Integrated CMC

 

Integrated Chemistry, Manufacturing and Control

Our truly Integrated Chemistry, Manufacturing and Control capabilities fully support drug substance and drug product development and GMP manufacturing from FIH to Phase III clinical development programmes on behalf of our partners around the world.

Our teams are composed of multi-disciplinary, industry-leading scientists who possess integrated knowledge of every step contained within CMC development activities, from laboratory to commercial scale for both API and drug product.

Straightforward, continuous processes from API to pre-clinical data and clinical supply enable end-to-end development of new chemical entities, without the need to align different providers. 

This allows time optimisation and risk mitigation for each single development project, in the capable hands of our expert project management professionals.

Our integrated CMC capabilities include:

  • API polymorph screening, salt-selection, co-crystals screening
  • API route scouting, process development and scale-up
  • API GMP manufacturing
  • Solid state characterisation
  • Pre-formulation 
  • Drug product formulation prototyping and development
  • Drug product process optimisation, scale-up and transfer to GMP production
  • Clinical manufacturing
  • Commercial manufacturing for small volume/niche product 
  • Analytical development and quality control
  • Project management, quality assurance, consultancy

Areas of Excellence

  • Superior expertise in both conventional and bio-enhanced oral formulations and inhalation development
  • Thought leadership in Accelerated Stability Assessment Programs (ASAP)

Integrated CMC: End-to-end development of New Chemical Entities

API
Pre-formulation
Drug Product
Synthetic route
Early formulation
Formulation design
Starting materials, reagents and intermediates control
Biopharmaceutics
Excipient compatibility
Reference materials
Manufacturability
API manufacturing
Drug product manufacturing
API Synthetic route
Pre-formulation Early formulation
Drug Product Formulation design
API Starting materials, reagents and intermediates control
Pre-formulation Biopharmaceutics
Drug Product Excipient compatibility
API Reference materials
Pre-formulation
Drug Product Manufacturability
API API manufacturing
Pre-formulation
Drug Product Drug product manufacturing

API capabilities

Since all drug development activities depend on the reliable supply of the Active Pharmaceutical Ingredients (APIs), a foremost Evotec capability is its comprehensive global API service. 

These services span from the interaction with our discovery team to commercial production of API at up to 1,600 L scale.

The spread of our capabilities allows Evotec team to cater for multiple need: From the preparation of advance intermediate to support the drug discovery programme to the development and manufacture of late phase manufacturing process for commercial application in our fully compliant and audited plants.

A notable aspect of Evotec’s API capabilities is the ability to manufacture highly potent compounds as well as manufacture and distribute controlled substances.

Chemical development activities

To achieve the successful support of the drug development cycle, starting from pre-clinical to clinical and commercial supply, Evotec will involve chemists from its pool of more than 60 development chemists, all bringing in their own expertise to support the key steps of the development of our partner’s API:

  • Route scouting and identification of a new route to enable efficient scale-up
  • Custom synthesis
  • Analytical method development and validation
  • Process development to enable scale-up
  • Genotoxic risk assessment according to ICH M7 guidances
  • Synthesis of reference standards and impurity markers as well as Stable Labelled Isotope Standard (SIL)

Our customers are asking us to use our expertise to support different development strategies going from "Fit For Purpose" for the pre-clinical to early phase to generate more knowledge and process understanding when the programmes are moving through the clinical phases. 
Our main objective is the development of a process that will be scaled to deliver the material of required quality and support successful regulatory interaction.

Using more than a quarter of century of experience, the teams have developed approaches enabling efficient and seamless transfer of the procedures from the laboratory to the pilot plant. 
An in-depth understanding of the API process chemistry enables Evotec scientists to develop efficient and sustainable synthetic processes to whatever level is required by our sponsors.  Such activities require strong links between our organic chemists, our physico chemists, our analysts but also our sourcing and quality assurance teams.

