Guide to Pharmaceuticals

Product and Personnel

Pharmaceutical manufacturing areas where pharmaceutical starting materials, intermediates, in-process materials and products, product contact utensils and equipment are exposed to the environment, should be classified as “clean areas”.

The achievement of a particular clean area classification depends on a number of criteria which should be addressed at the design stage and qualification. There should be a balance between the different criteria in order to create an efficient clean area.

Some of the basic criteria to be considered should include:

Air filtration and air change rates should ensure that the defined clean area classification is attained.

The air change rates should be determined by the manufacturer and designer, taking the various critical parameters into account. Primarily the air change rate should be set to a level that will achieve the required clean area classification.

Air change rates normally vary between 6 and 20 air changes per hour and are normally determined by the following considerations:

Each clean area class should be specified as achieving the clean area classification under “as-built”, “at-rest” or “operational” conditions.

The “as-built” condition should relate to carrying out room classification tests on the bare room, without any equipment or personnel.

The “at-rest” condition should relate to carrying out room classification tests with the normal production equipment in the room, but without any operators. Due to the amounts of dust usually generated in a solid dosage facility most clean area classifications are rated for the “at-rest” condition.

The “operational” condition should relate to carrying out room classification tests with the normal production process with equipment operating, and the normal number of personnel present in the room. Generally a room that is tested for an “operational” condition should be able to clean up to the “at-rest” clean area classification, after a short clean-up time. The clean-up time should be determined through validation and may typically be in the order of 20 minutes.

Materials and products should be protected from contamination and cross-contamination through all stages of manufacture (See also section 5.5 for cross-contamination control). Note: Contaminants may result from inappropriate premises (e.g. design, layout, finishing), poor cleaning procedures, personnel, and a poor HVAC system.

Contaminants should be removed through effective ventilation. Airborne particulates and the degree of filtration should be considered critical parameters with reference to the level of product protection required.

The level of protection and air cleanliness for different areas should be evaluated based on the product being manufactured, the process and the product’s susceptibility to degradation.

Level	Condition	Example of area
Level 1	General	An area with normal housekeeping and maintenance. (e.g. Warehousing, Secondary Packing)
Level 2	Protected	An area in which steps are taken to protect the exposed pharmaceutical starting material or product from contamination or degradation. (e.g. Manufacturing, Primary Packing, Dispensing.)
Level 3	Controlled	An area in which specific environmental conditions are defined, controlled and monitored to prevent contamination or degradation of the pharmaceutical starting material or product.

 

Air Filtration

The type of filters required for different applications, depends on the quality of the ambient air and the return air (where applicable) and also on the air change rates. The table below gives the recommended filtration levels for different levels of protection in a pharmaceutical facility. Manufacturers should determine and prove the appropriate use of filters.

Level of Protection	Recommended filtration
Level 1	Primary filters only (e.g. EN779 G4 filters)
Level 2 and 3	Production facility operating on 100% outside air: Primary plus secondary filters (e.g. EN779 G4 plus F8 filters)
Level 2 and 3	Production facility operating on re-circulated plus ambient air, where potential for cross-contamination exists: Primary plus secondary plus tertiary filters (e.g. EN779 plus F8 EN 1822 H13 filters)

 

Note: The filter classifications referred to above relate to the EN1822 and EN779 test standards, (EN 779 relates to filter classes G1 to F9 and EN 1822 relates to filter classes H10 to U16).

Filter classes should always be linked to the standard test method as referring to actual filter efficiencies can be very misleading (due to different test methods each resulting in a different value for the same filter.

In selecting filters, the manufacturer should have considered other factors, such as particularly contaminated ambient conditions, local regulations and specific product requirements. Good prefiltration extends the life of the more expensive filters downstream.

Materials for components of an HVAC system should be selected with care so as not to become the source of contamination. Any component with the potential for liberating particulate or microbial contamination into the air stream should be located upstream of the final filters

Ventilation dampers, filters and other services should be designed and positioned so that they are accessible from outside the manufacturing areas (service voids or service corridors) for maintenance purposes.

Personnel should not be a source of contamination. Directional airflow within production or packing areas should assist in preventing possible contamination. Airflows should be planned in conjunction with operator locations, so as to minimize operator contamination of the product and also to protect the operator from dust inhalation.

HVAC air distribution components should be designed, installed and located to prevent contaminants generated within the room from being spread.

Supply air diffusers of the high induction type (e.g. those typically used for office-type air-conditioning) should where possible, not be used in clean areas. Air diffusers should be of the non-induction type, introducing air with the least amount of induction so as to maximize the flushing effect. Whenever possible, air should be exhausted from a low level in rooms.

