Pharmaceutical Technology Oct 2021 Api

eBOOK SERIES
October 2021
APIs, EXCIPIENTS, AND

MANUFACTURING 2021
eBOOK SERIES
October 2021
APIs, EXCIPIENTS, AND

MANUFACTURING 2021
from the editor
Rethinking, Recalibrating, and Retooling

CPhI is set to provide the pharma community with an ideal
platform to engage with new value chain stakeholders post-COVID. Chris Spivey is
editorial director of
Chris Spivey Pharmaceutical Technology.
J
ust in time (JIT) manufacturing aims to reduce flow times within manufacturing systems while cutting response times from suppliers
and thence to customers. Under favorable circumstances, it’s a helpful tool for a manufacturer’s overarching strategy. With the emergence
of additive manufacturing alongside rising software sophistication, JIT’s dominance of supply chain management appeared assured.
And then COVID-19 hit.
MJH Life Sciences sees CPhI’s global event in Milan, Italy as an ideal meeting place to rethink, recalibrate, and retool for the next decade
of pharmaceutical manufacturing expansion. The ability to congregate face-to-face is a clear opportunity to build on that sense of community,
which is so strong in the pharmaceutical industry. Among the many trends accelerated by the pandemic, the urgent requirement to build multiple
additional supply partners into any future proofed supply and distribution chain has become clear. An anticipated vial shortage never became
a critical bottleneck, partly because the raw materials themselves failed to arrive. Large companies had leveraged their outsized influence over
suppliers—sometimes at the expense of customers, sometimes countries, and sometimes patients. This reinforces the necessity for face-to-face
meetings, to rebuild trust, and to reduce hoarding and the threatening implicit bias of regionalism.
Rejoin the pharmaceutical community in Milan to engage with new partners, and to energize a supply chain infrastructure strategy with
inherent adaptability and parallel inputs. Celebrate the obvious successes the industry had in meeting the COVID-19 challenge, and re-tool
with a new understanding of how best to face common goals—together. PT
Send your thoughts and story ideas to:
cspivey@mjhlifesciences.com.
Welcome to CPhI Worldwide
2 Pharmaceutical Technology APIs, EXCIPIENTS, AND MANUFACTURING eBOOK 2021 P h a r mTe c h . c o m

EDITORIAL SALES
Editorial Director Chris Spivey CSpivey@mjhlifesciences.com Publisher Mike Tracey MTracey@mjhlifesciences.com
Senior Editor Meg Rivers MRivers@mjhlifesciences.com East Coast Sales Manager Joel Kern JKern@mjhlifesciences.com
Managing Editor Susan Haigney SHaigney@mjhlifesciences.com Mid West, West Coast Sales Manager BJ Ghiglione
European Editor Felicity Thomas FThomas@mjhlifesciences.com BGhiglione@mjhlifesciences.com
Manufacturing Editor Jennifer Markarian European Sales Manager Linda Hewitt LHewitt@mjhlifesciences.com
JMarkarian@mjhlifesciences.com European Senior Sales Executive Stephen Cleland
Science Editor Feliza Mirasol FMirasol@mjhlifesciences.com SCleland@mjhlifesciences.com
Assistant Editor Grant Playter GPlayter@mjhlifesciences.com Sales Operations Executive Barbara Williams
BWilliams@mjhlifesciences.com
Contributing Editors
Jill Wechsler jillwechsler7@gmail.com Senior Vice President, Industry Sciences Michael Tessalone
Hallie Forcinio editorhal@cs.com
Susan J. Schniepp sue.schniepp@mac.com C.A.S.T. Data and List Information Michael Kushner
Cynthia A. Challener, PhD challener@vtlink.net MKushner@mjhlifesciences.com
Art Department Audience Development Research Director

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APIs, Excipients, and Manufacturing 2021
FROM THE EDITOR
2 Rethinking, Recalibrating, and Retooling

Chris Spivey
APIs
6 API Development and Manufacturing: Advantages of Working with Small Molecules

Meg Rivers
12 Seeking Economies of Scale for Biocatalysis

Mark Muldowney and Greg Holgate
18 Global Regulatory Approach to API Manufacturing

Meg Rivers
EXCIPIENTS
22 Building Robust Specifications Using Powder Testing

Jamie Clayton
MANUFACTURING
30 Containing and Enhancing Potent Particles with Micronization

Andy Maitland
36 Considerations for DPIs and MDIs in Inhalation Drug Delivery

Jennifer Markarian
44 Predicting Tablet Potency in Continuous Manufacturing

Ravendra Singh
DEVELOPMENT
50 Shining a Light on Photochemistry in Flow

Andrew Mansfield
QUALITY
58 Pharmaceutical Knowledge Management:

Experiences in Drug Development and Manufacturing
Marco Adami and Alessandro Regola
68 Ad Index
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APIs
API Development and

Manufacturing: Advantages of
Working with Small Molecules
Meg Rivers
A
Between dosage form pproximately 58% of drug products in development are
versatility, product stability, small molecules, according to a Thermo Fisher article
lack of storage restrictions or
(1). Moreover, a 2021 report by Market Research Future
need to refrigerate, and an
easier means of purification, estimates that the small-molecule API market will reach
small-molecule APIs present US$279,697.1 million by 2027 (2). This includes both in-house manufac-
an appealing market niche. turing and contract manufacturing. Some of the drivers of this growth,
according to the same report, include a “growing demand for newly de-
veloped small molecule drugs” and “the changing nature of drugs” (2).
But that isn’t the only upward prediction for the small-molecule API
market. In a report by Data Bridge Market Research, an 8.05% com-
pound annual growth rate market growth is predicted from 2021 to
2028, and technological advancement and innovations may lead to prof-
itable opportunities for players in the small molecule API market (3).
API manufacturing: advantages of working with small molecules

With this promising trajectory in mind, it’s no surprise that many
companies are wondering what some of the potential advan-
tages of working with small molecules (vs. large molecules) are in
API manufacturing.
“One of the advantages is that the majority of small molecules are solid
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materials that can be crystallized, which is the best and commercially

most attractive means of purification. Crystallized solids are also rather
stable, meaning most APIs can be stored for two years (or more) at ambi-
ent temperatures, which makes storage and logistics much easier,” says
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APIs
Michael Stanek, vice president, commercial operations, Between dosage form versatility, product stabil-
API global, pharma services, Thermo Fisher Scientific. ity, lack of storage restrictions or need to refrigerate,
“On the contrary, the biggest barriers to using vaccines and an easier means of purification, small-molecule
containing large molecules like mRNA [messenger APIs present an appealing, and strongly growing,
RNA] or proteins, such as the Pfizer and Moderna market segment.
vaccines, are transportation and storage, which can be
particularly problematic in countries with poor infra- Clinical vs. commercial API manufacturing
structure. The AstraZeneca and Johnson and Johnson The challenges faced during clinical-trial API manu-
vaccines also require refrigeration.” facturing differ from commercial supply API manu-
facturing. Turnaround times, especially, can be leaner
Between dosage form for clinical trial manufacturing.
versatility, product stability, “The vast majority of clinical trial APIs are or-
lack of storage restrictions or dered by small and emerging pharma companies.
These organizations operate within tight budgets
need to refrigerate, and an
and focus on speed, an approach that often does
easier means of purification, not allow for proper manufacturing preparation and
small-molecule APIs present overlooks the needs of commercial supply. This fre-
an appealing, and strongly quently leads to unexpected challenges during scale-
up from labs to large glassware to pilot plants,” says
growing, market segment.
Stanek. “As a result of this fast-tracked approach, we
Jamie Grabowski, PhD, MBA, vice president, may end up with a commercial process that is rather
portfolio and sourcing, Curia (formerly AMRI), costly. Driving down the cost of goods by stepwise
emphasizes the importance of understanding the learning, which is typical in most industries, is lim-
usage of small-molecule APIs. ited due to GMP [good manufacturing practice]
“Small molecules are used in more traditional requirements in a validated process. Changes are
pharmaceuticals—drugs like aspirin that have, possible, but they can only be implemented slowly,
in many instances, been around for more than a oftentimes involving authorities’ approval and piv-
hundred years. Large-molecule pharmaceuticals, otal clinical trials. This is in comparison to the car
on the other hand, started with insulin usage for industry, for example, where changes can be imple-
the treatment of diabetes and then, over time, be- mented within days or weeks.”
came synonymous with monoclonal antibodies, According to Grabowski, chemistry and/or scale-up
ADC [antibody-drug conjugate] drugs, etc.,” says issues can become more complex and multidimen-
Grabowski. “The advantage of a small molecule is sional as clinical trials progress.
the versatility in dosage forms such as tablets, thin “In clinical supply, processes aren’t typically vali-
films, inhalation powders, solutions, oral or inject- dated until Phase III; so, at that point, customers
able suspensions, transdermal patches, etc. With face unknown and sometimes difficult chemistry
large molecules, the applications are more limited.” and/or scale issues,” says Grabowski. “Handling
chemistry in the plant that isn’t well defined can These mostly focus on rare diseases, with patient
be challenging. There are a number of components numbers in the hundreds or thousands worldwide.
that need to be navigated, and you work to make These indications usually allow for fast approval, as
sure the customer can maximize their opportunity there is no medication in place yet,” says Schober.
at launch, helping patients who need them. Once “Additionally, we still see little demand for work on
the process is validated, manufacturing can begin tropical diseases, with only a few non-profit orga-
on a commercial scale.” nizations working on such. These include the Bill
Chris Seekamp, director of CMC, Sterling Pharma & Melinda Gates Foundation and the Drugs for
Solutions, agrees scale-up is one of the biggest chal- Neglected Diseases Initiative.”
lenges, particularly working through scale-up issues Seekamp adds that the industry is trending
that weren’t originally observed or well-defined in the toward highly-potent compounds that are
laboratory evaluation and/or development. typically (but not always) associated with an orphan
“When such scale-up issues arise, the develop- drug indication.
ment teams need to mobilize quickly to determine
the best path forward to maintain safety, integrity, A 2021 report by Market
strength, purity, and quality (SISPQ) of the prod- Research Future estimates
uct and also minimize any impact on the delivery that the small-molecule API
schedule,” Seekamp continues. market will reach US$279,697.1
In tandem, for commercial manufacturing, a con-
siderable challenge—according to Seekamp—is re-
million by 2027.
ceiving estimated forecast quantities from customers, “Highly potent APIs (HPAPIs) present unique
and then adjusting the manufacturing schedules as challenges to a contract development and manu-
the forecast becomes a binding delivery. facturing organization (CDMO) when being as-
sessed, including the containment strategy that
Trends in API manufacturing must be adopted; at what point in the synthesis
“Over the past several years we’ve seen trends toward the molecule becomes highly potent; and whether
more complex products and presentations along with the HPAPI is also classed as a DEA controlled sub-
an increased focus on intellectual property at an ear- stance,” says Seekamp.
lier stage in development,” says Grabowski. “We’ve Stanek raises another point, which relates to
also seen increased interest in orphan drugs to treat the challenges for generic-drug producers to
rare diseases, which require speed to market.” sustain revenue.
Bernt Dietmar Schober, senior business manager, “As more molecules with lower volume demand
API, pharma services, Thermo Fisher Scientific and are developed, it becomes increasingly difficult
Seekamp also say that rare diseases are (and will for generic producers to make money on ‘second
be) a focus area in the realm of API manufacturing. generation processes,’” says Stanek. “Medications
“Aside from numerous specific cancer targets, become more specific based on improved under-
‘unmet needs’ are another area of high activity. standing of the biological processes in the body.
Pharmaceutical Technology APIs, EXCIPIENTS, AND MANUFACTURING eBOOK 2021 9
APIs
Computer modelling has also allowed for an im- start working effectively. When clients resist proposed
proved design of APIs (fitting them to the target changes, significant amounts of time can be lost by
molecule more specifically like ‘lock and key’). the development team having to demonstrate why the
These new design approaches improve the chances process/analytical method needs amending. As time is
of success for the individual patient; however, they typically the most critical aspect for a client, any steps
also make the target population much more frag- that can be taken to accelerate the implementation of a
mented. For example, today, the target is no longer process at a PDMO are beneficial to all parties.”
‘lung cancer,’ but many different types of ‘lung can- For Stanek, it’s about striking a balance between
cer’ that are now specified and targeted by differ- speed, quality, and cost.
ent medications. As a result, the demand for API “Even under pressure, companies must maintain
quantity is significantly reduced. APIs requiring their focus on balancing the triangle of ‘speed, quality,
more than a few metric tons a year are very rare; and cost,’ particularly if they expect to carry the project
demand for most products will be in the range of forward themselves,” says Stanek. “Those looking to
hundreds of kilograms at maturity.” work with APIs should be cautious to not solely focus
on good clinical results, which are the trigger for sell-
Recommendations for partnering ing off, but keep sustainability in mind as well, such
with an API manufacturer as process robustness and crystallization. Companies
According to Grabowski, customers should find a must also educate their stakeholders about the bound-
CDMO that can partner with them to provide expe- ary conditions in chemical API manufacturing. For
rience, feedback, and guidance regarding IP, regulatory, example, APIs are usually manufactured in multi-step
quality, and/or supply chain concerns. However, for processes with each step being a manufacturing pro-
some prospective customers, the deciding factors for cess of its own, which may include custom-made raw
selecting an API manufacturer are the price tag and materials. This requires much longer manufacturing
lead time, which Seekamp cautions against. lead times than for drug products or even biologics
“When companies are evaluating API manufactur- (large molecule) APIs.”
ers, they should be looking at more than just price In summary, there is nothing small about the chal-
and lead time, and [they] should be asking how the lenges and complexities confronting small-molecule
manufacturer responds to problems when they occur API development and manufacturing, but from a mar-
during manufacturing. Unexpected events can occur ket standpoint, they are on course for a very big future.
during the transition from the laboratory to the pro-
duction plant, and how a company responds to those References
1. Patheon by Thermo Fisher Scientific, “Small Molecule API Devel-
incidents separates a partnership development and opment,” www.patheon.com/drug-development-services/small-
molecule-api-development, accessed Sept. 16, 2021.
manufacturing organization (PDMO) from a typical 2. Market Research Future, Small Molecule API Market Research Re-
port: Information, by Types (Synthetic/Chemical API and Biologi-
CDMO,” Seekamp continues. “Acknowledgement and cal API), Application (Cardiovascular, Oncology, Diabetes, Immu-
acceptance of the need for process changes by the cli- nological Disorders and others), Manufacturing Method (In-House
and Contract) and Region (North America, Europe, Asia-Pacific
ent will greatly speed the timeline for onboarding the and the Middle East & Africa)–Forecast To 2027 (February 2021).
3. Data Bridge Market Research, Global Small Molecule API Market–
program, and [it] will allow the development teams to Industry Trends and Forecast to 2028 (February 2021). PT

