Clean Room Design and QualificationAngel L. Salaman PhD

ObjectivesDefinitionsRegulation and StandardsClean Rooms design requirementsClean Rooms qualificationEnvironmental Monitoring

IntroductionSeveral changes have occurred within the

last years with regard to non-viable particulate monitoring, specifically the new Food & Drug Administration’s (FDA) Guideline on Aseptic Manufacture, September 2004 and the revision of the EU GMP Annex 1, September 2003.

In both, the focus on proving control over the manufacturing environment has been increased.

Clean Rooms and Clean Zones“A room which the concentration of airborne

particles is controlled, and which is constructed and used in a manner to minimize the introduction, generation, and retention of particles inside the room and in which other relevant parameters, e.g. temperature, humidity, and pressure, are controlled as necessary”.

ISO 14644Suites consist of different cleanrooms, where are

made several steps of production. It is continued until one reaches the moment of

product filling, closing and sealing. Less environmental conditions are required when a

sealed product coming for labeling and inspection.

Standards in the design process. The history of cleanroom standards started in the USA. By order of American Air Force first standard was

made in March 1961. It was called Technical Manual 00-25-203. There was description of entering, designing and cleaning. Also it involves airborne particle requirements.

In 1963 was published Federal Standard 209.It was entitled "Clean Room and Work Station

Requirements, Controlled Environments". There was determined measured size of particle more

than 0.5μm. It was so, because there was not better equipment to measure smaller particles at those days.

Today there are 2 StandardsISO 14644 - standard for Airborne Particulate

Cleanliness Classes in Cleanrooms and Clean Zones.

ISO 14698, Cleanrooms and associated controlled environments – Biocontamination control.

US FDAGuideline on Sterile Drug Products

Produced by Aseptic Processing.This document was published in 1987 by

USFDA and revised on September 2004

Critical AreaControlled Area

Critical Area:“one in which the sterilized dosage form,

containers, and closures are exposed to the environment. Activities that are conducted in this area include manipulations of these sterilized materials/product prior to and during filling/closing operations.”

US FDA

Not more than (NMT) 100 particles of 0.5µm per cubic footMeasured NMT 1 foot away from work siteUpstream of the air flow

Air must be supplied a the point of use as HEPA filtered laminar air flow.

Velocity 90 ± 20 feet per minuteNMT 1 colony forming unit per 10 cubic feet Must have positive pressure differential

relative to adjacent less clean areasA pressure differential of 0.05 inch of water

is acceptable.

Critical Area

Controlled Area:“An area in which it is important to control theenvironment, is the area where un-sterilized product, in-process materials, and container/closures are prepared. This includes areas where components are compounded, and where components, in-process materials, drugproducts and drug product contact surfaces of equipment, containers, and closures, after finalrinse of such surfaces, are exposed to the plantenvironment.”

US FDA

Controlled AreaNMT 10,0000 particles of 0.5µm per cubic

foot.NMT 25 colony forming units per 10 cubic

feet.Sufficient air flow.Positive pressure differential relative to

adjacent uncontrolled areas.20 air changes per hourPressure differential of at least 0.05 inch of

waterWhen doors are open, outward airflow should

be sufficient to minimize ingress of contamination.

Clean room ZonesA – local zone. For operations that affords high

risk for product quality, e.g. filling, closing, ampoule and vial opening zones. Usually in such zones is used laminar air flow which provides similar velocity 0.36-0.54 m/s.

B – zone, which is circled A-zone, is used for an aseptic preparation

C and D – zones for less critical stages of manufacturing.

ISO Standard – 14644-1

Class limits for Federal 209D and ISO Standards

Air particle classification system

Non-Viable Air Particles SamplingA non-viable particle is a particle that does not

contain a living microorganism but acts as transportation for viable particles.

Non-viable particles are monitored using particle counters which do not distinguish between viable and non-viable particles, but are much more technically advanced than air samplers.

Viable Air Particles SamplingMicrobial (Viable) Air Samplers collect a

predetermined volume of air and impact microorganisms against agar-based growth medium. Once that sample has been collected and the medium incubated, the results are expressed in colony forming units per cubic meter.

For sampling viable particles in the air use, R2STM (Remote Slit Sampler), Matson/Garvin, SASTM (Surface Air System), SMATM (Sterilizable Microbial Atrium), RCS(Reuter Centrifugal sampler), or other qualified air sampler units will be used.

For this sampling, sterile (irradiated or sterile filled) TSA plates, or media strips must be used.

