Expert Interview : 10 questions to our polymer experts
We sat down with Eric Busseron, R&D manager for Pharma Polymers in Aramon and Rajesh Shukla, R&D Director at our Boston’Lab to discuss polymers in healthcare and the main challenges when developing polymers.
Before diving into each of your expertise fields, can you give us some basics in polymer synthesis?
Rajesh: Polymer is derived from the Greek ‘many’ (poly) ‘parts’ (mer). The field is based on the idea that small molecules can be linked in order to form a larger structure (a macromolecule). The method for making macromolecules from smaller substituents (monomers) is the concern of polymer synthesis. The first synthetic polymer was invented in 1869 by John Wesley Hyatt.
Polymers can not only have similar attributes to their parent monomer, but as a result of the new architecture from the polymerization process, unique physical properties can appear.
Generally speaking, what are the type of applications for polymers?
Rajesh: The number and use of polymers is nearly unlimited. Polymers are a part of everyday life being used from household goods to space exploration. In the medical field, polymers have found a wide variety of applications ranging from implants and medical devices to carriers for genetic therapies, to poly(amino acids) acting as APIs directly. The more applications that have been found led to further innovation and growth in the field, making polymers for biomedical applications a vastly growing field.
How important are advanced polymers in the Healthcare sector?
Eric: The biomedical market in particular, is a huge growth area for polymer synthesis. Pharmaceutical grade polymers referring to biocompatible products are typically used in Drug Delivery systems, which include vaccine formulation and drug release control.
They have a central role in the development and manufacture of medical devices, since their physical, chemical properties and biocompatibility are enabling the next generation of implants, diagnostic medical devices, and packaging technologies.
Also, in Life sciences, polymers are used for producing chromatography resins as an example. Many new API have bioavailability issues or need a taxi to allow them to express their potential, this is where the pharmaceutical polymers can bring a lot to the sector.
Considering the diversity of polymers nature and structure, could you describe your expertise in polymer synthesis?
Eric: Many products require polymers to have unique properties that help them in their applications. Having experience and understanding the different techniques of synthesis is fundamental for tailoring the properties of a polymer to its intended application.
Being a CDMO brings us the opportunity to work on a wide diversity of polymer structures brought by our customers. We have build expertise on a large panel of polymer chemistry.
Rajesh : Here are the main polymerization techniques that we cover:
- RAFT Polymerization or Reversible Addition-Fragmentation Chain Transfer, is a type of polymerization that controls the molecular weight in addition-type polymers. In Seqens, we have significant experience, such as conducting synthesis on kilo scale (Block, Bottlebrush copolymers). We design reaction conditions to control Molecular weight.
- Condensation polymerization techniques involves the joining of monomers by adding small molecules to create products such as polyesters, polyamides, poly(ester-urea). We typically conduct synthesis on kilo scale with custom reaction setup and safety compliance. We deal with triphosgene, exotherm during transfer. We also produce polymers, such as polyurethanes, with precise addition of polydiol to control isocyanate number specification.
- Free radical polymerization, this technique allows us to conduct synthesis on kilo scale, for producing random copolymers.
- ROP or Ring Opening Polymerization. This technique is used to produce our broad range of polyesters, such as PLGAs (poly(lactic-co-glycolic) acid).
- Polymer Functionalization, Side-chain modification of synthetic or naturally occurring polymers at kilo scale (eg. Hyaluronic acid, Chitosan).
- PEGylation, Conjugation of PEG to fluorinated polymers (Done in several hundred-gram batches).
- Cationic Ring Opening Polymerization, Conducting synthesis on kilo scale (Polyoxazolines) (Ion-exchange chromatography).
What type of polymers does the Boston’Lab have experience in producing?
