How to manage an Injectable/Sterile/Parenteral manufacturing section
Detailed Guide to Managing an Injectable/Sterile/Parenteral Manufacturing Facility
Injectable (sterile/parenteral) manufacturing is one of the most critical and highly regulated areas in pharmaceutical production due to the direct introduction of drugs into the bloodstream, bypassing the body’s natural defenses. Any contamination—microbial, particulate, or endotoxin—can lead to serious patient harm, including sepsis or death.
This detailed guide covers facility design, personnel controls, sterilization methods, environmental monitoring, process validation, and regulatory compliance to ensure sterility assurance (SAL ≤ 10⁻³).
1. Facility Design & Environmental Controls
A. Cleanroom Classification & Layout
ISO 5 (Grade A): Critical zones (filling, stoppering, open ampoule/vial handling).
ISO 7 (Grade B): Surrounding background for aseptic processing.
ISO 8 (Grade C/D): Support areas (component prep, gowning).
Unidirectional Airflow (UDAF): HEPA-filtered laminar flow over critical zones.
Pressure Cascades:
Grade A/B → Grade C → Grade D (ensuring no backflow).
Differential pressure ≥ 10-15 Pa between zones.
B. HVAC & Air Handling
HEPA Filters: ≥ 0.3 µm efficiency at 99.97% (ISO 5).
Air Changes:
Grade A/B: ≥ 90-120 air changes/hour.
Grade C/D: ≥ 20-40 air changes/hour.
Temperature & Humidity Control:
20-24°C (comfort for operators in full gowning).
45-65% RH (prevents microbial growth and static).
C. Restricted Access Barrier Systems (RABS) vs. Isolators
| Feature | RABS | Isolators |
|---|---|---|
| Operator Interaction | Limited (glove ports) | Fully closed (no direct contact) |
| Decontamination | Manual (VHP, sporicidal agents) | Automated (H₂O₂ vapor, peracetic acid) |
| Risk of Contamination | Moderate (human interventions possible) | Very low (fully automated) |
| Cost | Lower | Higher |
Best Practice: Use isolators for high-risk products (e.g., biologics, cytotoxic drugs).
2. Personnel Training & Gowning
A. Aseptic Behavior & Hygiene
No jewelry, makeup, or perfumes (risk of shedding particles).
No direct talking over an open product (microbial shedding from saliva).
Slow, deliberate movements (minimize airflow disruption).
B. Gowning Procedure (Grade A/B Areas)
Pre-Gowning: Wash hands with sterile disinfectant (70% IPA + chlorhexidine).
Donning Order:
Hood → Facemask → Sterile Coverall → Boots → Gloves (double-gloving recommended).
Gowning Qualification:
Microbial settle plates test after gowning (must meet ≤1 CFU/plate).
C. Training & Monitoring
Media Fill Participation: All operators must pass at least one media fill per year.
Smoke Studies: Verify aseptic technique (no turbulence in critical zones).
3. Sterilization & Depyrogenation Methods
A. Sterilization Techniques
| Method | Application | Validation Requirement |
|---|---|---|
| Steam Sterilization (Autoclave) | Glass vials, rubber stoppers, tools | F₀ ≥ 15 min (121°C, 15 psi) |
| Dry Heat Sterilization | Glassware, metal parts | 250°C for 30 min (or 170°C for 2 hrs) |
| Ethylene Oxide (EtO) | Heat-sensitive plastics | Gas concentration, humidity, exposure time validation |
| Gamma Radiation | Pre-sterilized disposables (e.g., filters, tubing) | 25 kGy minimum dose |
| Filter Sterilization (0.22 µm) | Liquids (solutions, biologics) | Bubble point test, LRV ≥7 |
B. Depyrogenation (Endotoxin Removal)
Glass Vials/Syringes: 250°C for 30 min (validated endotoxin reduction ≥3 log).
Endotoxin Testing: LAL (Limulus Amebocyte Lysate) test (must be <0.25 EU/mL).
4. Environmental Monitoring (EM) Program
A. Non-Viable Particle Counts
ISO 5 (Grade A): ≤ 3,520 particles (≥0.5µm) per m³.
Continuous Monitoring: Laser particle counters with alarms for excursions.
B. Viable Monitoring (Microbial Contamination)
| Method | Frequency | Acceptance Criteria (Grade A/B) |
|---|---|---|
| Active Air Sampling | Every batch | <1 CFU/m³ (Grade A) |
| Settle Plates (90mm, TSA) | 4 hrs exposure | <1 CFU/plate (Grade A) |
| Surface Swabs (RODAC) | After each session | <1 CFU/25 cm² (Grade A) |
| Glove/Fingertip Testing | Post-operation | <1 CFU/glove |
C. Water System Monitoring (WFI/PW)
TOC: ≤ 500 ppb.
Conductivity: ≤ 1.3 µS/cm.
Endotoxin: ≤ 0.25 EU/mL (WFI).
5. Process Validation & Media Fills
A. Media Fill (Process Simulation Test)
Objective: Validate the aseptic process by filling sterile growth medium (TSB) instead of the product.
Frequency: Twice per year per shift (or after major changes).
Acceptance Criteria:
0 contaminated units out of ≥5,000 (for large batches).
If batch size <5,000, use 95% confidence limit (≤0.1% contamination).
B. Interventions & Worst-Case Simulation
Mimic real production: Include stoppering delays, machine adjustments, and glove changes.
Incubation: 14-20°C for 7 days + 30-35°C for 7 days (detects mesophilic & aerobic microbes).
6. Sterility Testing & Batch Release
A. Sterility Test (USP <71>, EP 2.6.1)
Membrane Filtration (preferred for liquids) or Direct Inoculation.
Incubation: 14 days (both aerobic and anaerobic conditions).
Sample Size:
≤10,000 units: 20 units tested.
>10,000 units: 2% or 20 units (whichever is less).
B. Container-Closure Integrity Testing (CCIT)
| Method | Application |
|---|---|
| Dye Ingress | Visual inspection (manual) |
| High Voltage Leak Detection (HVLD) | Sensitive for small leaks |
| Helium Leak Testing | Most precise (for biologics) |
7. Regulatory Compliance & Inspections
Key Regulations
FDA: 21 CFR 210/211, Annex 1 (EU GMP).
PIC/S: PE 009-17 (Sterile Manufacturing Guidelines).
WHO TRS 986 (Sterile Pharmaceutical Preparations).
Common Inspection Findings & How to Avoid Them
Failure: Inadequate media fill design.
Fix: Simulate all interventions, including worst-case scenarios.
Failure: HVAC system not properly qualified.
Fix: Perform smoke studies & airflow visualization.
Failure: Glove/fingertip monitoring failures.
Fix: Retrain operators, enforce strict gowning.
8. Emerging Trends in Sterile Manufacturing
Single-Use Systems (SUS): Disposable bioreactors, tubing, filters.
Advanced Aseptic Technologies: Robotic filling, closed vial transfer (CVT).
Rapid Micro Methods (RMM): PCR, ATP bioluminescence for faster sterility testing.
Final Takeaway
Managing a sterile injectable facility requires:
✅ Strict environmental controls (ISO 5, unidirectional airflow)
✅ Highly trained personnel (media fill qualified)
✅ Validated sterilization & depyrogenation
✅ Rigorous environmental & sterility monitoring
✅ Compliance with FDA/EMA/PIC/S guidelines
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