INDENA:
CAPITALIZINGON HIGH
CONTAINMENTEXPERTISE.

THE APIS MARKET BETWEENCHALLENGES AND OPPORTUNITIES
According to a recent report from Italy’s
Chemical Pharmaceutical Generic Association(CPA) [link 1], the traditional active
pharmaceutical ingredients (APIs) market isfacing a series of challenges which include risingcompetition, Governments’ pressure on drug
prices aiming at reducing healthcare spending,regulatory burden, enormous investments
required for the launch of a NME, environmental,
health and safety costs, and labor costs amongothers.
In addition, the traditional generic APIs businessis struggling, and many big generic APIs suppliers
are changing their strategies, shifting fromthe traditional generic APIs field to emerging
therapies, most of which in the biotech area.
Another analysis [link 2 ] about the industry
released on January 2019 informs that the global
APIs market is estimated to reach USD 245.2
billion by 2024 from USD 182.2 billion in 2019, ata CAGR of 6.1% during the forecast period. The
increasing incidence of chronic diseases, growing
importance of generics, and the increasing

locations such as India or China hasn’t got soappealing anymore in recent years mainly due toquality and safety issues. It’s not by chance that
regulatory agencies in the US, and other markets
highly dependent on outsourced or offshoredpharmaceutical production, have stepped up
scrutiny of manufacturing facilities abroad.

uptake of biopharmaceuticals are some of theAn analysis by Ned Pagliarulo of BioPharma

major factors driving the growth of the global

Dive in April 2018 found that 39, or 64%, ofAPIs market.

the 61 warning letters sent out by the Office ofOn the other hand, concerns are growing about
quality lapses, Good Manufacturing Practice(GMP) violations and compromised data integrity
at low-cost manufacturing plants for APIs: thoseconcerns have revived demand for reliable
sources of supply in the US and Europe.
Sourcing APIs from economically attractive

2

Manufacturing Quality in the FDA’s Center for
Drug Evaluation and Research were to facilities
in India and China, compared with 25, or 57%, ofa total 44 warning letters in 2016. Data integrity
is also a growing concern as there are cases not
only of weak data collection, processing andstorage, but also of deliberate violations and datafalsification.

HIGH QUALITY HPAPIS:AN INCREASING DEMAND

One consequence of this waning confidence
in low-cost manufacturing plants has been
increased investments by Western API
manufacturers in new technologies and customsynthesis facilities, including capacity to
manufacture highly potent APIs (HPAPIs).
Estimates for the size of the global HPAPI
market vary, but most analysts agree thatstrong growth can be expected over the next
5–10 years. MarketsandMarkets™ estimatesthat the global HPAPI market will expand at acompound annual growth rate (CAGR) of 8.7%
from $17.72 billion in 2018 to $26.84 billion in2023 (MarketsandMarkets™, “High Potency APIs
/HPAPI Market worth 26.84 Billion USD by 2023,”
Press Release, April 2018).
Given such a scenario, the market is increasing
its demand of high-quality HPAPIs and pharmacompanies are more frequently outsourcing
to specialized CDMOs, given the need forspecialized technologies and a high reliabilityof supply.

3A large portion of the HPAPI market serves
demand for highly potent cancer drugs: therapid expansion of the global oncology market
indicates where HPAPIs are going, as populations
age, new therapeutic options extend survival
rates, and cancer drug candidates dominate
pharmaceutical R&D pipelines.
The IQVIA Institute for Human Data Science
believes the global market for oncology
therapeutics will be worth as much as $200
billion by 2022, averaging 10% to 13% growthover the next five years. IQVIA says that a totalof 63 new cancer drugs have entered the market
within the past five years.
On the other hand, advances in drug
development have generated more targeted andpotent drugs, and also antibody-drug
conjugates, with fewer side-effects, again in thefields of oncology and also for otherage-related or chronic diseases. This has fueled
strong market demand and growth for HPAPIs
worldwide as well.