Rajesh : Here in the Boston’Lab, we have had over 10 years of experience in polymer development for biomedical applications in a GMP environment. In our experience we have participated in various forms of polymerization with different uses:
- Poly(oxazolines) up to 5 kg scale using controlled polymerization (CROP) for drug excipient and gene therapies
- Poly(β-amino esters) up to 100g in bulk step polymerization for use in gene therapies while tailoring molecular weights
- Poly(norbornenes) based polymers up to 1kg via controlled ring-opening metathesis polymerizations (ROMP) for targeted anti-cancer treatments
- Poly(acetals) up to 500g for use as a drug excipient
- Poly(ester amino ureas) up to 5kg for use as biodegradable medical supports and implants
- Poly(acrylates/methacrylates) up to 5kg using both controlled (RAFT)) and uncontrolled free radical polymerizations in biomedical supports of as a backbone for unique anti-cancer polymers
- Poly(urethanes) as biocompatible rapid-onset glues and gels for surgical and trauma treatment
We have dedicated reactors capable of stirring high viscosity polymers.
In many instances of the above examples, the Boston’Lab has been involved in the synthesis, optimization and characterization of the parent monomers that are then carried through to the final polymer.
In addition to the more common challenges found in small molecule API synthesis, polymer chemistry also requires an intrinsic understanding of the interactions of the microscopic and macroscopic during the synthesis process. For example, understanding that the rate of addition and dispersion forces in a reaction during scaling will impact the size and the shape of particles formed during polymerization. Adjustments based on data and experience enabled the Boston’Lab to optimize the process for a client’s specific needs.
Another recent example of applying structure-property relationships for optimization occurred when developing a polymerization to operate on a commercial scale. The initial solvents were used in a high-pressure bomb reaction were unfavorable for scaling. As such, an alternative solvent with a structure similar to the monomer (without the reactive group) was used and allowed for effective polymerization with control of the isolated polymer during the precipitation to give a fine powder as opposed to a hard to handle gum.
Is there some specific chemistry you can conduct in the Boston’Lab ?
Rajesh: Here is the Boston’Lab, our key features are:
- Experienced in Synthesis of polymer and poly amino acids systems;
- Experienced in biomedical polymers, hydrogels, drug delivery system.
- Experienced in specific polymerization techniques: Polycondensation polymerization, radical polymerization (uncontrolled and controlled), ring opening polymerization.
We also handle extractions, such as natural product extraction from Yeast at kilo scale.
What about Aramon?
Eric: The specificity of the Aramon site is the authorization to handle ethylene oxide on industrial scale. For the lab scale we are equipped, for example, with an automated autoclave reactor which can be used to perform neat polyethylene oxide polymerization and copolymerization with other monomers like propylene oxide for example.
Besides, as in Boston’Lab, we cover the broad range of polymerization techniques. We can also manufacture very high viscosity polymers without using solvent thanks to specific reactors able to stir mixture up to 12 millions of centipoise. Particularly we have a range of PLA/PLGA products which is described in our Expansorb® catalog.
When developing a process for polymer products, the purification stage must be challenging? How can you describe the R&D effort required for reaching the specifications of pharma grade?
Eric: Yes, the purification stage is often the step requiring the most energy during the development. The purity of polymers can greatly impact their performance and can even lead to products failing to meet performance standards.
Removal of impurities from a polymer matrix is usually challenging especially when you are dealing with sticky polymers. We brought a strong expertise within the team over the years and projects to be able to handle efficiently these challenges.
For the isolation/purification steps, both sites are equipped with techniques such tangential filtration TFF, lyophilization/freeze-drying, and pelletizing system.
In terms of characterization and analytical techniques, what are the specific challenges that you are dealing with?
Eric: The challenges are to characterize polymer structures which could be very complex, coming from multiples monomers, potentially with mix of block structures, with sometimes the presence of mixture like homopolymer/copolymer structure and finally with the presence of small impurities which have to be quantified to allow the product to be used in the pharmaceutical field. Within Seqens, we have best in-class techniques and expertise.
Thanks to our sensitive 500 MHz NMR on site we can access to both structural identification of the polymer structure and impurities quantification at few hundreds of ppm in only one analysis which is a very efficient way. However, when limit of quantification has to be to the ppm ranges, other technics as GC and HPLC must be considered, and the polymer could generate matrix effects which have to be overcome. At the end, it is a similar challenge to the purification, except that here you are interested by what you extract from the polymer, in order to quantify it.