From our multiples sites, we can call on a broad array of techniques that are getting embedded in our development activity:
  • Generate the required knowledge of the solid state property of our intermediate and API and deliver a robust crystallisation procedure securing purity, polymorphic and particle size control as needed
  • Identify a suitable salt to support isolation/purification but also as means to achieve chiral separation
  • Hydrogenation capacity (pressure up to 40 bars) and ability to rely on our screening experience and designated equipment supported by our specialised analytical group
  • Use of preparative chiral of achiral HPLC /SFC systems
  • Chiral synthesis, with an expertise in designing suitable processes that can be really and seamlessly scaled-up to dozen of kilos relying on the historical patrimony of some of our sites
  • The design of safe chemistry processes is guaranteed using our thermo hazard specialists relying on their experience and specific equipment (calorimeters type RC1, DSC, ARC)
  • Bring its skills to bear on detailed process studies, applying parallel experimentation, statistical tools (MVA, PCA, PLS), Design of Experiment (DoE), kinetics studies and Process Analytical Technology (PAT), either as part of QbD based strategy or as individual tools

As an average, the Evotec teams developed approximately 100-150 stages of chemistry a year for scale-up prior to operate them in kilo lab and about 50 stages of chemistry to be scale-up to plant scale. 

Our teams have developed a broad experience in many chemistry areas: 
  • Chiral chemistry
  • Organo-metallic, metal mediated transformation/coupling, hydrogenation
  • Hazardous chemistry:  Pyrophoric reagents (tBuLi); Azide Chemistry; toxic reagents (e.g. alkylating agents such as dimethyl sulphate)
  • Sugar chemistry at scale including azide chemistry
  • Developed processes with intermediates without UV chromophores
  • Impurity control via efficient work-up as well as a purification system for the early phase of the process life cycle

Evotec teams are composed of high standard chemists selected based on their scientific knowledge and experience. With a low turnover and a high ratio of PhD >75%, knowledge, experience, ability to understand our customer needs and communicate with our customer are probably our strongest tools.

Pilot Plant Manufacturing

As a clinical programme progresses and demand for API grows, Evotec is well positioned to seamlessly transfer suitable processes from its development laboratories to pilot facilities, all of which operate to the highest regulatory standards. Over the last decade Evotec has made and isolated literally thousands of intermediates, starting materials and final products to appropriate levels of cGMP, with API prepared from a single stages but up to more than 20 stages, involving most of the known chemical transformations.

Key aspects of Evotec’s pilot plant offering:
  • Facilities operating 18 reactions vessels up to 1,600 L and a total volume of >8,000 L
  • Filtration system from enclosed filters to filter dryers and centrifuge with fully contained off-loading
  • FDA, MHRA and AIFA inspected
  • Manufacture of non-cGMP material for pre-clinical support
  • Manufacture of clinical trial material and commercial supply up to several hundred kilos
  • Certified ISO14001 environmental quality standard
  • Class 100,000 clean rooms
  • Hydrogenation: high pressure vessel at up 20 L and from atmospheric pressure up to 7 bar at 1,600 L scale-also applicable for the use of other gases (CO, NH3..)
  • Cryogenic capability to –80°C and  up to +160°C
  • Supply of potent and toxic materials (HAPI) with OEL>0.5mg/m3
  • Use, manufacture and supply of controlled substances to Schedule 1

Commercial manufacturing

Evotec has licenses to perform commercial manufacture and accordingly, dependent on the volume of material required, can provide clients with the option of ongoing commercial supply for small volume APIs. 
Smooth scale-up of chemical processes is assured through reactor capacities up to 1,600 L that can produce kilogram to metric ton batches, both cGMP and non-GMP. 
High-potency APIs can be produced in capacities that range from 20 L to 1,500 L.

Highly potent APIs

A further distinction that supports Evotec’s leading industry position in API development is our ability to handle highly potent compounds (HPAPIs) at multiple global sites. HPAPI capabilities feature:

