18 SEPTEMBER/OCTOBER 2018

P H A R M P R O . C O M P H A R M P R O . C O M

The Significance of Humidity Controlin GMP Compliant ProductionMany phenomena are influenced by the relative humidity level,and they can cause production processes to be less efficient, lesspredictable, and more prone to producing products that don’t meetspecification.By Martin Ginty, Munters

GMP compliance in pharmaceuticalmanufacturing requires that any process,person, environment, or equipment withdirect impact on the quality and safety of

the product being produced must operate withinspecified limits.

These specified limits should be under thedirect control of the manufacturing team, withcountermeasures available in the event of aproblem. In addition, any other part of theproduction or storage processes that have anindirect impact must also be assessed for possiblerisk impact.

Humidity may not seem like an obvious causeof problems, or something that could even resultin production being non-compliant, but this canand does occur. Just because one does not see anissue doesn’t mean there isn’t a problem. Manyphenomena are influenced by the relative humiditylevel, and they can cause production processes tobe less efficient, less predictable, and more prone toproducing products that don’t meet specification.

Some common issues that can arise from poorhumidity control are:

• Increased energy consumption• Altered aesthetic presentation• Microbiological growth• Chemical reactions• Poor test equipment accuracy• Moisture regain• Changes in electrical conductivity• Effects on operators• Degradation of buildings and products• Condensation• Product drying issues

• Corrosion• Reduced refrigeration plant efficiency• Reduced productivity• Ice build up

Figure 1 shows the influence on storage of avariety of materials as relative humidity changes.Storage in this sense is not just restricted towarehousing, but also applies to any material,object, or equipment that remains stationary in afixed location for extended periods. So, think ofthis also in the context of equipment and fittingswithin a pharmaceutical manufacturing plant.

It is important to note the relationship betweenrelative humidity (RH%) and air temperature,as variations in temperature also will affect theRH%. For example, a sufficiently large drop in airtemperature can result in water vapor condensingout. Alternatively, cold surfaces will causecondensation to form if the surface temperaturedrops below the dew point of the air around it.

GMP Compliance

Figure 1: Effect of RH% on materials in static locations.

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Humidity in ManufacturingAreasIn pharmaceuticalmanufacturing, quality andconsistency are key. Considerthe following typical conditionsfound in areas related to soliddosage production:

From Figure 2, if the RH%levels therein are correctlymaintained for the designatedprocess and surrounding areas,then no humidity-related issuesare likely to occur, either tothe material produced or theproduction equipment itself.

Of course, the actual requiredRH% values for any givenprocess are dependent uponmany factors, including:

• The materials being usedand their sorption isotherms,hygroscopicity, and sensitivityto water.

• The manufacturing space itself:volume, building insulation,airflow control, number ofopenings, geographic location,climate, etc.

• SOPs and operator behavior:cleaning cycles, proceduresfor material transfers, etc.

• GMP specified values whichmay be influenced by otherfactors.

Often, issues can arise whenthere has been some changemade to the manufacturingconditions, such as a new

product formulation, the use ofdifferent fillers, or adding staffon the plant floor. Introducinga few extra tons of materialsor adding additional personnelin the space will alter the loadon the air handling system andresult in humidity issues.

Therefore, in all areas ofproduction, humidity levelsalways should be carefullyconsidered, not just to suit thematerial being produced, but alsoto take into account any othereffects arising from unexpectedRH% levels that could occur andpotentially disrupt production.

So, the questions thatpharmaceutical manufacturersmust ask themselves are:

• Do the relative humiditylevels within my facilityexceed GMP specified valuesat any time?

• If they do, for how long?What is the recovery time toreturn to the specified value?

• What is the impact of thisexcursion from the specifiedvalue, and do I need to reactto this?

• Is recovery time fixed orvariable? For example, witheffective humidity control therecovery will be quicker indry winter months or longerduring wet, humid periods.

Bearing all of the precedingpoints in mind, take a moment to

consider if you are experiencingmoisture related production orquality problems in productionareas. Issues may arise based on anumber of factors:

• The flow of API andexcipients is not as expected;it could be either too fastor too slow depending uponhow moisture affects thematerials.

• The angle of repose inpowder or granulate (Figure3) samples is not as expected.If a small amount of availablewater is able to bridge thegaps between particles,electrostatic attraction of thewater to surfaces will alter theangle of repose, another signthat flow characteristics mayhave changed.

• Do you experience anyvariations when weighingbatches of raw materials orfinished product that couldbe caused by fluctuations inwater content? This can bedetermined by referring tothe sorption isotherms of thematerials being weighed.

• Are there signs of clogging,caking, or other obstructionsin silos, bins, pipework, andprocess equipment? Doespneumatic transport takelonger than expected? Is thereadditional noise and vibrationthat might be attributedto blockages? It’s alsoimportant to remember thatthe increased air pressure ofpneumatic transport systemswill affect the dew point ofthe air within the system,and condensation could occurat higher than expectedtemperatures.

• When using moisture-permeable containers forpackaging, such as plastic

Production area Temperature Humidity

Weighing, Mixing 68 to 72°F (20 to 22°C) 35 to 40% RH

Compression 68°F (20°C) 25 to 35% RH

Pan coating 53 to 203°F (12 to 95°C) 10 to 70% RH

Filling and Packing 68°F (20°C) 10 to 35% RH

Storage 68 to 77°F (20 to 25°C) 45% RH

Figure 2: Typical conditions in solid dosage production.