Sample Air VolumeISO 14644-1 defines the minimum sample volume as “that volume whereby a minimum number of 20 particles would be detected if the particle concentration for the largest particle size were at the class limit for the designated ISO Class”. The formula is as follows:

Vs = 20/Cn,m  x 1000 Where……Vs : the minimum single sample volume per location in litersCn,m : the class limit (number of particles per cubic meter) for the largest considered particle size (n) specified for the class limit(m).

Calculate Sample Size ISO 5Assembly area         (ISO Class 5)       C0.5,5   =  3 520Assembly area minimum sample volume per locationVs = 20/3520  x 1000Vs = 5.68 LitersVs = 5.68 Liters at 2.83 Liters per minute

requires a nominal sample time of 2.0 minutes per location

Assembly area   (ISO Class 5)    3 x 1 minute per sample

Gowning area          (ISO Class 7)       C0.5,7   =  352 000Gowning area minimum sample volume per locationVs = 20/3520000  x 1000Vs = 0.0568 LitersVs = 0.0568 Liters at 2.83 Liters per minute requires a sample time of 0.02 minutes per location. Gowning area   (ISO Class 7)   3 x 1 minute per sampleNote that in the case of the Gowning area, 1 minute minimum sample period specified by ISO 14644-1 applies

Calculate Sample Size ISO 7

• Particle counters have four distinct components; a high intensity light source, (e.g. helium-neon laser), solid state laser diode; a photo detection electronics, sample flow system and counting electronics.

• Briefly, particles pass through the optical chamber of the particle counter, they are sized and counted in real-time, giving immediate information relating to contaminant levels.

ISO 5 (A)For Aseptic Filling operations these areas are

considered ”Critical” environments wherein drug product, stopper bowls , vials and closures are exposed to environmental conditions.

This is an aseptic area (eg, Room, Laminar Flow Hood (LFH), Biological Safety Cabinet (BSC), Isolator) where the environmental control is intended to maintain the sterility of drug product, containers and closures .

Activities conducted in these areas include critical aseptic manipulations (eg, making aseptic connections, sterile ingredient additions, sterile filling and closing operations).

ISO 6 (B)Room or Zone that is the immediate

background for ISO 5 Zone. Zones where production in-process steps are

performed. These environments “are designed” (actually

this is NOT TRUE) to consistently ensure and significantly limit total particulate contamination.

ISO 6 Room/Zone that is not the background for an ISO 5 Room/Zone and is not used for production activities. Examples of ISO 6 Support rooms/zones include airlocks, equipment/material storage, gowning rooms and other support areas.

ISO 7 (C)For some facilities, ISO 7 is the immediate

background for ISO 5. There the production in-process steps are performed.

Ensure limited exposure of materials to microbial and total particulate contamination.

Also serve as zones where nonsterile components, formulated product, in-process material, equipment and container-closure are prepared, held or transferred.

Herein processes are performed primarily in closed systems. These systems are designed to exclude the penetration of environmental microorganisms (eg, bioreactors purification equipment trains).

ISO 7 Room/Zone that is not the background for ISO 5 and is not used for production activities (e.g. airlocks, equipment / material storage, gowning rooms and other support areas.)

ISO 7 (C) cont.

ISO 8 (D)These areas are the zones where the

processes are performed primarily in closed systems.

The environmental control in these areas minimizes the contribution or buildup of the level of total particulate contaminants of articles and components that are subsequently sterilized.

These systems are designed to exclude the penetration of environmental microorganisms (eg, bioreactors and purification equipment trains).

Rooms or areas used for bulk production operations.

For some facilities these areas serve as zones where nonsterile components, in-process material are prepared, held or transferred. Examples of additional operations in ISO 8 Production areas include rooms or zones where Cell Culture, Buffer Preparation and Purification operations occur.

ISO 8 areas not in use for production activities (e.g. ingress/egress gowning rooms, equipment/material movement/storage, facility cleaning, corridors, production control/work rooms .

ISO 8 (D) cont.

Controlled Non-classifed AreasNon-classified areas or zones that are part of

the facility layout with defined environmental controls (ie, gowning, cleaning process, etc.) to reduce the introduction, generation and retention of contaminants within controlled classified areas.

After washing, components should be handled in at least a grade D environment.

The preparation of solutions which are to be sterile filtered is performed in a grade C environment; if not filtered, the preparation of materials and products must be done in a grade A environment with a grade B background.

The handling and filling of aseptically prepared products is performed in a grade A environment with a grade B background.

