Pharmaceutical Plants

ISO 14644-1 defines cleanroom classes by maximum particle counts: ISO Class 5 (Grade A): ≤3,520 particles ≥0.5µm per m³. Used for sterile product filling, aseptic processing, critical operations. Requires laminar airflow at 0.36-0.54 m/sec. ISO Class 7 (Grade B): ≤352,000 particles ≥0.5µm. Background environment for Grade A zones. ISO Class 8 (Grade C/D): ≤3,520,000 particles ≥0.5µm. Non-sterile manufacturing, packaging. Air change rates: Class 5 requires 240-480 air changes/hour (ACH), Class 7 needs 60-90 ACH, Class 8 requires 20-40 ACH. HEPA requirements: All classes require H13/H14 HEPA (99.95-99.995% efficiency at 0.3µm). Monitoring: Continuous particle counting during operations, at-rest testing between batches, annually requalify. Pressure differentials: Grade A +15 Pa vs Grade B, Grade B +15 Pa vs Grade C, maintaining contamination barriers. Cost impact: Class 5 cleanroom costs ₹50,000-1,00,000 per m² including AHU, HEPA, controls vs ₹15,000-25,000/m² for Class 8. Operating cost 5-10× higher due to high air volumes and filter changes.

Containment level: Pharma collectors are OEB-rated (Occupational Exposure Band) ensuring operator exposure Filter efficiency: Multi-stage: pre-filter (EU7/F7), main filter (H13 HEPA 99.95%), safety filter (H14 HEPA 99.995%) preventing any API release. Materials: All SS316L construction, electropolished Ra <0.4µm preventing product adhesion, fully drainable (no dead legs), documented material certs. Cleaning validation: Swab testing proving <10 ppm product carry-over between campaigns, cleaning SOPs, validated cleaning agents. Documentation: Complete validation package (DQ/IQ/OQ/PQ), filter integrity testing (DOP challenge), change control for any modifications. SafeChange systems: Bag-in/bag-out allows filter replacement without operator exposure—spent filter sealed in plastic before removal, critical for cytotoxic/hormonal compounds. Explosion protection: For solvent-based processes, ATEX-certified with inert gas purge, conductive filters, proper grounding. Cost: Pharma collector 3-5× standard industrial (₹15-40 lakh vs ₹5-12 lakh for equivalent CFM) but regulatory compliance mandates investment.

cGMP (current Good Manufacturing Practice) are FDA/WHO regulations ensuring pharmaceutical products are safe, pure, and effective. Air system cGMP requirements: (1) Design qualification (DQ): Documented URS (User Requirement Specification), design rationale, risk assessment (FMEA). (2) Supplier qualification: Vendor must have pharma experience, proven quality system, documented change control. (3) Installation qualification (IQ): Verify equipment installed per drawings, materials traceable, calibrations current. (4) Operational qualification (OQ): Test all functions—airflow uniformity (±20% across HEPA face), pressure differential maintenance, alarm functionality, filter integrity (DOP/PAO test showing <0.01% penetration). (5) Performance qualification (PQ): Demonstrate consistent performance under actual conditions—particle counts during simulated production, recovery testing after door opening, worst-case challenge. (6) Change control: Any modification (damper adjustment, filter change, control setpoint) requires documented change request, impact assessment, revalidation if needed. (7) Preventive maintenance: Scheduled with documented procedures, calibrated tools, trained technicians, records retained. Audit trail: All operations logged (21 CFR Part 11 compliant if electronic), deviations investigated, CAPA implemented. Non-compliance consequences: FDA Warning Letters, import bans, product recalls, facility closure. Example: Company received Warning Letter for inadequate cleanroom monitoring losing ₹200 crore in export sales. cGMP compliance is not optional—it's survival.

