APR Nov/Dec 2022 - 18

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DRUG DEVELOPMENT
»
A Practical Analytical Risk Survey Program for
Active Pharmaceutical Ingredient Synthesis that
Enhances Analytical Control Strategies for Early
and Mid-Stage Development
Li Li, Peter Tattersall, Qinggang Wang,
Jonathan Shackman, Lianjia Ma and
Adrian Doggett
Chemical Process Development
Bristol Myers Squibb
Overview
Active pharmaceutical ingredient (API) process development requires
a comprehensive analytical control and a set of wide-ranged analytical
methods. In the early to mid-stages of development, i.e., at phase I and
II clinical trials, the analytical controls in manufacturing processes are
still evolving. The analytical methods designed to gather data on APIs,
intermediates, starting materials, and reagents are also progressing,
but knowledge regarding method robustness is limited. Despite being
in clinical development, there is a requirement for scientifically sound
data to provide confidence in key decisions, establish reproducible
testing at contract manufacturing organizations (CMOs), and, most
importantly, guaranteeing consistent quality to ensure patient safety.
As every project is different, how do we drive consistency between
projects in handling and learning from risk mitigation? To address this,
an analytical risk survey program to evaluate common risk factors was
developed. In this article, we introduce a new workflow that is simple
and widely applicable to assess analytical gaps and risks for early- to
mid-stage projects. The workflow combines a checklist with common
risk factors and a spreadsheet with scored ranking to facilitate the
collation of an experimental 'to do' list for evolution of analytical
method conditions and optimization of controls. The impact of this risk
survey program has shown to be value added for both the analytical
teams and overall portfolio development at Bristol Myers Squibb.
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| November/December 2022
Introduction
In the pharmaceutical industry, a scalable synthesis involves
development of practical, safe, sustainable, and cost-effective
chemistry and process design. The synthetic route, process, and
analytical chemistry all evolve with the clinical development. At
early clinical stages, i.e., phase I and II clinical trials, the process for
small molecule APIs is usually grounded in the drug discovery route
and fit for mid-scale (gram to 10's of kilogram) production needs. At
the late clinical stage, the chemical process should be well defined,
robust for commercial regulatory filings, and ready for full commercial
manufacturing scale. The analytical controls and methods of each stage
follow these needs similarly. Analytical risk assessment should have the
flexibility to meet the evolving demands of process development. To
account for the analytical risk assessment needs, we designed a topdown
approach which we call an " analytical risk survey " . This survey
program is designed for early-stage projects, and the terminology of
risk survey is utilized to differentiate a more involved risk assessment
program for late-stage projects. In Figure 1 both process and analytical
activities at different stages are summarized. Our analytical risk
assessment program holistically views the analytical activities and how
they collectively connect to the process to drive simple and effective
method development. When viewed through the intent of the current
analytical control strategy (not from an individual method), the risk
survey helps highlight areas of concerns.
APR Nov/Dec 2022

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