUL
Donald Trump and members of his administration. This inclusion is not equivalent to authorization by a medicines
meeting prompted media reports of an American plan to buy licensing agency (7).
all of CureVac’s COVID-19 vaccine output or even to acquire The organization also refers to the EUL scheme covering
the whole company, all of which has been strongly denied by one or more additional waves of COVID-19. Both itself and
CureVac executives. other medicines and public health agencies are preparing for
Even for small companies, such as the UK-based start-up COVID-19 to be around for some time.
vaccine developer and producer Stabilitech, national
regulatory approval of their COVID-19 vaccine is regarded as References
merely a stepping-stone to global distribution. A global goal 1. WHO, “WHO Recommended Criteria for Declaring end of the
is especially the case for UK-based companies because the Ebola Virus Disease Outbreak,” who.int, Technical Information
country formally left the EU on 31 January 2020 and, hence, Note, 4 March 2020.
also left the EU’s medicines licensing network. 2. WHO, “Coronavirus Disease 2019 (COVID-19): Situation Report,
Prior to the COVID-19 pandemic, Stabilitech’s technology 69,” apps.who.int, 29 March 2020.
platform was already known to the UK’s Medicines and 3. ECDC, “Rapid Risk Assessment: Novel Coronavirus Disease
Healthcare products Regulatory Agency (MHRA) because of 2019 (COVID-19) Pandemic: Increased Transmission in
the company’s plans for authorization of a vaccine against the EU/EEA and the UK—Sixth Update,” ecdc.europa.eu,
the Zika virus (6). The company has developed a formulation 12 March 2020.
technology that enables vaccines to be produced in 4. CureVac, “Conference Call on Current Developments,”
temperature-resistant capsules, simplifying distribution and curevac.com, 17 March 2020.
administering to patients. 5. EC, “Coronavirus: Commission Offers Financing to Innovative
“Before COVID-19, we have been talking a lot to MHRA Vaccines Company CureVac,” ec.europa.eu, Press Release,
about our Zika vaccine, whose technology is similar to that 16 March 2020.
for our COVID-19 vaccine,” Jeff Drew, Stabilitech’s chief 6. WHO, “Zika Epidemiology Update,” who.int, 2 July 2019.
scientific officer, told Pharmaceutical Technology Europe. 7. WHO, “Emergency Use Listing Procedure—Version 9 January
“After clinical trials and completion of arrangements for 2020,” who.int, 9 Jan. 2020. PTE
8 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com
Building Better
Manufacturing Facilities
Whether refitting existing spaces or building new, the need for quick build times,
flexibility, and production efficiency is driving trends in bio/pharma facility construction.
Jennifer Markarian
I n adding manufacturing capacity—whether through
new, greenfield sites or by retrofitting existing
spaces—biopharma and pharma companies seek
containment and cleaning operations are other active
areas in OSD, he adds.
An ongoing drive toward closed processing simplifies
flexible and efficient production. Getting a facility up facilities and allows lower room air cleanliness
and running quickly with a tight budget is increasingly classifications, which corresponds to savings in capital
important. and operational costs, adds Eric Bohn, partner at
Flexibility is crucial in biopharmaceutical JacobsWyper Architects. Similarly, the smaller equipment
manufacturing, because companies increasingly have associated with continuous processing and the smaller-
multiple modalities (e.g., monoclonal antibodies, cell scale processing associated with advanced therapy
therapies, and gene therapies) in their pipelines. New medicinal products (ATMP) result in smaller production
biopharma facilities often use single-use technology, suites that are easier to support and operate, says Bohn.
and modular buildings and systems are becoming “Facilities are being more closely tailored to the needs of
more popular. the process,” he notes.