  • State-of-the-art containment facilities for both drug substance and drug product development and production
  • Class 100,000 clean rooms
  • Clean-in-place systems
  • Gram to kilogram capacities
  • Barrier (isolator) technology on reactors and solid handling systems
  • Automated and validated computer controls
  • Containment suites for the formulation of potent drug compounds
  • Separate HEPA-filtered air handling systems
  • Exposure and environmental monitoring
Clinical Phase I
Clinical Phase II/III
Commercial manufacture
Batch sizes
1 to 2 kg
3 to 50 kg
up to 120 kg
Scale
20/50 L glass vessels
20 to 1,600 L, glass, glass lined steel, Hastelloy
100 to 1,600 L
Equipment
Pressure hydrogenation up to 40 bar, Cryogenic up to -80°C, PAT tools: Lasentec, Raman 
Cryogenic up to -80°C (OXF - 400 L), Hydrogenation (OXF – up to 1,600 L & 7 bar), enclosed Hastelloy filter dryers, high-potent handling from 0.5 µg/m3 at up to 1,600 L scale (Abingdon), Centrifuge, Lasentec
Same as clinical Phase II/III
Containment
OEB 4
OEB 4 up to 1,600 L 
OEB 5 up to 1,600 L 
Batch sizes
Clinical Phase I 1 to 2 kg
Clinical Phase II/III 3 to 50 kg
Commercial manufacture up to 120 kg
Scale
Clinical Phase I 20/50 L glass vessels
Clinical Phase II/III 20 to 1,600 L, glass, glass lined steel, Hastelloy
Commercial manufacture 100 to 1,600 L
Equipment
Clinical Phase I Pressure hydrogenation up to 40 bar, Cryogenic up to -80°C, PAT tools: Lasentec, Raman 
Clinical Phase II/III Cryogenic up to -80°C (OXF - 400 L), Hydrogenation (OXF – up to 1,600 L & 7 bar), enclosed Hastelloy filter dryers, high-potent handling from 0.5 µg/m3 at up to 1,600 L scale (Abingdon), Centrifuge, Lasentec
Commercial manufacture Same as clinical Phase II/III
Containment
Clinical Phase I OEB 4
Clinical Phase II/III OEB 4 up to 1,600 L 
Commercial manufacture OEB 5 up to 1,600 L 

Material sciences

The Material Sciences team provide support to guarantee the quality of API/ drug products developed and manufactured in the pharmaceutical development area, to support the development phases from advanced lead optimisation to commercial. Our areas of expertise are: version selection, form control, crystallisation development, particle engineering and solid state landscape determination. Our support encompasses API, DP, and intermediate material. Our locations are at the Verona and Toulouse Evotec sites.

Materials Characterisation

  • State-of-the-art solid state analytical technologies and expertise including spectroscopy (FTIR, Raman, NMR), diffraction (XRPD, also non ambient and 2D), SAXS, thermal analysis (DSC, TGA, TGA-IR), microscopy (PLM, ESEM+EDX), micromeritics (particle size, surface area, DVS, pycnometry, powder rheology, wettability)
  • Method development and cGMP validation such as qualitative or quantitative methods on both API and drug product
  • Investigational studies – assessment of materials (to help determine origin and resolution of issues), e.g. batch-to-batch variability, performance determinations (dissolution, bioavailability, flow properties), content uniformity, presence of unknown materials focusing on API, DP, or delivery devices
  • Strong and close cooperation with external partners for particular solid-state techniques like ssNMR, single crystal XRD, synchrotron radiation based x-rays diffraction

API Version/ Form Selection and Control

  • Polymorph screening to reduce the risk of failure during development, to meet regulatory requirements and to preserve IP
  • Salt/Co-crystal selection to improve drug performances and enhance physicochemical properties
  • Amorphous dispersions development to increase solubility and bioavailability
  • Forms thermodynamic-kinetic relationships, relative physico-chemical stability, key properties differentiators, phase diagrams
  • Crystallisation development to control established critical quality attributes via the final API production route (e.g. version, crystal form, particle size, particle morphology, chemical purity) with a particle engineering approach

Areas of Excellence

  • State-of-the-art analytical techniques/ instrumentation in the physical properties characterisation labs
  • Robotic solid form screening and modern multi-parallel reaction stations with PAT tools (e.g. FBRM, Raman) in the solid state chemistry area
  • Integrated expertise and facilities for both solid state chemistry and physical properties: same team is following the project from API to DP
  • Possibility to serve as analytical service as well as support group to API and DP (stand alone and integrated projects)
  • Transfer knowledge from API to DP manufacturing influencing the critical quality attribute and the choice of the final formulation
  • High performance and flexibility (adaptable to any turnaround time for data production)
  • Focus on data reliability, quality and integrity
  • Proven expertise in the pharmaceutical material sciences – solid state chemistry fields and well recognised reputation by the scientific community

Analytical development and Quality Control

The analytical department offers unique integrated analytical capabilities and expertise, delivering complete and high-quality packages of analytical services for drug discovery and development, customised for each phase - from early definitions to analytical tech transfer, in a fully validated GMP environment.