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P H A R M P R O . C O M P H A R M P R O . C O M

bags and semi-rigid, low-density polyethylene (LDPE)pouches for large volumeparenterals (LVPs), and LDPEampoules, bottles, and vials,due consideration should begiven to the stability of thecontents under high humidityconditions.

• Moisture may have anundesirable effect onchemical stability (e.g. someantibiotics may undergohydrolysis) and physicalstability (e.g. dissolution ratemay change). Drugs withfunctional groups such asesters, amides, lactones, orlactams may be susceptible tohydrolytic degradation, whichis a commonly encounteredmode of drug degradation.Many polymers that aresusceptible to hydrolysis, forexample, the polyesters PLAand PLG degrade by randomhydrolysis that takes placehomogeneously throughout

the bulk of the polymerdevice.

• Consider the impact ofmoisture in bulk materialsand finished product.

Even when taking all of thesefactors into account, moreradical action might be needed.It may be appropriate to goright back to the start and ask,“How was the RH% level forproduction and storage processesdetermined in the R&D phase?”

In some cases, theenvironmental conditions forproducing a new product areadopted from a similar, existingproduct already in productionbased on the assumptions that:

a. These conditions workand are proven, and theredoes not appear to be anysignificant dissimilaritiesbetween the two products.

b. Particularly in cases wherean existing manufacturing

area is being repurposed fora new product, the availableHVAC system can producethose conditions.

Storage and WarehousingIt is important to considera pharmaceutical product’sexposure to humidity throughoutthe entire production process.In storage and warehousing,deviations from the desiredtemperature and humidityconditions must be minimized,controlled, and documented.

Unfortunately, temperature andhumidity excursions are almostinevitable, but automated controlof HVAC and humidity controlsystems will improve responseand recovery, and also canprovide historical and trend datato track these excursions.

Although minor deviationsprobably have no significantimpact, it’s important to considerthe effects of temperature orhumidity deviations on everyitem held in storage. This canbe a daunting task, as it isnot unusual for warehousesto contain hundreds or eventhousands of different inventoryitems.

It also is worth consideringthat new items will be added inthe future, which will requiresome form of assessment. Theimpact assessment, therefore,has the potential to become anenormous task.

It is easier to ensuretemperature and humidity arecontrolled within defined limits(e.g. 72°F/22°C at 50% RH)supported by automaticallygenerated logs. Keep in mindthat varying air handlingstrategies may be necessarybased on the location and localenvironment of each storagefacility.

GMP Compliance

Figure 3: The angle of repose of a powder or granulate is the steepest angle ofdescent or dip relative to the horizontal plane to which a material can be piledwithout slumping. Often a measurement is taken in pre-production as a qualitycheck to ensure material is flowing as it should.

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Psychrometrics and HumidityControlThere are different ways tocontrol humidity, or morecorrectly, to attempt to controlhumidity.

One way is using outdoorair for ventilation. With thismethod, the ventilation air musthave a lower moisture contentthan the air within the buildingto be effective, and is thereforeat the mercy of changing weatherand seasonal conditions.

Thus, for the most part, weshould ignore using untreatedoutdoor air because of itsvariability. Instead, let’s reviewmore effective ways to treat theair either entering or alreadywithin the building. Thesemethods include:

• Heating – This applicationwill lower the relativehumidity, but absolutehumidity remains unchanged.There still is the same massof water vapor and thedew point is unchanged.This might be a reasonablehumidity control strategy forheating the area for comfort,but in energy terms it can berelatively expensive.

• Cooling – Using cooling coilsto reduce the air temperature

below its dew point is morecommon. This methodwill lower the RH% aftercold air is re-heated, andit also will reduce absolutehumidity. However, efficiencyfalls significantly as airtemperatures fall below50°F (10°C). In addition, theinevitable condensation thatforms on the cooling coilscan become a maintenanceissue if they are proneto corrosion. Finally, thewet conditions are a goodbreeding ground for bacteriaand mold, which are notwanted anywhere nearpharmaceutical production.

• Desiccant Dehumidification(DH) – This method reducesboth relative and absolutehumidity, and also reducesdew point, while not beingtemperature sensitive, withan operating range between100°F to -40°F (40°C to-40°C). The system allowsfor lower airflows whencompared to other methodsof air treatment, resultingin energy savings. Thisform of precise humiditycontrol also is very flexiblefor multiple energy sources(e.g. gas, steam, LPHW,etc.), so available utilities

and waste heat can be used.Additionally, the systemruns dry, which reducesthe possibility of microbialgrowth and maintenancearising from wet conditions,and also can translateto longer equipment life.Furthermore, this form ofhumidity control can drydown to a -94°F (-70°C) dewpoint, which may be requiredfor sensitive APIs.

ConclusionOnce a target RH range isspecified for a facility, those setpoints should be maintainedfor quality and consistencyin production. Implementingan effective humidity controlstrategy in pharmaceuticalproduction and storage willensure year-round GMPcompliance and enhance productsafety.

About the AuthorMartin Ginty is GlobalPharmaceutical IndustryManager for Munters, a providerof air treatment solutions forhumidity and climate control.He has more than 20 years ofexperience in implementingnational and international levelautomation and HVAC projects.

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