Unidirectional Airflow

Unidirectional airflow should be used where appropriate to provide product protection by supplying a clean air supply over the product, minimizing the ingress of contaminants from surrounding areas.

Where appropriate the unidirectional airflow should also provide protection to the operator from contamination by the product.

Sampling should be carried out in the same environmental condition that is required for the further processing of the product. In some cases, sampling cubicles located in warehouses are used. These cubicles should normally provide a unidirectional airflow screen to ensure that clean air is flowing over the container when it is opened. (Note: Unidirectional flow normally provides a Class A (ISO Class 5, operational, 0.5 mm) environment, but for a sampling cubicle this degree of protection may not be required).

In a weighing booth situation, the aim should be to provide dust containment. A dispensary or weighing weigh booth should be provided with unidirectional airflow for product and operator protection. The source of the dust and the position in which the operator normally stands should be determined before deciding on the direction of unidirectional flow.

The unidirectional flow velocity should not disrupt the sensitivity of balances in weighing areas. Where necessary the velocity may be reduced to prevent scale inaccuracies, provided that sufficient airflow is maintained to provide containment.

The position in which the operator stands relative to the source of dust liberation and airflow should be determined to ensure that the operator is not in the path of an airflow that could lead to contamination of the product

The manufacturer should select either vertical or horizontal unidirectional flow or an appropriate air flow pattern that provides the best protection for the particular application.

Infiltration

Air infiltration of unfiltered air into a pharmaceutical plant should not be the source of contamination.

Manufacturing facilities should be maintained at a positive pressure relative to the outside, in order to limit the ingress of contaminants. Where facilities are to be maintained at negative pressures relative to ambient, in order to prevent the escape of harmful actives to the outside (such as penicillin and hormones), then special precautions should be taken.

The location of the negative pressure facility should be carefully considered with reference to the areas surrounding it, and particular attention given to ensuring that the building structure is well sealed.

Negative pressure zones should, as far as possible, be encapsulated by surrounding areas with clean air supplies, so that only clean air can infiltrate into the controlled zone.

Cross Contamination

Where different products are manufactured at the same time, in different areas/cubicles, in a multi-product OSD manufacturing site, measures should be taken to ensure that dust cannot move from one cubicle to another.

Correct directional air movement and a pressure cascade system can assist in preventing cross-contamination. The pressure cascade should be such that the direction of air flow is from the clean corridor into the cubicles, resulting in dust containment.

The corridor should be maintained at a higher pressure than the cubicles, and the cubicles at a higher pressure than atmospheric pressure.

Containment can normally be achieved by the displacement concept (low pressure differential, high airflow), or the pressure differential concept (high pressure differential, low airflow), or physical barrier concept.

The choice of pressure cascade regime and choice of airflow direction should be considered in relation to the product and processing method used).

Highly potent products should be manufactured under a pressure cascade regime that is negative to atmospheric pressure.

The pressure cascade for each facility should be individually assessed according to the product handled and level of protection required.

Building structure should be given special attention because of the pressure cascade design.

Airtight ceilings and walls, close fitting doors and sealed light fittings should be in place.

 

Displacement concept (low pressure differential, high airflow)

With this concept the air should be supplied to the corridor, flow through the doorway, and should be extracted from the back of the cubicle. Normally the cubicle door should be closed and the air should enter the cubicle through a door grille, although the concept can be applied to an opening without a door.

The velocity should be high enough to prevent turbulence within the doorway resulting in dust escaping.

This displacement airflow should be calculated as the product of the door area and the velocity, which generally results in fairly large air quantities.

 

Pressure differential concept (high pressure differential, low airflow)

The high pressure differential between the clean and less clean zones should be generated by leakage through the gaps of the closed doors to the cubicle.

The pressure differential should be of sufficient magnitude to ensure containment and prevention of flow reversal, but should not be too high so as to create turbulence problems.

In considering room pressure differentials, transient variations, such as machine extract systems, should be taken into consideration

The pressure differential between adjacent rooms could be considered a critical parameter, depending on risk analysis. The limits for the pressure differential between adjacent areas should be such that there is no risk of overlap, e.g. 5 Pa to 15 Pa, 15 Pa to 30 Pa, resulting in no pressure cascade.

Low pressure differentials may be acceptable when airlocks (pressure sinks or pressure bubbles) are used.

Pressure control and monitoring devices used should be calibrated and qualified. Compliance with specifications should be verified and recorded on a regular basis. Based on a risk analysis, pressure control devices should be linked to an alarm system. Generally, the pressure differential and the duration of excursion are considered when triggering audio/ visual alarms. Production operators and other users of the premises must be notified of the alarms in a timely manner in order to take corrective/ mitigating actions.

