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Special Report Special Report

Sustainability through continuous manufacturing: hydrogenation, oxidation, chlorination, even at large scale in each parallel cation by extraction, with a ﬁ nal poli-
ﬂ uorination, ethoxylation, amidation,
shing step by batch crystallization);
reactor, which allows identical per-
Necessity, urgency, opportunities and challenges ammoxidation, pyrolysis, sulfonation, formance at different scales.  SRI International (SynFini platform
and ProSyn digital twin tool and on
diazotization, polymerization, cyanation,  Faster reactions: Large heat trans-
Preamble ﬁ ed, continuous, minimal to zero dis- DR. AMOL A. KULKARNI* lithiation, reactions involving organic fer area per unit volume, excellent scaling up to a modular platform);
he beginning of the chemi- charge, compact, green, solvent-free DR. SATYAM NAIDU VASIREDDY peroxides, etc. mass transfer and mixing rates  Virginia Commonwealth University’s

cal industry in India happened etc. While these aspects are not easy to MR. ANIL V. PALGHADMAL allow the reactions to be carried out Medicines for All Institute (M4ALL);

Tthrough the indigenous efforts achieve immediately, a steady develop- Chemical Engineering & Process Advantages of moving into CFS at very different conditions than a  Phlow Corporation (continuous
by Prof. P.C. Ray (Calcutta Univ.) ment will deﬁ nitely happen. Development Division Depending on speciﬁ c type of reac- batch operation, primarily reducing processes for US-based manufac-
through Bengal Chemicals and Pharma- CSIR-National Chemical Laboratory tions, CFS has more advantages over the reaction rate signiﬁ cantly. turing of essential medicines);

ceutical Works in 1892, followed by Considering the projected growth Dr. Homi Bhabha Road, Pashan the conventional batch process. For  Enhanced control: Flow chemistry  Pﬁ zer’s PCMM [Portable, Continu-

start of a few more exemplary chemi- of the Indian economy and per capita Pune – 411008, India development of new molecules, as well allows for more precise control of ous, Miniature, and Modular] system;
cal industries, viz. Alembic Chemical income, the specialty chemical industry E-mail: aa.kulkarni@ncl.res.in/ as formulations, it is more convenient reaction parameters, such as tempera-  Novartis-MIT Center for Continu-
Works (Vadodara), Unichem, Chemo is expected to grow at a higher rate than microreactors@ncl.res.in to screen the reagents, solvent, and ture and pressure, which can improve ous Manufacturing;
Pharmaceuticals, Zandu Pharma Works, before (also because of a growing and additives in batch. Simple small volume reaction selectivity and yield.  Continuous Pharmaceuticals (Inte-
Chemical Industrial and Pharmaceuti- demanding population). It is essential pumped through a reactor under con- ﬂ ow-reactors can be used for doing  Minimal waste: For the selectivity- grated Continuous Manufacturing

cal Laboratories (CIPLA), and East to enhance innovation and competitive trolled conditions, allowing for precise these studies simultaneously using sensitive reactions, CFS facilitates (ICM) technology) Mobile Pharma-
India Pharmaceutical Works, all before performance of this sector in order to control of reaction time, temperature, high throughput systems. The reactions producing minimal waste because ceuticals (MoP) plant;
the country got freedom. As of now, the position Indian specialty chemicals on and other reaction parameters and the involving multiphasic systems are often the reactions can be optimized to  Center for Regulatory Aspects for

number of chemical industries in India the global map and to meet the ever- reactions happen in a ﬂ owing stream limited by mass transfer and compact produce the desired product with Continuous Manufacturing, Univer-
is over 11,000 and the market size of growing needs as well as expectations of reactants. Some key beneﬁ ts of ﬂ ow ﬂ ow reactors can offer at least 10 to maximum selectivity, which re- sity of Maryland; and
the chemical and petrochemical sector of a prospering society. In this article chemistry include increased reaction 100 times higher mass transfer coefﬁ - duces the formation of unwanted  Biological Medicines on-Demand

