11.

E Environmental monitoring
Up07 Christian Gausepohl, PhD, Paolomi Mukherji

Here you will find answers to the following questions:

● How can monitoring be prepared, carried out and evaluated?

11.E.1 General
Monitoring is used to review the effectiveness of the plant hygiene measures. The constant evaluation of the hygiene
status is used to verify the classification of the cleanliness grades. This can result in optimisation of cleaning and
disinfection measures. Trend analysis uncovers deviations prior to occurrence and enables early changes to processes.
In addition to microbiological investigations, the particle load is checked in sterile areas.

It is recommended to have the co-ordination of the monitoring measures and the evaluation and trend analysis carried
out by quality assurance as an independent group. Depending on the size of the plant, it may be advisable to appoint a
hygiene officer. Evaluation is carried out in collaboration with quality control and the head of production. The resulting
measures are defined by the head of production.

Monitoring is carried out in several stages (see Figure 11.E-1). As the sampling plan is often subject to change, it can be
designed practically in the form of an appendix to the procedural instructions.

Figure 11.E-1 Monitoring process

Monitoring process

● Risk analysis with limit definition

● Sampling plan

● Sampling

● Evaluation

● Modifications

As a first step, the environmental standards for each production and laboratory area should be determined:

● Define the needs of each area Uncontrolled, controlled, aseptic, sterility testing area

● Define the activity that is to occur in each area Identify formulating and manufacturing areas, washing and
cleaning areas, sterilization areas, non-sterile filling areas, aseptic filling areas, labeling and packaging areas.
● Define the environmental parameters
● Identify the temperature range, humidity range and the frequency of air changes for each area,

● Identify airflow rate and patterns required in each area, pressure differentials required between different classes
and areas within a class,
● Identify the particulate matter requirements and the viable microorganism quality requirements for each area

● Define other environmental requirements: Identify the lighting requirements for each area & the noise control
requirements for each area

In a second step, it should be determined what environmental tests need to be performed in each area:

● Define the classification of each area: Uncontrolled, Class 100, Class 1000, Class 10000, Class 100000

● Determine the parameters to measure: Non-viable airborne particles, Viable particles, Airborne, Surface, Personnel

For microbiological aspects of environmental monitoring, see Chapter 12.J Microbiological monitoring for detailed
information.

11.E.2 Sampling plan

When defining the sampling points for routine monitoring, the experiences from the initial monitoring and the product
features should be taken into account. You should try to find the points at which the microbial count is estimated to be at
its highest (near wash basins, door handles, etc.) or which are directly next to the product. In sterile areas, so-
called mapping is also carried out to compile the sampling plan. This involves splitting the entire room into squares,
from each of which a direct contact test is taken. The points with the highest microbial count are included in the
sampling plan. The plan contains various details, which are listed in Figure 11.E-2.

Figure 11.E-2 Content of the sampling plan

Sampling plan

● Sampling points (related to the location and function)

● Number of samples

● Frequency of sampling

● Sampling method (for quantitative or qualitative determinations)

● Sample size

● Auxiliary liquids (dilutions, rinsing agents, neutralisers, etc.)

● Factors with possible impact on incubation results

● Operating conditions/at rest

It is subject to an in-plant approval procedure, i.e. it requires the approval of the responsible persons (quality control,
head of production, quality assurance).

Sampling is carried out according to the authorised plan and written procedures. Each sample is declared as clearly
identifiable. The sampling carried out is documented in the record. An easy way to generate the record is to turn the
sampling instructions into the record by signing them accordingly.

Important contents of the sampling procedure are given in Figure 11.E-3.