Validation protocol per ISO 14644-3 and FDA guidance: Step 1: Filter integrity test. DOP (dioctyl phthalate) or PAO (polyalphaolefin) aerosol challenge upstream of HEPA, scan downstream with photometer. Must show <0.01% penetration (99.99% efficiency) and no leaks at seal. Step 2: Airflow velocity. For laminar flow (Class 5), measure at 30 cm from HEPA using calibrated anemometer or Velocicalc. Target 0.36-0.54 m/sec (70-110 ft/min). Map grid of 2×2 ft, accept if all points within ±20% of mean. Step 3: Airflow visualization. Smoke studies demonstrating unidirectional flow, no turbulence or dead zones. Step 4: Air change rate. For turbulent flow (Class 7/8), calculate ACH = (60 × CFM) ÷ room volume cubic ft. Verify meets design (Class 7 = 60-90 ACH). Step 5: Pressure differential. Magnehelic gauges at each room verify cascades (Class 5 +15 Pa vs Class 7 +15 Pa vs Class 8). Step 6: Recovery test. Introduce particle challenge (nebulized PAO), time for return to baseline showing system can recover from upsets. Step 7: Particle count mapping. Sample at multiple heights and locations during operation, demonstrating consistent ISO classification. Acceptance: All parameters meet specification for 3 consecutive runs. Revalidation: Annually or after any significant change (HVAC modification, room layout change). Complete protocol with raw data, deviations, and approvals required for regulatory inspections.

Airflow patterns: Unidirectional flow disrupted by equipment, personnel movement, or improper room placement creating turbulence that transports particles from dirty to clean zones. Pressure differential failure: Loss of positive pressure (due to AHU malfunction, door left open, filter loaded) allowing corridor air into cleanroom. Product carry-over: Inadequately cleaned equipment, ductwork, or dust collectors retaining API residues from previous campaign contaminating next product. Personnel practices: Improper gowning (skin flakes, hair, clothing fibers), poor aseptic technique, bringing materials from unclassified areas. Material transfer: Transferring raw materials through airlocks without proper decontamination. Equipment shedding: Poorly maintained equipment releasing particles (worn seals, corroded surfaces, lubricant migration). Prevention strategies: (1) Segregation: Dedicated areas/equipment for high-risk products (penicillins, cephalosporins, hormones, cytotoxics). (2) Airlocks: Pass-through chambers with interlocked doors preventing simultaneous opening, HEPA-filtered supply, material decontamination (70% IPA wipe). (3) Cleaning validation: Swab testing proving residues <10 ppm (or 1/1000th of therapeutic dose, whichever lower), documented procedures, visual cleanliness. (4) Campaign manufacturing: Produce single product in sequence, clean between campaigns vs multi-product requiring frequent changeovers increasing contamination risk. (5) Monitoring: Continuous particle counting, settle plates for microbial monitoring, routine swabbing of surfaces. Regulatory view: Cross-contamination is a major cause of FDA Warning Letters and product recalls—prevention through proper design and discipline is critical.

Working principle: Negative pressure enclosure with HEPA-filtered exhaust preventing operator exposure to hazardous powders during dispensing, sampling, or transfer. Design features: (1) Airflow: Inward velocity 0.4-0.5 m/sec through front opening preventing powder escape while allowing operator access. Too low = inadequate containment, too high = turbulence dispersing powder. (2) Filtration: Dual HEPA (primary + safety) ensuring 99.995% capture even if primary filter fails. (3) Pressure: -25 to -50 Pa vs room creating inward airflow. (4) Construction: SS316L electropolished smooth surfaces, cove radius corners, sloped surfaces for complete cleaning. (5) Interlocks: Alarms if airflow drops below setpoint, auto-shutdown of operations if failure. Containment levels: Class II biosafety cabinet for general use with 70% recirculated air. Downflow booth with 100% exhaust for higher containment with toxic compounds. Isolator with complete physical barrier and glove ports for highest containment (cytotoxics, high-potency hormones). Validation: DOP/PAO challenge testing showing <0.005% leakage, visual smoke test demonstrating inward flow, operator exposure monitoring via breathing zone sampling during simulated worst-case (target Applications: API dispensing preventing cross-contamination and operator exposure, sampling of batches, transfer of potent intermediates. Cost: Simple downflow booth ₹3-8 lakh, full containment booth ₹12-25 lakh, isolator ₹35-80 lakh. Investment justified by preventing operator health effects and regulatory compliance.