Specific study types, services and technologies

Evotec analytics benefits from a broad range of analytical technique expertise and capabilities to provide for any development phase and API process development:

Method development, validation and technological transfer 

Analytical experts take a structured, straightforward and reliable approach for method development and validation based on Quality by Design (QbD) principles.
Evotec scientists are aided by the latest generation software tools, such as DryLab®, Empower™ and Method Validation Manager (MVM) to support both development and validation and to deliver effective solutions for each pharmaceutical development phase

Forced degradation studies (FDS)

FDS studies performed for development purposes on drug substances and drug products to prove the stability indicating power of the assay/degradation products method.

Stability studies
  • Specialised personnel with solid experience and cutting-edge facilities make Evotec an ideal, trustworthy partner for analytical and stability services
  • Fully electronic data management through proprietary LIMS and stability information system (CFR 21 Part 11 compliant) ensure an unequalled level of quality, traceability, security and control of your data and samples
  • Stability experts offer all key ICH and WHO storage conditions, tailored stability study design from formulation screening to market registration and regulatory submission support
  • Stability data intended for use in Investigational New Drug (IND) or Investigation Medicinal Product Dossier (IMPD) submissions, or where the data is intended to be used in a regulatory submission (NDA, MAA etc.) or in response to a stability related regulatory question or comment
  • All of the above studies are managed within the analytical and material sciences department
Stability facilities
  • All ICH-like stability studies on active pharmaceutical ingredients and drug products (oral form and inhalation DPI products) for climatic Zones I-II and World Wide registration (Zones IVa and b included), are guaranteed by the following climatic conditions: 
    • 5˚C/Amb.H 
    • 25˚C/60% RH
    • 30˚C/65% RH
    • 30˚C/75% RH
    • 40˚C/75% RH
    • 50˚C/Amb.H 
    • 50˚C/75% RH 
    • -20˚C/Amb.H
    • Photo-stability chamber
  • All of the above conditions are continuously kept in the acceptance limits of the ICH Guidance
Accelerated stability assessment programme studies (ASAP studies)

The ASAP study approach is a very powerful and versatile accelerated stability study tool, targeted at predicting and understanding API & DP stability on a short-term basis and the results evaluated by statistical assessment.

Inhalation analytical laboratories
  • Fully equipped inhalation lab for mono-dose and multi-dose DPI testing
  • Drug product characterisation studies & in vitro equivalence. Significant experience in reverse engineering of multiple innovators DPI products. Device verification testing and design verification testing
  • Next generation impactor (NGI) used to test in vitro lung dose (<5 µm, aerodynamic particle size distribution) in controlled temperature and humidity
Evotec GxP analytical capabilities for 

APIs, Oral DP forms (e.g. tablets, capsules, suspensions, spray drying material etc.) and dry powder inhaled products are supported by

  • Assay, related substances content by HPLC-UPLC-LC/MS, CAD, Ion Chromatography, Fluorimeter, GC, GCHS, GCMS techniques
  • UV / IR spectroscopy
  • NMR (400 MHz with broadband probe & 600 MHz with cryo-probe) and HRMS 
  • Enantiomeric purity by HPLC and polarimetry 
  • Water content by KF 
  • Dissolution (apparatus I, II, III, IV and IDR) and disintegration test 
  • Physical properties and solid state characterisation by particle size distribution, SD, optical & electron microscopy, SSA, XRPD, Rheology-FT4, TGA, spectroscopy, DSC
  • Aerodynamic particle size distribution by NGI 
  • Uniformity of delivered dose

Compliance and informatics systems

Evotec is distinguished by a long track record of scientific expertise in the application of a wide range of analytical techniques and relies on three key significant strengths:

  • Web-based computer systems developed in-house using various technologies support the analytical workflow
  • A fully validated GMP Laboratory Information Management System (LIMS) for data acquisition, recording, evaluation and reporting, tailored to pharmaceutical QC needs
  • Data integrity and the management of analytical data is guaranteed by Evotec Verona LIMS that is interfaced with the CDS (Chromatographic Data System) by a bespoke interface designed for the management of weighing process (including a direct weight capture from balances) and chromatographic sequence
  • A large suite of automated platforms to ensure high data quality, prompt test responses and productivity

Pre-clinical formulation - Addressing your complex formulation issues fast from an early stage

Evotec’s pre –clinical formulation team can assist you in developing "phase-appropriate" formulations tailored to your compound properties.