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APIs
Seeking Economies
of Scale for Biocatalysis
Mark Muldowney and Greg Holgate
T
New enzymes and protein he advantages that enzymes have as biocatalysts are well
engineering have advanced known within the pharmaceutical manufacturing industry,
biocatalysis processing not least that they can give excellent specificity and yields,
toward commercial
acceptance. Technology and even facilitate reactions that are difficult with chemi-
and economic roadblocks cal catalysts. Their credentials towards improving sustainability are also
must be overcome for the increasing the levels of interest for process development, as biocatalytic
process to be widely reactions can be more efficient in terms of solvent and material use.
embraced by pharma.
The efficacy of some enzymes can be very high. For example, the en-
zyme carbonic anhydrase has been shown to catalyze the hydration of 4
million molecules of carbon dioxide per second, which is near the limit
of turnover dictated by diffusion. While this is an extreme case, a well-
chosen enzyme should be able to give a high yield in a short time.
Humans have long benefitted from biocatalytic reactions—despite not
understanding the scientific processes—with yeasts reportedly being
used in brewing about 8000 years ago. It was not until the 1830s, however,
that the source of the reaction was determined by chemists in a French
sugar factory, when they isolated the enzyme diastase. It was another 60
years before the German chemist, Eduard Buchner, showed that enzymes
could be used as chemical catalysts without cells, and it was for this work
that he was awarded the Nobel Prize in Chemistry in 1907.
SERGEY YAROCHKIN - STOCK.ADOBE.COM
Thousands of enzymes that catalyze chemical reactions are now known,

and significant technological advances since Buchner’s day have made
it easier to find an appropriate enzyme catalyst for a specific reaction.
Mark Muldowney is head of
Catalysts can be designed to make novel enzymes that efficiently cata-
technology, and innovation and
Greg Holgate is biocatalysis lyze reactions where natural enzymes cannot. The growth in industrial
chemist, both with Sterling
application is significant: the global market for biocatalysts is expected
Pharma Solutions.
to grow by about 15% between 2019–2024 (1), reaching $10 billion (2).
The pace of discovery of new enzymes has risen organic material—a micro-environment can be cre-
with their use in the pharmaceutical industry. Ap- ated around it, effectively encapsulating the enzyme
proximately 1000 new enzymes have been intro- in a small pocket of solvent (usually water). This helps
duced since 2017 across a number of classes, and to stabilize the enzyme if the macro environment has
with research continuing, many more can be ex- a pH that is too high or low for the enzyme to oper-
pected in coming years (3–4). Biocatalysis is now a ate efficiently, or if the presence of organic solvent is
mainstay of the manufacture of products ranging inhibiting its activity. The reaction can then occur
from foodstuffs to cosmetics to medicines. in a heterogeneous environment, with the substrate
Multiple scientific advances underpin the growth in diffusing into the pores where the reaction happens,
biocatalysis. First, the advent of ultra-high through- followed by the product diffusing out.
put next-generation sequencing has led to vast data Immobilizing the enzyme has the potential to be
stores of protein and gene sequences. The open-source advantageous in terms of cost. For cheap, commodity
protein database TrEMBL, for example, now contains enzymes, this is not such an issue as for novel catalysts
substantially more than 200 million entries (5). generated by directed evolution, where the ability to re-
Advances in protein engineering have also had a cover and reuse the enzyme has a huge bearing on the
dramatic effect. Natural enzymes have evolved with economics of a reaction. If an enzyme is reused once,
very specific functions over billions of years and, for the cost will be halved; this calculation must be offset
the most part, work most efficiently under very specific with the cost of immobilization and the medium onto
and mild conditions, such as ambient temperature and which it is immobilized. If the enzyme can be reused
pressure, and a relatively neutral pH. Directed evolu- several times, process costs can fall dramatically.
tion has allowed DNA to be manipulated in such a way The technology for immobilizing biocatalysts exists
that tailored enzymes can be created (6), with prop- and is proven, with examples cited in the literature of
erties optimized for specific reactions and, potentially, multiple cycles of enzyme use, followed by filtration
more forcing conditions. It is for this evolution of the and reuse (7). In a confidential project, a nutraceutical
technology that the American scientist Frances Arnold ingredient has been manufactured using an enzyme
was awarded the Nobel Prize in Chemistry in 2018. that has been immobilized onto beads and enclosed
within a cartridge that resembles a water filter. Both
The advantages of immobilization starting materials for the process and the product are
Despite the advantages that biocatalysis offers, en- liquids, allowing the catalyst cartridge to be removed
zymes are expensive and are difficult to recover and once the reaction is complete and put into storage
reuse. One solution to these downsides is to immobi- until it is needed again. The reuse of the enzyme has
lize the enzyme in some way, so that it can be filtered been demonstrated on more than 20 process cycles
off from the reaction solvent and washed for reuse, and has the potential to be used for many more.
rather than used in solution. Immobilization can also reduce concerns about
Immobilization can also improve an enzyme’s sta- cross-contamination, particularly in multipurpose
bility. If an enzyme is immobilized onto and within pharma facilities. An immobilized enzyme is far less
cavities of a porous surface—such as a polymer or in- likely to cause contamination, although a key part
APIs
of the process development is to determine whether zyme aggregates (CLEAs) or crystals (CLECs). From
there is leaching of the enzyme from the substrate, an industrial point of view, however, the most viable
and if so, how much there is (8). option is to attach it covalently to the surface of a bead.
The simplest way to immobilize an enzyme is Covalent bonding does have some challenges. If
to adsorb it onto the surface of beads or into the nucleophilic amino acid residues are close to, or
pores within them. The beads are covered by a so- even in, its active site, and these residues bond to
lution of the enzyme, and when they are filtered the bead, the activity of the enzyme can be dimin-
off, the enzymes are held on the surface by a weak ished as the diffusion of substrates into the active
attraction such as van der Waals forces and salt site would be hindered. The covalent bonding can
bridges. However, as they are only weakly bound also be done in a more directed manner, potentially
to the surface and within the pores of the beads, by tagging the enzyme at one end and using this tag
there is no guarantee the enzyme will not leach out, to attach it to the surface rather than leaving the
which is a regulatory issue. For this method of im- binding position to chance. This approach would
mobilization to be appropriate for industrial and avoid these diffusion problems.
commercial manufacturing, work to demonstrate There are some instances when immobilization is
the consistency and reproducibility of the process less advisable, and principally this would be when
with no impact on product quality is essential. binding the enzyme to a resin negates the activity
An alternative would be to use either cationic or it has, compromising the speed and cost benefits. If
anionic beads, similar to an ion exchange resin. If the enzyme demonstrates poor activity in the first
the protein has a net positive or negative charge, place, it is unlikely that immobilization would en-
then ionic bonds could be formed between the hance it, and a better, more active enzyme should
resin and the appropriate amino acids, holding be considered instead. Additionally, for cheap, off-
them in place on the surface. the-shelf biocatalysts, there is little point in spend-
The most secure way to attach the enzymes to the ing resources to immobilize them, particularly for
beads would be through some form of covalent bond. the pharma sector, where speed is often the primary
If the beads have epoxide groups on the surface, these driver for development.
groups are susceptible to nucleophilic attack from There is no definitive measure for how immobili-
amino acid residues such as lysine or serine, form- zation affects an enzyme’s activity, other than that it
ing covalent bonds. Alternatively, the beads could be will probably be lower than that of the free enzyme,
functionalized with amines and can be treated with perhaps as high as 65% as active or as low as 1%. But
glutaraldehyde, which acts as a linker between the as the enzyme is recoverable and reusable, an excess
beads and the enzyme; and any free aldehyde groups can be used in a reaction, on the understanding that
that remain can react with nucleophilic side chains. it will not be used just once. Other factors to consider
The enzymes might also be encapsulated in alginic are the ease of handling the enzyme, and whether the
beads or even crystallized out of solution and cross- filtration process to remove the beads is significantly
linked with a molecule such as glutaraldehyde to easier than removing a free enzyme from the reaction
make solid ‘lumps’ of enzyme called crosslinked en- mixture.
APIs
Immobilizing a biocatalyst also makes it compatible revised approach, issues with product stability and
with a flow chemistry process, either using a cartridge yield on the hydrolysis step were identified.
of packed beads or lining the inside surface of a flow The stability issues were overcome when using a
reactor with the biocatalyst, so the starting materials lipase-catalyzed hydrolysis as the first of the two
simply have to flow through it at an appropriate rate steps. Research on the second step using both
for reactions to occur. chemical and biocatalytic processes is ongoing, as
are efforts to determine how best to immobilize en-
Immobilization in action zymes for scale-up to a commercially viable synthe-
The challenges of developing a synthetic route for an sis. Early indications and calculations suggest that to
API in development are illustrated in a case study. The manufacture a ton of the API material would need
current process uses one of two commercial routes; an enzyme created via directed evolution that would
however, both have issues, particularly relating to in- be cost prohibitive unless immobilization and reuse
tellectual property (IP). A biocatalyzed reaction would was possible. While the project is still embryonic, it
offer advantages not only in process efficiency and does demonstrate the challenges of biocatalysis and
cost benefits but would also avoid the IP issues. the potential of immobilized enzymes to open up
The original, classical route to the API works well. new areas of chemistry and manufacturing.
The two-step process involves a coupling followed by
a hydrolysis; however, one step is protected by a patent. More work to be done
The second route uses a slightly different synthetic The potential of biocatalysis in pharmaceutical man-
path to avoid this IP-protected step; however, the ufacturing has been well-established, and much re-
product yield of approximately 25% is not ideal as the search and academic discovery has assisted in its prog-
two principal starting materials are expensive. ress. While there are examples of processes proven to
Research was conducted to determine if the first be wholly possible using only enzymes, such as the
route was viable by replacing the hydrolysis step with human immunodeficiency virus drug islatravir (9),
a biocatalyzed reaction; however, there were no natu- the commercial reality is that the technology will only
ral enzymes in the literature that could perform the be embraced where it is economically viable to do so,
step. In a collaboration with Northumbria University, and this will involve specific synthetic steps.
in-silico screening of other potential enzymes was
conducted to create a shortlist of alternative enzymes References
1. Research and Markets, World Biocatalysis & Biocatalyst Market
known to work on molecules with similar substitu- Analysis to 2024–Market Forecast to Grow at a CAGR of 15% from
2019 to 2024, Report (2020).
tion patterns. However, none showed activity when 2. E. Abdelraheem, et. al., React Chem Eng, 4, 1878-1894 (2019).
trialed on the actual molecule. 3. I. Schomburg, et.al., Journal of Biotechnology 261, 194–206 (2017).
4. BRENDA, “The Comprehensive Enzyme Information System,”
Further in-silico modeling showed that changing brenda-enzymes.org, accessed Sept. 19. 221.
5. UniProt Knowledgebase, “UniProtKB 2020_06 Results”, uniprot.
the order of the reactions gave potentially more op- org/uniprot/.
6. A. Kan and N. Joshi, MRS Commun. 9 (2) 441–445 (2019).
tions for biocatalysis and circumvented the IP pro- 7. S. More, Chem. Eng. Journal 15 (334) 1977–1987 (2018).
tection. Using standard chemical reagents, perform- 8. A.A. Homaei et. al., J Chem Biol 6,185–205 (2013).
9. M. Satyanarayana, M. “Scientists Made an HIV Drug Using Noth-
ing the steps in reverse was feasible; however, in this ing but Enzymes,” Chemical & Engineering News, Dec. 20, 2019. PT

Oral Delivery Innovation
APIs
Global Regulatory Approach

to API Manufacturing
Meg Rivers
P
Navigating a complex global rior to the commercialization phase for API manufacturing,
regulatory landscape there is a lot to juggle as well as a tricky global regulatory
involves upfront research
landscape to navigate. API manufacturers must meet the
into the expectations of the
different regulatory bodies, standards for the country where the drug will be distrib-
thorough documentation of uted, and every country has their own regulations as well as their own
every step of the API interpretation of those regulations.
manufacturing process, and
“Ahead of commercialization, regulators expect pharmaceutical
good communication.
companies to document a robust manufacturing process. The pro-
cess must be validated prior to commercialization, and the data and a
succinct discussion must be available for regulatory assessment,” says
Jakob Bonde, head of regulatory affairs, small molecules (DS and DP)/
associated regulatory affairs director, Lonza. “The validated process
should implicitly reflect the required process knowledge for control
of materials, impurities, and physical properties, as well as stability of
the API. A good manufacturing and development partner can help
speed this process by ensuring that the right data are provided in ap-
plications, and the relevant details on materials are included.”
According to Steven Lynn, RCA executive VP, pharmaceuticals, and
Susan Schniepp, RCA distinguished fellow, Regulatory Compliance
MAGELE-PICTURE - STOCK.ADOBE.COM
Associates, well-documented standard operating procedures are a

