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Clinical Thermal Analysis

BioC Conducts Thermal Analysis During Clinical Phase for a Small Biotechnology Company

The Challenge

Our client’s lyophilized new drug product successfullly completed early clinical testing and their production date for Phase 3 clinical supplies was set.  However, Phase 2 study results established their product required five times the dose given at one thrid the frequency for Phase 2 studies.  To provide clinical supplies, they needed a new presentation capable of delivering the higher dose.  But there was a potential glitch – they has conflicting development history data and theories regarding the formation of crystalline mannitol during lyophilization and its role in solubility, reconstiution, and product stability.  Early studies indicatied a relationship between lyophilized plug dimensions relative to vial dimensions and crystalline mannitol formatoin.  However, the product formulation, lyophilization cycle and vial presentation had remained the same since preclinical development and cGMP clinical production had delivered acceptable product quality, reconstituion, and stability results.  therefore, no additonal development studies had been performed to prove or disprove the theory regarding crystalline mannitol formaton.  To develop a new larger dose presentation, they needed to understand the intersection of these key product design parameters for their current formulation and presentation.

The Solution

The first step was to conduct studies on the current product to determine the presence and level of crystalline mannitol.  The client provided 6 vials from each of 9 product lots currently undergoing ICH stabiliity.  BioConvergence development scientists used 2 vials each to perform:

  • Thermal analysis by differential scanning calorimetry (DSC) and freeze dry microscopy (FDM),
  • Moisture analysis by Karl Fischer (KF), and
  • Reconstitution studies.

Due to the presence of mannitol and known issues with drug substance crystallization, attention focused on identifying evidence of increased crystallization.

The Results

Thermal analysis studies, analyzing both solids and solutions, produced:

  • No observations of significant endothermis events near 160°C during DSC analysis (i.e. typical melt range for amnnitol of 164-169°C),
  • DSC endotherms identifying 2 significant thermal events with a glass trasition temperature of -24.4°C and ice melt at -4°C, and
  • FDM results of the collapse temperature onset at -24.4°C/111mTorr and full collapse at -20.3°C/111mTorr.

Although relevant to client’s product development, moisture and reconstitution study detail are not covered in this case study.

The Conclusions

  • Thermal analysis by DSC provides a viable method for detecting crystalline mannitol melt in the final product even at concentrations as low as 1%.
  • No significant crystalline mannitol formation was found in existing product lots.
  • Engineering and clinincal product batches produced using multiple drug substance lots, at various scales, in different lyophilizers and by several contract manufacturers yielded similar thermal, moisture, and reconstiution profiles.
  • Critical lyophilization cycle parameters for the current presentation maintain product temperature sufficiently below the collapse temperature of the formulation while prodviding for efficient vapor transfer.
  • Thermal analysis by DSC and FDM results provide the necessary design data for primary dying temperature and vacuum settings for the new larger product presentation.
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