Figure 11.E-3 Content of a sampling procedure for environmental monitoring

Sampling procedure

● Take samples when area is at rest:

● Non-viable particulates - only during facility qualification,

● Viable particulates – critical surface and personnel samples only,

● Airflow Patterns – only during facility and equipment qualification

● Take samples when area is in operation: All routine airborne samples – non-viable and viable

● Determine sample sites: Include maps of sampling sites in the procedure (Non-viable sampling points, Viable
sampling points (Airborne, Surface), Personnel sampling points)
● Determine frequency of sampling

11.E.3 Establishment of limits and frequencies

11.E.3.1 European requirements

The limits for clean rooms can be taken from the Annex 1 Manufacture of Sterile Medicinal Products of the EU-GMP-
Guide (see chapter C.6.1). In addition to the cleanliness grades A–D prescribed by the classifications, it is also
advisable to define levels for bordering areas as well as for non-sterile production steps (Figure 11.E-4 and Figure 11.E-
5). Alert and action limits must be established for all classes. Such values are established according to experience with
similar facilities, as well as the values from the qualification phase.
Figure 11.E-4 Limits of cleanliness grades A–G (air)

A B C D E F G

cleanliness grade
Annex 1 EU-GMP-Guide Own definition

Particle load

(at rest) 0,5 µm 3,520 3,520 352,000 3,520,00 n.d. n.d. n.d.
0

0,5 µm 20 29 2,900 29,000 n.d. n.d. n.d.

(in operation) 0,5 µm 3,520 352,000 3,520,000 n.d. 3,520,000 3,520,00 n.d.
0

5 µm 20 2,900 29,000 n.d. 29,000 29,000 n.d.

Microbiological load

(in operation) Air [CFU/m3] <1 10 100 200 200 500 n.d.

Settling plate (90 mm) [CFU/4 hours] <1 5 50 100 100 200 n.d.

Contact plate (55 mm) [CFU/plate] <1 5 25 50 100 150 (300)

Gloves (5 fingers) <1 5 n.d. n.d n.d n.d. n.d.

n.d. = not defined; CFU = colony-forming unit

Figure 11.E-5 Categorisation of the cleanliness grades

Assignment of the cleanliness grades to production areas

A Sterile aseptic processing and filling

preparations

B Sterile surrounding area in sterile rooms of A

preparations

C Sterile weigh-in for sterile preparations, preparation of solution (subsequent sterile filtration)
preparations

D Sterile preparation of solution (subsequent sterilisation) with additional measures to minimise

preparations contamination, e.g. closed containers

Non-sterile inhalation preparations

products

E Non-sterile production and primary packaging area for ointments, liquids

products

F Non-sterile production and primary packaging area for solid oral dosage forms
products

G Surrounding area
of F
Alert and action levels should be set by using historically generated levels for each area and operation, considering the
use of statistical program(s). In order to verify if levels are appropriate, they should be compared to actual readings as
well as to published guidance or requirements1. If the actual readings are significantly different from the specified alert
and action levels, a root cause analysis should be initiated.

Exceeding the alert limit is a clear deviation from the base value, which does not, however, lead to remedial action. The
number of samples and the frequency of sampling are usually increased during further observation. When the action
limit is reached, remedial action is taken immediately, such as modification of the disinfecting procedure. This is to be
established in advance (see Figure 11.E-6).

Figure 11.E-6 Alert and action values

Limits and consequences when exceeded

Alert level Modification of the sampling plan

Action Immediate action

level

For aseptic processes, microbiological monitoring during production is required for air testing. As the cleanliness grade
decreases, the sampling frequency falls. Precise requirements for sterile production are given in Annex 1 of the EU-
GMP-Guide. The frequency of sampling should also be fixed for non-sterile production areas (see Figure 11.E-7)

Figure 11.E-7 Frequencies of sampling

A, B C D E F G

Annex 1 EU GMP Guideline Own definition

Air Batch-based at the end of Room “in operation”: Room “in quarterly to half-yearly to yearly
microbes production or during use, if daily to fortnightly operation”: half-yearly yearly
this does not result in an (depending on monthly (depending on (depending on
increased risk through exposition of the risk to product) risk to product)
measurement product)
Room “at rest”:
weekly, if no
measurement could
be carried out in the
operated room within
a week (not used)