“The biggest challenge is to map the current need
for flexibility in manufacturing processes to the Renovating facilities
facility,” says Stefan Kappeler, technology manager for In the past year, multiple life-sciences companies
life sciences at Exyte. He notes that facilities must be have updated or expanded manufacturing capacity
prepared for changes in process flow, in scale, and in by renovating existing facilities. In the United States,
manufacturing technologies. GlaxoSmithKline (GSK), for example, completed a
Flexibility is important in oral solid dosage drug (OSD) retrofit of its Rockville, MD site in October 2019 that
manufacturing, as well. Manufacturers are seeking increased capacity for its injectable drug Benlysta
to “right size” their operations and capacity based on (belimumab) and involved demolition of existing suites
their product portfolios and to upgrade processes, and installation of new equipment (1). The company
nasir1164 - Stock.adobe.com
equipment, and technology for improved efficiency and also renovated its Upper Merion, PA site and updated
faster product changeovers, notes Dave DiProspero, laboratory and manufacturing capabilities, including
director of pharmaceutical process technology at adding single-use bioreactors (2). A nearby, former GSK
CRB. Improving equipment and facilities for product facility is being transformed into The Discovery Labs
Pharmaceutical Technology Europe APRIL 2020 9Cover Story: Manufacturing Trends
biotech campus, which announced in to build their own capacity using industry is changing, agrees Noel
January that it would be the home of modular, box-in-box facilities that can Maestre, Life Science Core Team
The Center for Breakthrough Medicines, be delivered in a year or less. leader at CRB. “These novel therapies
a new contract development and “In many cases, having a facility are quickly proving a need for process
manufacturing organization for cell and up-and-running and licensed may be closure and automation, which in
gene therapies (3). the critical path to gaining approval for turn is driving equipment vendors
Renovating an existing facility can a new product. As such, site startup to create and test novel equipment
save time compared to a greenfield timing is critical,” says Mitch Lower, solutions,” notes Maestre.
site, where approvals can be complex vice-president of global engineering for
and potentially last a year or more, AveXis, a Novartis company specializing OSD trends
says Bohn. Although renovations in gene therapies. The company In OSD manufacturing, facility
typically have costs for demolition, received an honourable mention in layout is becoming more important
waste disposal, and the need to bring the 2019 International Society for as equipment and processes are
roof structures up to current building Pharmaceutical Engineering (ISPE) moving toward greater integration,
codes, for example, a significant Facility of the Year Awards (FOYA) for says DiProspero. Continuous
cost savings is often found in site being one of the first companies to manufacturing and processes such
infrastructure, he notes. scale up a gene-therapy manufacturing as direct compression, which are
“The most common refurbishments process and doing so on a short growing in use, are examples of
we see are from mothballed timeline. To build its Libertyville integrated systems, but integrating
facilities,” says John Noble, vice- site near Chicago, IL, AveXis used unit operations is also preferred in
president and general manager, G-CON Manufacturing’s prefabricated more traditional OSD processes.
life sciences, at Jacobs. “If you cleanroom PODS—built off-site in “A typical integrated equipment
can start with a building shell that parallel with facility construction— train will incorporate material
accommodates your process and which expedited startup. handling, high shear granulation,
meets planning needs, you can save AveXis also purchased and wet milling, fluid bed drying, dry
nine-plus months in construction.” refurbished a facility in Longmont, milling, and granulation collection in
Facility refurbishment and CO in 2019 to add manufacturing a linked, semi-continuous contained
renovations represent more than capacity. The facility is operational operation,” explains DiProspero.
60% of Fluor’s work, adds Dave and is undergoing the remaining Efficient product flow is crucial.
Watrous, vice-president, advanced steps to become licensed, which the “Good facility design is marked by
technologies and life sciences, Fluor company expects to occur in 2021. uninterrupted uni-flow process
Corporation. Reconfiguring existing A facility the company is building in direction, with appropriate hold
life-sciences manufacturing space North Carolina is also anticipated to and work-in-progress spaces and
or using suitable vacant buildings for become licensed in 2021. minimization of cross/backflow.
a box-in-a-box approach can both “There are benefits and challenges Specifically, modern washing
accelerate speed to market. to both purchasing an existing facility operations make use of a dirty-
and building a new facility,” says wash-clean uni-flow arrangement for
ATMP capacity crunch Lower. “Purchasing an existing facility improved efficiency and compliance.”
