Credit to: PharmaZonner
🏥 Types of Validation in Pharmaceuticals
Ensuring Quality, Compliance & Patient Safety
Validation Lifecycle Relationships
Process Validation (PV)
Establishes documented evidence that a process consistently produces a result meeting predetermined specifications.
FDA Three-Stage Lifecycle:
Define process based on knowledge from development and scale-up. Includes risk assessment and control strategy.
Confirm process design through execution of qualification protocols. Typically 3 consecutive successful batches.
Ongoing assurance that process remains in control during routine production. Includes trending and statistical analysis.
Cleaning Validation
Demonstrates that cleaning procedures effectively remove residues to prevent cross-contamination between products.
Key Requirements:
API residue: 10 ppm or 0.1% of normal therapeutic dose (whichever is lower). Cleaning agent residue and microbial limits must also be established.
Swab sampling for direct surface contact and rinse sampling for difficult-to-reach areas. Both methods should be validated.
Validate hardest to clean product, longest hold time, largest batch size, and most difficult to clean equipment.
Analytical Method Validation
Confirms that analytical methods are suitable for their intended purpose and generate reliable results.
ICH Q2(R1) Parameters:
Closeness of test results to true value. Typically 9 determinations over 3 concentration levels (80%, 100%, 120%).
Repeatability (same day), Intermediate Precision (different days/analysts), and Reproducibility (different labs).
Ability to measure analyte in presence of interferences like impurities, degradants, and matrix components.
Linearity: 80-120% of target concentration. Range: from LOQ to 120% with correlation coefficient ≥ 0.999.
Limit of Detection (LOD) and Limit of Quantitation (LOQ) based on signal-to-noise ratio or standard deviation method.
Method’s capacity to remain unaffected by small variations in parameters like pH, temperature, flow rate.
Equipment Qualification
Systematic approach to ensure equipment is properly installed, operates correctly, and performs as intended.
Qualification Phases:
Review URS (User Requirement Specification) and design documents to ensure equipment is designed for intended use.
Verify equipment installed per specifications. Check utilities, calibration, documentation, and safety features.
Demonstrate equipment operates within specified parameters across operating range under simulated conditions.
Confirm equipment consistently performs as intended under actual production conditions with real materials.
Computer System Validation (CSV)
Ensures computerized systems operate reliably, produce accurate results, and maintain data integrity throughout their lifecycle.
Key Components:
Categorize systems by GAMP 5 categories (1-5) and apply appropriate validation rigor based on GxP impact and complexity.
Electronic signatures, audit trails, system validation, record retention, and controls for open systems.
Attributable, Legible, Contemporaneous, Original, Accurate + Complete, Consistent, Enduring, Available.
Planning → Specification → Configuration → Testing → Release → Operation → Monitoring → Change Control → Retirement.
Utility Validation
Validates critical utilities that support manufacturing operations and directly impact product quality.
Critical Utilities:
USP/EP compliance, TOC <500 ppb, conductivity <1.3 μS/cm @ 25°C, microbial limits, endotoxin levels.
Temperature, humidity, air changes/hour, pressure differentials, HEPA filter integrity, particle counts per ISO 14644.
Dew point, oil content, particle contamination, microbial limits for product contact applications.
Non-condensable gases, dryness value, superheat, chemical contaminants for sterilization applications.
Cleaning Process Validation
Verifies that established cleaning procedures consistently remove residues to acceptable levels.
Validation Strategy:
Identify worst-case scenarios: most toxic product, hardest to clean, longest hold time, maximum batch size.
Demonstrate reproducibility through three successful consecutive cleaning cycles meeting all acceptance criteria.
Validated methods for API detection (HPLC/UV), cleaning agent residues (TOC), and bioburden (microbial testing).
First critical step – equipment must be visibly clean before analytical testing. Define acceptable appearance.
Establish maximum dirty hold time (before cleaning) and clean hold time (after cleaning before next use).
Why Validation Matters
Meet FDA, EMA, and global regulatory requirements
Ensure product quality and protect patient health
Achieve consistent, reproducible production
Maintain inspection-ready documentation
Minimize batch failures and product recalls
Ensure ALCOA+ compliance throughout lifecycle