Where manual control systems are used, these should be set up during air balancing activities during commissioning and should not change unless other system conditions change.

Airlocks can be important components in setting up and maintaining pressure cascade systems

Doors should open to the high pressure side, and be provided with self-closers. Door closer springs, if used, should be designed to hold the door closed and prevent the pressure differential from pushing the door open. Sliding doors are not recommended. Use of interlocks on doors ensures that pressure differentials designed are achieved within airlock areas before doors leading to clean areas and corridors are opened. Audio/ visual alarms within the airlocks may be used. Pressure differential data may also be captured by the building management system.

Central dust extraction systems should be interlocked with the appropriate air handling systems, to ensure that they operate simultaneously.

Room pressure imbalance between adjacent cubicles which are linked by common dust extract ducting should be prevented.

Air should not flow from the room with the higher pressure to the room with the lower pressure, via the dust extract ducting.

 

Physical barrier concept

Where appropriate, an impervious barrier to prevent cross contamination between two zones such as barrier isolators or pumped transfer of materials, should be used.

Spot ventilation or capture hoods may be used as appropriate.

 

Temperature and relative humidity

Temperature and relative humidity should be controlled, monitored and recorded where relevant, in order to ensure compliance with materials and product requirements, and to provide operator comfort where necessary

Maximum and minimum room temperatures and relative humidity should be appropriate.

Temperature conditions should be adjusted to suit the protective clothing worn by the operators.

The operating band or tolerance between the acceptable minimum and maximum temperatures should not be made too close. Temperature and humidity excursions and the duration of excursion are considered when triggering audio/ visual alarms. Production operators and other users of the premises must be notified of the alarms in a timely manner in order to take corrective/ mitigating actions. Temperature and humidity data may also be captured by the building management system.

Cubicles, or suites, processing products requiring low humidity, should have well-sealed walls and ceilings and should also be separated from adjacent areas with higher humidity, by means of suitable airlocks.

Precautions should be taken to prevent moisture migration that increases the load on the HVAC system.

Humidity control should include removing moisture from the air, or adding moisture to the air, as relevant.

Dehumidification (moisture removal), may be achieved by means of either refrigerated dehumidifiers or chemical dehumidifiers.

Appropriate cooling media for dehumidification should be used such as low temperature chilled water/glycol mixture or refrigerant.

Humidifiers should be avoided if possible as these may become a source of contamination (e.g. microbiological growth). Where humidification is required, this should be achieved by appropriate means such as the injection of steam into the air stream. A product contamination assessment should be done to determine whether pure or clean steam is required for the humidification purposes.

No chemicals (such as corrosion inhibitors/chelating agents) which could have a detrimental effect on the product steam humidifiers used should be added to the boiler system.

Humidification systems should be well drained. No condensate should accumulate in air handling systems.

Other humidification appliances such as evaporative systems, atomizers and water mist sprays, should not be used due to the possible microbial contamination risk

Duct material in the vicinity of the humidifier should not add contaminants to air that will not be filtered downstream.

Final air filters should not be installed immediately downstream of humidifiers. There should be insulation of cold surfaces in order to prevent condensation within the clean area or on air-handling components, where high humidity is required. When specifying relative humidity, the associated temperature should also be specified.

Chemical driers may be used to achieve conditions lower than 45% RH at a temperature of 22°C. Chemical driers or dehumidifiers employing a desiccant, such as silica gel or lithium chloride to remove the moisture from the air, should have desiccant wheels of the non-shedding type and should not support microbial growth. Appropriate air filters are to be used downstream to prevent desiccant particulates from entering the productions premises.

Dust Control

Wherever possible, the dust or vapour contamination should be removed at source. Point extraction, as close as possible to the point where dust is generated, should be employed.

Point extraction known commonly as ‘elephant trunks’, ‘fish tails’, etc should be either in the form of a fixed high velocity extraction point or an articulated arm with movable hood or a fixed extract hood.

Dust extraction ducting should be designed so as to have sufficient transfer velocity to ensure that dust is carried away, and does not settle in the ducting. Risk during product changeovers must be assessed and periodic cleaning of the dust extraction ducting is to be carried out.

The required transfer velocity should be determined as it is dependent on the density of the dust (the denser the dust, the higher the transfer velocity should be, e.g. 15-20 m/s).

Airflow should be carefully planned, to ensure that the operator does not contaminate the product, and so that the operator is not put at risk by the product

Dust-related hazards that operators may be subjected to should be assessed. An analysis of the type of dust and toxicity thereof should be done and the airflow determined accordingly.