Speed is crucial in biologics may be more cost effective and Modular and prefabricated
manufacturing, especially in the have an expedited startup schedule. construction is being used in
fast-growing cell therapy and gene However, the existing infrastructure OSD manufacturing. “This type of
therapy industry as products are and facility layout may drive additional construction is well suited for powder
reaching clinical phase and there is a costs to retrofit to accommodate the processing operations due to good
lack of manufacturing capacity. necessary manufacturing process. cleanability, visual aesthetics, and
“For manufacturing these When building a completely new the ability for use of glass to bring
advanced therapies, CDMOs [contract facility, the timeline may be longer; light into the spaces and provide
development and manufacturing however, you will have the flexibility for a user/operator-friendly working
organizations], can be scheduling six to build the facility to meet the environment,” says DiProspero.
to 18 months out, and this wait time needs of your unique and novel
is disruptive to a company’s go-to- manufacturing processes.” Modular approaches
market strategy,” says Joe Makowiecki, Although AveXis is today mainly using Modular approaches are transforming
Enterprise Solutions director of manual processes, it is moving towards the way the industry builds facilities.
business development at GE Healthcare automation in its existing and new Both modular design methods using
Life Sciences. He says that despite equipment and facilities, says Lower. standardized templates and modular
CDMOs adding capacity, many cell and The lack of automation that is construction methods for buildings
gene therapy companies are deciding currently common in the novel ATMP and systems can improve speed
10 Pharmaceutical Technology Europe APRIL 2020 PharmTech.com| Your molecule Our mission Drug substance | Drug product | Analytical services Discover why we’re the small molecule company, with end-to-end capabilities and experts you’ll enjoy working with. Jesper Kumlin Process Op erator www.cambrex.com
Cover Story: Manufacturing Trends
to market, says a report by the reports that it has sold close to 70 Standardized equipment improves
BioPhorum Group (4). FlexFactories globally to date. Four speed to market. For example, WuXi
Modular construction includes of these FlexFactories were installed Biologics moved from purchase order
factory-fabricated utility skids, wall inside of the company’s KUbio facility, of the Vanrx workcell to their first GMP
panels, or entire rooms or building which is the FlexFactory inside of a batch release in only 15 months, says
sections, which can save time and modular, prefabricated facility. Pfizer’s Procyshyn. Placing standardized filling
improve quality and construction Biotechnology Center located in machines inside a modular cleanroom
safety, explains Bohn. He points Hangzhou, China, for example, is a further increases speed, he adds.
out that, although the initial cost of KUBio facility, and it won an ISPE FOYA The Microcell POD is an integrated
modular construction is typically more 2019 award for project execution. solution from Vanrx and G-CON
than that of field-built alternatives, the In 2019, GE Healthcare launched that meets the “increasing industry
savings that comes from a shortened the KUBio Box for viral-vector-based need for rapidly deployable turnkey
timeline is quantifiable. Factory gene therapy manufacturing; in this aseptic filling capability for small
testing reduces problems in the field box-in-box approach, the FlexFactory batch therapies, specifically in the
and makes commissioning, validation, platform in a modular cleanroom cell and gene therapy space,” adds
and start-up faster. facility is intended to be placed Powers. Standardization lends itself
G-CON’s PODs, for example, are inside a new or repurposed space or to “scaling out” rather than “scaling
prefabricated, autonomous, plug-and- shell-building. The KUBio box for viral up.” The standard POD design can
play cleanroom environments, which vectors is a cGMP, biosafety level 2 be replicated to rapidly increase
can be installed within an existing modular facility solution. manufacturing capacity, he notes.