must, which includes information about personnel, facilities, equip-
ment, and documentation as well as the responsibility for all produc-
tion activities. Everything must be clearly defined and documented
at each step. They add that following the proper quality management
system (QMS) will ensure companies adhere to API standards.
Lynn and Schniepp add that they have also seen should be the main priority to meet global qual-
many APIs designed to accommodate specific cus- ity standards. The safety standard is inherent with
tomer biological targets. As the science continues a high-quality standard,” says Bonde. “Choosing
to improve, the industry will see new compounds a manufacturer in a country with global mutual
even more potent than what we have today. Fur- recognition agreements in place, [and] bearing in
thermore, they believe regulatory expectations mind regulators’ increased use of risk-based assess-
will remain high in terms of hygiene control, bio- ments and desktop inspections, might reduce time
contaminants, and equipment validation. to market while keeping quality high. The height-
Drug shortages have long been a major concern for ened quality is reflected in the source documenta-
the bio/pharmaceutical industry; the COVID-19 pan- tion used to write the regulatory CMC [chemis-
demic further magnified the importance of establish- try, manufacturing, and controls] documentation,
ing a reliable supply chain for crucial materials. which will lead to fewer assessor questions.”
Easy availability of starting materials and other
API manufacturers must
chemicals is important, says Mahender Rao Sirip-
ragada, president, R&D, Neuland Labs, noting the
meet the standards for the
importance of a short and de-risked supply-chain. country where the drug will be
All raw material supply companies should meet distributed, and every country
current good manufacturing practice (CGMP) has their own regulations and
requirements, and the API manufacturing pro-
their own interpretation of
cess should be robust to have consistent quality.
In addition, impurities should be controlled at all those regulations.
stages, including the source of formation, type of Lynn and Schniepp add that having strict and effec-
impurity (e.g., process impurity versus degrada- tive QMS and quality risk management processes in
tion impurity), and control strategy for the impu- place will help companies conform to whatever mar-
rities, Siripragada adds. ket they are involved in. Knowledge about the current
global laws, regulations, and standards should be kept
Meeting quality and up-to-date and checked regularly since these stan-
safety standards in a global market dards change. They also add that performing internal
Regardless of where raw materials are sourced, API audits through the lens of global API laws, regula-
manufacturers with a global presence must adhere tions, and standards allow manufacturers to identify
to the quality and safety standards of each country and address any gaps or nonconformities they may
a drug product is distributed to. As such, it’s no sur- have regarding specific markets.
prise that CGMP sits comfortably at the forefront. Moreover, International Council for Harmonisa-
“The local in-country health authority acceptance tion (ICH) guidelines should be consulted. Specifi-
of the active substance manufacturer’s compliance cally, Lynn and Schniepp reference the ICH Q7 Good
to CGMP in a developed country, as documented Manufacturing Practice Guide for Active Pharmaceu-
in the manufacturing license and GMP certification, tical Ingredients for thoroughness and clarity.
APIs
For Siripragada, quality-by-design technology should “Despite the increased global harmonization of re-
be prioritized and implemented during the develop- quired information and format for drug substance to
ment stage, as it provides an indication of the quality support a drug product registration, agencies and as-
of manufactured products prior to testing them. Ac- sessors still have different expectations and interpre-
cording to Siripragada, if a company can adopt all the tations,” says Bonde. “Some countries like China ex-
quality and safety standards at the development stage, pect additional details for specific process equipment
it can meet all the requirements of global market. and material suppliers while other countries’ regula-
tors mainly refer to a local translated summary of
Before preparing the eCTD [electronic common technical document].”
documentation, companies “There are also procedural and interpretation
should familiarize themselves differences between agencies like the FDA and
EMA,” Bonde continues. “Some regulatory expec-
with the specific requirements
tations—for example, the availability of validation
of the country and regulatory data, the extension of justifications, impurity risk
agencies they are submitting assessments, and process development descrip-
the information to. tions—might need additional information or need
to be modified for a specific regulator. However, we
Regulatory hurdles for the registration of APIs find that to some extent expectations are often up
The first hurdle, according to Lynn and Schniepp, to the individual assessor. The FDA, in our experi-
is knowing the requirements of the country you ence, has a more pragmatic or flexible scientific ap-
want to register the API within. After that, they add proach to the required manufacturing documenta-
that the second hurdle is determining what needs tion, especially if the approach has been discussed
to be submitted for the registration. For example, in a scientific meeting prior to submission, while
in the United States, there is the US Drug Master the EMA is more conservative in nature.”
File (DMF). In Europe, there is the European DMF. Bonde adds that a contract development and
While there are similarities between the two, where manufacturing organization (CDMO) with in-house
and how to file them are different. In the European global regulatory experts can help companies develop
Union (EU), the DMF is handled by two different a comprehensive plan for global regulatory approvals.
agencies, the European Medicines Agency (EMA) “Experience with different regulatory bodies is
and the European Directorate for the Quality of key to securing useful feedback on filings, includ-
Medicines and Healthcare. In the United States, ing clarity on risk assessment, de-risking processes,
FDA oversees DMFs. Companies should check and anticipating potential questions to ensure a
DMF requirements for the applicable country. molecule reaches the market faster,” says Bonde.
But even when requirements for registering APIs in
the different countries are known, there can be room Preparing documentation
for interpretation—thereby creating differing expecta- Before preparing documentation, it’s important for
tions for each regulatory body. companies to familiarize themselves with the specific
requirements of the country and regulatory agencies tween companies and regulatory bodies that can
they are submitting the information to (as discussed (and should) be improved.
above). But once it comes down to assembling the “I wish customers would interact more with regu-
files—which will ultimately be submitted using eCTD lators and CDMOs, and much earlier in the devel-
format—anything that is related to the manufacture, opment process,” says Bonde. “This would help to
testing, and release of the API should be included. circumvent issues ahead of commercialization and
According to Lynn and Schniepp, some of the nec- provide flexibility for changes to manufacturing
essary files include, but are not limited to: processes and analytical methods.”
• Records of raw materials receipt, sampling, Most companies tend to focus on the clinical
and release aspect, Bonde says, particularly smaller biotech
• Master batch records, labeling, and testing companies with limited GMP manufacturing expe-
information rience and/or lack of capacity inhouse. “As a devel-
• Details of the equipment used during the opment and manufacturing partner, we can advise
manufacturing on processes and the implementation of accelerated
• Validation records. pathways, such as breakthrough or priority assess-
Bonde adds that it’s particularly important to in- ments, to optimize the use of the designations. In
troduce GMP early, as different agencies might have our experience, a lean and concise CMC file often
different understandings of the requirements. leads to a better regulatory outcome. It is important
“Early discussions in scientific meetings help ensure to know ahead of time what information will be
a shorter GMP route of synthesis, which can improve required by global regulators as part of the roll out
manufacturing flexibility in the future,” says Bonde. strategy for each stage of commercialization.”
“It is further essential to characterize the drug sub- Knowing the requirements to develop and manu-
stance and the process to manufacture the drug sub- facture APIs is the first step to a smooth commer-
stance, including descriptions of impurities resulting cialization process, according to Lynn and Schniepp.
from the process, material used in the process, and the This includes laws, regulations, guidances, stan-
potential purging of genotoxic impurities. All regu- dards, and more. After that is a practical under-
lators require a manufacturing process description standing of how to apply those requirements and
with a discussion on the critical process controls and comply with the applicable laws and regulations of
proven acceptable ranges and parameters regarding the country the drug product is being distributed
the influence on quality.” to. Furthermore, companies should also know what
information is required in the submission for each
Going forward: what bio/pharma applicable regulator. Finally, transparency with
companies should know the regulators is key, says Lynn and Schniepp. By
One thing that is important for manufacturers to combining all the above along with having a robust
remember is CGMPs apply to APIs/drug substances, quality management system, companies will be able
just as much as they do to finished dosage forms. to ensure regulatory adherence and a successful ex-
But according to Bonde, it’s communication be- ecution of their commercialization plans. PT
Excipients
Building Robust
Specifications Using
Powder Testing
Jamie Clayton
T
Advanced powder
testing is a useful tool to he COVID-19 pandemic has drawn attention to
differentiate materials and pharmaceutical supply chains, notably increasing public
optimize the supply chain. awareness of how and where drugs and vaccines are
made. While the United States and European Union
(EU) retain the two top spots in terms of number of FDA-registered
manufacturing plants, China and India, together, now account for
31% of these facilities. India alone supplies 40% of the world’s
generic drugs but relies on China for 70% of the raw materials
and APIs used to make them (1). This complex supply network
has flexed rapidly and successfully to answer to the demands of
the pandemic, with manufacturing plants switched to the produc-
tion of hand sanitizer, manufacture of materials in short supply
due to regional outbreaks, or, for the longer term, making respi-
ratory drugs and vaccines. However, changes in supply chain or
plant use are challenging for this heavily regulated industry,
particularly given the criticality of product quality and safety.
Reliable specifications, for products and raw materials, pro-
vide a secure foundation for those navigating the global phar-
maceutical supply network and are increasingly important as the
industry regroups, drawing on lessons learned. Powders are par-
PAYLESSIMAGES - STOCK.ADOBE.COM
ticularly challenging in this regard, with conventional specifica-

Jamie Clayton, jamie.
tions often failing to successfully differentiate materials. This
clayton@freemantech.co.uk, is article explores reasons why specifications for products and raw
operations director, Freeman
Technology (a Micromeritics
materials fail, and experimental data illustrating how powder test-
company), Gloucestershire, ing can be used to establish better, more robust specifications will
UK.
be provided.
Excipients
A new era for supply chain management Same specification, different powder
Supply chains for established processes nec- Successfully switching suppliers relies on being
essarily evolve over time, as the marketplace able to identify materials that will perform as
changes. Legacy processes are often running with well, if not better than a current ingredient or
materials that have changed incrementally over feedstock. This identification is the purpose of
the years, and efficiency losses due to sub-op- a specification. A robust specification defines
timal processing performance may be largely acceptable ranges for all the properties that
hidden. For example, the full impact of a slow inf luence performance, thereby safeguarding
downward drift in tableting speed only becomes consistent behavior. Using existing plants to
evident when production figures are compared manufacture an alternative product is similarly
with those of a decade ago. For off-patent drugs dependent on establishing specifications for ma-
and for those manufacturing generic drugs or terials that are well-matched to specific pieces
over-the-counter (OTC) products, the economic of equipment.
impact of deteriorating efficiency is particu- Developing a robust specification for powders
larly difficult to sustain, and financial pressures is more difficult than for other materials. Along-
have long been an important stimulus to switch- side compositional data, notably impurity levels, a
ing supplies. powder specification typically includes just a few
However, the pandemic has brought new moti- physical properties. Particle size information is
vation to supply chain management. For example, common, as are bulk density values, which often
regional variations in disease levels and manu- relate to packaging and the quantity of material
facturing output, as well as the need to increase delivered, and sometimes a simple f lowability
manufacture in line with demand on a regional metric is also included; but there tends to be lit-
basis, may now be an important trigger for re- tle else. This lack of information is problematic
valuation of supply chains. More broadly, recent because these data alone are often insufficient to
events look likely to accelerate pre-existing trends securely differentiate a powder with acceptable
towards national self-sufficiency in critical thera- performance, notably with the flowability, com-
peutic areas, and an associated reshaping of the pressibility, or permeability required for efficient
supply network. Finally, many manufacturers processing or use. It is not uncommon for a pow-
are facing the task of rapidly deploying existing der to meet a defined specification and then go on
plants to make alternative ingredients or drugs to perform poorly, for example, to exhibit erratic
for which demand has soared. For powder pro- flow through the process or to fail to compress to
cesses, such efforts are reliant on being able to form a stable tablet because the specification fails
match raw materials and ingredients with pro- to capture a critical aspect of behavior.
cessing equipment that is suitable for them, and
on identifying the physical properties that define How powder testing can help
process performance in a given unit and accept- Robust specifications for powders must include
able ranges for them. both particle and bulk powder properties. Though
Figure 1. The intra-batch variability of the lactose products is low (relative standard deviation [RSD]<5%). LCFP is
Lactochem Fine Powder.
there is some understanding of the influence of Dynamic powder properties, measured using
particle properties, such as size, shape, surface a powder rheometer, are routinely identified as a
roughness, and density, on bulk powder properties, critical element of specifications developed in this
such as flowability, the relationships are complex, way. Such properties are highly reproducible and
with system variables, such as degree of aeration sensitive and have a proven track record of process
and moisture content, also having a significant in- relevance (4). Given that a powder rheometer speci-
fluence. Predicting bulk powder properties is not fied for dynamic powder testing also offers shear
feasible; measurement is essential. and bulk property measurements, such instrumen-
The question of which properties to measure is tation can be a good place to start when building a
crucial. An approach gaining traction (2,3) is to bulk powder property database to support supply
measure a broad range of properties, thereby devel- chain optimization (5).
FIGURES COURTESY OF THE AUTHOR
oping a material property database for the powder, Case study 1: Evaluating pharmaceutical excipients.
and to then identify relevant properties through Flowability testing was performed on six com-
correlation with process performance. This ap- mercial samples of lactose intended for oral solid
proach pinpoints the properties that capture the dosage formulation. Three were milled products
majority of variability in a given unit operation and from DFE Pharma (Goch, Germany): Pharmatose
that can be used to develop a robust specification. 200M EU, Pharmatose 200M NZ, and Lactochem
Excipients
Figure 2. Inter-batch variability is significant for certain lactose products indicating that they could exhibit variable
process performance. RSD is relative standard deviation, and LCFP is Lactochem Fine Powder.
Fine Powder (LCFP); the others were competitor Figure 2 shows data comparing inter-batch vari-
products. Dynamic f low properties were mea- ability (the %RSD associated with measurements
sured in triplicate (FT4 Powder Rheometer, Free- on three different batches of each product). These
man Technology) for each of three batches of each results highlight significant differences, which, be-
product. The relative standard deviation (RSD) of cause of the repeatability of the instrument already
basic flowability energy (BFE), a baseline dynamic demonstrated by the low intra-batch variability, can
property that quantifies flowability under forced- securely be associated with batch-to-batch variabil-
flow conditions, was used to assess consistency. ity. While three of the products exhibit relatively low
Figure 1 shows data comparing intra-batch vari- RSDs of ~6% or less, that of Competitor 3 is around
ability (the %RSD associated with the triplicate 15%. BFE has been securely correlated with perfor-
measurements of each batch). These results show mance in processes such as die-filling and blend-
no evidence of variability within an individual ing (4), so variability in this parameter could be sig-
batch, for any of the products. They also highlight nificant from the perspective of process efficiency.
the repeatability of the measurement technique. More generally, the study demonstrates the ability
Many powder testing techniques exhibit poor re- of dynamic testing to reliably differentiate the con-
peatability, compromising their ability to detect sistency of supplies and support supplier selection.
variability between samples, so this is an impor- Case study 2: Focusing on flow additives. In a second
tant observation. study, dynamic, shear, and bulk powder proper-
Excipients
powder property that, like BFE, quantifies the
Figure 3. Specific energy (SE), compressibility, and
permeability values for five commercial untreated flowability of powders in a low stress state. How-
fumed silica supplies show clear differences between
ever, in contrast to BFE, SE is measured with an
the materials.
upward traverse of the powder rheometer blade
that subjects the powder to a gentle, lifting action.
Therefore, SE quantifies how a powder will be-
have in an unconfined state, when flowing under
gravity, rather than under the forcing conditions
applied in BFE measurement. Higher SE values
are typically associated with a greater degree of
mechanical interlocking and friction between
particles in the powder, as a result of particle
morphology—particle size, shape, and/or surface
roughness.
Sample 1 generates the highest SE value, which
is almost double that of the lowest, Sample 4. This
suggests that Sample 1 may be significantly more
difficult to mix and disperse through a bulk sub-
strate, which is an important characteristic for a
flow aid. SE values provide a useful ranking of
the supplies, in terms of this behavior.
Compressibility is quantified in terms of per-
centage change in volume (or density) as a func-
tion of applied normal stress. The results show
that Sample 5 is the most compressible material
ties were measured for five different commercial tested, while Samples 1, 2, and 3 have similar,
samples of untreated fumed silica, which is a flow much lower compressibility. Powders that are
aid used routinely in the pharmaceutical industry. more cohesive typically exhibit high compress-
Each of the samples was purchased from a different ibility because of their ability to entrain air
supplier but all had a similar D50 (median particle within an inefficiently packed powder bulk. As
size) and particle size distribution. All properties normal stress is increased, this air is forced out,
were measured using standard test protocols for significantly reducing volume. From a practi-
the instrument (FT4 Powder Rheometer, Freeman cal perspective, powders that exhibit high com-
Technology) (6). pressibility are more susceptible to consolidation.
Figure 3 highlights differences between the five These results indicate that Samples 1, 2, and 3 are
supplies with respect to specific energy (SE), com- less likely than Sample 4 and most of all Sample 5
pressibility, and permeability. SE is a dynamic to exhibit substantial consolidation during long-
term storage under stress, for example, under likelihood of detecting differences, thereby maxi-
their own weight in a hopper or storage vessel. mizing a manufacturer’s ability to judge whether
Such compressibility can also indicate a potential supplies are equally acceptable.
for difficulty in feeding or tableting operations.
Permeability values quantify a powder’s ability Looking ahead
to transmit air and are determined from measure- New pressures on supply chain management in-
ments of pressure drop across a powder bed at a tensify requirements for robust specifications for
constant, defined air flow rate. Sample 5 gener- products and raw materials. Identifying the prop-
ates the highest pressure drop, indicating that it is erties that define the in-process performance of
the least permeable sample. Like compressibility, raw ingredients and feedstocks, and their com-
permeability is often linked with cohesion in the patibility with different equipment, is critical
powder bed, with more cohesive powders exert- for manufacturers. Powders can be particularly
ing greater resistance to air flow. Powders with challenging in this regard, with specifications
low permeability do not release air easily and this routinely failing to detect a material that goes on
can be problematic in processes such as die fill- to exhibit poor performance.
ing and tableting. Complete, uniform die-filling The data presented here illustrate how advanced
relies on the powder settling to form a uniform, powder testing based on the measurement of dy-
efficiently packed dose; tablets containing air are namic, shear, and bulk properties, can sensitively
more likely to be physically unstable and prone differentiate materials that are notionally com-
to capping. More generally, low permeability can parable, helping manufacturers to make a smart,
also adversely impact gravitational flow (4). informed choice of supplier. Armed with a clear
Shear stress, a shear property, was also mea- understanding of exactly what constitutes an ac-
sured in this study, but the results provided no ceptable supply, manufacturers are in a better
differentiation, exhibiting a %RSD of ~6% across position to build a supply network that answers
all five materials. Shear cell analysis is a valu- to economic constraints while simultaneously
able technique for assessing the ease with which meeting evolving needs. Such understanding also
a powder transitions from the static to dynamic provides a secure foundation for the adaptation
state following consolidation, and the data sug- of existing processes to deliver new drugs, in
gest that in such circumstances, the powders may response to disrupted supply chains or grow-
behave comparably. Set against this result are the ing demand.
dynamic and bulk property data that suggest the
powders may behave differently. In reality, the rel- References
1. R. Mullin, Chem. Eng. News, 98 (16) 30 (2020).
evance of different properties varies from process 2. B. Van Snick, et al., Int. J. Pharm., 549 (1–2) 415–435 (2018).
3. M.S. Escotet-Espinoza, et al., Powder Technol., 339, 659–676
to process, highlighting the importance of testing (2018).
powders under relevant conditions and identify- 4. J. Clayton, Org. Process Res. Dev., 19 (1) 102–109 (2015).
5. J. Clayton and T. Mollner, “Integrating Powder Characteriza-
ing which properties are most applicable. Sensi- tion into Raw Material Selection and Process Optimization,”
PharmTech.com, Article (Oct. 1, 2019).
tive, multi-faceted powder testing maximizes the 6. R. Freeman, Powder Technology, 174 (1) 25-33 (2007). PT

