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Overview of process development & optimization of APIs & small molecules from route selection & scale up to commercialization, by CDMOs and CMOs.

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01 Angelini Pharma

02 Anhui Ribobay Pharmaceutical Co.,Ltd

03 Appco Pharmaceutical Corp

04 Aragen Life Sciences

05 Arevipharma

06 Bio-Technology General Israel Ltd.

07 CARBOGEN AMCIS AG

08 CLEARSYNTH LABS LIMITED

09 CTX Lifesciences

10 ChemGenix Laboratories Pvt Ltd

11 Concord Biotech

12 Curia

13 Dalton Pharma Services

14 Dishman Carbogen Amcis

15 Evonik

16 Fermion Oy

17 GGC Chemicals and Pharmaceuticals

18 Grace

19 Huvepharma Italia S.r.l

20 Inabata France S.A.S

21 Interquim SA

22 Kekule Pharma

23 KriSan Biotech

24 LEBSA

25 Magle Chemoswed

26 Maithili Life Sciences

27 Menadiona

28 Minakem

29 Neuland Laboratories

30 Olon S.p.A

31 Onyx Scientific

32 PMC Isochem

33 Pfizer CentreOne

34 Piramal Pharma Solutions

35 Polpharma

36 Procos

37 Recipharm AB

38 Robinson Brothers

39 SAS Yslab

40 SIMS Srl

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42 Servier

43 Shanghai Chemspec Corporation

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48 ZACH System SA

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Overview of process development & optimization of APIs & small molecules from route selection & scale up to commercialization, by CDMOs and CMOs.

Q1. What is API process development?

Process development is the strategy via which a manufacturing process is identified for a drug substance from an early stage through scale-up and tech transfer to commercialization. Process development is carried out by process developers who work closely with process engineers and technology transfer teams to define suitable drug manufacturing routes in order to ensure seamless production, from milligrams to kilograms. 

Generally, process development studies provide the basis for process improvement, process validation, continuous process optimization, and any process control requirements. They anticipate and identify development and manufacturing steps which could affect the quality of the product, in order to control these variables during large scale custom API production. 

As drug development begins with API development and manufacturing itself, it is well worth considering the level of small to large scale custom API capabilities required for the substance of interest and outlining the goals for the API manufacturing and development project. A CDMO for API process development works with large and small molecule APIs as well as niche APIs.

Contract development and manufacturing organizations or a CDMO for API development provide such pharmaceutical API CDMO services including, but not limited to, advanced process development, scale up, analytical development, process safety assessment, and route development. Process development routes can differ from one CDMO for API development to another as it depends on variables like the quality of raw materials, target protein stability, purification strategies, downstream yields, scale, etc.

API process development is the work that leads to the efficient, reproducible, economical, safe and environmentally friendly API manufacturing and development in a regulated environment. During API process development special attention is paid to the chemical synthesis routes chosen for the drug substance.

 

API process development involves:

-  Route development and process safety assessment

-  Development of new, scalable API route options

-  cGMP Starting Material assessment

-  Starting material and other raw materials sourcing and development

-  Polymorph screening & salt selection

-  Analytical method screening and preliminary stability profile

-  Pre-formulation and preclinical supply

 

API process development is a crucial step in drug manufacturing for the following reasons:

-  Optimization of expression level and cell culture suitability for entering downstream processing

-  Purification of the target protein

-  Ensuring target protein stability through processing

-  Design for process robustness

-  Process meets criteria for process yields and cost of goods sold

-  Ensuring an acceptable drug substance storage time

-  Provide the correct drug substance composition

-  Design for process scale-up

Q2. What are the different pharmaceutical API CDMO services from process development to commercialization?

CDMOs for API development with small to large scale custom API capabilities provide a range of pharmaceutical API CDMO services which enable API development and manufacturing. These pharmaceutical API CDMO services, from early phase development to commercialization, are explored below: 

Step 1: Physicochemical Studies

In this stage of API development & manufacturing , the physicochemical properties of a drug substance are characterized and established. Every drug substance has intrinsic chemical and physical properties which need to be considered before API manufacturing & development can be conducted at a larger scale.

Therefore, physicochemical studies provide relevant information for formulation selection for later stages of clinical development and commercial contract manufacturing. Physicochemical studies further anticipate the need for molecular modifications.