facility or as part of new greenfield “We’re also having discussions
construction, for any type of bio/ around building biomanufacturing Collaborating on integration
pharma manufacturing, including campuses and shell facilities to house Although standardizing improves
OSD, aseptic filling, and cell and gene the modular boxes. A best practice quality and speed, integration of the
therapy, says Dennis Powers, vice- approach here is to build for what equipment into the facility building
president of business development and you need today but allow for enough is still important. For example, in
sales engineering at G-CON. The mobile space in your facility or facility shell to building the Bayer facility in California
facilities provide flexibility because they expand,” explains Makowiecki. in 2019 using GE’s FlexFactory, Fluor’s
can be transported anywhere to quickly Makowiecki also expects the team helped design the optimal
add or subtract capacity. KUBio box offering will expand into people, product, and material flows
Modular construction started out in additional product modalities and around the established FlexFactory
the bio/pharma industry for building biomanufacturing scales. set-up, and then integrated these
infrastructure in developing countries flows in the building envelope and
with a lack of skilled construction Standardizing associated utilities and infrastructure.
capabilities, but now speed is the Standardization of facility modules, This collaborative process with an
primary driver. “Modular construction equipment, unit operations, integrated end result reflects the
and prefab cleanrooms are often must- automation, and consumables are future of the industry, says Watrous.
have components in any new facility. essential to the speed of deploying
Even in very mature market locations, modular facilities and efficient and References
these strategies help simplify and effective technical transfer. These 1. PharmTech, “GSK Completes Retrofit
accelerate the market delivery strategy capabilities support the trend to of Maryland Facility,” PharmTech.com,
for most products,” adds Watrous. distributed manufacturing, with the 4 Oct. 2019.
“The modular facility concept same company manufacturing a drug 2. GSK, “GSK Invests $120 Million in Next-
is a paradigm shift that provides in multiple regions rather than one Generation US Biopharmaceutical
companies with options for centralized location, notes Makowiecki. Manufacturing Facility,” Press Release,
establishing rapid and flexible “Standardized, closed systems 25 Sept. 2019.
in-house production,” says provide optimal aseptic processes 3. The Discovery Labs, “The Center for
Makowiecki. “With standardized, that support very high drug product Breakthrough Medicines is Building the
modular systems, typically 80% of quality,” adds Chris Procyshyn, World’s Largest Cell and Gene Therapy
the design work has been completed, CEO and co-founder of Vanrx CDMO to Launch in King of Prussia,
which reduces design time and Pharmasystems, which makes closed PA,” Press Release, 23 Jan. 2020.
results in faster speed to delivery,” robotic workcells. He notes that other 4. BioPhorum Group, “Improving the
explains Makowiecki. industries rely on standardization for Biomanufacturing Facility Lifecycle using
GE Healthcare’s FlexFactory is a reliability and safety, and he says that a Standardized, Modular Design, and
modular end-to-end biomanufacturing the pharma industry needs to move Construction Approach,” White Paper,
platform, and the company to this model. June 2019. PTE
12 Pharmaceutical Technology Europe APRIL 2020 PharmTech.comimmune system protects against viral
infections and can rapidly identify the
critical parts of a new virus to target for
vaccine development,” he says.
Platform
technologies are ideal
Traditional vaccines, like the seasonal
flu vaccine, are made by growing up
large quantities of the virus and in some
way killing or inactivating it so that it
can be used safely as a vaccine. This
approach is an old technology from the
middle of the past century, according
to von Hofe. “The main problem here
Can Vaccine Development is the time it takes to produce the
vaccine, which is at least a year and
Be Safely Accelerated?
can be several. Ideally, we’d have a
platform technology that could be used
to produce a vaccine in a few months,”
Biopharma companies responding to the COVID-19 outbreak he observes.
think accelerating the development of vaccines is safe. Such technology platforms should
be flexible enough to respond to any
new viral threat. “We would like to
Cynthia A. Challener
is a contributing editor to
Pharmaceutical Technology
H uman coronaviruses (HCoVs) in the past were considered to cause
nothing more than the common cold in healthy people. That changed
with the advent of severe acute respiratory syndrome coronavirus
have a simple ‘plug-and-play’ setup
where the critical components of a
new virus required to make the vaccine
Europe. (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) can be determined by rapid computer
in the past decade. The latest coronavirus—2019-nCoV, since renamed by analysis and plugged into the platform
the World Health Organization as COVID-19—emerged in December 2019 in to generate a vaccine,” von Hofe notes.
