Towards a Continuous Manufacturing Process of Protein-Loaded Polymeric Nanoparticle Powders
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Brief/Technical Note Towards a Continuous Manufacturing Process of Protein-Loaded Polymeric Nanoparticle Powders Stefan Schiller,1,2,5 Andrea Hanefeld,3 Marc Schneider,1 and Claus-Michael Lehr1,4
Received 20 April 2020; accepted 9 September 2020 Abstract. To develop a scalable and efficient process suitable for the continuous manufacturing of poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing ovalbumin as the model protein. PLGA nanoparticles were prepared using a double emulsification spray-drying method. Emulsions were prepared using a focused ultrasound transducer equipped with a flow cell. Either poly(vinyl alcohol) (PVA) or poloxamer 407 (P-407) was used as a stabilizer. Aliquots of the emulsions were blended with different matrix excipients and spray dried, and the yield and size of the resuspended nanoparticles was determined and compared against solvent displacement. Nanoparticle sizes of spray-dried PLGA/PVA emulsions were independent of the matrix excipient and comparable with sizes from the solvent displacement method. The yield of the resuspended nanoparticles was highest for emulsions containing trehalose and leucine (79%). Spray drying of PLGA/P-407 emulsions led to agglomerated nanoparticles independent of the matrix excipient. PLGA/P-407 nanoparticles pre-formed by solvent displacement could be spray dried with limited agglomeration when PVA was added as an additional stabilizer. A comparably high and economically interesting nanoparticle yield could be achieved with a process suitable for continuous manufacturing. Further studies are needed to understand the robustness of a continuous process at commercial scale. KEY WORDS: continuous manufacturing; PLGA nanoparticles; focused ultrasound; spray drying; protein delivery.
INTRODUCTION A major challenge in the translation and commercialization of nanomaterials in medicine is the development of adequate pharmaceutical production processes that work equally well at large scale as at lab scale as (1,2). While several marketed pharmaceutical products employ nanotechnology, very little is publicly known about production processes and the translation from research to commercial scale (3). Continuous processes are often investigated (2,4,5), as they are considered easy to scale and more efficient, allow for simple process monitoring, and typically lead to less batch-to-batch variation. Although 1
Department of Pharmacy, Biopharmaceutics & Pharmaceutical Technology, Saarland University, Saarbrücken, Germany. 2 Department of Pharmaceutical Technologies, Merck Healthcare KGaA, HPC D039/002, Frankfurter Str. 250, 64293, Darmstadt, Germany. 3 Global Healthcare Operations Innovation Network, Merck Healthcare KGaA, Darmstadt, Germany. 4 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI), Saarland University, Saarbrücken, Germany. 5 To whom correspondence should be addressed. (e–mail: [email protected])
continuous nanoparticle precipitation methods—sometimes called flash nanoprecipita
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