Surfaces Table, wall: batch-based at Table, wall, floor: monthly quarterly to quarterly to yearly
the end of production or weekly to monthly yearly yearly
during use, if this does not (depending on use)
result in an increased risk
through measurement. Floor:
weekly to monthly (depending
on use of room)

Personnel

Hand Batch-based at end of not defined not defined yearly yearly

production

Forearm monthly not defined not defined

Hood/face monthly not defined not defined

mask
1

EU-GMP-Guide – Annex 1, USP Monograph <1116>, Parenteral Society Technical Monograph 2 on Environmental
Contamination Control Practice

11.E.3.2 US requirements

The US requirements for airborne particulate cleanliness classes are defined in the FDA Guidance for Industry: Sterile
drug products produced by aseptic processing – current Good Manufacturing Practice (see Chapter D.10). This
Guidance was issued to help manufacturers to meet the requirements in the FDA's cGMP regulations as compiled in the
legally enforceable federal regulations 21 CFR 210 and 211. Contrary to the European determinations, FDA has
established class limits only for particles ≥0.5 µm and for the occupancy state in operation (Figure 11.E-8). FDA
distinguishes between critical areas and supporting clean areas. For more detailed informations see Chapter 3.C.2.2
FDA Guidance for Industry: Sterile drug products produced by aseptic processing – current Good Manufacturing
Practice.

Figure 11.E-8 Air cleanliness classifications for aseptic manufacturing operations according to the FDA Guidance for
Industry for aseptic processing.

FDA air cleanliness classificationsa according to the aseptic processing guide

Clean area Microbiological settling plates

classification (0.5 µm ISO Particles Microbiological active action levelsc,d (diam. 90 mm,
particles/ft3) designationb ≥0.5 µm/m3 c 3
air action levels (cfu/m ) cfu/4 hours)

100 5 3 520 1e 1e

1 000 6 35 200 7 3

10 000 7 352 000 10 5

100 000 8 3 520 000 100 50

a All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity.
b ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO
5 particle concentration is equal to Class 100 and equals EU Grade A.
c Values represent recommended levels of environmental quality. You may find it appropriate to establish alternative
microbial action levels due to the nature of the operation or method of analysis.
d The additional use of settling plates is optional.
e Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

11.E.3.3 ISO standards

Because of the large number of cleanroom standards produced by individual countries it is very desirable that one
world-wide standard of cleanroom classification is produced. The first ISO standard on cleanrooms has been published
in June 1999 as 14644-1 Classification of Air Cleanliness. It has then been adopted as a European standard and hence
a standard for all countries in the EU. This standard is available from standard organisations throughout the world and in
the UK is available from the BSI. Shown in Figure 11.E-9 is the classification that has been adopted.

Figure 11.E-9 Airborne particulate cleanliness classes for cleanrooms and clean zones according to ISO 14644-1

Classification numbers Maximum concentration limits (particles/m3 of air) for particles equal to and larger
(N) than the considered sizes shown below
 0.1 µm 0.2 µm 0.3 µm 0.5 µm 1 µm 5.0 µm

ISO 1 10 2

ISO 2 100 24 10 4

ISO 3 1 000 237 102 35 8

ISO 4 10 000 2 370 1 020 352 83

ISO 5 100 000 23 700 10 200 3 520 832 29

ISO 6 1 000 000 237 000 102 000 35 200 8 320 293

ISO 7 352 000 83 200 2 930

ISO 8 3 520 000 832 000 29 300

ISO 9 35 200 000 8 320 000 293 000

The table is derived from the following formula:

where:

● Cn represents the maximum permitted concentration (in particles/m3 of air) of airborne particles that are equal to or
larger than the considered particle size. Cn is rounded to the nearest whole number.
● N is the ISO classification number, which shall not exceed the value of 9. Intermediate ISO classification numbers
may be specified, with 0.1 the smallest permitted increment of N.
● D is the considered particle size in µm.

● 0.1 is a constant with a dimension of µm.