Wuhan, China. As of late February 2020, it had sickened tens of thousands “Getting all of the critical components
and killed nearly 3000 people. produced and structured in a way that
Four of these large, enveloped, positive-strand RNA viruses are endemic perfectly models the vaccine is the big
globally and thought to cause 10–30% of upper respiratory tract infections challenge,” he adds.
in adults (1). They possess a surface spike (S) glycoprotein that binds to host
cell receptors, and the nature of this protein is believed to determine the A reductionist
main properties of each coronavirus. SARS-CoV was the first coronavirus to approach is best
jump from animals to humans; MERS-CoV and COVID-19 have as well. The best way, von Hofe says, is to
The genetic sequence for COVID-19 was released to public databases follow a reductionist strategy to
on 10 January 2020 by the Shanghai Public Health Clinical Center & identify key viral components that
School of Public Health (1). The three-dimensional (3-D) structure of the alone produce complete protection
spike protein suggests that it binds more tightly to human cell surface in a safe vaccine that can be
receptors than SARS-CoV, a possible reason that this coronavirus exhibits manufactured rapidly and in a cost-
greater infectivity (2). effective manner. “Clearly this is a tall
Platform diagnostic methods have been rapidly adapted to include order, but we’re making good progress
COVID-19 for early identification of cases. Several academic and industrial in that direction,” he asserts.
researchers have also focused on applying novel vaccine development As an example, he points to the
and manufacturing platforms to the accelerated development of a development of subunit vaccines that
COVID-19 vaccine. rely on recombinant DNA to encode
In terms of vaccine development and protection against dangerous a critical subunit of the vaccine that
viral pathogens, there is nothing particularly unique about coronaviruses, generates a response. There are
Mongkolchon - Stock.adobe.com
according to Eric von Hofe, chief scientific officer of NuGenerex Immuno- additional challenges to this approach,
Oncology. “All of the recent potentially pandemic viruses, including SARS however. “While responses can be
and MERS and two flu viruses (avian and swine flu), have the common produced, the protection may be
feature that they simply had never been seen before by the human short-lived, as there is no guarantee
immune system. That said, we now know a lot about how the human that immunological memory will be
Pharmaceutical Technology Europe APRIL 2020 13Development
generated as is possible with a whole (CEPI). The collaboration with Beijing new vaccine. The rapid discovery
virus vaccine,” von Hofe comments. Advaccine is anticipated to accelerate approach and the manufacturing
developed on INO-4800 in China by agility of mRNA vaccine design and
The DNA approach providing access to not only its vaccine production also make it an effective
against COVID-19 expertise, but also its relationship platform technology.
San Diego, CA, USA-based Inovio and experience with Chinese Just 42 days after sequence
Pharmaceuticals is one company regulatory authorities and clinical trial selection, Moderna shipped the first
developing a DNA-based vaccine management in the country. batch of mRNA-1273 to NIAID for use
against COVID-19. The biotech was the in a planned Phase I clinical study in
first to advance a vaccine (INO-4700) Prophylactic mRNA Vaccines the US. The mRNA vaccine encodes
against MERS-CoV into human testing Two companies, both also supported for a prefusion stabilized form of the
and is currently preparing to initiate a by grants from CEPI, have developed COVID-19 S protein.