Manufacturing
Containing and Enhancing

Potent Particles with
Micronization
Andy Maitland
M
A multilayered processing icronization is an important tool for developing new
approach ensures safe drugs, its primary advantage being that it is scalable
handling and content
from the early stages of development through to com-
uniformity of highly
potent APIs. mercial volumes. The micronization process is both
well-understood and cost-effective.
With the increased number of potent drugs in development, having
the capabilities to handle and process them is becoming imperative. De-
velopment partners with the specialized expertise and infrastructure
required to handle potent APIs play a key role in the supply chain of next
generation medicines.
Particle-size reduction leads to an increase in the surface area of drug
molecules, enabling a faster dissolution rate while potentially improv-
ing the bioavailability of poorly soluble compounds. By controlling the
particle size, better content uniformity is achievable, as well as reduced
segregation/sedimentation of formulation blends.
For high potency APIs (HPAPIs), micronization is a cost-effective
method of helping to ensure content uniformity. For HPAPIs, where
batch volumes are often smaller and of higher value, ensuring dose uni-
formity and reducing process waste is crucial. Beyond HPAPIs, microni-
zation is useful for the development of inhaled powders, oral suspensions,
and ocular formulations, as these approaches require a specific particle
KWANCHAIFT - STOCK.ADOBE.COM
size to ensure formulation performance and patient acceptance.
Andy Maitland is Micronization for oral drug delivery

operations and supply
The Developability Classification System (DCS), which is an exten-
chain director, Catalent.
sion of the Biopharmaceutics Classification System (BCS) shown in
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Table I, is used as a formulation development tool to Co-micronization consists of two steps: blending
help assess the best formulation for an API. The DCS the API with an appropriate surfactant and subjecting
categorizes APIs according to their dose solubility the mixture to the standard micronization process.
ratio and permeability. Those APIs that are amenable The surfactant enables more of the drug to dissolve
to simple tableting or powder-in-capsule delivery are and is more commonly used to overcome develop-
likely to fall into Class I, as molecules that are both ment challenges with drugs that are both highly po-
soluble at their administered dose and fully permeable, tent but poorly soluble. Along with improving solu-
whereas those that are neither soluble at a given dose bility, co-micronization can improve flowability of
nor permeable, fall into Class IV. Many drugs now in micronized powders, reduce re-agglomeration, and
development fall into Class II, having low solubility improve the wettability of micronized particles.
at the given dose but high permeability. Drugs that
have poor permeability properties but readily dissolve Jet milling process
represent DCS Class III compounds. Of the micronization options available to devel-
The DCS gives greater insight into the solubility opers, jet milling is one of the most common, as
behavior of molecules in Class II, by splitting it into it allows material with an average particle size of
two sub-classifications. This split is made based on the 1–10 microns to be produced. A jet mill has no
concept of a solubility-limited absorbable dose (SLAD), moving parts, does not heat up, and is relatively
which represents the dose above which absorption of simple to operate.
a compound is limited by its solubility. At doses below Jet mills use high-pressure nitrogen gas to force
the SLAD, designated DCS IIa compounds, a drug’s the API into the mill, where the API particles collide
absorption is limited by its dissolution rate, whereas with each other and the sides of the mill, reducing
at doses above the SLAD, the absorption is limited particle size. The flexibility and scalability of the
by the drug’s intrinsic solubility. These are designated process allows quantities from just a few grams of
DCS IIb compounds. API, right through to metric ton quantities, to be
Micronization is effective at improving the dissolu- micronized as the size of the mill is increased.
tion rate for DCS Class IIa compounds and making
them easier to dissolve. It is not typically the primary Handling HPAPIs
tool to address the challenges of DCS IIb molecules, As with handling HPAPIs at any stage of process-
but for those that are close to the border between ing, when looking to micronize potentially potent
DCS IIa and IIb, co-micronization can be an effec- and harmful compounds, there are many consid-
tive method to improve solubility. erations to weigh. Depending on the drug develop-
Table I. The Biopharmaceutics Classification System (BCS).
BCS Class Solubility Permeability Absorption Pattern

I High High Well absorbed
II Low High Well absorbed
III High Low Variable
IV Low Low Poorly absorbed

FORMULATION DEVELOPMENT IS SCIENCE
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advanced formulation technologies, and the art of accelerated technology selection and optimization.
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Manufacturing
ment stage, adequate toxicity information could be flags in the molecule and comparator molecules.
lacking, and therefore it is common to use default For preclinical programs, in-vitro genotoxicity data
classifications (both potent and toxic) to ensure may be available, as well as information on the
worker safety during manufacturing. Matching the mechanism of action and cytotoxicity. Through
compound to the micronization capabilities, and the clinical phases, information on animal stud-
securing appropriate containment equipment, are ies, expected dosage levels and human data will be
the next steps of program onboarding. generated, and as the data package increases with
A materials categorization group, perhaps sup- information, assessment on necessary handling
ported by expert opinion, reviews API data to and containment may need re-evaluating.
decide whether a company’s facilities and equip- When working with full commercial products, a
ment are capable of undertaking the manufactur- full data package is required as a safety data sheet
ing process. Typically, the information required at (SDS) is unlikely to be enough, and a permitted
this stage includes matching the API characteris- daily exposure (PDE) limit or an occupational ex-
tics to facility capabilities; identifying the needs for posure band (OEB)/occupational exposure limit
equipment containment and the equipment scale re- (OEL) report from a toxicologist is important.
quired; specifying the cleaning of multi-use equip-
ment; the desired yield; and whatever containment Onion skin approach
monitoring may be necessary. Other information The onion skin model (Figure 1) illustrates a design
to be considered may cover restricted drug classes, philosophy that allows containment activities to
controlled drugs, and environmental issues. be built out from a core to ensure all controls and
Once the material categorization has been assessed measures are in place for effective handling and
alongside the necessary control measures, options operator safety.
can range from processing of non-potent APIs in an At the center is “control at source,” which involves
open bay, the use of flexible containers, or processing the appropriate equipment to be installed within a
in hard-wall isolators for HPAPIs. facility to carry out the micronization, at the ap-
The priority is to ensure operator safety and hav- propriate scale, and with the correct seals to handle
ing the appropriate containment measures and equip- potentially hazardous materials. Beyond that are
ment cleaning processes in place to reduce risk of ex- the engineering controls that cover the contain-
posure. Investment in equipment, operator training ment and isolation requirements. The third layer is
in current good manufacturing practices, process the transfer ports and interface into the isolators,
safety, and cleaning procedures are paramount. which are crucial to ensure containment integrity.
The development phase of a drug will influence The final, “physical” layer is the design of the facility,
what data should be available; and a more conser- with its extraction system, and access controls for
vative approach may be required if data are miss- staff into the area handling the materials.
ing. For a drug at a very early development stage, Above the physical installation are the processes
clues to its potency may need to be taken from that dictate the safe handling, the establishment
the targeted therapeutic area, alongside structural of standard operating procedures and paperwork,
Figure 1. The “onion skin” design philosophy.
is highly efficient at protecting
operators, and is designed to give
maximum external environmen-
tal protection from the HPAPI.
Other benefits include accurate
control of temperature and rela-
tive humidity, and the capability
to operate under controlled light-
ing conditions when processing
light-sensitive compounds.
and the cleaning and maintenance of the facility. Assessing outsourcing needs
Staff must be trained and educated on safe work- For developers looking to choose an outsourcing
ing practices along with ongoing monitoring of the partner for HPAPI drug development, it is crucial
facility to ensure its continued compliance with to assess the needs of the project in terms of end
regulations and design protocols. result, but where safety is paramount, the invest-
ment and operating practices of a company are a
Hardwall containment top priority. Finding a partner that has the expe-
For maximum containment when processing rience, infrastructure, and capabilities to handle
HPAPIs, a hardwall approach is the most effective, projects as development progresses can help re-
and can enable facilities to handle OELs as low as duce the risk of projects being delayed and im-
tens of nanograms per cubic meter. pacting the success of a commercial launch.
In these scenarios, micronizers can be installed With the growing number of drugs that are being
within isolators purged with nitrogen for enhanced developed considered potent or highly potent, the
manufacturing safety, eliminating the risk of dust outsourcing industry has adapted, and there has
explosion for compounds with low minimum ig- been large-scale investment among service compa-
nition energy values. The size of the facility can nies to accommodate the need for manufacturing
be up to commercial scale, and can provide better with HPAPIs. What is also known is that HPAPIs
efficiency by utilizing continuous milling opera- have formulation challenges in terms of solubility
tion, eliminating the need to stop and change out and dose uniformity, and micronization can play a
raw material or micronized drums. An automated key part in ensuring these new drugs can be deliv-
FIGURE COURTESY OF THE AUTHORS.
washing system can be included to reduce operator ered effectively to patients. Its applicability to HPA-
intervention, as well as options to accommodate PIs in terms of yield efficiency, scale up capabilities,
flexible sampling schemes without the need for cost-effectiveness, and regulatory understanding
external equipment. means micronization is a solution that can assist at
Such a system requires significant capital expen- early stage development and continue throughout a
diture, but gives a very high degree of automation, drug’s journey towards commercialization. PT
Manufacturing
Considerations for DPIs

and MDIs in Inhalation
Drug Delivery
Jennifer Markarian
I
Experts share best practices n inhalation drug delivery, various milling and micronization
in designing, manufacturing, processes have been used to manufacture particles for dry pow-
and scaling up dry powder der inhaler (DPI) and metered dose inhaler (MDI) drug–device
inhaler and metered dose
inhaler drug–device combination products. The trend today, however, is an increas-
combination products for ing use of engineered particles, such as those made by spray drying
inhalation drug delivery. for DPI applications. Pharmaceutical Techology spoke with Carolyn
Berg, vice-president, Inhalation and Carla Vozone, vice-president, In-
halation Strategy, Innovation, and Partnerships, at Catalent; Robin
Heath, head of new product innovation and commercial management,
and Peter Hirst, commercial vice-president, at Recipharm; and Sandy
Munro, senior vice-president, pharmaceutical development, at Vec-
tura. These contract development and manufacturing organization
(CDMO) experts shared their perspective on trends and consider-
ations for choosing and designing a drug delivery device.
Inhalation delivery trends