The preparation and filling of sterile ointments, creams, suspensions and emulsions is performed in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered.

Aseptic Operations

Recommended limits for microbial contamination in the operation

(a) Individual settle plates may be exposed for less than 4 hours.CFU – colony-forming unit.Limitation of warning and action for contamination by particles and microorganisms depends on results of controlling. Also you should provide for corrective action in case of exceeding these limits

Cleanroom standards and GMP guidelines require that rooms are maintained at different pressures to guarantee different conditions that held in each cleanroom.

It is possible to reduce contamination transfer to prevent an unacceptable flow of air from a lower area to a higher area.

Sensible relative room pressure level and its later support offers main design, commissioning and operational problems.

Contamination Controls

Cleanroom Contamination Classification

The standards say that the room pressure difference between cleanrooms should be 10-15 Pa.

These values can be quickly reached, easy to control and appears to prevent contamination transfer.

It is good to understand that cleanroom requirements may define a pressure difference of 10 or 15 Pa but this guideline is only a means to an end.

The pressure difference is lesser important when there is no adverse air flow between the rooms in the suite (this statement can not be clear).

Pressure difference between cleanrooms

The same situation may happen with isolators. But, in this case due to controlled environment is small, the displacement effect of gloves is important and must be taken into account when selecting and finding pressure differences.

Ordinary pressure differences for isolators are 15-60 Pa.

Pressure difference between cleanrooms

The exhaust of the cleanroom can be in an outside neighboring corridor coming through an airlock or changing area and can be in area where pressure is in two levels lower than the room.

Surplus of pressure difference of over 30 Pa can cause “whistling” through the door cracks and it can be difficult to open and close swing doors.

Pressure difference between cleanrooms

It can be presented in a tunnel process where a component is washed, sterilized, and filled as it passes from a component preparation area into an aseptic filling room.

The pressure difference will cause air to flow between the two areas connected by the tunnel.

This air flow can change the heating descriptions of the hot air oven and can bring hot spots and damage the tunnel.

Fluctuation of pressure difference will cause changes in the volume of air flow.

This can bring changes in efficiency and difficulty in validating the system.

Pressure difference between cleanrooms

It is important to guarantee that the rooms are built in an air-tight way to minimize the air flow out of the room's envelope.

But, it is impossible to prevent air flow through the door cracks from an area of high pressure to one of low pressure.

Using the following formula we can calculate the amount of air leakage through small gaps and holes.

Q = A×a Dp where Q – air volume (m3/s),A – area of air leakage (m2),p – pressure difference (Pa), andα – coefficient of discharge (0.85)

Pressure difference between cleanrooms

An estimation of door leakage can be calculated if the detailed sizes of the door are given but the total leakage will depend on the quality of building detailing.

This data can not be known until the commissioning of the room (e.g. balancing) is made.

So it is necessary to guarantee that the air handling system has enough capacity to accommodate more leakage than is expected.

Pressure difference between cleanrooms

Air flow (m3/s) through suite with doors closed

The isolator technology minimizes human influence on processing zones.

In aseptic manufacturing it can considerably decrease the risk of microbial contamination of product from environment.

Transferring materials inside and outside of an insulator is the main potential source of pollution.

The environment should be controlled and corresponds to aseptic manufacture, at least, to zone D.

Isolators Technology

http://www.bioquell.com/applications/isolators/

http://www.pharmaceutical-int.com/article/isolator-technology.html

"blowing - filling - hermetic sealingPackages which are filled with a product and sealed

are formed during one continuous work cycle. All these operations are spent within one automatic

complex.The equipment "blowing - filling - hermetic sealing",

used in aseptic manufacture zone A with an effective air flow, can be established in a zone C if personnel will wear clothes applied in zones A and B.

The "blowing - filling – hermetic sealing" equipment, which is used in manufacturing of the products which sterilized, should be established, at least, in zone D.

http://machinedesign.com/content/advanced-blow-fill-seal-0908

"blowing - filling - hermetic sealing

The design of a pharmaceutical cleanroom suite, must include the following features :Exclusion of the environment external to

the suite of cleanroomsRemoval or dilution of contamination

arising from the manufacturing processRemoval or dilution of contamination

arising from personnel working in the areaContainment of hazards arising from the

productControl of product-to-product cross-

contamination

Protection of personnelControl and management of the flow of

material through the process steps by means of layout and configuration

Control and management of personnel movement by optimizing the arrangement and connection of individual rooms

Overall security of the operation by control of the entry and egress of personnel and materials

The design of a pharmaceutical cleanroom suite, must include the following features :

Optimum comfort conditions for personnelSpecial environmental conditions for

products, e.g. low RH for powder fillingAccommodation of process plant and

equipment to ensure safe and easy use, as well as good access for maintenance.