Phase II trial for INO-4700 in the Middle platform technologies based on German biotech CureVac also has an
East. This vaccine, however, cannot be messenger RNA (mRNA). Cambridge, mRNA platform technology for vaccine
used against COVID-19 because the two MA-based Moderna—which has development and manufacturing suited
coronaviruses are too different. developed numerous prophylactic for rapid response to viral outbreaks,
To develop a new vaccine, Inovio mRNA vaccines with positive Phase it says (6). Using an extensive in-house
first converts the virus’ RNA into I clinical readouts and also has a nucleotide sequence library, CureVac is
DNA and identifies short sections fully integrated clinical-material able to identify optimum sequences for
that will, according to computer manufacturing site—is progressing its any given vaccine target and eliminate
simulations, generate the greatest COVID-19 vaccine candidate (mRNA- the need for chemical modification,
immune response. The plasmids are 1273) into the clinic (4,5). The Vaccine shrinking the development timeline.
then produced in large quantities using Research Center (VRC) of the National The company has also developed
bacteria. The overall development Institute of Allergy and Infectious specific carrier molecules for its mRNA
and approval timeline is thereby Diseases (NIAID), part of the National products, including lipid nanoparticles
significantly reduced. Institutes of Health (NIH), collaborated (LNPs), developed in partnership with
Inovio began animal testing of INO- with Moderna to design the vaccine. Acuitas Therapeutics and Arcturus
4800, its COVID-19 vaccine candidate, NIAID will conduct investigational new Therapeutics. It is developing The RNA
in February 2020 and is aiming to begin drug-enabling studies and a Phase I Printer, a mobile, automated production
human safety testing in early summer clinical study in the US. unit for rapid supply of LNP-formulated
2020. The company will conduct tests Moderna’s mRNA vaccines can mRNA vaccine candidates.
in both the United States and China, contain multiple mRNAs coding for
the latter in collaboration with Beijing different proteins and mimic natural Stabilizing the
Advaccine Biotechnology Co. (3). Work infection, thus stimulating a more pre-fusion virus form
in the US is supported by a $9-million potent response, according to the A fourth group receiving funding
(€8.2 million) grant from the Coalition company. Only the coding region of from CEPI for application of a vaccine
for Epidemic Preparedness Innovations the mRNA must be changed for each platform technology to accelerated
J&J ramps up COVID-19 vaccine R&D
Johnson & Johnson (J&J) plans to initiate human clinical trials The company also announced plans to ensure rapid production
of its lead COVID-19 vaccine candidate by September 2020 and of a vaccine—with the goal of providing 1 billion doses of a vac-
have the first batches available for emergency use authoriza- cine globally—by establishing new US vaccine manufacturing
tion in early 2021, the company announced on 30 March 2020 capabilities and scaling up capacity in other regions. The company
(1). J&J also announced plans to expand its vaccine manufac- “is committed to bringing an affordable vaccine to the public on a
turing capacity, as well as a joint commitment of more than not-for-profit basis for emergency pandemic use” (1).
$1 billion (€915 million) with the Biomedical Advanced Research Under the agreement with BARDA, J&J will use its validated
and Development Authority (BARDA) at the US Department of vaccine platform and allocate personnel and infrastructure as
Health and Human Services to fund vaccine research, develop- needed to focus on the R&D efforts.
ment, and clinical testing. Reference
J&J said the company selected a lead COVID-19 vaccine candi- 1. Johnson & Johnson, “Johnson & Johnson Announces a Lead
Vaccine Candidate for COVID-19; Landmark New Partnership
date from several that have been in development since January with US Department of Health & Human Services; and Com-
2020 using Janssen’s AdVac technology. If trials are launched in mitment to Supply One Billion Vaccines Worldwide for Emer-
gency Pandemic Use,” Press Release, 30 March 2020.
September 2020, the company expects to have clinical data on
safety and efficacy by the end of the year. —The editors of Pharmaceutical Technology Europe
14 Pharmaceutical Technology Europe APRIL 2020 PharmTech.comDevelopment
development and manufacture of fragments of the virus needed to Sanofi’s insect (baculovirus) expression
a COVID-19 vaccine is located at produce an immune response. These platform. The technology is used for
Australia’s University of Queensland short fragments of proteins are Sanofi’s licensed recombinant influenza
(UQ) School of Chemistry and identified by a computer algorithm vaccine and a SARS vaccine that has
Molecular Biosciences (7). Its and can be made rapidly by entirely been shown in non-clinical studies to
rapid response technology relies synthetic means. They are modified be immunogenic and afford partial
on molecular clamp technology, to ensure that they activate immune protection in animal challenge models.
an approach developed by UQ cells that are key in producing
researchers and patented by immunological memory. “While these References
UniQuest. virus fragments may not produce 1. C. I. Paules, H. D. Marston, and A.
