A Road Map to GMP Readiness for Protein Therapeutics – Drug Product Process Development for Clinical Supply

In recent years, solid form screening has become an integral and mandatory part of drug development. Solid form screening typically involves producing and characterizingmaximum possible solid forms of a potential drug candidate. Different types of solid forms for future drug product development includes salt screening, co-crystal screening, crystallization process development, polymorph screening as well as amorphous solid dispersion screening.Screening studies of a solid form is a set of carefully designed experiments that requires use of advanced analytical techniques to collect analytical data followed by a thoughtful data analysis.This solid form screening studies guide an important decision-making of lead solid form whichis likely to play a vital role during the pharmaceutical product development lifecycle. The selection criteria include pharmaceutically relevant properties, such as therapeutic efficacy and processing characteristics as well as role of physicochemical properties (i.e. solubility, dissolution rate, hygroscopicity, physical stability and chemical purity) in drug product development. A selected solid form, if thermodynamically unstable, it may undergo solid form changes upon exposure to environmental conditions such as temperature and relative humidity as well as manufacturing stress during the pharmaceutical unit operations. In thepresent work, fundamentals of solid form screening are discussed, including the experimental screening methodologies as well as characterization and analysis of solid forms. The importance of drug product risk assessment pertaining to the desired solid form are also discussed here.

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Product design, process development and manufacturing – a road map for the technologist

Case Studies in Food Product Development ◽

10.1533/9781845694135.6.333 ◽

2008 ◽

pp. 333-353

Author(s):

Ed Neff

Keyword(s):

Product Design ◽

Design Process ◽

Process Development ◽

Road Map ◽

Product Design Process

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Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing

Annual Review of Chemical and Biomolecular Engineering ◽

10.1146/annurev-chembioeng-060817-084355 ◽

2018 ◽

Vol 9 (1) ◽

pp. 253-281 ◽

Cited By ~ 22

Author(s):

Christopher L. Burcham ◽

Alastair J. Florence ◽

Martin D. Johnson

Keyword(s):

Flexible Manufacturing ◽

Process Development ◽

Drug Product ◽

Good Manufacturing Practice ◽

Continuous Manufacturing ◽

Continuous Processing ◽

Pharmaceutical Ingredients ◽

Regulatory Bodies ◽

New Applications ◽

Processing Steps

The pharmaceutical industry has found new applications for the use of continuous processing for the manufacture of new therapies currently in development. The transformation has been encouraged by regulatory bodies as well as driven by cost reduction, decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent drug product. Continuous drug product is currently used in approved processes. A few examples of production of APIs under current good manufacturing practice conditions using continuous processing steps have been published in the past five years, but they are lagging behind continuous drug product with respect to regulatory filings.

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Expectations for Phase-Appropriate Drug Substance and Drug Product Specifications for Early-Stage Protein Therapeutics

Journal of Pharmaceutical Sciences ◽

10.1016/j.xphs.2018.11.042 ◽

2019 ◽

Vol 108 (4) ◽

pp. 1442-1452 ◽

Cited By ~ 7

Author(s):

Juliana Kretsinger ◽

Neha Frantz ◽

Scott A. Hart ◽

Wayne P. Kelley ◽

Bob Kitchen ◽

...

Keyword(s):

Drug Product ◽

Early Stage ◽

Protein Therapeutics ◽

Drug Substance ◽

Product Specifications

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Translational simulation: from description to action

Advances in Simulation ◽

10.1186/s41077-021-00160-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Christopher Peter Nickson ◽

Andrew Petrosoniak ◽

Stephanie Barwick ◽

Victoria Brazil

Keyword(s):

Process Development ◽

Clinical Performance ◽

Work Environments ◽

Future Directions ◽

Targeted Interventions ◽

Road Map ◽

Service Outcomes ◽

Case Vignettes ◽

Collective Experience ◽

Process Output

AbstractThis article describes an operational framework for implementing translational simulation in everyday practice. The framework, based on an input-process-output model, is developed from a critical review of the existing translational simulation literature and the collective experience of the authors’ affiliated translational simulation services. The article describes how translational simulation may be used to explore work environments and/or people in them, improve quality through targeted interventions focused on clinical performance/patient outcomes, and be used to design and test planned infrastructure or interventions. Representative case vignettes are used to show how the framework can be applied to real world healthcare problems, including clinical space testing, process development, and culture. Finally, future directions for translational simulation are discussed. As such, the article provides a road map for practitioners who seek to address health service outcomes using translational simulation.

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A Reproducible and Scalable Process for Manufacturing a Pfs48/45 Based Plasmodium falciparum Transmission-Blocking Vaccine

Frontiers in Immunology ◽

10.3389/fimmu.2020.606266 ◽

2021 ◽

Vol 11 ◽

Author(s):

Susheel K. Singh ◽

Jordan Plieskatt ◽

Bishwanath K. Chourasia ◽

Amanda Fabra-García ◽

Asier Garcia-Senosiain ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Clinical Evaluation ◽

Disulfide Bonds ◽

Process Development ◽

Drug Product ◽

Protein A ◽

Surface Protein ◽

Size Exclusion ◽

Transmission Blocking ◽

Transmission Blocking Vaccine

The cysteine-rich Pfs48/45 protein, a Plasmodium falciparum sexual stage surface protein, has been advancing as a candidate antigen for a transmission-blocking vaccine (TBV) for malaria. However, Pfs48/45 contains multiple disulfide bonds, that are critical for proper folding and induction of transmission-blocking (TB) antibodies. We have previously shown that R0.6C, a fusion of the 6C domain of Pfs48/45 and a fragment of PfGLURP (R0), expressed in Lactococcus lactis, was properly folded and induced transmission-blocking antibodies. Here we describe the process development and technology transfer of a scalable and reproducible process suitable for R0.6C manufacturing under current Good Manufacturing Practices (cGMP). This process resulted in a final purified yield of 25 mg/L, sufficient for clinical evaluation. A panel of analytical assays for release and stability assessment of R0.6C were developed including HPLC, SDS-PAGE, and immunoblotting with the conformation-dependent TB mAb45.1. Intact mass analysis of R0.6C confirmed the identity of the product including the three disulfide bonds and the absence of post-translational modifications. Multi-Angle Light Scattering (MALS) coupled to size exclusion chromatography (SEC-MALS), further confirmed that R0.6C was monomeric (~70 kDa) in solution. Lastly, preclinical studies demonstrated that the R0.6C Drug Product (adsorbed to Alhydrogel®) elicited functional antibodies in small rodents and that adding Matrix-M™ adjuvant further increased the functional response. Here, building upon our past work, we filled the gap between laboratory and manufacturing to ready R0.6C for production under cGMP and eventual clinical evaluation as a malaria TB vaccine.

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