The occupancy state is defined in this standard as follows:

● As built: the condition where the installation is complete with all services connected and functioning but with no
production equipment, materials, or personnel present.
● At-rest: The condition where the installation is complete with equipment installed and operating in a manner agreed
between the customer and supplier, but with no personnel present.
● Operational: The condition where the installation is functioning in the specified manner, with the specified number of
personnel present and working in the manner agreed upon.

The ISO 14644 standard also gives a method by which the performance of a cleanroom may be verified i.e. sampling
locations, sample volume etc. These are similar to FS 209 which is valid for US. It also includes a method for specifying
a room using particles outside the size range given in Figure 11.E-9. Smaller particles (ultrafine) will be of particular use
to the semiconductor industry and the large (>5 µm macroparticles) will be of use in industries such as parts of the
medical device industry, where small particles are of no practical importance.

11.E.4 Methods
11.E.4.1 Direct contact test

Direct contact tests are usually used for surfaces, with the help of RODAC plates (corresponding to 25 cm2area). These
consist of a convex agar culture medium. The plate is pressed against the area to be sampled for about 5 seconds with
average pressure (do not turn!) and immediately sealed and labelled. As a film of the culture medium always remains on
the surface, it must be cleaned afterwards with 70% isopropanol. Curved surfaces can be sampled with flexible agar
foils. The culture mediums contain usually already substances to deactivate the disinfectant, so that the microbial count
is not negatively influenced by residues of disinfectant.

11.E.4.2 Measurement of airborne microbes

Measurement of airborne microbes can be split into passive and active procedures. Passive collection of airborne
microbes is carried out via settling plates (with Petri dishes filled with culture medium). The pertinence of such a
determination is very limited, as it only reflects a small section of a possible microbial particle load in the air
(dependencies on flow rates, particle size, affinities). However, it is deployed in accordance with the EU-GMP-Guide.
Active microbe collectors are used with different procedures, e.g. RCS collector. The equipment used for sampling must
be calibrated. Equipment parameters, such as aspiration speed and time, must be exactly complied with in order to
achieve reproducible results. Depending on the requirements, measurements are taken when at rest or in operation.

A basic requirement for all sampling procedures is that they influence the environment as little as possible. It goes
without saying that measuring instruments and sample collectors must be subject to the same hygiene measures as the
equipment or instruments used for production. The determination methods used for monitoring must, like other methods
in microbiological quality control, be validated and measuring instruments (airborne microbes counters, particle
counters) must be calibrated. A statement of the method used is important for the evaluation of the results, as results in
the microbiological area indicate strong variations between the individual methods. When establishing a viable
particulate air monitoring program, the following steps have to be considered (see Figure 11.E-10):

Figure 11.E-10 Viable particulate air monitoring program

Viable particulate air monitoring program

Define parameters
● Establish room classifications,

● Identify critical and non-critical areas,

● Determine levels when area is active

Establish passive air sampling program

● Note: FDA does not accept passive air sampling alone!

● Identify procedure for use of fallout plates,

● Establish exposure times (minimum –4 hours),

● Describe procedures for collection and transportation to laboratory,

● Describe media used, procedures and incubation parameters

Establish active air sampling program

● Note: FDA requires active air sampling

● Identify which system(s) will be used (impaction on agar, liquid impingers, membrane filtration),

● Establish volume of air to be sampled

● Class 100: minimum 10 ft3, preferably 35.3 ft3 or 1.0 m3;

● Class 10,000 or greater: minimum 1.0 ft3, preferably 10 ft3 or 0.28 m3),

● Describe procedures for collection and transportation to laboratory,

● Describe media used, procedures and incubation parameters

Establish sampling plan

● Determine locations for different types of sampling,

● Determine frequencies for sampling,

● Include a map of the sampling locations

Establish alert and action limits for the different types of sampling and locations
● Based on sampling history, EU-GMP-Guide Annex 1, USP-Guidance, FDA-Guidance
11.E.5 Investigation areas
All possible influencing factors that come into question for contamination are investigated.