PharmTech: What do you see as the key trends in manufacturing of
inhalation drugs?
Berg (Catalent): There is a trend toward spray drying and away from
milling/micronization for a variety of reasons. These include a desire to
overcome formulation challenges where high doses of drugs are needed,
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[where] the molecules are potent and, most importantly, to meet the target
product profile of the products in development. Achieving an exact par-
ticle size and characteristic that will translate into a clinical benefit is key.
Inhaled particle engineering has paved the way for drugs to be devel-
oped to tackle more complex diseases, such as lung cancers and infec-
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Manufacturing
tions caused by viruses, fungi, and bacteria, as well drug to the lung. In the DPI world, these same particle
as airborne pathogens such as tuberculosis, influenza, engineering technologies can again reduce the inter-
Ebola, measles, and SARS-CoV-2. action between powder particulates, allowing a freer
Perhaps the biggest challenge for CDMOs in spray flowing, easily dispersed powder, which can be tuned
drying is being able to scale up from bench/lab spray- to a specific size distribution and appearance and ulti-
ers to [current good manufacturing practice] CGMP mately deliver the drug to the correct area of the lungs.
commercial scale, and understanding how the tem- The infrastructure to handle these complex drug
perature, flow rate, spray position, droplet size, and products successfully is significant, with health
drying time influence particle size and [how the] and safety requirements, environmental conditions
electrostatic charge of the particle needs to be opti- (temperature and humidity), and use of solvents to
mized to ensure efficient particle aerosolization in a consider along with the physical handling of these
drug delivery device. Developing inhaled drug prod- free-flowing powders when it comes to device filling.
ucts will always be more technically challenging than These may pose a challenge for drug developers, and
for other more conventional routes of administration. CDMOs can bring their expertise and facilities to
However, advances in both the knowledge of the the forefront in this new wave of challenging inhala-
physicochemical properties of inhaled drug particles, tion drug development.
and manufacturing knowhow, can help to accelerate
the development of more molecules for inhalation. “Inhaled particle engineering
Heath and Hirst (Recipharm): Many existing drugs are has paved the way for drugs to
low molecular weight, crystalline substances, which be developed to tackle more
can be micronized into a targeted size suitable for in-
complex diseases.”
halation product development. These drugs are stable
and well understood, and they are relatively low-dose
—Carolyn Berg, Catalent
products in the range of micrograms. Many new drugs
being developed, however, are complex biomolecules, For biologics, such as proteins, peptides, nucleic
which have issues with physical stability and are often acids, and bacteriophages, we are seeing new meth-
delivered in higher doses owing to their low potency. ods to manufacture drug products. Inhaled biolog-
A recognition of new global pressures towards more ics have high specificity that may reduce ‘off target’
sustainable products is driving the investigation into side effects. These new inhaled treatments may be
alternative propellants in pressurized MDIs (pMDIs), for local (lung diseases) and also systemic delivery
providing new potential formulation opportunities. A for the treatment of other illnesses, due to the non-
suspension pMDI can be prone to issues with physical invasive method of delivery and rapid absorption.
stability, where the suspended crystals grow and alter Munro (Vectura): There is huge interest in the develop-
the performance of the product over time. Particle en- ment of inhaled biologic products for the treatment
gineering technologies offer unique opportunities to of niche diseases or the more intractable areas of the
protect against this detrimental effect as well as offer- major respiratory diseases such as asthma and [chronic
ing enhanced dispersibility and targeted delivery of the obstructive pulmonary disease] (COPD). In turn, this
interest in biologic therapy drives an increased inter- the patient remembering to take their medicine regu-
est in nebulization, particularly via more sophisticated larly. In the earlier stages of development, the advan-
smart nebulization technologies. tage to this type of technology is in the clinical trial
setting, where it could potentially be used to validate
“Another area that is clinical trial outcomes for individual patients.
beginning to gain traction
is connected device Selecting a device
PharmTech: What are the considerations for choos-
technologies for all delivery
ing DPI vs MDI?
platforms ... where the issue Munro (Vectura): The tendency is for pMDIs to be
is often around the patient used for very established potent small molecules or
remembering to take their combinations of the same, typically for the treat-
ment of asthma and COPD, whereas DPIs, which
medicine regularly.”
are also used in these indications (often to deliver
the same molecules as for the pMDI), can also be
—Sandy Munro, Vectura
used much more broadly than pMDIs because they
In the DPI space, simple, capsule-based inhalers are able to deliver much higher doses. So in an en-
continue to be popular. The design is not especially vironment where the trend is towards higher doses
sophisticated, but these non-proprietary, off-the-shelf and where biologic therapies are becoming much
device types are cost effective, flexible, and perform more common, typically requiring higher doses,
well. They can either be used through development, the DPI platform along with nebulization is much
or they can be used early on in development and more likely to be used. Additionally, pMDIs are
then switched to a more sophisticated device for final very easy delivery devices to use but can be quite
commercial presentation. Another key trend is the difficult to use well. This is fine where the pMDI
emergence of intranasal products as a delivery sys- delivery platform is being used to deliver low-cost
tem. [There has been an] explosion of interest in the potent small molecules with a broad therapeutic
use of intranasal delivery in nose-to-brain delivery for window but will be less acceptable in an environ-
a broad range of [central nervous sytem] indications ment where there needs to be more assurance that
and vaccine delivery, removing the requirement for the patient has received the correct dose. The other
delivery via injection. COVID-19 has also generated major difference is that pMDIs are reservoir devices
many intranasal therapy ideas. so typically need to be overfilled by as much as 40%
Another area that is beginning to gain traction is to ensure that they reliably deliver each dose up to
connected device technologies for all delivery plat- the end of the stated use period so the overfill be-
forms. The thought [is] that this technology can offer comes waste assuming that the patient discards the
huge advantages in the battle against major diseases device after the stated number of uses. This waste
such as asthma and COPD, where there are many can be expensive for more valuable drugs. As part
good medicines but where the issue is often around of the trend towards biologics, less regular dosing
Manufacturing
is a likely outcome so a reservoir device that makes portunities for the formulation to interact
sense for a month’s treatment of a regularly taken with the elastomeric components of the valve.
medicine makes less sense for a therapy that may Reservoir DPIs contain bulk formulation,
only be taken once a month whereas a unit dose which is dispensed in small doses each time
DPI or a nebulization therapy is entirely suited to the patient actuates the device. The inherent
this new treatment paradigm. The pMDI definitely design of this device type potentially leaves it
has an important role to play in the fight against more exposed to the elements, and it can be
respiratory disease but this tends to be with long challenging to dispense doses accurately.
established molecules more than it is with the ther- • Excipient compatibility is one of the most
apies of the future. critical aspects during development for any
Berg (Catalent): The real choice when selecting one inhalation platform. Although there are a
delivery device over another centers on the type of limited number of approved excipients for in-
molecule, type of formulation, molecule stability, haled products, they must be managed and
and the respirable dose that can be delivered from screened for early in the process.
the device. DPIs provide better physicochemical sta- In addition, if a drug developer wishes to utilize
bility, as MDIs have limitations such as sedimen- a bespoke delivery device for patent protection
tation and crystal growth. Furthermore, MDIs are purposes, then a DPI will be selected. These de-
constrained by high dose requirements, as in the vices tend to be bespoke, rather than ‘off the shelf’,
case of inhaled antibiotics with nominal doses up to often requiring simultaneous development of the
~600 mg. As previously mentioned, inhalation drug device, the formulation, and the filling and assem-
development is increasingly tackling complex dis- bly process, all of which adds complexity into the
eases and looking to deliver larger molecules such product development and approval processes.
as oligonucleotides, peptides and proteins, antibod- Conversely, the design of a pMDI is generally
ies, and nanobodies. The structure of these mole- more universal and more cost-effective. It does not
cules, their potencies and formulation parameters, require the design of a bespoke device, and the
make them candidates for dry powder formulations device is typically able to be filled using already
achieved through spray drying. installed filling equipment.
Heath and Hirst (Recipharm): When selecting an ap-
propriate device for a specific drug formulation, Design and scale-up
several factors must be considered: PharmTech: What are some best practices in design,
• pMDIs as a platform are limited by the volume manufacture, and scale-up?
of the formulation in the metering chamber Heath and Hirst (Recipharm): It is important to iden-
(typically <100 µL), and there are considerations tify, optimize, and control the parameters that
with drug solubility if making a solution. will influence the finished product’s performance,
• In terms of protection from the environment, in terms of dose delivery and therapeutic effect.
a pMDI formulation is contained within a These include API particle size, device component
sealed aluminium cannister, but there are op- dimensions, and the formulation. Manufacturing
process parameters, such as time and temperature, new product accordingly. This forethought will
are also important to consider. save considerable development time and capital
Above all, it is important to design development outlay associated with modifying existing equip-
processes with the commercial stage in mind. ment or procuring new.
Scale-up often entails moving to multiple items Munro (Vectura): One important consideration is
of equipment and the involvement of multiple working in development with equipment and ma-
people, which means a process that was originally terials that are felt to be representative of what will
designed at small scale using single items of equip- be used at the clinical or commercial scale. A good
ment and a restricted group of people has to be example in the DPI space might be to use the same
replicated multiple times. filling principle to fill the powder into the capsule
or blister as is going to be used in the clinic and
“Developing robust processes, the commercial product. The methodology used to
including robust analytical fill powder products can have a huge influence on
test methods, is key from the how well the powder aerosolizes when the device
very beginning of the project is used, so there can be a clear connection between
the filling technology used and the performance of
to streamline scale-up.” the product; every effort should be made to keep
the performance of products consistent throughout
—Robin Heath and the development process. Often, what makes the
Peter Hirst, Recipharm most sense is getting to a commercially relevant
Developing robust processes, including robust manufacturing scale as soon as possible or picking
analytical test methods, with minimized varia- processes that are more readily scalable.
tion of critical parameters, is key from the very The early adoption of lean manufacturing tech-
beginning of the project to streamline scale-up. The niques ensures optimal utilization of resource and
ability to automate or at least semi-automate pro- equipment. Bottlenecks and constraints are iden-
cesses needs to be considered during the product tified early, enabling efficient capacity planning.
development process. Repurposing existing equipment and challenging
In addition, it is critical to ensure a robust existing set-up, clean-down, and turn-around pro-
manufacturing strategy is in place prior to in- cesses aid in efficient utilization. It is important
dustrialization. An understanding of the factors that new equipment should be sourced that is di-
that influence the finished product batch size and rectly scalable from that used during early-phase
manufacturing throughput is fundamental in de- development to prevent unnecessary duplication
termining both capacity and unit price. in setting critical quality attributes and critical
Where commercial-scale equipment already ex- process parameters. Involving late-phase manu-
ists, which is more often the case for pMDIs, prod- facturing teams early in the development phases
uct development should consider the process that to ‘debug’ any potential challenges early in the
is already installed and, where possible, design the product lifecycle really helps streamline scale-up.
Manufacturing
Perhaps the anticipated increase in the develop- Almost anything can have the potential to impact
ment of biologic processes will result in a need to product performance. Even the way in which com-
think differently about the manufacturing equip- ponents are cleaned can matter, so every aspect
ment employed. Traditional pharmaceutical man- relating to the manufacture of components needs
ufacturing processes have typically used stainless to be tracked and understood, even if these steps
steel equipment designed to be used many times in the manufacturing process are at the supplier’s
and often with multiple actives. In the future, the sub-supplier, because the merest change has the
absolute requirement to determine that equipment potential to impact product performance.
is free from any contamination may either drive Vozone (Catalent): From a regulatory standpoint,
the use of more dedicated equipment, or perhaps, inhaled combination products are a single entity
to single-use disposable manufacturing equipment. that involves multi-center review by the Center for
Really understanding the raw materials going Drug Evaluation and Research, Center for Biolog-
into the process is important. Fully characteriz- ics Evaluation and Research, and Center for De-
ing the raw materials, while also trying to submit vices and Radiological Health, and are approved
multiple different batches of the raw materials via a new drug application. However, developing
into the process, preferably covering the range of a combination drug–device product brings to-
anticipated material properties, allows for better gether two distinct competencies that often reside
understanding of the impact of these raw material in separate companies, with different develop-
properties on the performance of the final product. ment approaches. Drug development and medi-
Within Vectura, the process of developing the cal device experts need to cooperate closely to
device is not separate to the pharmaceutical de- develop an effective and safe integrated product
velopment process for a medicine. Everything is for patients. The design of the device is an itera-
progressed in a very integrated way because every tive process framed by the intended use, patient
change, either to the device, the formulation, the population, and environment of use, and requires
manufacturing process or even the analytical human factors studies to demonstrate a patient’s
methods used to characterize it can have a huge ability to operate the device in a safe and effective
impact on how the device is seen to perform. It manner. With the introduction of digital inhalers,
is very dangerous to look at variables in isolation electromechanical compatibility and the software
when there can be such significant interactions be- and data integrity need to be also factored in dur-
tween the many different types of variables ing the development process.
Immediate challenges in the short term revolve CDMOs play a critical role in the integration
around speed of supply due to increased demand of device considerations for customers to ensure
for device components, as well as excipients and that the target product profile and product perfor-
APIs, with potential pinch-points around lead mance are adequately achieved. Early communi-
times to be overcome. In terms of device, [other] cation between all parties involved is particularly
considerations relate to materials of construction important for a successful combination of both
or the quality of the mold tools for plastic parts. drug and device design. PT
BIG
SMALL
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SERVICES
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FIND OUT MORE

Manufacturing
Predicting Tablet Potency in

Continuous Manufacturing
Ravendra Singh
I
A modular toolbox n continuous pharmaceutical manufacturing, real-time
enables residence time assurance of critical quality attributes (CQAs) is highly desired.
distribution-based control for
Among CQAs, control and assurance of tablet potency has
continuous pharmaceutical
manufacturing. been challenging due to lack of real-time measurement sensors
tied to optimization programs. A modular self-contained toolbox
developed using Python programming has been demonstrated to
predict tablet potency based on a residence time distribution (RTD)
model and apply a diversion strategy to divert out-of-specification
tablets. The modular toolbox can be integrated with any commer-
cially availabe tools to control tablet potency, can automatically
calibrate the RTD model for different formulations and processes,
and can be used to predict outlet concentrations, assuming accu-
rately quantified inputs.
Using RTD to evaluate quality

Quality control is always an important topic in continuous pharmaceu-
tical manufacturing. To ensure high quality tablets, examinations after
and predictions during production can be applied (1). Using RTD-based
control systems to predict the quality of tablets is an efficient method
(2). The following describes the theory supporting a toolbox to predict
certain component outlet concentrations of a continuous pharmaceutical
Ravendra Singh is
manufacturing plant and shares simulation results.
ANTON - STOCK.ADOBE.COM
Assistant Research Professor,

NSF-ERC C-SOPS,
The toolbox can work in a standalone mode reading and writing
Department of Chemical and
Biochemical Engineering, data between .csv files and can make real-time predictions based on
Rutgers, The State University
inlet concentration reads from these .csv file. The toolbox can output
of New Jersey.
a diversion signal for the rejection gate, to divert tablets containing
Figure 1. Workflow of stand-alone self-contained tool.
Figure 2. Prediction module workflow.
RTD parameters Inlet concentration
Calculated
Pulse response Convolution
outlet concentration
Rejection signal Comparison