The molecular clamp technology as complete a response as whole S. Fauci, JAMA, online, doi:10.1001/
is used to create subunit vaccines inactivated viruses, they basically jama.2020.0757 (23 January 2020).
against class I and III enveloped produce a ‘memory’, so when a 2. T. Hesman Saev, “To Tackle the New
viruses by stabilizing the pre-fusion person treated with our vaccine does Coronavirus, Scientists Are Accelerating
form of viral fusion proteins, thus encounter the virus, he or she is the Vaccine Process,” www.science-
mimicking the protein conformation more prepared to mount an effective news.org, 21 February 2020.
found on live virus and generating response,” von Hofe explains. 3. Inovio, “Inovio Collaborating with
a strong immune response. A The technology is also a platform Beijing Advaccine To Advance INO-4800
polypeptide is used to maintain the approach because it can be applied Vaccine Against New Coronavirus in
pre-fusion structure and prevent the to virtually any virus that may emerge China,” Press Release, 30 January 2020.
protein from folding after entry into as a threat. 4. Moderna, “Moderna Announces
the cell. Funding Award from CEPI to Accelerate
The platform technology, which Big Pharma Development of Messenger RNA
does not require prior knowledge has programmes too (mRNA) Vaccine Against Novel
of a protein’s quaternary structure, While these smaller biotechs Coronavirus,” Press Release, 23 January
facilitates the expression of have generated attention for their 2020.
recombinant viral glycoproteins accelerated development platforms, 5. Moderna, “Moderna Ships mRNA
without loss of native antigenicity (8). Big Pharma companies have also been Vaccine Against Novel Coronavirus
It has previously been used to actively working on COVID-19 vaccine (mRNA-1273) for Phase 1 Study,” Press
produce chimeric polypeptides that candidates. Both Johnson & Johnson Release, 24 February 2020.
mimic the pre-fusion conformations and Sanofi are collaborating with the 6. CureVac, “CureVac and CEPI extend
of several enveloped viruses. The US Department of Health & Human their Cooperation to Develop a Vaccine
goal is to complete preclinical Services (HHS). against Coronavirus nCoV-2019,” Press
development within 16 weeks and Johnson & Johnson’s Janssen Release, 31 January 2020.
then progress directly to Phase I Pharmaceutical Companies unit is 7. University of Queensland, “Race to
clinical trials, with completion of collaborating with the HHS’ Biomedical Develop Coronavirus Vaccine,” Press
that step in 10 weeks, followed by Advanced Research and Development Release, 24 January 2020.
large-scale production of more than Authority (BARDA) to rapidly advance 8. K. Chappell, D. Watterson, and P. Young,
200,000 doses in eight weeks. the initial stages of Janssen’s COVID-19 “Rapid Response Pipeline for Stabilized
For its COVID-19 vaccine, the UQ vaccine development programme, Subunit Vaccines,” Presentation at the
researchers created a first candidate which is based on its AdVac and PER. Vaccine Technology VIII Conference
in the laboratory in just three weeks C6 platform technologies (10). BARDA (June 2018).
(9). This work confirmed that the is funding accelerated development 9. University of Queensland, “Significant
engineered vaccine candidate is of a candidate into Phase I clinical Step in COVID-19 Vaccine Quest,” Press
readily recognized by the immune trials, while Janssen is upscalling its Release, 21 February 2020.
system and triggers a protective manufacturing capacities (Sidebar). 10. Johnson & Johnson, “Johnson &
immune response. Plans for preclinical Sanofi Pasteur, the vaccines Johnson Announces Collaboration with
testing were underway as of late global business unit of Sanofi, is also US Department of Health & Human
February, and the researchers hope to collaborating with BARDA, using Services to Accelerate Development of
begin clinical testing by mid-2020. its established recombinant DNA a Potential Novel Coronavirus Vaccine,”
technology platform to accelerate the Press Release, 11 February 2020.