Effective monitoring of the conditions of the room.

The design of a pharmaceutical cleanroom suite, must include the following features :

Phase Plan:Analyze production stagesPrepare process flow diagramsDefine activities associated with roomsDefine environmental quality

requirementsQuantify production, process and space

requirementsPrepare room association diagrams

Define the accommodation needsDevelop layouts and schemesPrepare designs and specificationUndertake the detailed design and

construction process

Phase Plan:

Layout of cleanroom suite for terminally sterilized injectables

Process FlowThe staff who works in this manufacture would enter the

suite of cleanrooms through the 'clean changing area'. In this room clothes are removed, hands washed, and

appropriate cleanroom clothes put on. Raw materials and components, such as containers,

would enter through their corresponding entry airlocks. In these airlocks procedures are used to decrease the

contamination which may come from outside to the cleanrooms.

Solutions are prepared in the “solution preparation” room for transfer, directly or indirectly, by pipes or mobile containers, to the filling operation in the “clean filling” room.

Primary containers and closures would be prepared and washed in the “component preparation” room and manually transferred to the filling stage or by using a conveyor system.

Containers are filled and packed under the unidirectional flow clean zone in the “clean filling” room.

Filled and packed, containers of product leave the cleanroom suite through the terminal sterilization autoclave.

At the ending of a work period, personnel would leave the suite through the changing room where cleanroom protective suite would be removed.

Process Flow

Layout of cleanroom suite for aseptic filling

The differences in the process requirements refer to the following key variations:Rooms are separated into clean and aseptic rooms. The barriers between them are created by the

oven, autoclave and transfer hatch for items entering the aseptic suite, and through the separation of the “solution preparation” and “aseptic filling” rooms.

Separate and more exact changing room control is provided for the aseptic suite, due to the differences between environmental control of the clean and aseptic suites.

Also the isolator can be used in place of the unidirectional flow workstation.

The most difficult requirement to achieve correct level of cleanliness of the internal environment usually is caused by:The amount of contamination released in the

room.The quality of the air supplied to the room.The quantity and method of supply of room

air, i.e. conventional/turbulent ventilation or unidirectional flow, or a combination of both.

The amount of incoming contamination from areas adjacent to the room. When isolators are used, many of the same considerations are required, but generally the ingress of contamination from outside the isolated volume is minimized.

Nonunidirectional Airflow Zone

An area in which the filtered air entering the zone or passing through the work zone is characterized by non-uniform velocity or turbulent flow. Such rooms exhibit non-uniform, random airflow pattern throughout the enclosure

Turbulent flow air distribution

Unidirectional Airflow Zone

An area in which the filtered air entering the zone makes a single pass through the work area in a parallel-flow pattern, with a minimum of turbulent flow areas. Unidirectional airflow rooms typically have HEPA or ULPA filter coverage of 80% or more of the ceiling (vertical flow) or one wall (horizontal flow).

Unidirectional downflow air distribution

Obstruction caused turbulence in a laminar flow cleanroom

Filtration and supply airThe use of high-efficiency particle stopper (HEPA) filters including pleated packs of high-density glass fibre paper with aluminium or craft paper separators, sealed into a timber or metal frame with urethane, influenced by cleanroom technology. In pharmaceutical industry it is required to install HEPA and ULPA filters of H14 – U17 classes. The most penetrable particle size in below classification (Table 7) is more than 0.1μm but less than 0.3μm.

Impact of Human activities in the

cleanroom

Environmental Qualification

Qualification / Characterizationis the process by which classified

rooms/zones are verified to meet established microbial and total particulate environmental standard requirements upon sampling testing protocols.

General RequirementsRisk assessments documentation containing

the rationale for sampling sites, sampling frequency, and use of settling plates (for filling only).

Programs must provide data to make effective decisions about the level of the environmental control necessary to maintain the required levels of microbial and total particulate cleanliness.

Contamination control procedures.

Contamination control procedures:Access and flow of personnel and materials within the

facilityFacility shut-down/start-up and requalification

requirementsFacility sanitization, including disinfectant

effectiveness and rotationPersonnel gowning, including training/certification,

results from sampling(s) and good cleanroom practicesFacility monitoring (eg, temperature, humidity,

differential pressure, and baseline performance)Initial and routine facility HEPA Certification (eg,

airflow, air velocity, particulate levels,).