 

Route Development & Route Optimization:

Synthetic route development or route scouting is an analytical development service carried out during the early stages of drug development that offers significant benefits by decreasing processing times, improving quality and safety profiles (via process safety assessments), reducing chemical waste production, and improving scalability. Route development further helps in identifying small to large scale custom API capabilities and custom synthesis technologies required to successfully carry out API production.

Furthermore, route development leads to route optimization. Route optimization can reduce costs, increase the efficiency of drug substance development processes, increase the safety of drug products, and accelerate the drug substance development and manufacturing process altogether. Route development and route optimization can be achieved by outsourcing API production to well equipped CDMOs for API process development.

 

Step 2: Reactor Treatment

API starting materials, selected during the early stages of analytical development, are treated in reactors with custom synthesis technologies to obtain the required intermediates.

Step 3: Purification

Intermediates are purified to obtain individual drug products via sedimentation, filtration, centrifugation, etc. Purification is an important step of API development as removing impurities without detrimentally affecting API yield is important. CDMOs for API development possess small to large scale custom API capabilities including reactor treatments and purification.

Step 4: Scale up

Scale up is generally defined as the process of increasing batch sizes. In process scale up, a formula is transformed into a viable, robust product by the development of a reliable and practical method of manufacturing that affects the orderly transition from laboratory to routine processing in a full-scale production CDMO facility. Scale up is further supported by technology transfer services.

Commercialization

The development of drug substances via contract manufacturing services, are usually followed by packaging selection, late stage analytical development services, and finally commercialization. Product commercialization processes involve complex multi-departmental (and often multi-organizational) collaboration to establish market access, patient and provider awareness, sales force readiness, customer support programs, supply chain preparedness, and more. CDMOs for API development may support commercialization activities by offering regulatory support and other services.

Q3. When does it make sense to use a CDMO for API development?

Before commencing the API development and manufacturing steps outlined above an organization needs to decide whether they will produce APIs or drug substances in house or engage in outsourcing their production activities to contract development and manufacturing organizations or CDMOs for API process development and manufacture. 

A pharmaceutical contract development and manufacturing organization or a CDMO, is a company which specializes in providing CDMO services ranging from drug substance development & manufacturing to pharmaceutical packaging services including pharmaceutical serialization and aggregation, with complete trust and transparency.

Outsourcing API and finished pharmaceutical drug product manufacturing to CDMOs has gained traction in the past few years. The decision to develop and manufacture in-house is becoming an exception as the complexity of drug candidates rises and cost pressures increase. Many pharma firms are turning to CDMOs to reduce capital investment and gain valuable specialized expertise without having to hire expensive, highly specialized scientists and other professionals.

With a CDMO for API process development and manufacture, sponsors get access to advanced process development services, custom synthesis technologies, equipment and facilities that would be hard to justify purchasing for isolated projects. Furthermore, CDMOs practice regulated GMP API manufacturing and development which ensures the production of high quality APIs with reduced risks of contamination and impurities. 

 

The following situations, amongst various others, warrant outsourcing a part or the entirety of ones’ manufacturing process to a CDMO:

-  Companies that want to focus on late stage activities such as marketing their product.

-  Companies that want extensive process safety assessments to ensure safety of drug products for clinical development.

-  Companies looking to reduce costs of production such as investing in costly custom synthesis technologies and qualified personnel.

-  Companies looking to accelerate the time to market their products.

-  Companies that want external regulatory support.

-  Companies that want access to advanced process development and planning services.

-  Start-ups with limited resources and capabilities.

Q4. What is the role of putting “D” in CDMO with advanced process development?

Organizations enabling the outsourcing of diverse activities associated with the pharmaceutical supply chain include CROs, CMOs, and CDMOs.

- Contract Research Organization (CRO): These organizations support preformulation development and lack expertise in scale up, technology transfer, and commercialization activities.

- Contract Manufacturing Organization (CMO): These organizations focus on large scale manufacturing activities leading to commercialization, and may provide preformulation services. However, their focus is more heavily centered around manufacturing and less on early stage development. 

- Contract Development and Manufacturing Organization (CDMO): These organizations are fully equipped to handle a project from early phase discovery and development to late stage bulk manufacturing and commercialization activities. 

Contract manufacturing organizations that engage in development activities like analytical development, early phase development, and advanced process development add “D” in their names to distinguish themselves from organizations solely focused on manufacturing activities (CMOs). 

While CMOs have been around for longer, more and more organizations are attempting to expand the services they offer and transition into full service, end-to-end CDMOs as outsourcing the entire development and manufacturing process with support along each step is more appealing to partnering customers.