Point extraction alone is usually not sufficient to capture all of the contaminants, and general directional airflow should be used to assist in removing dust and vapours from the room.

Typically in a room operating with turbulent airflow the air should be introduced from ceiling diffusers and extracted from the room at low level.

The low level extract should assist in drawing air down and away from the operator’s face. The location of the extract grilles should be positioned strategically to draw air away from the operator, but at the same time prevent the operator from contaminating the product.

When dealing with the extraction of vapours the density of the vapour should be taken into account. If the vapour is lighter than air, then the extract grilles should be at high level, or possibly at high and low level.

When dealing with particularly harmful products, additional steps, such as handling the products in glove boxes or using barrier isolator technology, should be used.

For products such as hormones or highly potent products, operators should wear totally enclosed garments, as indicated in Figure 22. In this instance a portable of fixed tubing air-breathing system should provide a supply of HEPA filtered and conditioned air to the operator. The air supply to this type of breathing apparatus should normally be through an air compressor. Filtration, temperature and humidity need to be controlled to ensure operator safety and comfort. Re-usable pressurized air suits must be checked for leakages as this could lead to contamination of the production environment.

Protection of the Equipment

Exhaust Air Dust

Exhaust air discharge points on pharmaceutical facilities, such as from fluid bed driers and tablet compression/ coating equipment, and exhaust air from dust extraction systems such as house vacuum, carry heavy dust loads and should be provided with adequate filtration to prevent ambient contamination.

Where the powders are not highly potent, final filters on a dust exhaust system should be fine dust filters having a filter classification of F9 according to EN779 filter standards.

Where harmful substances such as penicillin, hormones, toxic powders and enzymes are exhausted, the final filters should be HEPA filters with at least an H12 classification according to EN1822 filter standards, as appropriate.

For exhaust systems where the discharge contaminant is considered particularly hazardous, it may be necessary to install two banks of HEPA filters in series, to provide additional protection should the first filter fail.

When handling hazardous compounds safe change filter housings, also called “bag-in-bag-out” filters, should be used. All filter banks should be provided with pressure differential indication gauges to indicate the filter dust loading.

Filter pressure gauges should be marked with the clean filter resistance and the change-out filter resistance. Monitoring of filters should be done at regular intervals in order to prevent excessive filter loading that could force dust particles through the filter media, or could cause the filters to burst, resulting in ambient contamination.

More sophisticated computer-based data monitoring systems may be installed, with preventive maintenance plans by trend logging. (This type of system is commonly referred to as a building management system (BMS), building automation system (BAS) or system control and data acquisition (SCADA) system).

An automated monitoring system should be capable of indicating any out-of-specification condition without delay by means of an alarm or similar system. Where reverse pulse dust collectors are used for removing dust from dust extract systems, these should usually be equipped with cartridge filters containing a compressed air lance, and be able to operate continuously without interrupting the airflow.

Alternative types of dust collectors (such as those operating with a mechanical shaker, requiring that the fan be switched off when the mechanical shaker is activated) should be used in such a manner that there is no risk for cross contamination. There should be no disruption of airflow during a production run as the loss of airflow could disrupt the pressure cascade.

Mechanical shaker dust collectors should not be used for applications where continuous airflow is required.

When wet scrubbers are used, the dust-slurry should be passed to a suitable drainage system. The exhaust air quality should be determined to see whether the filtration efficiency is adequate with all types of dust collectors and wet scrubbers.

Where necessary, additional filtration may be required downstream of the dust collector. In the event of power failure, ‘fail-safe’ systems should be in place to prevent backflow of residues from the ductwork.

Fume removal

Fume, dust and effluent control should be designed, installed and operated in a manner that these do not become possible sources of contamination or cross-contamination, e g. an exhaust air discharge point located close to the HVAC system fresh air inlet.

Removal of fumes should be by means of wet scrubbers or dry chemical scrubbers (deep bed scrubbers).

Wet scrubbers for fume removal should normally have various chemicals added to the water to increase the adsorption efficiency.

Deep bed scrubbers should be designed with activated carbon filters or chemical adsorption granular media. The chemical media for deep bed scrubbers should be specific to the effluent being treated.

The type and quantity of the vapours to be treated should be known, to select the type of filter media as well as the volume of media required.

HVAC Systems and Components

General Requirements

There should be no failure of a supply air fan, return air fan, exhaust air fan or dust extract system fan. Failure can cause a system imbalance, resulting in a pressure cascade malfunction with a resultant airflow reversal.

