Introduction
In pharmaceutical manufacturing, utility gases like compressed air must meet stringent quality standards to ensure product safety and regulatory compliance. Yet many facilities, especially new or expanding ones, lack fully developed qualification programs for these critical systems. This article presents a real-world case study involving a pharmaceutical company in Bethlehem, PA, where we implemented a comprehensive utility validation program, investigated and resolved hydrocarbon contamination, and supported the qualification of associated systems including purified water, cleaning validation, and environmental monitoring, through to routine monitoring support.
PART 3 – Cleaning Validation for Oral Solid Dosage Equipment
Title:
Proving Clean: TOC-Based Cleaning Validation for Solid Dose Manufacturing Equipment
Intro:
Cleaning validation is a cornerstone of Good Manufacturing Practice (GMP), ensuring that residues from previous batches do not contaminate subsequent products. In a new oral solid dosage facility in Bethlehem, PA, we designed and executed a cleaning validation program leveraging Total Organic Carbon (TOC) analysis and Surface Bioburden to demonstrate consistent and verifiable cleaning effectiveness across multiple product contact surfaces. TOC and Bioburden were identified as the methods of choice by the system owners due to the variability of product they would be manufacturing. In other systems, HPLC or other analytical methods may be used instead.
Defining the Validation Strategy
We began by developing a risk-based matrix that considered:
- Worst-case active pharmaceutical ingredients (APIs), detergents, and other ingredients based on solubility and potency
- Shared equipment train and product contact surfaces
- Cleaning agent selection and cycle parameters
Acceptance criteria were established per FDA and EMA guidance, factoring in health-based exposure limits and analytical method capabilities.
Why TOC?
TOC provides a non-specific, sensitive measurement of residual organic material on equipment surfaces or rinse samples. For this program:
- TOC limits were derived from maximum allowable carryover (MACO) calculations
- Recovery studies confirmed method suitability on stainless steel and polymer surfaces
- TOC provided faster turnaround compared to traditional HPLC methods
Protocol Execution
- Worst-Case Selection: Equipment with hardest-to-clean geometry and highest-risk product
- Sampling Points: Swab samples from designated “hard-to-clean” locations, plus final rinse water
- Validation Cycles: Three consecutive successful cleaning runs were required for each equipment type
Results
- All TOC results were below established MACO limits
- Visual inspections passed per SOP
- Rinse water samples confirmed the absence of residual cleaning agents and organics
A validated, reproducible cleaning process was documented, approved by Quality, and integrated into batch release criteria.
Key Takeaways
- TOC-based cleaning validation offers speed, sensitivity, and cost-effectiveness
- Early risk assessment and matrix design streamline execution
- Robust documentation builds regulatory confidence for future inspections
Coming up in Part 4: We’ll close out the series by detailing the Environmental Monitoring Program (EMP) we implemented to ensure long-term cleanroom control in this new facility.