Leveraging development of a potential COVID-19 11. Sanofi, “Sanofi Joins Forces with
computer technology vaccine (11). This technology produces US Department of Health and
NuGenerex Immuno-Oncology is an exact genetic match to proteins Human Services to Advance a Novel
focusing on what von Hofe refers found on the surface of the virus, Coronavirus Vaccine,” Press Release, 18
to as the smallest and simplest which are then expressed using February 2020. PTE
Pharmaceutical Technology Europe APRIL 2020 15and clinical testing, has been a
challenging task,” she states.
For Rich Shook, director, Drug
Product Technical Services and
Business Integration, Cambrex,
there are two main obstacles facing
developers in ensuring the optimal
level of drug substance is available
with a targeted window of transit
in the gastrointestinal tract (GI).
“One of the main obstacles is the
pH dependent solubility and/or
degradation of the API, which can
decrease the overall absorption of
the drug substance and result in
a negative impact to the intended
therapeutic response,” he says. “The
Delivering the Goods other obstacle is in-vivo delivery
of a specific therapeutic dose at a
targeted therapeutic site in the GI
The new molecules entering the development tract based on the mechanism of
pipeline are bringing forth exciting challenges in drug delivery. action. Some drug substances have
a topical mechanism of action on a
disease making it important to ensure
Felicity Thomas
A s drug pipelines have expanded to include a wide range of
novel, and sometimes difficult-to-handle molecules, so too
has the number of methods available to deliver these innovative
the release of a high dose of drug
substance to that targeted area.”
“In terms of inhalation delivery,
therapies and drugs. Not only do developers need to consider the the main challenge is the diversity
route of administration, but it is also necessary to consider solubility, of molecules coming through the
bioavailability, the precise target of the active ingredient, patient pipeline into development,” adds
convenience and safety, and reducing toxicity, among other factors. Sandy Munro, vice-president,
“It is now more common for formulators to be presented with Pharmaceutical Development,
‘non-druglike’ molecules and yet be tasked with formulating them Vectura. “Historically, the inhalation
to achieve high oral bioavailability, good pharmacokinetic properties space was dominated by small-
with minimal toxicity, and good stability,” emphasizes William Wei-Lim molecule therapies for moderate
Chin, manager, Global Scientific Affairs, Catalent. “The key challenges asthma and chronic obstructive
of these molecules can be attributed to their poor aqueous solubility, pulmonary disease treatments. These
poor permeability, or in worst cases both.” days, the interest is much broader
both in terms of the diseases that the
Challenging aspects developers are interested in, and also
These challenging attributes of molecules entering the development the range of molecule types.”
pipeline are largely associated with the increasing complexity of
molecules, agrees Srini Shanmugam, technical director, Pharma Available approaches
Product Development and Manufacturing, Avomeen. “Formulators There are several approaches
must balance targeted release profiles for therapeutic efficacy with available that are in use by
patient safety and convenience of use,” he says. “Furthermore, every developers to help overcome
drug delivery system has unique characteristics that come with the challenges associated with
specific formulation challenges.” drug delivery. Approaches such
Developing the optimal drug delivery strategy for molecules that as pH adjustment, co-solvent
are classified as poorly soluble according to the biopharmaceutical complexation, solid‑dispersion,
classification system (BCS)—that is those molecules in class II and micellar formulations, among others,
class IV—is a major challenge for industry, notes Archana Akalkotkar, help to improve solubility, confirms
Serhii- stock.adobe.com
PhD, research scientist II, Charles River. “To come up with alternative Akalkotkar.
approaches that are appropriate for the drugs’ physicochemical “A tremendous amount of
properties, as well as the limitations of choice of excipients, which knowledge has been accumulated
are safe-to-use in the intended species dosed during the preclinical in modern pharmaceutics so that
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