FIGURES COURTESY OF THE AUTHOR.
components outside of the preset limits. Addition- and real-time inlet concentration. The toolbox
ally, the toolbox can fit the RTD model to a series will compute the convolution of the RTD model
of experimental data to calculate RTD parameters. with the inlet concentration and provide real-
The current version of the RTD based toolbox time predictions of the outlet concentrations of
has two modules. For prediction of the outlet con- the product. Figure 1 shows the general workflow
centration, the inputs are RTD model parameters of this module.
Manufacturing
The toolbox can be integrated with sensor de- point per second. Higher frequency is supported, but
vices and real-time monitoring software to col- modification of the code is needed. Once the direc-
lect data from the plant. The prediction and the tion and filename are selected, the RTD-based control
diverge signal can be sent to control platforms to toolbox will monitor the .csv file and read new inlet
communicate with the reject gate or a direct com- concentration data points from the file.
munication with the plant can be established. For Similar to the inlet concentration, the RTD model
RTD model fitting, a measured pulse or step re- parameters should be stored in a .csv file. Parameters
sponse of certain inlet concentrations is needed as fitted in an RTD model fmodule can be read as well
inputs. Fitting will be done by the program auto- as other parameters generated from different sources.
matically with RTD model parameters as outputs. After reading all inputs, the RTD-based control
toolbox convolutes the data point with the RTD
Real-time prediction of model. According to the properties of convolution,
tablet content uniformity adding the convolution results of each input data
An RTD model is used to predict the outlet con- point in time series will lead to the convolution of the
&'()*+)
centration of the tablets from a continuous phar- whole input signal. Each time the prediction of outlet
&'()*+) maceutical manufacturing plant
!!"# "#$ % & !$% "#$ ' ("#$!! !
based Equation 1: concentrations will be compared with the preset upper
!"#$%&'%
and lower limits, before running the program. If the
!!"# "#$ % & !$% "#$ ' ("#$!! ! !"#$%&'%
&'(),+) prediction falls within the limitation, the reject signal
[Eq. 1] of tablets will be 0, meaning that the tablets produced
&'(),+) '#(#! )"#$ '
#"&'('! )
)
where E(t) ("#
is the)pulse
#& $ %response%of" an * RTD% model, are qualified. Otherwise, the reject signal will be 1,
&! !"#$%('%
'%*+),- .
Cin is the real time input concentration,
'#(#! )"#$ ' and
"
) out is
#"&'('! ) C and the rejection gate will reject the produced tablets.
("# ) #& $ % % " * % &! !"#$%('%
the outlet concentration. This RTD-based
'%*+),- . control
" !"#$%&'()*+)
toolbox keeps computing convolution of the inlet RTD modeling and experimental data
concentration with the pre-fitted RTD !"#$%&'()*+)
model. !!"# "#$ %
The tank-in-series modeling ' ("#$!! has! been
& !$% "#$ approach !"#$%&'%
used
to develop! this"#$
toolbox.
% & !$%The
"#$ module
' ("#$!!is used
! to!"#$%&'%
fit an
The toolbox can output !"#$%&'(),+)
!"#
RTD-model based on Equation 2:
a diversion signal for the
!"#$%&'(),+) '#(#! )"#$
#"&'('! )
' )
("# ) #& $ % "* &! !"#$%('%
rejection gate, to divert tablets %
'%*+),- .
"
%
#"&'('! )
'#(#! )"#$
containing components ("# ) #& $ % % "
'%*+),- .
*'
&! !"#$%('%
%
)
) " [Eq. 2]
outside of the preset limits. Here, E(t+td) is the response signal, n is the number
)
The inlet concentration should be a real-time of tanks that need to be determined, τ and td are fur-
updated .csv file, which can be generated by a real- ther parameters which need to be determined. Among
time prediction tool (e.g., Process Pulse II [CAMO]). them, τ is the mean residence time and td stands for the
The real-time prediction tool should receive inlet delay time. To determine RTD parameters, an experi-
raw data (spectra) from near infrared sensors and ment was performed to generate the outlet concentra-
update the input file frequently, less than one data tion response of a pulse or step input concentration.
Figure 3. The verification of the tool. Measured concentration and fitted model.
The parameters, n, τand td are Figure 4. Pulse response of residence time distribution (RTD) model.
obtained through parameter esti-
mation, which minimizes the dif-
ference between the experimental
and predicted outlet concentration
E(t+td). This optimization is based
on Nelder-Mead method, which is
integrated into the Python library
scipy.optimize and with the help of
open-source tool fminsearchbnd.py.
Figure 3 shows verification of the
toolbox. Note that, the experimen-
tal data points are measured from
a different unit operation (feeder)
and are not the RTD data needed
Manufacturing
Figure 5. Prediction of outlet concentration and reject signal. 1: accept, 0: reject.
for diversion decisions. The purpose here has been

The modular toolbox
to verify the functionality of the developed tool. The
toolbox fits the model well with the data. This module
can be integrated
of the toolbox is implemented based on tank-in-series with any commercially
model. However, this module has the flexibility to use available tools to control
the axial dispersion model as well. tablet potency.
Results and discussions ing plant. The toolbox has two integrated mod-
Figure 4 shows the pulse response of the RTD model ules to complete each task. These modules can be
with real feed frame RTD parameters. Figure 5 used together in a continuous process or be used
shows the convolution prediction result with the separately. The data transmission between the
model and measured inlet concentration data. The toolbox and control platform, and also among the
red dashed line are limits of the concentration and toolbox itself, is based on .csv files. These provides
the black line is the reject signal. When outlet con- the flexibility to use this tool with any commer-
centration falls in limits, the signal goes to 0, other- cially available complementary tools. This feature
wise the signal goes to 1. guarantees the openness of the toolbox and its
overall convenience.
Conclusion
Python implementation of the RTD-based control Acknowledgements
toolbox can finish not only the task of fitting the This work is supported by FDA.
RTD tank-in-series model, but also use the model References
and an input signal to predict the outlet concentra- 1. A. Bhaskar, F.N. Barros, and R. Singh, Int J Pharm 534(1–2)
159–78 (2017).
tion of a continuous pharmaceutical manufactur- 2. A. Bhaskar, R. Singh, J Pharm Innov) 14 (3) 316–331 (2019). PT
Development
Shining a Light on
Photochemistry in Flow
Andrew Mansfield
C
The ever-increasing interest hemists in academia and industry have been performing
in photochemistry has reactions that are initiated by heat or a chemical reagent
inspired the development of for many centuries. Advancements in technology com-
innovative, modular flow
photochemistry reactors. bined with the rediscovery of new ‘reagentless’ activa-
tion methods—such as using light in photochemistry and electrons
in electrochemistry—have changed the way researchers devise syn-
thesis routes toward novel molecules and set up their experiments.
Photochemistry has gained much recognition over the past 20 years,
and this growing trend has led to the development of innovative,
modular flow photochemistry systems that allow users to efficiently
switch between chemistries—saving time and money.
Historical background
Photochemistry is a branch of science concerned with the chemical
effects of light, and, in nature, it is the basis of photosynthesis. In
chemistry, the fundamental aim is the selective activation of mol-
ecules to promote novel chemical transformations that are cleaner
and greener under mild conditions. Traditionally, natural light from
the sun and mercury or xenon lamps were used to perform photo-
SERGEY YAROCHKIN - STOCK.ADOBE.COM
chemical reactions—involving cycloadditions (1), cyclizations (2,3),

rearrangements (4), and oxygenations—for the synthesis of natural
products and molecules of interest in industries such as pharmaceu-
ticals and agrochemicals, as well as in research institutions. Using
photons from a broad spectrum of wavelengths served as a powerful
Andrew Mansfield is flow
chemistry leader at Syrris. tool to access singlet and triplet states for the conversion of simple
structures into complex products inaccessible by thermal processes.
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Development
Each bond in a molecule absorbs photons with a dis- activation methods have expanded the range of
crete wavelength, causing a change in its electronic available chemistry for this technique while reduc-
configuration. Having knowledge of this prior to ing the number of reagents required.
activation allows chemists to finely tune reactions
for the required transformation. These light sources, Flow photochemistry reactors to the rescue
however, required filters to narrow the wavelength Parallel to the increasing awareness of new photo-
bandwidth, and over irradiation of the reaction chemistry methods is the growing use of modern
mixture often led to decomposition of starting ma- flow chemistry techniques to enhance the control of
terials and products, resulting in the formation of these reactions. Chemists ask many questions when it
byproducts via undesired reaction pathways. comes to planning experiments, from specifics about
There has been a surge in research in this area reaction conditions—based on the stereoelectronic
of chemistry and, over the past 15 years, the de- properties of the molecules involved and the experi-
velopment of single—or near enough monochro- mental set-up—to the analysis and purification of
matic—wavelength light-emitting diodes (LEDs). the target product. They also follow trends of new
LEDs have emerged as a more economical and techniques, transformations, and catalysts, which is
environmentally friendly alternative to broad exactly what has happened in the area of continuous
spectrum lamps for activating molecules or func- flow photochemistry, where its uptake is reflected in
tional groups of interest. Not all organic molecules the dramatic increase of publications and conferences
are photoactive, so the field of photochemistry in recent years (1).
has moved on to include the use of valuable or-
ganic and transition metal photocatalysts such as Benefits of flow photochemistry
tris(bipyridine)ruthenium(II) [Ru(bpy)3]2+ to aid The benefits of flow chemistry over traditional
the desired process (5). The photoexcited catalyst batch techniques are widely known, and these
generates reactive radicals of the starting materials, benefits translate equally to flow photochemis-
therefore offering an alternative reaction pathway try. Most of the benefits offered by flow chemistry
via homolytic bond cleavage and single electron come from the precise control of reaction param-
transfer processes. Photochemistry—with or with- eters, such as temperature, mixing, stoichiometry,
out a photocatalyst—tuned to a specific wavelength and reaction times, in a chemical reaction. In a
can therefore provide access to transformations in flow photochemistry reactor, this control can be
which the user can make and break bonds in a further increased over traditional batch photo-
unique fashion. This not only allows for cleaner chemical techniques by improved irradiation of
reaction mixtures that are easier to purify, but also the reaction for better selectivity, reaction scal-
reduces the number of steps required to get to the ability, and reproducibility. It is also possible to
desired product. Photochemistry also allows access control reaction exposure times to prevent over ir-
to chemistries that cannot easily be achieved using radiating, minimize product degradation, and pre-
round bottom flasks and traditional methods. For vent unwanted side reactions. Further benefits of
example, photocatalyzed carbon–hydrogen (C–H) particular importance include the increased safety
window of reactors of this type and the ability to chemistry—or by increasing the number of reactors,
perform multiphase chemistry. either by linearly expanding the number of reactors
in series, or by external or internal numbering, which
Flow photochemistry reactors can be a more costly approach. The photon flux into
Photochemistry reactors increasingly use single wave- the reaction can also be increased. In photochemistry,
length LED light sources to control reaction selectiv- the photon is considered a reagent. In a photo-medi-
ity, but this is not the only benefit. LEDs are energy ated reaction, increasing the light intensity increases
efficient and have a low heat load, enabling them to the number of photons, allowing the use of the same
be used at high intensities with relatively low cooling photochemistry reactor for process scale-up.
required. Their small irradiation window also allows
them to be directed toward the channel’s in-flow re- Applications
actors. However, even with more efficient LED light Photochemistry has already been successfully used
sources, the problem with light irradiation still persists; across a broad range of chemistry applications, in-
photons lose energy quickly over very short distances cluding organic synthesis in drug discovery, fine
from their source. This light attenuation, described by chemicals and agrochemicals, polymer synthesis
the Bouguer-Lambert-Beer law equation, is a problem in materials science, water treatment, and degrada-
with round bottom flasks used in batch processes as tion studies. From the point of view of a synthetic
only the outer region of the reactor is irradiated. In organic chemist, it is only in more recent years that
contrast, the microcapillaries used in flow reactors en- key transformations have been developed in flow
able transmission of much more light to the center of photochemistry. These include photocycloadditions,
the reaction, giving a more homogeneous irradiation. photoisomerizations, photooxygenations, cyanation
Reaction scalability. It could be argued that the popu- and halogenation reactions, light-induced cross-
larity of photochemistry among synthetic organic coupling reactions, and late-stage C–H activation.
chemists in industry has suffered from its limited Halogenations. The development of flow photochem-
scale-up potential. This can be attributed to the at- istry for halogenations such as bromination and fluo-
tenuation effect of photon transport, which increases rination is of great value to the pharmaceutical and
with reactor volume, limiting the scalability of pho- agrochemical industries. Brominated compounds
tochemistry even on a laboratory scale under batch are common building blocks for organic synthe-
conditions. It also limits the classical method of flow sis, whereas fluorinated compounds—containing a
chemistry scale-up—increasing reactor volumes and single fluorine substituent or a trifluoromethyl (CF3)
flow rates. Reactor volumes are often increased in a group—provide improved chemical stability, modu-
dimension-enlarging fashion, and this too is restricted late lipophilicity, and binding selectivity due to acid/
by the attenuation of light. base characteristics. The need to access aryl bromides
Flow photochemistry offers some strategies that is widespread in fine chemicals synthesis, such as, in
can help in the scale-up of photocatalytic reactions. the synthesis of antibacterial, antifungal, and antiviral
Throughput can be enhanced by running the reactions compounds. Flow photo-bromination can be achieved
for longer—a well-known benefit of traditional flow using N-bromosuccinimide, which requires light acti-
Development
vation. Unlike batch procedures, flow does not need a chemistry and provides easier access to 1O2 in a
toxic radical initiator, such as azobisisobutyronitrile much safer process than in batch due to the inher-
(AIBN), and presents a much higher yield and selec- ent ease of pressurizing flow reactors and, therefore,
tivity for mono- over di-brominated products on both to control and scale reactions using reactive gases.
small and large scales in a shorter time (6). These reactions also meet some principles of green
The importance of fluorine atoms in molecules chemistry, such as atom economy. For example, the
has sparked an interest for many research groups continuous flow approach with blue LEDs has been
in academia, especially those working on building used to obtain a key cannabidiol intermediate, giv-
flow reactors. Photocatalytic trifluoromethylation ing 44% conversion and 55% selectivity from (R)-
and perfluoroalkylation of a range of heteroarenes, limonene in five minutes, at a productivity value
using inexpensive gases and reagents, has been ap- of 580.8 µmol/min after increasing radiant flux,
plied successfully in the presence of low loading temperature, and flow (Figure 1) (9). This would
of a transition metal photoredox catalyst and blue otherwise have required a more challenging syn-
LEDs (7). This has also been performed using the thetic route employing large amounts of explosive
organocatalyst, Eosin Y, as a more cost-efficient al- oxidants under high temperatures, with long reac-
ternative to metal-based photocatalytic processes, in tion times, low atom efficiency and yields of less
a white LED microreactor (8). High conversion and than 20%, as well as low stereo- and regioselectivity.
isolated yields are obtained in a very short time in Light-induced cross coupling reactions. Another huge
continuous flow compared to in batch. benefit of flow chemistry is the ability to generate un-
Photooxygenations. Photooxygenations use oxygen stable intermediates or reagents in situ and use them
to produce singlet oxygen (1O2) from triplet (3O2)— on demand. Cross-coupling reactions are common
or ground state—oxygen by light irradiation in the in organic chemistry and are particularly important
presence of a suitable photosensitizer. Flow pho- in the formation of carbon–carbon bonds. The irra-
tochemistry has the ability to perform multiphase diation of light has, in some cases, proven beneficial
Figure 1. Photooxgenation set-up in flow to make a key cannabidiol intermediate from (R)-limonene. TPP is
tetraphenylporphyrin. BPR is back pressure regulator. GPR is gas pressure regulator. LED is light-emitting diode.