in India is US$178-bn. (refs.: Invest we focus on necessity, urgency, oppor- efﬁ ciency, reduced waste generation, cient than a typical batch reactor; over by-products, provided the choice of (Bio-MOD platform).
India). In the recent past, a lot of tunities and challenges in adapting con- and improved safety. Additionally, ﬂ ow 50 to 500 times higher heat transfer reactor is correct. In general, such
impetus is being given on the pos- tinuous manufacturing. chemistry can facilitate the synthesis of area per unit volume; and can with- plants are more modular. These large scale efforts are back-up
sible opportunities for Indian chemical complex molecules that are difﬁ cult to stand extreme conditions. This helps by a large number of start-up ﬁ rms and
industry to be one of the options for Some information on continuous ﬂ ow produce using traditional batch methods. in carrying out exothermic reactions or A few challenges in its practice are government-led efforts including Con-
China or to reduce our import dependence synthesis (CFS) Some notable examples of ﬂ ow temperature-sensitive reactions in a far given separately towards the end of this tinuous Pharma, Snapdragon Chemis-
or to be self-sustained in certain areas, CFS, ﬂ ow chemistry, continuous chemistry include the synthesis of vari- better manner in continuous ﬂ ow mode article. try, NJ Biopharmaceuticals, Lonza
viz., pharma, which is almost like a manufacturing, etc. are synonyms of ous antiviral drugs, anti-inﬂ ammatory by even applying the desired tempera- Pharma & Biotech, Ampac Fine Chemi-
strategic sector when it comes to health the concept of carrying out a reaction or drugs (e.g., naproxen), the antimalarial ture proﬁ le along the reactor length. Necessity & urgency cals, TCG GreenChem, (Curia) AMRI
of the entire population in our country. any unit operation in continuous man- drug artemisinin, and some of the Global, Adesis, Phlow Corporation,
ner, known to chemical engineers for most expensive drugs (e.g., Ivacaftor). A few more advantages of ﬂ ow An international outlook Advanced Tech. & Manufacturing Insti-
In the last two years, a large number ages. Unlike batch operations, where Besides, the production of ﬁ ne chemicals chemistry include: For the ﬁ ne and specialty chemicals tute, J-Star Research, Continuity Pharma,
of new expansions (brown ﬁ eld) and the composition of the reaction mass and materials where synthesis time has  Safety: CFS using compact ﬂ ow industry in the Europe and Japan, the RAPID Institute (all from USA). A simi-
many new green ﬁ eld chemical plants and hence the heat demand continues been reduced to few minutes from several reactors as well as CSTRs in series concept of microreactors was getting lar number of efforts are ongoing in other
have got approvals from the Ministry to change with time, making it an un- hours in batch or semi-batch mode are also is inherently safer than batch reac- popular in early 2000 with very large countries (UK, Germany, The Nether-
of Chemicals and Fertilisers and its steady operation, a continuous opera- being realized at various scales. tions because of the small reacting efforts from IMM (Mainz) and Japanese lands, Spain, France, Canada, Russia,
afﬁ liated departments. These come from tion is always at a steady state and deli- inventory in the reactor at any point consortium on microreactor techno- Israel, Japan, South Korea, China, etc.).
a wider range of APIs, intermediates vers a consistent product quality at the A few reaction features where ﬂ ow of time. It can also reduce the risk of logy. Even now, while the world of The big pharma companies – Pﬁ zer,
for agrochemicals, dyestuff intermedi- outlet for a given set of inlet composi- chemistry is the best approach include: thermal runaways and explosions. ﬂ ow synthesis has moved from concept Merck, Amgen, Corteva, Dupont-Dow,
ates, fragrances, etc. Our industries are tion, temperature set along the length of (i) moderate to highly exothermic reac-  Scalability: Continuous ﬂ ow reac- to reality at large scale production, the Sanoﬁ , Inycte, Mirati Therapeutics,
making long term plans and exploring reactor, mixing and the extent of mass tions; (ii) reactions that are done at very tors are scale-up using the num- facilitation has largely happened through BMS, Lonza, Novartis, GSK, Takeda
possible ways to meet the desired pro- transfer (for multi-phase reactions). low temperatures for very long time; bering-up strategy; however, it also efforts by various consortia across the Pharma, Eli Lily, Abbot, etc. – also
duction capacities, secure raw materi- Continuous ﬂ ow synthesis gets away (iii) reactions that need to be performed poses a challenge of uniform ﬂ ow world, along with a few private players. have well-established programmes on
als through long term contracts, ensure from the batch-to-batch variations and at very high temperature in a very short distribution in a large number of Some such ongoing efforts include: continuous ﬂ ow synthesis and manufac-
processes in green ﬁ eld plants are safe thus is an excellent processing option time (e.g.., pyrolysis); (iv) reactions parallel reactors, which has multi-  CC Flow consortium in Austria turing, at lab, pilot scale and, in some
and with reduced carbon footprint, etc. for small as well as large volume chemi- involving highly reactive chemicals; ple solutions known at this moment. (University of Graz) and industrial cases, at commercial scales.
However, it is now necessary to move cal manufacturing. (v) selectivity sensitive reactions, etc. Numbering-up approach helps in partners;
towards more sustainable manufactur- Typical reactions that fall in these cate- ensuring laboratory scale condi-  Continuity Pharma (portable units What is the urgency?
ing platforms that are highly intensi- In CFS, reactants are continuously gories include aromatic nitration, tions in a single reactor are retained for continuous synthesis and puriﬁ - In the Indian ﬁ ne and specialty chemi-

166 Chemical Weekly October 31, 2023 Chemical Weekly October 31, 2023 167

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