Engineering Runs in the ASTM E2500 Validation Lifecycle

Engineering runs (ERs) represent a critical yet often underappreciated component of modern biopharmaceutical validation strategies. Defined as non-GMP-scale trials that simulate production processes to identify risks and optimize parameters, Engineering Runs bridge the gap between theoretical process design and manufacturing. Their integration into the ASTM E2500 verification framework creates a powerful synergy – combining Good Engineering Practice (GEP) with Quality Risk Management (QRM) to meet evolving regulatory expectations.

When aligned with ICH Q10’s pharmaceutical quality system (PQS) and the ASTM E2500 lifecycle approach, ERs transform from operational exercises into strategic tools for:

• Design space verification per ICH Q8
• Scale-up risk mitigation during technology transfer
• Preparing for operational stability
• Continuous process verification in commercial manufacturing

ASTM E2500 Framework Primer: The Four Pillars of Modern Verification

ASTM E2500 offers an iterative lifecycle approach to validation:

1. Requirements Definition
   Subject Matter Experts (SMEs) collaboratively identify critical aspects impacting product quality using QRM tools. This phase emphasizes:
   • Process understanding over checklist compliance
   • Supplier quality systems evaluation
   • Risk-based testing prioritization
2. Specification & Design
   The standard mandates “right-sized” documentation – detailed enough to ensure product quality without unnecessary bureaucracy.
3. Verification
   This phase provides a unified verification approach focusing on:
   • Critical process parameters (CPPs)
   • Worst-case scenario testing
   • Leveraging vendor testing data
4. Acceptance & Release
   Final review incorporates ICH Q10’s management responsibilities, ensuring traceability from initial risk assessments to verification outcomes.

Engineering runs serve as a critical bridge between design verification and formal Process Performance Qualification (PPQ). ERs validate critical aspects of manufacturing systems by confirming:

1. Equipment functionality under simulated GMP conditions
2. Process parameter boundaries for Critical Process Parameters (CPPs)
3. Facility readiness through stress-testing utilities, workflows, and contamination controls

	Demonstration/ Training Run prior to GMP area	Shakedown. Demonstration/Training Run in GMP area	Engineering Run	cGMP Manufacturing
Room and Equipment
Room	N/A	IOQ Post-Approval	Released and Active
Process Gas			Generation and Distribution Released Point of use assembly PQ complete
Process utility
Process Equipment		Functionally verified or calibrated as required (commissioned)	IOQ Approved	Full released
Analytical Equipment			Released
Alarms		N/A	Alarm ranges and plan defined	Alarms qualified
Raw Materials
Bill of Materials	RM in progress		Approved
Suppliers	Approval in Progress		Approved
Specifications	In Draft		Effective
Release	Non-GMP Usage decision		Released
Process Documentation
Source Documentation	To be defined in Tech Transfer Plan		Engineering Run Protocol	Tech Transfer closed
Batch Records and product specific Work Instructions	Draft		Reviewed Draft	Approved
Process and Equipment SOPs	N/A	Draft	Effective
Product Labels	N/A		Draft Labels	Approved Labels
QC Testing and Documentation
BSC and Personnel Environmental Monitoring	N/A		Effective
Analytical Methods	Suitable for use		Phase Appropriate Validation
Stability	N/A		In place
Certificate of Analysis	N/A		Defined in Engineering Protocol	Effective
Sampling Plan	Draft		Draft use as defined in engineering protocol	Effective
Operations/Execution
Operator Training	Observe and perform operations to gain hands on experience with SME observation		Process specific equipment OJT Gown qualifiedBSC OJT Aseptic OJT Material Transfer OJT (All training in eQMS)	Training in Use
Process Lock	As defined in Tech Transfer Plan		6-week prior to execution	Approved Process Description
Deviations	N/A	N/A	Process – Per Engineering Run protocol FUSE – per SOP	Per SOP
Final Disposition	N/A	N/A	Not for Human Use	Per SOP
Oversite	PP&D		MS&T	QA on the floor and MS&T as necessary