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Development
for increasing yields and selectivity in these types of ible light photoredox catalysis (450 nm blue LEDs and
reactions. The work of Alcázar and coworkers (10) an iridium or ruthenium photocatalyst) (11).
demonstrates this well, combining continuous flow Increasing complexity. Flow photochemistry has seen
synthesis with solid materials, for instance, zinc, for an increase in researchers developing novel method-
the light-induced conversion of in-situ formed organo- ologies that combine several transformations into a
metallic intermediates and innovative analytical tools single step reaction, allowing for shorter reaction times
for process control. While these reagents may be com- and higher product yields compared to batch synthesis,
mercially available, they are dangerous to handle and and improved safety profiles. For example, tetrahydro-
can be air and moisture sensitive, meaning that the β-carbolines were coupled with α-keto vinyl azides
purity is different every time they are used, which through a visible light-mediated photocascade strategy
makes it difficult to reproduce the results. involving photosensitization, photoredox catalysis, and
A photoinduced Negishi coupling over two-steps a [3 + 2] cycloaddition reaction (Figure 3) (12). The mi-
is described, with the formation of the organozinc croreactor was fed with the substrates and a solution of
reagent in flow followed by coupling with the aryl- the catalyst, and the reaction was triggered by incidence
halide halide in the presence of blue LEDs, a nickel of white light, resulting in 18 examples with 62–81% iso-
catalyst, and ligand (Figure 2) (10). lated yields, obtained in a residence time of 43 minutes.
These cross-coupling reactions traditionally use a
transition metal catalyst; however, recent research dem- The future is bright
onstrates the desired transformation being achieved in The vision of continuous flow photochemistry is to
the absence of a catalyst by using only light in a flow have a broad portfolio of reactions that can be seam-
photoreactor. The obvious advantage of this workflow lessly implemented, while meeting the key trends
is further limiting the amount of
Figure 2. An automated flow system for a light-mediated Negishi cross-
material used and wasted. coupling reaction. NMR is nuclear magnetic resonance. BPR is back
pressure regulator.
Late-stage C–H activation. The di-
rect C–H functionalization of het-
erocycles has become an increas-
ingly valuable tool in modern drug
discovery, but there are relatively
few methodologies for synthesiz-
ing complex organic molecules.
More recently, late-stage alkyla-
tion—ethylation, methylation, and
cyclopropanation—of biologically
active heterocycles, such as the po-
tent vasodilator, Fasudil, has been
successfully achieved using stable
organic peroxides activated by vis-
in synthetic organic chemistry
Figure 3. Flow photochemistry for building complexity in molecules. TBHP
for use in the pharmaceutical, is tert-butyl hydroperoxide. LED is light-emitting diode.
agrochemical, and fine chemical
industries as well as in academia.
The increased demand for, and
interest in, photochemistry re-
volves around the continuing use
of flow systems that deliver ef-
ficiency, control, and scalability
unmatched by batch chemistry,
as well as ongoing innovation in
reactor technology.
References
1. D. Cambié, et al., Chem. Rev. 116 (17) 10276–10341 (2016). 7. N.J.W. Straathof, et al., ChemSusChem 7 (6) 1612–1617 (2014).
2. J.H. Rigby, et al., J. Am. Chem. Soc. 122 (28) 6624–6628 (2000). 8. N.J.W. Straathof, et al., J. Flow Chem. 4 (1) 12–17 (2014).
3. C. Sambiagio, et al., Trends Chem. 2 (2) 92–106 (2020). 9. A.R. Aguillón, et al., Org. Process Res. Dev. 24 (10) 2017–2024
(2020).
4. M.B. Plutschack, et al., Chem. Rev. 117 (18) 11796–11893 (2017). 10. I. Abdiaj, et al., J. Org. Chem. 84 (8) 4748–4753 (2019).
5. N. Hoffman, Chemical Photocatalysis, B. König, Ed., pp. 111–138 11. D.A. DiRocco, et al., Angew. Chem. Int. Ed. 53 (19) 4802–4806
(De Gruyter, Berlin, 2013). (2014).
6. M. Waterford, et al., Aust. J. Chem. 74, 569–573 (2021). 12. D. Chandrasekhar, et al., Org. Lett. 18 (12) 2974–2977 (2016). PT
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Quality
Pharmaceutical Knowledge
Management: Experiences
in Drug Development
and Manufacturing
Marco Adami and Alessandro Regola
K
Knowledge management nowledge management has always been a key factor for the
has gained increasing successful development and manufacture of pharmaceu-
importance in the tical products. Understanding the chemical and physical
pharmaceutical industry
over the past 10–15 years processes underlying material interactions in dosage forms
formulation, production processes, and product storage along its shelf-life
is fundamental in assuring quality, efficacy, and safety of medicinal prod-
ucts. Knowledge has always directed the design of dosage forms (e.g., in
terms of selection of excipients and primary packaging materials) and the
development of production processes (e.g., in terms of process technology
applied and process controls implemented).
Knowledge is normally assumed to be a combination of education and
experience. Advanced education on chemistry, physics, microbiology, biol-
ogy, analytics, materials properties, process technology, pharmacokinetics,
pharmacology, toxicology, and physiology must be available in the phar-
Alessandro Regola,*
a.regola@libero.it, is the AFI maceutical industry. Nowadays this ‘traditional’ form of education has to
vice president in Milan and
be integrated with a decent knowledge of information technology, data
coordinator of the AFI Quality
Section, and Marco Adami is management, and processing. In addition, highly innovative and special-
an AFI member in Milan and
ized areas, like biotech or advanced therapy, require specific knowledge
coordinator of the Validation
WRIGHTSTUDIO - STOCK.ADOBE.COM
Group within the AFI Quality of biochemistry, genomics, and cell engineering.
Section. They both serve as
To be successful in the pharmaceutical industry, scientific knowledge
pharmaceutical consultants in
quality systems and research must be supported by skills in other areas such as project management,
and development, respectively.
risk analysis, budgeting and cost controlling, and regulatory affairs.
*To whom all correspondence Given the large and different number of fields of knowledge required
should be addressed.
to develop and manufacture medicinal products, it goes without say-
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Quality
ing that these activities are mostly team based, and Figure 1. The scale of knowledge.
the necessary knowledge must be efficiently made
available and shared between the different people
within the team to ensure success.
All the above-mentioned considerations are in-
cluded in the International Council for Harmonisa-
tion (ICH) Q10 guideline on Pharmaceutical Quality
System (1). In chapter 1.6.1, knowledge management
is described as follows:
“Product and process knowledge should be man- As an example, when the ICH Q10 guideline
aged from development through the commercial
life of the product up to and including product dis- defines the goal of technology transfer activities,
continuation. For example, development activities the term knowledge rather than information is ap-
using scientific approaches provide knowledge for
product and process understanding. Knowledge propriately used:
management is a systematic approach to acquiring, “[…] the goal of technology transfer activities is
analysing, storing and disseminating information to transfer product and process knowledge between
related to products, manufacturing processes and development and manufacturing, and within or
components. Sources of knowledge include, but are between manufacturing sites to achieve product
not limited to prior knowledge (public domain or realization” (1).
internally documented); pharmaceutical develop-
ment studies; technology transfer activities; process
validation studies over the product lifecycle; manu-
facturing experience; innovation; continual im- Types of knowledge in
provement; and change management activities” (1). the pharmaceutical industry
Several types of knowledge can be identified in the
Types of knowledge pharmaceutical industry.
To be efficient, any organization should not only Product/process and quality system knowledge. Knowl-
process information but also create information edge related to product/process is of a scientific–tech-
and knowledge. Though often used interchangeably, nical nature, is typically developed and gained during
knowledge and information are not the same thing. product and process development, and is captured and
Knowledge is neither data nor information, though maintained in technical documentation such as quality
it is related to both (2). All organizations need data, specifications, manufacturing methods, qualification,
but data give only a partial description of a situation, and validation reports. This type of knowledge is typi-
though it is important because it is the ‘raw material’ cally transferred from development functions to man-
which, after contextualization, creates information. ufacturing departments during scale-up and indus-
FIGURES COURTESY OF THE AUTHORS
In the same way, information is a flow of messages trialization steps of product lifecycle. It might also be
that, after using logical deductions and consolida- transferred from one manufacturing site to the other
tion, becomes knowledge. Knowledge develops over during technology transfers in the marketing phase of
time, through experience. At last, expertise is the the product. Product/process knowledge typically in-
efficient use of knowledge. The hierarchy is graphi- creases rapidly during development to reach a plateau
cally expressed in Figure 1. in the commercial phase; however, during the lifecycle
of product ‘quantum leap’ increases of knowledge may This is quite evident in development activities where,
occur typically originating by changes in technology by definition, knowledge about products and processes
or by trouble-shooting activities due to manufactur- builds up by following standard company develop-
ing problems. It is of utmost importance that these ment procedures. The quality-by-design (QbD) ap-
increases in product/process knowledge are captured proach in development activities facilitates and further
and consolidated in company documentation. strengthens knowledge build up and capture in this
Quality system-related knowledge is more in line crucial phase of product lifecycle.
with good practice (GxP) guidelines—regulatory in The importance of the knowledge gained during
nature and typically developed through adaptation pharmaceutical development activities is empha-
to changing laws and guidelines, self-assessments, au- sized in ICH’s Q8 guideline (3). It is in pharma-
thority inspections, and deficiency letters. This type of ceutical development that the knowledge is created
knowledge is usually kept and maintained in policies, leading to product and process understanding and
procedures, and manuals, and is less impacted by the product realization after transfer to the manufactur-
type of products manufactured and the field of activ- ing site. A pharmaceutical development department
ity of the company than the product/process related plays a central role in the development phase of a
knowledge. Several quality system elements (e.g., how product, not only from the technical point of view
to manage complaints or changes) are independent but also due to collaborative interactions with most
of the technology in place for manufacturing. Being of the company functions, as illustrated in Figure 2.
related to regulatory aspects, this type of know-how This is a unique opportunity for people to gain
is usually impacted by the regulatory classification knowledge and grow professionally. In view of the
of products (prescription vs. over-the-counter [OTC], inherent complexity of product development, it is
generic vs. proprietary, biotech vs. small molecule vs. evident that empiricism or personal initiative would
advanced medicinal therapy product [ATMP]), and by never allow these goals to be achieved. There must
the reference market (worldwide vs. local). be an integrated knowledge management system.
Internal vs. external knowledge. Another way to classify One example of internally developed knowledge
knowledge is its origin. We can distinguish between during manufacturing is process validation. By per-
knowledge internally developed in the company from forming this exercise, companies develop significant
the one gained by means of external contacts and re- information about the impact of material attributes
lationships. The classification is not of minor impor- and process parameters on product quality. This is
tance as it impacts significantly on the methods neces- the case in both prospective validation and ongoing
sary to capture and consolidate the know-how. process verification. The knowledge gathered is usually
Internally developed knowledge originates from captured in process validation reports.
routine activities performed according to company Another opportunity to internally develop knowl-
procedures. Despite being standard processes, these edge on products and processes is the management
activities always generate new information on proof nonconformities. Deviations in the manufactur-
cesses and products. In this case, knowledge develops ing process or in the stability profile of some batches
and increases in the frame of standardized process. trigger investigations, which result in an increased
Quality
Figure 2. Collaboration is at the heart of pharmaceutical development. Blue and yellow circles outline intra-
Figure 2. Collaboration is at the heart of pharmaceutical development. Blue and yellow circles outline intra-pharmaceutical development
pharmaceutical development interactions and inter functions interactions, respectively. ADME is absorption,
interactions and inter functions interactions, respectively. ADME is absorption, distribution, metabolism, and excretion; QA is quality
distribution, metabolism,
assurance; andand
R&D is research excretion; QA is quality assurance; R&D is research and development.
development.
QA
Corporate
ADME Operations
Toxicology
Marketing
QA
Pre-
formulation R&D
Discovery Formulation
development
Clinical
supply
Analytical
development
Stability
Clinical
team
Regulatory
affairs Documentation
knowledge about the interaction between material at- or from low-shear mixing to high-shear homogeniza-
tributes and process parameters with product quality tion in creams manufacturing. All these cases, while
attributes. For instance, unexpected results might be potentially negatively affecting product quality or sta-
observed when changes in raw material quality are bility, lead to an increased understanding of products
implemented, even within the approved specifica- and related processes and are typically captured in the
tions. For example, slight changes in the particle size adaptation of materials specifications or manufactur-
of excipients may impact the compression behavior of ing methods, in other words, in the revision of critical
a dry mix for direct compression or slightly increased materials attributes and critical process parameters.
amounts of peroxides in raw materials may lead to Knowledge is frequently acquired externally. This
significant variations in the degradation rate of the is the case, for instance, of attendance to courses,
active ingredient in the formulation. Also, changes in meetings, and symposia organized by academic,
production technology, usually made to improve not professional, industry, or health authorities, orga-
only productivity but quality reproducibility as well, nizations, or associations. Other opportunities to
can lead to an unexpected adverse impact on product gain new information and understanding of prod-
quality. This may happen, for example, when moving ucts and processes are the interaction with materials,
from conventional granulation to high-speed or fluid- equipment, or instrument suppliers, with providers
bed granulation in solid oral dosage forms production of special good manufacturing practice (GMP) ser-
vices (e.g., in the area of qualification and validation for regulators in the manufacture of medicinal prod-
or analytical testing) and with external subject matter ucts. For example, this topic was not mentioned at all
experts and consultants. Self-training on scientific in the 2001 version of the European Union (EU) GMP
and technological literature and on new or revised Annex 15 (Qualification and Validation), while the
guidelines issued by professional/industry asso- term ‘knowledge’ is reported several times in the 2015
ciations or by authorities may also be regarded as a current version (8), which also includes a definition of
source of external acquisition of knowledge. Partici- knowledge management in its glossary section. Other
pation in interest or discussion groups in professional guidelines, such as ICH Q8 (Pharmaceutical Develop-
and industry associations on specific topics is another ment) and ICH Q9 (Quality Risk Management) (3,9)
route to gain externally acquired knowledge. emphasize the concept of scientific knowledge. This
Externally acquired knowledge is typically more alignment between knowledge and science is referred
difficult to capture in the company quality system to the explicit knowledge, while the concept of tacit
