Compressed Air for Pharmaceutical Industry GMP Requirements

General GMP Requirements for Compressed Air

China GMP (2010 revision) appendix and EU GMP Annex 1 both have requirements for compressed air. Domestic regulation's original text is "compressed air in direct contact with drugs should be purified to meet production requirements." FDA 21 CFR Part 211.68 requires gases used in production to be appropriately filtered. Regulations only give principles, specific metrics are set by enterprises themselves.

Pharmaceutical

GMP Compressed Air System

Quantitative metrics reference ISO 8573-1:2010. This standard grades particles, moisture, and oil content separately. Pharmaceutical industry selects corresponding grades based on air use scenarios. Note that microbiological metrics aren't covered by ISO 8573. ISPE guidelines suggest referencing cleanroom environment standards as supplement. This area frequently gets asked about during audits.

On testing methods, particles and dew point can be monitored online continuously. Lighthouse and Met One particle counters and Vaisala dew point meters are common choices. Oil content is more troublesome. Draeger detector tubes only give qualitative or semi-quantitative judgment. Precise results need gas chromatography lab testing, long report turnaround. Microbial testing uses impaction samplers with TSA media, count after 48 hours of incubation.

Compressed Air in Direct Contact with Drugs

Injectable production shops have strictest requirements for compressed air. Pre-sealing ampoule blowing, vial stoppering before crimping, lyophilizer loading dust blowing, air goes directly into containers. Any contaminant carried stays inside. Solid dosage fluid bed granulation and spray drying are also direct contact. Air serves as fluidizing medium or atomizing carrier, thoroughly mixing with material.

Particles must be Class 1. Some companies' internal controls are stricter, directly referencing Grade A area particle limits. Oil content Class 0. This grade means must choose oil-free compression technology. Atlas Copco ZR/ZT series has highest installed base domestically. Price is two to three times same power oil-flooded machines. Procurement approval often needs special explanation of this expense's necessity. Dew point generally controlled at -40°F. Lyophilization companies often require -94°F because residual moisture is very sensitive to lyophilized cake appearance and reconstitution time.

Microorganisms are easily underestimated. ISPE recommends compressed air directly contacting sterile drugs achieve less than 1 CFU/m³. In practice many companies handle it as "investigation triggered on any detection." Terminal sterilizing filters select Pall or Sartorius 0.22μm capsule elements. Integrity testing annually. Not cheap. All piping uses 316L stainless steel with electropolished inner walls. Welding uses automatic TIG. Manual weld seam roughness won't pass endoscope inspection.

Compressed Air Indirectly Contacting Drugs

Filling line pneumatic valves, packaging machine robot arms, automated warehouse shuttles. Compressed air in this equipment is separated by valve bodies and seals, doesn't touch drugs.

Control level is much more relaxed. Particles Class 3 is sufficient. SMC and Festo pneumatic component manuals require 5μm filtration. Dew point +37°F, as long as shop temperature doesn't go below this, no condensation. Northern winter warehouses with low temps, tighten to -4°F. Oil content Class 2 or Class 3 both acceptable.

Equipment investment can be saved. Oil-lubricated screw machine with refrigerated dryer, aftertreatment goes through C-T-A three-stage filtration. Cyclone separation, oil removal, precision filtration, three steps done. Refrigerated dryer energy consumption much lower than desiccant type, maintenance also simple. Basically just periodic cleaning of condenser and drain valve.

Cleanroom Environment Compressed Air

Compressed air for cleanroom positive pressure maintenance and airlock air curtains eventually mixes with room air. Particle class has to follow the room. Grade B background pairs with Class 1. Grade C, Grade D, Class 2 acceptable.

Dew point needs to consider HVAC system. Room controlled at 45% RH, compressed air dew point between -4°F and -40°F is appropriate. Oil content Class 1 is the floor. Oil mist entering cleanroom attaches to equipment and walls, very easy to find during cleaning validation swab sampling. Installing HEPA filter before use point is common practice.

Cleanroom

Controlled Environment

Filtration

HEPA Point-of-Use

Validation and Monitoring Requirements

IQ phase checks hardware. Equipment nameplate versus purchase order, piping material certificates versus design drawings, three-way verification. Welding records, slope measurements, support spacing, these look trivial, but rework costs are high if problems come up later.

OQ phase tests function. Pressure, flow, temperature, dew point tested item by item. Alarms and interlocks triggered one by one. Desiccant dryer regeneration switching cycle, filter differential alarm setpoints, all adjusted during this phase.

PQ phase extends the timeline. Run continuously over three production batches minimum, use dynamic data to prove system maintains stability under fluctuating air demand conditions. This data set becomes baseline for routine monitoring.

Critical use point dew point and particle data connects to DCS, automatic alarm on excursion. Microbial sampling done periodically. Sterile shops most companies do weekly. Solid dosage lines monthly is enough. All records kept at least one year past product expiration date.

Common Deviation Handling

Dew point drifting high, troubleshooting sequence: first check if dryer regeneration valve is stuck. Solenoid coil burnout and spool sticking are high-frequency faults. Then check if aftercooler fouling is causing inlet temp to exceed spec. Trickiest is adsorbent poisoning. Upstream filtration let oil through contaminating the molecular sieve. Replace whole tower. Long downtime, high cost.

Particles exceeding spec mostly relates to filters. Element expired but not changed, O-ring deformed causing bypass, inlet liquid punching through filter media, these few are most common. Carbon steel piping used for years with inner wall corrosion will also continuously release particles. Changing filter element doesn't solve root problem, need to switch to 316L piping.

Oil content exceeding spec, look at two situations. Oil-flooded systems check separator element and activated carbon element. Former has reduced separation efficiency when differential is high. Latter has adsorption capacity limit. Oil-free machines theoretically shouldn't have oil. If positive detection, first rule out sampling contamination. Confirm it's not false positive before checking airend seals.

Quality

CAPA Process

Maintenance

PM Schedule Update

After each deviation completes CAPA, update inspection items and replacement cycles in preventive maintenance plan. Same type of deviation recurring means maintenance strategy has gaps. Change the plan when it needs changing.