FACING MANUFACTURING CHALLENGES
OF A HIGH-QUALITY HPAPIS PRODUCTION
The rapid market growth in the highly potent
segment and the broader shift away from API
sourcing in low-cost territories make indeed
HPAPIs a winning proposition for Western
manufacturers. At the same time, they present a
number of manufacturing challenges, including
tough specifications for handling and producing
high-potency compounds, to guarantee a safe,
high-quality working environment free fromcross-contamination and exposure risk.
Upgrading existing API facilities requests
specialized containment provisions to makesure employees and their environment areprotected from exposure to toxic substances.
Such a choice, instead of investing in brandnew capabilities tailored specifically to HPAPIs,

may be not very cost-effective. Manufacturers
must also face the need to protect the active
pharmaceutical ingredients themselves fromcontamination or cross-contamination by otherHPAPIs produced at the same site.
A further complication is the lack of a universally
accepted definition for HPAPIs. One generally
acknowledged measure is an Occupational
Exposure Limit (OEL) of 10 μg/m3 of air or less.
The lower the OEL is, the more potent thesubstance and the greater the need for rigorouscontainment. That is assuming the manufacturer
has the necessary data to classify a substanceas a HPAPI, which is not always the caseespecially for early stage NCEs (in such a case, aconservative approach has to be adopted havingin mind the safey first).
Indeed, the risk-assessment process needs totake into account factors such as the differences
between potency and toxicity (e.g., a highpotency compound may be pharmacologicallyeffective at a low dose but toxic only at a muchhigher dose); or the difficulty of extrapolating
effects from clinical trials, designed specificallyto address predetermined endpoints in people
with preexisting conditions, to occupational
exposure of nominally healthy workers in HPAPI
facilities.

4INNOVATIVE TECHNOLOGY AND QUALITY
FOR A REAL COMPETITIVE EDGE
Given the challenges emerging in the global

production site: a kilolab dedicated to HPAPIs andmarket for HPAPIs, CDMOs have to face thetwo more new suites.

manufacturers’ increasing requests of expertise,safety and high quality products.

The new kilolab dedicated to HPAPIs (natural,semisynthetic and total synthetic) has been

Indena, the world’s leading company in theopened at the beginning of 2018. The kilolab

identification, development and production ofis designed to handle the production of toxic

active principles derived from plants, for use in

substances endowed with an Occupational

the pharmaceutical, health-food and personal

Exposure Limit (OEL) of 20 ng/m3. This investment

care industries, has being investing for years incomplements the already existing large scaleinnovative technologies and services, to further

suites and is capitalizing on more than thirty years

broaden its technological offer.

of experience in handling HPAPIs.

As a strategic approach, Indena treats other

Moreover, in 2019 the company will inaugurate twocompanies as partners rather than customers:

new suites: a pilot pharmaceutical plant for small

that’s why the company is able to offer a fullscale GMP productions and a new spray drying

commitment in order to develop new HPAPIs

system, both available from next June.

from early clinical stages up to commercial
manufacturing.

The new Indena’s pilot pharmaceutical plant willsummarize all the technologies available at theThe last important investments of Indena arecompany, but will be dedicated to productions

related to recent new plants at its Settala main

requiring a smaller scale (hundreds kg/year)

5and a higher flexibility. In this way, Indena will

The new equipment can handle organic solvents

be able to produce APIs for clinical trials (up toand is designed to carry out the production ofphase 3) and for small commercial requirements,

APIs and pre-formulated APIs (through sprayassuring a complete compliance with cGMP

drying in the presence of excipients) with an

guidelines. The new plant will work for extraction,

Occupational Exposure Limit (OEL) of ≥10 μg/m3.

chromatographic purification and synthesis.
Equipped with hastelloy, glass lined, stainlesssteel reactors, the new pilot plant can manage
processes at a temperature ranging from -80°C
to +200°C; reactors capacity ranges from 200 to1000 liters, suitable for batches from few kg to30/50 kg of APIs.
The second suite Indena is about to complete is a
PSD2 spray dryer. It will complement the existing

The new spray dryer will be completed withancillary equipment to manage all the production
processes, including secondary drying, sifting,blending, packaging, thus supplying a complete
service. Full analytical capabilities are supporting
the spray drying activities.
A further expansion is already planned andforesees the installation of another new smaller

equipment devoted to large scale spray drying

spray dryer (evaporation rate of 2 kg of water perfrom organic solvents, an activity the companyhour), able to handle APIs with an OEL of ≥1 μg/m3.

has been carrying out for more than 20 years.

On top of that, a multipurpose fermentation plant,

The PSD2 new spray drying system is a medium

suitable also for toxic APIs, from 1000 to 20000

size equipment for clinical and commercial needs.

liters is also available.

THE IMPORTANCE
OF A WELL TRAINED STAFF
In such a high-risk area as HPAPI production,
the deep preparation of the staff who manages
and handles HPAPIs on a routine basis is suchimportant as the quality and efficiency of theequipment and the facilities.
From Indena’s point of view, the “human element”– meaning highly qualified, motivated and trained
technical staff – as well as corporate culture
strongly oriented to quality and to tight HSE
policies are the two fundamental requirements
to ensure that HPAPI operations run safely,
seamlessly and efficiently.

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