because it needs to be stored/retrieved/changed dif- knowledge is a bit lacking. Also, there are no doubts
ferently from the knowledge acquired over the years that the highly regulated environment of the pharma-
by a company formulation scientist or a manufactur- ceutical industry has traditionally given higher value
ing engineer. However, quantum leaps in company to the explicit knowledge (in its standard operating
know-how are often obtained through external ex- procedures [SOPs], reports, specifications, best prac-
perience and competence. tices, training, etc.). From this perspective, ICH Q10
Categorization of knowledge. Many authors have dealt is the turning point as it not only refers to the ‘infor-
with the process of knowledge creation. Knowledge mation’, which is explicit knowledge-related, but also
has been classified into various categories; for exam- emphasizes concepts such as ‘product and process un-
ple it has been categorized as explicit, implicit, or tacit, derstanding’, ‘manufacturing experience’, ‘innovation’,
while other authors refer to implicit, explicit, proce- ‘continual improvement’, and ‘change management ac-
dural, declarative, or strategic knowledge. However, tivities’, which are clearly tacit knowledge-related.
this is not the goal of this paper and the reader is re- Both types of knowledge, explicit and tacit, are
ferred to the literature on the subject (2,4–7). Distinc- required for a project to be successful. However, ac-
tion between tacit knowledge and explicit knowledge is cording to the so-called 80/20 rule of knowledge (7),
commonly found in many publications. Although sim- the majority (approximately 80%) of knowledge is
plistic, this classification is very useful for the purpose tacit, and therefore linked to experience and exper-
of this paper. In simple terms, ‘explicit’ is transmittable tise, while only 20% is explicit, and therefore easily
knowledge while ‘tacit’ is what is in everyone’s head. documented. It is recognized that the latter usually
Explicit knowledge is easily documented and captured solves approximately 80% of the problems, while the
for example in protocols, reports, procedures, and so former typically solves about 20% of the higher-grade
on. Tacit knowledge is person-related and, therefore, is problems. Knowledge management is key to ensure
hard to formalize and transfer. knowledge flow within organizations.
There are no doubts that between 2001 and 2015 For example, let us assume that we are dealing with
knowledge management became an important topic the formulation of a low-dose direct compression tab-
Quality
let. Typically, a pre-blending of the active ingredient quite easy to update a raw material quality specifica-
with an excipient is used to ensure good uniformity tion, justify it, and make the information available to
of the final mixture. In this case, technical discus- all involved personnel, it might be more difficult to
sions with manufacturers/suppliers of excipients can record and trace all the steps and the processes that
be extremely useful, not only for the selection of the led the company to the change. Additionally, that
most appropriate grade of a given excipient but also for change would likely be treated individually with-
process optimization. Aspects such as previous experi- out any correlation with other similar or connected
ence and thorough practical knowledge of the material changes implemented on the same or other materi-
characteristics usually play a key role in making the als. For instance, the change in specification for per-
best decision. But this type of knowledge is something oxide content of a raw material could originate from
that is not easily retrievable in textbooks and can be a deviation or non-conformity experienced in batch
considered as a typical example of tacit knowledge, manufacturing, be the outcome of lengthy and com-
which can be converted to explicit thanks to interac- plex investigations, and be applicable to some for-
tions between people. Also, it is believed that this ex- mulations and not to others. It is difficult to assure
ample clarifies the difference between information and that the traceability of the development of this type
knowledge and highlights a key aspect of knowledge of knowledge increases for all products managed by
that it is related to human actions. a company and all over a long period of time. Prod-
uct quality reviews/annual product reviews partially
Knowledge documentation fulfill these requirements. They include all changes,
The easiest way to capture knowledge and to make it deviations, complaints, and quality events impact-
available to all potential beneficiaries is its incorpo- ing a product; however, they do normally cover a
ration into the quality system documentation imple- 12-month period and are limited to one product
mented in the company. New information, data, and only. In addition, their contents are strictly defined
results can be included, as applicable and appropri- by correspondent regulations (EU GMP or US 21
ate, in procedures, working instructions, methods, Code of Federal Regulations) and not always suitable
specifications, reports, and so on. The advantage of to capture all knowledge collected on the product
this system is that knowledge is consolidated in the and process during the period covered.
company and that the necessary information and The ideal document to collect and update the
training of all appropriate personnel is already or- knowledge gained must be designed to cover the
ganized according to company procedures and pro- entire lifecycle of a product and related processes,
cesses. Good examples would be a new analytical from the early formulation studies until the termi-
method or a new tool for risk analysis, which would nation of commercial manufacturing. The docu-
be respectively included in new versions of analytical ment could be defined as the ‘product lifecycle file’
methods or risk management procedures. and could be organized by topics (e.g., raw ma-
Unfortunately, this system is not applicable to and terials, packaging materials, production process,
not suitable for all types of new knowledge made analytical methods, analytical specifications).
available at the company. For instance, while it is Each topic (and subtopic) could describe all the
change history, with interconnection with other incremental innovation. This innovation testifies
topics for the same or other products. Of course, to increases of knowledge typically associated with
reference to quality system documentation could the concept of continual improvement throughout
be used to avoid unnecessary repetitions. For in- the life cycle of a product. Whereas, continuous
stance, using the above-mentioned example of the manufacturing or process analytical technology
change in specification for the peroxide content belong to the category of radical innovation.
of an excipient, this change could be traced in the Based on the authors’ experience, knowledge
section dedicated to raw materials and referenced management can promote innovation according to
to both the deviation report, which includes all the following drivers:
the investigations bringing to the change, and the • Knowledge management creates an open and
file managing the corresponding supplier change. transparent system favoring relationship build-
Reference could also be made to all other impacted ing and people interactions. This means acquir-
products and processes, if any. ing knowledge through collaboration which, in
turn, is a way to innovation.
Knowledge management and innovation • In current market scenario of intense competi-
In today’s complex pharmaceutical business world, tion, the industry is being forced to innovate
quality and innovation are the drivers for profit- to maintain this success. Innovation is strictly
able revenue growth and long-term sustainability. dependent on the availability of knowledge
Now more than ever, partnership and collabora- and has become increasingly complex. There-
tion are essential to advance drug delivery innova- fore, this complexity can be managed by
tion. There are several definitions of innovation in knowledge management.
the literature, but the ones that best clarify the role • Knowledge management favors the integration of
of knowledge management in innovation are those internal and external knowledge, thus making it
that look at innovation as a process of knowledge. more easily accessible and helping the conversion
Simply stated, innovation is the creation of new from tacit to explicit knowledge.
knowledge, and this could in turn result in changes • Knowledge management favors collaboration,
in the organization’s knowledge system (5,10–11). which means that knowledge can be shared and
Interestingly, in some of these papers, a distinction enriched. The skills acquired through collabora-
is made between radical and incremental innovation make innovative solutions more easily avail-
tion. The former is a sort of line extension of an ex- able, and this is particularly important in the de-
isting product, while the latter involves the applica- velopment of a new product and in fields where
tion of new technologies. Incremental innovation there is relatively little explicit knowledge, such as
is more tactical while radical innovation is key to gene therapy or cell therapy.
long-term success. Thinking of the pharmaceutical
world, the improvements that typically occur in Knowledge dissemination
technology transfer activities and/or in the man- An effective dissemination system has to be imple-
ufacturing phase of a product are an example of mented in the company to avoid knowledge loss
Quality
and dispersion. One simple way to disseminate nated to all potentially interested people in the
knowledge is through a training program, which company (e.g., by means of emails, newsletters,
each company must have in place to be GxP com- and/or regular update meetings).
pliant. It is essential that the training program Oral dissemination is also important; short
does not only reiterate the information currently briefings on new technologies, frequently associ-
available at the company or current regulatory or ated with new development projects running at the
GxP requirements but is continuously updated by company, could be organized to inform and trans-
subject matter experts. Regarding GxP require- fer knowledge to people not directly involved. Reg-
ments, it seems useful to have a regular review on ular information exchange sessions could involve
news and trends, even if not strictly related to the the attendance of different company functions and
operations ongoing at the company. For instance, departments, where each participant could pres-
a company operating in the field of non-sterile ent on ongoing projects and share experiences and
products would definitely benefit by a general knowledge gained through day-to-day activities.
training on requirements for sterile production. A The same approach could be used to disseminate
company manufacturing small molecules could information gained at external events, such as con-
get good ideas for improvement in knowing what gresses, meetings, or courses.
the requirements to produce biotech products are.
In respect of GxP regulations, it is important to Knowledge loss
establish a systematic monitoring program to be There are many situations where scientific, tech-
continually updated on new regulations and re- nological, and GxP/regulatory knowledge may
quirements, even in draft form, at least for the area be lost. Typical examples in the pharma industry
of operations. The most important organizations are subject matter experts leaving the company,
publishing norms and guidelines (e.g., European product transfer from development to commercial
Medicines Agency, US Food and Drug Adminis- production, product transfer to contract manufac-
tration, ICH, Pharmaceutical Inspection Conven- turing organizations (CMOs) or other manufac-
tion and Pharmaceutical Inspection Co-operation turing sites, and product discontinuation. Another
Scheme, World Health Organization, European critical situation may be a company acquisition or
Pharmacopoeia, United States Pharmacopeia) as change of ownership.
well as professional and industry organizations The key issue is almost always the change in
(e.g., Parenteral Drug Association, International product/process ownership; knowledge is not al-
Society for Pharmaceutical Engineering, Associa- ways and completely transferred when responsi-
tions for Professionals in Infection Control and bility for the product/process is transferred. This
Epidemiology, International Pharmaceutical Ex- issue is common when knowledge is documented
cipients Council, International Organization for in a very fragmented way; some pieces of the
Standardization) must be continuously monitored puzzle can be lost. The puzzle’s integrity must be
for new publications. The information about new maintained during transfer. Therefore, it is recom-
requirements or trends must be timely dissemi- mended that the scientific and technological know-
how is consolidated as much as possible into one or product quality must be under control), or between
a few documents. One document is easier to transfer manufacturing sites to achieve product realization.
without any loss of information, compared with many However, without the implementation of a skillful
different documents belonging to different company efficient knowledge management system, allowing
areas and functions. It is of utmost importance that people to interact directly, all these aspects would
these few documents collecting the vital information bring inefficiencies which, in turn, would lead to
for our products and processes are kept updated dur- missed business opportunities.
ing the ownership change. Very often the ownership People should perceive knowledge management
change itself generates new knowledge (e.g., in tech- as a routine part of their daily work. This is a cul-
nology transfer projects); this new knowledge must tural change and cultural changes are not easy to
be included in the documentation in a timely fashion. implement, they take time. Thus, knowledge man-
Loss of knowledge due to people leaving the com- agement requires strong sponsorship first from se-
pany or retiring can be prevented with a well-orga- nior management.
nized succession planning or back-up program. These Only a small part of the huge amount of infor-
programs identify persons that can substitute in the mation created by the pharmaceutical industry is
short-, medium-, or long-term persons in charge of utilized effectively. Knowledge management helps
key positions in the company; it is important that this generate an integrated source of information. The
program not only covers hierarchical positions, as it requirement is not to convert all the tacit knowl-
is often the case, but also key subject matter experts, edge into explicit knowledge, but rather to cre-
even if not positioned high in the hierarchy. In other ate a knowledge-driven culture, which promotes
words, a ‘knowledge back-up or succession plan’ must innovation. This is vital to provide competitive
be in place and continuously updated. Successors and advantage.
back-ups should not only be trained by the subject
matter experts but should also receive organized and References
1. ICH, Q10 Pharmaceutical Quality System, Current Step 4 Ver-
planned scientific and/or GxP training. sion (ICH, 2008).
2. T.H. Davenport and L. Prusak, “Working Knowledge: How
Organizations Manage What they Know,” Ubiquity, Research
Article, Aug. 1, 2000.
Conclusion 3. ICH, Q8(R2) Pharmaceutical Development, Current Step 4
Version (ICH, 2009).
The increased complexity of the pharmaceutical 4. I. Nonaka, Organ. Sci. 5 (1) 14-37 (1994).
5. P.V. Søberg and A. Chaudhuri, Knowl. Process Manag. 25 (2)
environment makes knowledge management an 88-96 (2018).
6. ISPE, “Knowledge Management,” a Supplement to Pharma-
essential requirement. Mergers and acquisitions ceutical Engineering (May 2014)
undoubtedly bring opportunities, but they also 7. N. Calnan, “The 80/20 Rule of Knowledge,” in Supplement to
Pharmaceutical Engineering, pp. 54–58 (May 2014).
raise challenges. Troubleshooting across a prod- 8. EC, EudraLex Volume 4, Annex 15: Qualification and Valida-
tion (Brussels, March 2015).
uct lifecycle also provides the opportunity for con- 9. ICH, Q9 Quality Risk Management, Current Step 4 Version
(2005).
tinual improvement. ICH Q10 recognizes the key 10. M. Du Plessis, J. Knowl. Manag. 11 (4) 20-29 (2007).
11. M. Gloet and M. Terziovski, J. Manuf. Technol. Manag. 15 (5)
role played by the technology transfer process for 402-409 (2004). PT
its interposition between development (where the

knowledge is created) and manufacturing (where
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APIs, EXCIPIENTS, AND

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FROM THE EDITOR

2 Rethinking, Recalibrating, and Retooling

6 API Development and Manufacturing: Advantages of Working with Small Molecules

12 Seeking Economies of Scale for Biocatalysis

18 Global Regulatory Approach to API Manufacturing

22 Building Robust Specifications Using Powder Testing

30 Containing and Enhancing Potent Particles with Micronization

36 Considerations for DPIs and MDIs in Inhalation Drug Delivery

44 Predicting Tablet Potency in Continuous Manufacturing

50 Shining a Light on Photochemistry in Flow

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Global Regulatory Approach

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