Rajesh: As mentioned above, the introduction of macromolecules requires a unique set of tools and skill sets in order to properly relate the properties of the monomer to tailor the resulting polymer to meet the target specifications and characteristics. In addition to the more common analysis for small molecule API development such as NMR (liquid and solid state), IR, HPLC, etc., polymers may require other physical analyses as well such as polymer chain characterization (SEC), particle size analysis (DLS), thermal stability (TGA, DSC) and intrinsic elasticity/viscosity (MI, DMA, Rheometry). The tools required for each project is unique and tied intimately with the target end-use of the polymer. We can specifically offer analytical method development services related to polymer characterization.
The Group has recently invested in capacities and analytical tools for producing advanced polymers in France and Boston. For which purpose?
Eric: Our customers working with advanced polymers for pharmaceutical applications usually need small quantities for their initial clinical trials and high-performance analytical tools to characterize these advanced structures. Based on these needs, we invested in our Aramon center more than 10 M€ to :
- Extend our R&D capabilities, especially towards tangential flow filtration, freeze drying and also continuous reaction monitoring system (NIR and vibrational viscosimeter probes)
- Extend our analytical development and quality control tools with a GMP 500 Mhz NMR, several triple detection GPC systems, double detection UV/ELSD HPLC systems, etc
- Create a brand new GMP workshop equipped with cleanrooms (ISO8/Class D and ISO7/Class C) for the manufacturing of pilot batches of pharmaceutical polymers, in addition to our existing capabilities of manufacturing melt polymerization products and polymers at larger scale.
Rajesh : Since 2022, Seqens has invested more than $6 million in the re-development of Devens site (Boston’Lab) to ensure that the new facility leverages the most advanced technologies, equipment, and design, while adhering to the highest levels of quality, sustainability and safety on custom pharma polymer synthesis, purification, and analysis.
For you, what are the current trends in polymer development and/or products in the pharmaceutical field?
Eric: Recent advances in catalyst design have led to more efficient polymerization reactions, enabling the formation of polymers with precise structures and properties. Innovations allow for more precise control over molecular weight distribution, leading to materials with better performance characteristics.
During the past years, I have seen more pharmaceutical polymers considered for the nucleic acid vectorization (DNA, siRNA) which is likely due to “Covid vaccine effect”, but also more polymeric prodrug approach which is an elegant way to allow the improvement of API bioavailability.
Smart polymers that react to environmental stimuli, like temperature or pH, offer exciting new applications in the field of responsive materials, expanding the potential uses of polymers in healthcare.
3D printing technology has also influenced polymer synthesis, pushing the development of printable materials with properties tailored to specific functions, from flexible, impact-resistant construction materials to soft, biocompatible medical devices.
Is it a growing field? If so, why?
Rajesh: Yes, polymer is a growing field especially in pharmaceutical industry. One of the major reasons is that polymer chemistry is relatively new compared to organic synthetic chemistry of small molecules. It is still in a developing stage with new polymers and techniques especially for pharmaceutical related applications. Another reason is the development of other techniques like nano-technology. Nano-particles in the range of 20-200nm is optimal for drug delivery applications. Take anti-cancer polymer-drug complex as an example. A nano-particle, based on polymer-drug formulation, with the particle size of 20-200nm can make use of the enhanced permeability and retention (EPR) effect. This will help the polymer-drug complex to accumulate in the tumor tissue avoiding renal clearance.
Finally, what makes your expertise within Seqens unique?
Eric & Rajesh : Seqens is an expert in the field of polymer chemistry and can provide cost effective methods to help you effectively and efficiently reach your research and development goals up to the commercial scale.
We offer customized solutions targeting specific polymers. We evaluate existing synthetic routes and can propose optimized/new synthetic routes. We also have a strong expertise in analytical development.
Within both GLP and cGMP polymers, we can perform synthesis of polymer from 100 mg scale to multi-kilo grams.
Within our extended experience, there are several key attributes that should be present when selecting a CDMO for development:
- A track-record of successfully developing various polymer processes
- Understanding of the challenges in scaling polymerizations for commercial application prior to initiation of the project
- Knowledge of the structure-property relationships of monomers and polymers for efficient optimization
- Access to the analytical tools to appropriately evaluate polymers to achieve target applications
info.cdmo@seqens.com