Health hazards: Many pharma solvents (methanol, acetone, dichloromethane, toluene, hexane) are toxic, carcinogenic, or teratogenic. OSHA PELs: Methanol 200 ppm, Acetone 1000 ppm, Dichloromethane 25 ppm. Fire/explosion risk: Most solvents flammable with low flash points (methanol 11°C, acetone -20°C, hexane -22°C). Vapor-air mixtures within explosion limits ignite from spark/hot surface causing catastrophic damage. Environmental regulations: VOC emissions regulated—typically <120 mg/m³ stack concentration. Control methods: (1) Source capture: Enclosed reaction vessels, sealed transfer lines, vapor collection at process vents. (2) Ventilation: Fume hoods for R&D labs (100 FPM face velocity minimum), general exhaust 6-12 ACH for solvent areas preventing accumulation below 10% LEL. (3) Vapor recovery via activated carbon: Carbon bed adsorbs vapors from exhaust air (efficiency 95-99%), regenerated with steam or hot air desorbing solvent for recovery/reuse. Capital ₹25-75 lakh for 5,000-20,000 m³/hr system. Refrigerated condensation: Chill vapor-laden air to 0 to -40°C liquefying solvents. Suited for single-solvent, high-concentration streams. Thermal oxidation: Incinerate vapors at 700-850°C destroying organics to CO2+H2O. Capital ₹50 lakh-₹3 crore. (4) Explosion protection: ATEX Zone 1/2 electrical equipment, inert gas blanketing (nitrogen) in vessels, LEL monitoring with alarm at 20-25% LEL. Economics: Solvent recovery systems pay back in 2-5 years from recovered solvent value (₹200-600/liter) plus disposal cost avoidance (₹50-150/kg).

Product stability: APIs and excipients degrade with temperature/humidity exposure. Hygroscopic materials: Lactose, starch, PVP, gelatin absorb moisture increasing weight (impacting dose accuracy), reducing flowability (causing hopper bridging), promoting microbial growth, and accelerating chemical degradation. Tablet compression: Granule moisture 2-5% optimal—too dry causes capping (tablet splitting), too wet causes sticking to punches. Coating operations: Film coating requires 35-45% RH. Higher humidity prevents film drying causing tack, lower causes cracking. Lyophilization: Requires <20% RH in formulation area preventing moisture pickup before freezing. Chemical reactions: Hydrolysis degrades esters and amides in APIs. Example: Aspirin hydrolyzes to salicylic acid + acetic acid causing stability failure. Static electricity: Low humidity (<30%) increases static causing powder adhesion to equipment, dust explosions, operator shocks. High humidity (>60%) reduces static but causes condensation risk. Control requirements: Precision AHUs with chilled water cooling plus reheat achieving ±2°C, steam humidification or desiccant dehumidification for ±5% RH. Set points by application: API manufacturing 20-25°C at 40-50% RH. Tablet coating 22-26°C at 35-45% RH. Capsule filling 20-24°C at 30-40% RH (gelatin brittle if too dry, sticky if humid). Packaging 18-25°C at 25-35% RH. Cold storage 2-8°C for refrigerated products. Monitoring: Calibrated sensors (±0.5°C, ±3% RH) with continuous data logging, alarm at ±3°C or ±10% RH from setpoint, annual recalibration. Validation: Temperature/humidity mapping demonstrating uniformity, challenge testing proving recovery after door opening, seasonal qualification (summer/monsoon/winter).