Poor solubility/ low bioavailability are significant issues during drug development. It is reported that up to 75% of compounds currently under development are poorly water-soluble, with this figure rising to 90% for new chemical entities. This is of concern because solubility issues can compromise the developability of compounds, resulting in project delays and ultimately increase the overall cost of a project. Therefore, it is important to understand and address bioavailability issues early with "phase-appropriate" formulation strategies. 

A fast, cost effective and flexible approach in each stage of development focusing in meeting the project needs:
  • Evotec has considerable expertise in formulation and can expedite early phase formulation development from discovery to clinic
  • Evotec’s early formulation team can tackle your formulation problems fast, in support of pre-clinical testing using small amounts of compound
  • This dedicated and responsive team of pre-clinical formulation scientists has an in-depth knowledge of a wide range of formulation capabilities and expertise to support your project, ranging from simple to complex, bio-enhanced approaches
  • The team works in synergy with Material Science/ DMPK investigators and toxicologists to design an effective formulation screening programme that can quickly solve your formulation problems 

How do we work with your team?

We work with your team using 4 very simple steps to improve the outcome of your pre-clinical studies:

Review
Design
Develop
Supply
Our team of experts will review all relevant information related to your compounds
After reviewing the available information, the team will design a formulation screening programme including bio-enhanced strategies
A range of pre-formulation and formulation studies will then be executed in a fast and flexible approach using limited amounts of your compound 
We supply formulations for GLP and non-GLP studies and can design/ perform your in-life studies
We will you provide with the consultative input to enable you to make the best decision
Our team of material scientists and DMPK/ toxicology experts combined with powerful in silico models will assist us with the study design
The formulation will be tested in vitro to ensure the best outcome during in-life studies
Stability and scalability trials included
Review Our team of experts will review all relevant information related to your compounds
Design After reviewing the available information, the team will design a formulation screening programme including bio-enhanced strategies
Develop A range of pre-formulation and formulation studies will then be executed in a fast and flexible approach using limited amounts of your compound 
Supply We supply formulations for GLP and non-GLP studies and can design/ perform your in-life studies
Review We will you provide with the consultative input to enable you to make the best decision
Design Our team of material scientists and DMPK/ toxicology experts combined with powerful in silico models will assist us with the study design
Develop The formulation will be tested in vitro to ensure the best outcome during in-life studies
Supply Stability and scalability trials included

Our capabilities

Analytical support
  • Compendial in vitro dissolution testing (USP I and II)
  • Dynamic dissolution testing using pHysio-stat® automated system (predictive dissolution testing)
  • Precipitation studies in simulated gastro-intestinal fluids and plasma from different animal species 
  • In vitro lipolysis tests
  • Hemolytical potential 
  • Franz cell studies 
  • Stability assessment of developed prototypes 
  • Accelerated stability testing 
Pre-formulation
  • pH solubility profile in bio-relevant media
  • pKa, Log P/ Log D
  • Solubility/ Stability in pharmaceutical solvents/ excipients 
  • Permeability measurements 
  • Characterisation techniques such as SEM, light and polarised microscopy, PSD, GVS, TGA, XRPD and mDSC
Formulation
  • Design of well tolerated pre-clinical dose-vehicles in support of PK/ PD and toxicological investigations 
  • Micronisation (ball/ air jet milling)
  • Nano-suspension
  • Amorphous solid dispersions by spray drying, hot melt extrusion, drug layering and emulsification approaches
  • Emulsion development (SMEDDs/ SEDDs)
  • Lyophilisation
  • Liposomes 
  • Film coating (pellets, tablets, capsules) and drug layering (size 9h to 00)
  • Microparticles (controlled/ sustained release)

Our team works on formulations planned for any route of administration (oral, pulmonary, dermal/transdermal, intra-ocular, parental)

Supply for GLP studies
  • Proven experience in effective use of formulation approaches under GLP requirements also for non-conventional technologies
  • Analytical and bioanalytical support integrated in the service including stability study under GLP
  • Superior knowledge of excipient tolerability to design well tolerated and to administer complex vehicles based on species, route of administration and dose requirement for toxicology assessment

Contact us

Evotec

Business Development

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