Risk analysisA documented risk analysis is suggested to

select the monitoring sites during characterization. The risk analysis must document the rationale for site selection and shall be based on the needs of the process and classified area .

Sample site selectionReal or potential microbial and particulate

contamination associated with the specific process performed therein.

The site selection must be challenged under “as-built”, “at rest” and “in use” conditions.

The sites selected shall be qualified to demonstrate their suitability to demonstrate control and microbial cleanliness in air and on surfaces.

The analysis must include the identification of product contact sources and potential microbial contamination that are most likely to have an adverse effect on product quality.

Sites having greater opportunity for contributing bioburden to the product should be sampled more frequently.

Sampling locations must include those locations which may have an impact on the product and must be sampled more often.

In addition to wall and floor surfaces, representative surface samples must be taken where human activity occurred.

Sampling must not be intrusive to the process to avoid the probability of product contamination.

Sample site selection

Sample sites numberSample sites for Total Particulate monitoring by room can be determined using the following:

Where:NL represents the minimum number of

samples A is the surface area of room in m²

• The calculation result that is not an integer is to be rounded up to the next whole number

Airflow velocity, volume & uniformity tests HEPA/ULPA filter installation leak tests Air generated aerosol challenge & aerosol

photometer filter scan test method Alternative source aerosol particle challenge &

discrete particle counter filter scan test method Airborne particle count test Room pressurization test Airflow parallelism test Temperature/RH tests

Cleanroom tests

Cleanroom tests (cont.)Lighting level test Sound Pressure (Noise) level Test Flooring Resistance Test Point to Point Test Point to Ground Test Testing of Swing / Balance voltage and decay

time of ionizers (Electrostatics / Air Ionizer Performance

Sampling plan must include the followings:Room classificationRoom configurationCriticality of operations in this roomProcess and material flowSample sites with greatest potential for

particulate contaminationGowning requirementsCleaning and sanitation procedures

Personnel quantity per roomPersonnel traffic patternsEquipment HVAC system (e.g. airflow patterns/design)Duration of campaign/manufacturing processProcess / engineering controlsIn-process monitoringHistorical data, if available

Sampling plan must include the followings:

Non Viable Particles SamplingTake three (3) one-minute, one-CFM (28.3

liters) samples per location for better statistical reliability.

Test Laminar Flow work stations and Barrier isolators the same way.

Testing must be performed after any repairs, or renovations.

When sampling, test for viable organism at the same time.

Viable Surface Sampling SitesThe number of sites for air and surface may be established using the following information:Dimension of the room in m2

formula NL= √A, Room classificationAs stated before, the number of sites for Viable and Non-Viable Total particle counts may be established using the dimension of the room and the formula above mentioned

There is no industry guidance that defines required number of surface sample sites. A preliminary number of surface viable sample sites (foot, walls and ancilliary surface) may be determined by dividing each classified area by a “key” as follows:

Viable Surface Sampling Sites

Room Classificati

on

key m2 NL NL

/ key

A Filling Line

1 200 14 14

A surroundings filling line

2 200 14 7

B 3 200 14 5

C 4 200 14 4

D 5 200 14 3

Rationale for Sample Site selectionFor routine monitoring must be based on the results of the testing performed during qualification activities plus the following factors:The location must be based on the process needs

and environmental conditions necessary for the manufacturing process.

Equipment surface samples must be included every time possible.

Additional sample sites for the filling line, and other critical production areas (eg, open processing), must be included when may have a direct impact on the product as compared to surrounding areas.

The clean room performance is tested studies under the following stages:”As built”, a test used to establish that

the cleanroom constructor has met his contractual obligations.

“At rest”, a test taken with the room fully equipped ready for production but with no equipment running and personnel absent.

“In use”, a test taken with the room fully operational.

Clean room performance testing

As Built MonitoringThis operational mode or phase refers to a facility that is

complete and ready for operation with all services connected and functional, but without equipment or operating personnel in the facility.

As Built monitoring is performed when manufacturing related activity is not taking place. In addition, such monitoring is appropriate for data gathering during facility qualifications, to demonstrate baseline data, or other validation activities.

As Built monitoring may be used to demonstrate the state of the environmental control in the manufacturing facility before cleaning and prior to the start of manufacturing operations.

As Built monitoring includes total and viable particulate monitoring of the ambient environment, and surface microbial monitoring.

