Process Optimization Using Design of Experiments

The challenge:
Can you validate my cGMP process and get my product to market faster at a lower cost?

How we said yes:
Albemarle has extensive expertise in the Design of Experiments (DoE) approach - the modern alternative to single-variable experimentation. In our research facilities, DoE is used to conduct process optimization in a rapid, responsive fashion, while supporting efforts for cGMP process validation. (The DoE approach can also be applied to non-GMP process development.) In our experience, DoE is an excellent course for facilitating reduced costs and time to market.

Current Trends in ICH Guidelines
Albemarle's DoE methods fully support the FDA ICH Quality by Design (QbD) initiative. FDA publications that have had an impact on our work:

  • PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Final) Sept. 2004
  • ICH Q7 - Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (Final) August 2001
  • ICH Q8 (R2) - Pharmaceutical Development (Final) Nov. 2009
  • ICH Q9 - Quality risk management (Final) June 2006
  • ICH Q10 - Quality systems (Final) April 2009
  • Process Validation: General Principles and Practices (Final) Jan. 2011

Our approach for this particular client included:

Step 1:

Conducting a thorough quality risk review of the process as per the FDA's Q9 approach to risk analysis:

  • Identified relevant Critical Quality Attributes (CQAs);
  • Initiated a 3-factor, 21-experiment central composite DoE to understand the relative impacts of the putative Critical Process Parameters (CPPs); and
  • Performed the DoE on one of Albemarle's parallel reactor systems, drastically shortening the amount of time required to complete the study.

Step 2:

Three factors were tested in the context of the DoE. The process was a bimolecular reaction (A + B > C):

  • Relative amount of input B
  • Reaction concentration
  • Reaction temperature

Step 3:

Three responses were tested in each of the 21 parallel experiments:

  • Amount of isomer of C found
  • Overall conversion to C
  • Product purity assay

Step 4:

The DoE results were verified on 2-L equipment, then the information was explicitly applied to validations at 1,000- and 4,000-gallon scale.

The yes formula direct customer benefits:

  • The Albemarle DoE determined that performing the reaction at a higher concentration could save time and money.
  • A distillation step was removed.
  • The process was improved when relative Green Metrics were analyzed.
  • The customer gained a better understanding of the process.
  • The Albemarle DoE facilitated the process validation according to the FDA's guidance on the topic (Quality by Design). As a result:
    • Our team has a firm grasp on the process design space.
    • We have the confidence to operate this process, which is characterized by very high raw material input costs.
    • We minimized the risk of encountering a quality-related incident due to the DoE work.
    • Albemarle has created value by applying "big pharma" industry and FDA-endorsed best practices for process optimization and subsequent validation.
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Albemarle Americas
Fine Chemistry Services
Tel: +1 800 535 3030

Albemarle Americas
EMA Fine Chemistry Services
Tel: +1 800 535 3030

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Last Updated: 6/27/2017 5:11:38 PM