While all New Chemical Entities (NCEs), or New Molecular Entities (NMEs) as the FDA calls them, involve challenging new chemistry, the chemistry involved in creating and manufacturing medical grade polymers is even more difficult for the following three reasons:
- Physical characteristics such as vessel geometry have a far more significant effect on the polymerization.
- Process variables such as agitation or temperature often have an outsized influence on the quality of the final product and must be carefully managed.
- Efficient scale-up to GMP manufacturing requires a great deal of art, which is often born out of experience.
New polymeric materials are essential for creation of the rapidly growing number of combination products that are becoming so prevalent in pharmaceutical development. Examples include insulin pumps, drug-eluting stents and a host of innovative drug delivery systems that provide important new therapies for patients – and new revenue streams for pharmaceutical companies.
However, even when approved drugs are used, combination products that include a polymeric delivery mechanism are considered as new by the FDA. They must undergo a rigorous approval process known as a de novo process.
That development/manufacturing/regulatory approval process is expedited when the same CDMO team developing the polymers is then performing the cGMP manufacturing, has broad experience in polymer synthesis, and also has core expertise in scaling up polymers to cGMP.
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7 key steps in polymer synthesis
While this article outlines seven key steps, it’s important to note that not all steps are necessary or appropriate. That’s because polymer synthesis combines science and art, and based on your team’s experience, polymer synthesis may require all or a subset of these key steps:
- Controlling particle size and composition.
- Targeting molecular weight.
- Introducing an active functional moiety.
- Incorporating particles into delivery mechanisms.
- Manipulating physical properties to achieve narrow particle size distributions.
- Co-polymerization of different monomers.
- Degree of cross linking
The following are examples of some of the projects the PCI Synthesis Advanced Polymer Manufacturing Group has undertaken recently, incorporating one or more of the steps above.
- Size-controlled synthesis of poly(methacrylate) random copolymers beads then used as an enzyme-immobilizing substrate.
- Used as a food contact material to adjust nutrient content.
Biodegradable Poly(ester) Copolymer
- Condensation of polymerization of modified amino acids polymers with defined molecular weight and copolymer composition.
- Used as a biodegradable antibiotic drug-release substrate in medical implants.
Post-Polymerization Modification of Polysaccharides
- A commercially available polymer is modified by changing the functional groups of the repeat unit and introducing an active functional moiety. The modified polymer is then used in the formation of nanoparticles of controlled size and water content.
- Used as a Hemostat in surgical applications.
Anti-oxidant Poly(ester) Copolymer
- A polyester copolymer was developed with targeted molecular weight and composition. The polymer was then incorporated into PVA nanoparticles as a delivery mechanism.
- Used as a free-radical-scavenger in cardiac patients.
- A water-insoluble poly(acetal) is formed by condensation polymerization. The drug-loaded hydrophobic cores are suspended in water using a PEG copolymer.
- Used as a drug delivery vector in cancer therapy.
- Solution polymerization cross linking epichlorohydrin with a commercial PEG material.
- Mobile phase used in RNA/DNA drug synthesis.
- cGMP extraction, purification, and physical manipulation of a fermentation-derived biodegradable polymer.
- Used post-surgically for wound suturing and webbing.
Cross-linked Divinyl Benzene Co-Polymer
- Co-polymerization of divinyl benzene and a derivatized styrene. The co-polymer was then linked to a substrate.
- Used in an imaging application after the addition of a radioactive element.
- Cryogenic, free radical initiated solution polymerization.
- Used in the formulation of a coating with an active ingredient for implantable medical devices.
EVA Polymerization and Processing
- cGMP precipitation, extraction, and physical processing of an industrial grade material.
- Used as an implantable drug delivery system.
Butadiene-Malaic Anhydride Co-Polymer
- cGMP extraction and purification of biodegradable polymer derived from a fermentation process.
- Used as a bioadhesive for proprietary drug delivery systems and the coating of oral tablets.
Carbohydrate based polymers
- Carboxymethyl cellulose cross-linked with epichlorohydrin.
- Used for loading with an API for a drug delivery system.
- Butyl Methacrylate emulsion polymerization that required extensive physical manipulation to achieve a narrow particle size distribution.
- Used in the manufacture of implantable materials.
- Developed the synthesis and supplied a Methylene Malonate monomer.
- Used downstream in an ionic polymerization in a point-of-use medical device.
- Derivatization of an acrylate co-polymer linked with several amino acids, then attached to an API.
- Used as part of an oral oncology system.
As with API synthesis, polymer synthesis involves numerous essential, rigorous processes. As readers of this blog are aware, we are fully committed to process optimization, which is never ending. Every CDMO learns something from each and every project. We make every effort to put that knowledge to good use, noting lessons learned for future reference.
We have become quite adept at scale-up of polymers partly because we continue to tweak all aspects of medical grade polymer synthesis and manufacturing for efficiency, and at the same time maintain the highest quality standards, meticulously documented, always with an eye to winning regulatory approval.
About the Author
Ed is President & CEO of SEQENS North America (formerly PCI Synthesis). He serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA)...
Do you have questions? Talk to Ed.