Drying of air should be done with a chemical drier (e.g. a rotating desiccant wheel which is continuously regenerated by means of passing hot air through one segment of the wheel).

Additional components that may be required on a system should be considered depending on the climatic conditions and locations. These may include items such as:

Appropriate alarm systems should be in place to alert personnel if failure of a critical fan occurs. Low level return or exhaust air grilles are always preferred. However, where this is not possible, a higher air change rate to achieve a specified clean area classification may be required, e.g. where ceiling return air grilles are used.

Recirculating System

There should be no risk of contamination or cross-contamination (including fumes and volatiles) due to recirculation of air.

Depending on the airborne contaminants in the return air system it may usually be acceptable to use recirculated air, provided that HEPA filters are installed in the supply air stream to remove contaminants and thus prevent cross-contamination. The HEPA filters for this application should have an EN1822 classification of H13.

HEPA filters may not be required where the air handling system is serving a single product facility and there is evidence that there is no possibility of cross-contamination. Recirculation of air from areas where pharmaceutical dust is not generated such as secondary packing, may not require HEPA filters in the system.

Energy recovery wheels should normally not be used in multi-product facilities. When energy wheels are used these should be not become a source of possible contamination. The potential for air leakage between the supply air and exhaust air as it passes through the wheel should be prevented. The relative pressures between supply and exhaust air systems should be such that the exhaust air system operates at a lower pressure than the supply system.

Commissioning, Qualification and Maintenance

Commissioning

Commissioning should involve the setting up, balancing, adjustment and testing of the entire HVAC system, to ensure that the system meets all the requirements, as specified in the User Requirement Specification, and capacities as specified by the designer or developer.

The installation records of the system should provide documented evidence of all measured capacities of the system

The data should include items such as the design and measured figures for airflows, water flows, system pressures and electrical amperages. These should be contained in the operating and maintenance manuals (O & M manuals).

Acceptable tolerances for all system parameters should be specified prior to commencing the physical installation. Training should be provided to personnel after installation of the system, and should include operation and maintenance.

O & M manuals, schematic drawings, protocols and reports should be maintained as reference documents for any future changes and upgrades to the system.

Commissioning should be a precursor to system qualification and validation. Manufacturers should qualify HVAC systems on a risk based approach that addresses different operating modes e.g. operational and non-operational modes. The basic concepts of qualification of HVAC systems are set out below

 

A realistic approach to differentiating between critical and non-critical parameters is required, in order not to make the validation process unnecessarily complex. Example:

 

Systems and components, which are non-critical, should be subject to GEP and may not necessarily require full qualification.

A change control procedure should be followed when changes are planned to the HVAC system, its components and controls that may affect critical parameters. Acceptance criteria and limits should be defined during the design stage. The manufacturer should define design conditions, normal operating ranges, operating ranges, alert and action limits. Design condition and normal operating ranges should be set as wide as possible to set realistically achievable parameters.

All parameters should fall within the design condition range during system operational qualification. Conditions may go out of the design condition range during normal operating procedures but they should remain within the operating range.

A very tight relative humidity tolerance, but a wide temperature tolerance, should not be acceptable as variances between the maximum and minimum temperature condition will give an automatic deviation of the humidity condition.

For a pharmaceutical facility some of the typical HVAC system parameters that should be qualified may include:

Room return or exhaust air is a variable which should be used to set up the room pressure. As room pressure is a more important criteria than the return air, the latter should have a very wide Normal Operating Range.

The maximum time interval between tests should be defined by the manufacturer. The type of facility under test and the product Level of Protection should be considered.

 

Schedule of Test for Continuing Compliance
Test Parameter	Clean area Class	Max Time Interval	Test Procedure
Particle Count  Test (Verification of Cleanliness)	All classes	6 months	Dust particle counts to be carried out and result printouts produced. No. of readings and positions of tests to be in accordance with ISO 14644-1 Annex B.
Air Pressure Difference (To verify non cross-contamination	All classes	12 months	Log of pressure differential readings to be produced or critical plants should be logged daily, preferably continuously. A 15 Pa pressure differential between different zones is recommended. In accordance with ISO 14644-3 Annex B5
Airflow Volume (To verify air change rates)	All Classes	12 Months	Air flow readings for supply air and return air grilles to be measured and air change rates to be calculated. In accordance with ISO 14644-3 Annex B13
Airflow Velocity (To verify unidirectional flow or containment conditions)	All Classes	12 months	Air velocities for containment systems and unidirectional flow protection systems to be measured. In accordance with ISO 14644-3 Annex B4
HEPA filters (Certification from manufacturers)	All classes	24 months	Filter integrity e.g. DOP testing