Dissolution failure and failure mode analysis of a Hot melt extrusion product – a case study
Saji Thomas, M. Sc.
The regulatory guidance and the CFR requirements were discussed as an introduction to the main theme of the talk. The high
lights of the Barr decision along with FDA’s Guidance on investigating OOS results for pharmaceutical products were discussed.
Determining root cause and establishing CAPA is the key to successful OOS investigation. Failure mode analysis tool like
Fish bone diagram was discussed as a mean to identify the root cause. The step by step investigation of a dissolution failure
of a melt extrusion product was discussed as case study. The product failed at 6 months at accelerated stability condition.
Since the initial investigation did not result in identifying the root cause it was decided to evaluate the robustness of
the method. A five factorial/eight experiment design was used to evaluate the robustness of the method. The method was found
to be very sensitive to the salt added in the dissolution media. A normal probability plot was used to assess robustness of
the method using the data generated from the DOE.
Other analytical techniques had to be used since the evaluation of the method did not conclusively prove the root cause of
the failure. The product was analyzed using Solid state NMR, Environmental electron scanning microscope, time of flight-secondary
ion mass spectroscopy (TOF-SIMS). Products cured at 50c were used for the analysis. SSNMR analysis showed that stearyl alcohol
in the formulation if behaving differently after curing the product. A white coating on the product was observed when the
product was viewed in an ESEM. The white coating was identified to be stearyl alcohol by TOF-SIMS.
Based on a scientific investigation it was concluded that the dissolution failure was due to the stearyl alcohol migrating
to the surface of the product when exposed to heat.
Stability Testing to Support Distribution of Temperature Sensitive Pharmaceuticals
Robert H. Seevers, Ph.D.
All drugs are, to some extent, temperature sensitive. Stability testing makes it possible to determine the appropriate long
term storage condition and to evaluate the risk to product quality posed by exposure to temperatures outside that condition.
The ICH stability guidances primarily focused on storage conditions and shelf lives for drug substances and drug products.
This presentation discussed the other types of testing which may be done in addition to the standard ICH conditions that permit
a stability budget to be created for a pharmaceutical.
A stability budget is created using data from long term and accelerated testing such as that provided for in the ICH guidances,
but adds freeze-thaw and temperature cycling studies to create a fuller picture of a drug’s susceptibility to changes in temperature
that it may experience during the entire distribution process from manufacture to transport, to storage, to end use. The concept
of time out of refrigeration has been used to allow for room temperature operations such as packaging and labeling on refrigerated
products. This presentation showed how this concept can be expanded to the entire distribution process.