Page created by Laurie Chavez
APRIL 2020 Volume 32 Number 4

        Building Better
Manufacturing Facilities
             Accelerating Vaccine Development
                       Optimizing Drug Delivery

                        HPAPI Tabletting Safety

                             Supplier Oversight

                             Cleaning Validation

                          Cold-Chain Packaging

                     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                                            

development, manufacturing, formulation and drug
delivery, API synthesis, analytical technology and testing,
packaging, IT, outsourcing, and regulatory compliance           Cover: nasir1164 -
in the pharmaceutical and biotechnology industries.             Art direction: Maria Reyes

                  36                                      16                                                                9                         26

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,
  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?
   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
                                                                  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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4     Pharmaceutical Technology Europe                       APRIL 2020

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, 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,”, 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,”, 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                     
•    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
     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

                            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”
                            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 -

                            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
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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,”, 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,”, 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,”,
                   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, 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,”, 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,”, 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,”, 9 Jan. 2020. PTE

8   Pharmaceutical Technology Europe    APRIL 2020
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 -

                                                       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   9
Cover 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
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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,”,
                  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
immune system protects against viral
                                                                                                                                                infections and can rapidly identify the
                                                                                                                                                critical parts of a new virus to target for
                                                                                                                                                vaccine development,” he says.

                                                                                                                                                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 -

                                                              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       13

                  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

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,”
mimicking the protein conformation         more prepared to mount an effective , 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   15
and 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

                          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

16   Pharmaceutical Technology Europe   APRIL 2020
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