Is performed once.

Static MonitoringThis operational phase refers to a facility that is complete, with

all services functioning and with equipment installed and operable or operating, on specified, but without operating personnel in the facility.

Static monitoring is performed when manufacturing related activity is not taking place. In addition, such monitoring is appropriate for data gathering during facility qualifications, to demonstrate baseline data, or other validation activities.

Static monitoring is used to demonstrate the state of the environmental control in the manufacturing facility after cleaning and prior to the start of manufacturing operations.

Static monitoring includes total and viable particulate monitoring of the ambient environment, and surface microbial monitoring.

Three (3) sampling is performed after 24hrs of the cleaning process

In Use MonitoringThis phase refers to a facility in normal operation, with all

services functioning and with equipment and personnel, if applicable, present and performing their normal work functions in the facility.

“In Use” monitoring is performed to demonstrate the level of environmental control during production and support operations in the production environment.

Routine monitoring should be performed during dynamic conditions when possible.

Dynamic monitoring will include total and viable particulate monitoring of the ambient environment, as well as surface microbial monitoring.

Three (3) sampling is performed after 24hrs of the cleaning process.

Sampling FrequencyThe frequency of monitoring may vary from one plant to another depending of:Sample site selectionType of facilitySeasonal variationsRoom designManufacturing processHuman activity and interventionsClaning and Sanitization proceduresGowning requirementsHistorical data

Critical Areas MonitoringThe EU Annex 1 says, “A continuous

measurement system should be used for monitoring the concentration of particles in the grade A zone, and is recommended in the surrounding grade B areas”.

The FDA says, “Regular monitoring should be performed during each production shift. We recommend conducting nonviable particle monitoring with a remote counting system. These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters”.

Grade A Critical Environments If we look at a filling line the locations that must be monitored are identified as:Sterilisation tunnel - where the sterile vials

exit from The fill area - location where product is

filled into vial or syringesThe stopper area - where stoppers are

placed onto vial The capping area - where the crimping or

capping occurs

EM program requirements for each facility must be outlined in site level

procedures which describe the following:Sampling and testing methodsMonitoring frequencyClassification and Identification of the areas to be

monitored and sites to be sampledAlert and action levelsExcursion response/investigation, including re-

sampling requirementsOrganism identificationLength of tubing for sampling and the radii of any

bends in tubing

Sampling Frequency for Routing Monitoring for C and D ClassesTEST MINIMUM FREQUENCY

Air Particle Monitoring

Three Months

HEPA Filter Integrity

Testing Yearly

Air Change Rate Calculation 6 Months

Air Pressure Differentials

Daily

Temperature and Humidity

Daily

Microbial Monitoring

Once a month / During manufacturing process

Viable Particle Monitoring during Critical in process activities.Air, Surfaces and Personnel Monitoring

Should be done During Aseptic Operations

Product Contact Surfaces Should be Monitored at the End of the Aseptic Operation.

Sampling frequency reductionA reduction in or the number of sites for routine monitoring can be performed. Such an approach would require the following:A risk analysis and evaluation of historic data

collected from environmental surface sites and air sites, to assess the potential impact on the overall environmental cleanliness.

An analysis of adverse trends must be conducted to demonstrate that current and proposed sampling frequencies and sites are adequate for assuring the overall state of control.

A review of the validated cleaning and sanitizing procedures and facility control (HVAC) program to ensure they have not changed significantly during the period under review.

Documentation of the analysis performed.Approval of the reduction plan by site Quality

Head, or designee.Periodic review of the environmental data to

determine if the reduced sampling frequency and number of sites remains appropriate.

Sampling frequency reduction (cont.)

Last RemarksA well designed and executed monitoring

plan is a must.The monitoring plan has to be designed

using good Judgment so that it can be defended during a compliance audit.

ReferencesFDA Guidance for Industry- Sterile Drug Products

Produced by Aseptic Processing - Current Good Manufacturing Process

http://www.particlecounters.org/ ISO 13408 Aseptic Processing of Health Care Products ISO 14644-1 Cleanrooms & associated controlled

environments – Part 1 : Classification of air cleanliness ISO 14698, Cleanrooms and associated controlled

environments – Biocontamination control.PIC/S Recommendation on the Validation of Aseptic

ProcessesUSP 35 <1116> “"Microbiological Evaluation of Clean

Rooms and Other Controlled Environments".USP 35 <797> “Pharmaceutical Compounding—Sterile

Preparations”