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Risk Assessment in Manufacturing Processes; Business and Regulatory Benefits

Bob Seely rseely@amgen.com


Define Terminology Regulatory issues Process Characterization Risk Assessment tools How we have used FMEA New FDA Policy Guide

Operational Parameters Input variables that can be directly controlled, and when run properly the process will consistently produce product meeting predetermined specifications. Flow rate, temperature, pressure Characterized, not validated Performance Parameters Output variables, not directly controllable, that most meaningfully indicate the process performed as expected. Yield, concentration, purity, Validated, with acceptance criteria

Critical Parameters FDA: process parameters that must be controlled within specifications to ensure that the API or intermediate will meet specifications for quality and purity. But ALL parameters must be controlled! Therefore: process parameters that must absolutely be controlled within narrow specifications to ensure that the API or intermediate will meet specifications for quality and purity.


<----------Acceptable range----------> ----------Acceptable range----------> |-------------------|-------|--------------------| = Non-critical -------------------| -------| --------------------| NonOperating range |-------------------|-------|-| -------------------| -------| = Critical (2, 3)


Acceptance criteria For In-process assays used to demonstrate process consistency. Failure means investigation Specifications For intermediate or final product release. Failure means product disposal

Key Operational Parameter v. non-Key Determined during process characterization List Key in protocol Justify non-keys Control Limits Demonstrates statistical process control Excursion requires an investigation Rejection Limits Required by European regulators Excursion requires discarding the material

Process Characterization

Determine acceptable ranges Test the important ones, not all Based on a risk assessment tool Determine interactions and (some) points of failure Design of experiments Identify key parameters Turn-over package to Validation TurnKey/non-key parameters Key/nonPerformance parameters to validate Acceptance criteria to use

Risk Assessment Tools

Hazard Assessment and Critical Control Points Failure Mode and Effect Analysis

Ayyub, B.M., Risk Analysis in Engineering and Ayyub, Economics, Chapman & Hall/CRC Press, Boca Raton, 2003. Stamatis, D.H., Failure Mode and Effect Analysis: Stamatis, FMEA from Theory to Execution, Second Edition, ASQ Quality Press, Milwaukee, 2003.

Rigorous and systematic method to identify potential failures before they occur Team based, structured decision making process Documents that process Quantitatively identifies highest risk parameters; i.e., those that require further characterization

Elements of FMEA
List all operating parameters for a given unit operation Identify effects operating outside the chosen range (failure mode) Assign a value for 3 orthogonal impacts of failure: Severity of failure Occurrence of failure Detectability of failure Risk Priority Number = S*O*D

Pareto Chart
13 12 11 10 9 8 7 6 5 4 3 2 1 0 20 40 60 80 100 120 140

Application in Bio-processing
Process Characterization; Pare down the multitude of parameters to evaluate Process Transfer; Identify all changes, however small, and ensure sufficient data are available or can be generated Shared Equipment/Utilities for Multi-Host Facility; Risk mitigation of possible cross-contaminations Support Utilities; to ensure rapid recovery

Compliance Policy Guide FDA, March 12, 2004

Deletion of reference to three validation runs Process Analytical Technologies Operating ranges justified; Process Characterization

recognition of the role of emerging advanced engineering principles and control technologies in ensuring batch quality. For drugs produced using these new principles and technologies, this CPG provides for possible exceptions to the need for manufacturing multiple conformance batches prior to initial marketing. This version also deletes the previous reference to "three" validation (or conformance) batches at commercial scale as adequate minimum proof of process validity a number is no longer suggested. Also, this version further clarifies the importance of post-market information gathering especially for those batches released to market concurrent with the manufacture of the initial conformance batches.