Figure 11.E-11 Investigation areas

Investigation areas

● Surfaces
● Air

● Cleansing agent and disinfectant

● Personnel

● Utilities

11.E.5.1 Surfaces

This includes the product contact surfaces and the rooms and facilities in the wider sense. It is recommended that you
also consider bordering areas, in addition to the actual production rooms. In this way, deterioration with possible
implications for critical areas can be ascertained in advance.

The aspects to be considered when establishing a surface monitoring program are given in Figure 11.E-12.

Figure 11.E-12 Surface Monitoring Program

Surface monitoring program

Define parameters
● Identify product contact and non-product contact surfaces,

● Determine levels when area is active

Identify which means of sampling will be used

● RODAC plates, Swabs

Establish sampling plan

● Determine locations to be sampled,

● Include a map of the sampling locations,

● Determine frequency of sampling,

● Describe procedures for collection and transportation to laboratory,

● Describe media used, procedures and incubation parameters

Establish alert and action limits for the different classes, areas and sites sampled
● Based on historical data collected during media fills, EU-GMP-Guide Annex 1, USP Guidelines, Parenteral Society
Guidelines (UK)
11.E.5.2 Air

The bioburden and particle count of the air are checked as standard. The flow rate, flow direction and pressure
differential are also of interest for sterile production (see Chapter 3.G Heating Ventilation Air Conditioning (HVAC)).
Important aspects to be considered for the implementation of a physical environment monitoring program are described
in Figure 11.E-13.

Figure 11.E-13 Physical environment monitoring program

Physical environment monitoring program

Define what parameters require monitoring

● Determine critical elements product requirements, process requirements,

● Define monitoring parameters temperature, humidity, differential pressure and airflow, velocity
of air (unidirectional air flow), non-viable particulates

● Base program on the requirements of the processes and products

Define responsibilities for each part of the program

● Sampling,

● Analysis of data,

● Calibration of measuring equipment,

● Reaction to failing results

Temperature and Humidity

● Define areas that need temperature and humidity cleanrooms, general manufacturing and packaging areas, bulk
control manufacturing area, laboratory

● Define specifications based on product or process requirements, operating ranges,

alarm levels

● Define system for monitoring temperature and frequency of monitoring, frequency of recording data, validate
humidity monitoring system

Differential Pressure and Airflow

● Define areas to be monitored cleanrooms, areas where product is exposed to the

environment, areas where product containment is required

● Define system for monitoring differential pressure frequency of monitoring pressures or differential pressure,
frequency of recording data, validate monitoring system

● Perform smoke studies doors open, doors closed, verify correct direction of airflow
during above tests

● Define specifications ● between different cleanliness classes,

● between areas where containment is required,

● positive or negative pressure

● positive: protection of product,

● negative: containment of product,

● minimum 12.5 Pascals

● Calibrate pressure sensors and or manometers

Air velocity (Applies to unidirectional flow)

● Establish measurement frequency minimum: 90 ft/min ±20% or 0.45 m/s ± 20%

● Measure at work height,

● Use calibrated measurement instrument

Non-viable particulates

Develop counting method

● particle counter operation operating SOP, personnel training

● establish size of particles to be measured ● U.S.: only ≥0.5 µm;

● EU: ≥0.5 and ≥5.0 µm

● sampling procedure ● individual particle counters,

● multi-port sampling system with one sensor,

● remote sensors with data acquisition

● Decide sample size for each room classification ● Class 100 (Class A): minimum 10 ft3 per site;

● Class 10,000 (Class B): minimum 1.0 ft3 per site;

● Class 100,000 (Class C): minimum 1.0 ft3 per site

Establish sampling plan

● Determine sample locations Document sampling locations, include a map of the sampling
locations, based on data obtained during facility qualification
studies

● Samples measured within 12 inches (30 cm) of ● Infeed of open containers

critical operations, Samples taken at critical
operations ● Filling operation

● Stoppering operation

● Samples taken during manufacturing operations ● Samples taken minimum of once per shift per filling room

● Samples taken at work height in room

Develop action and alert levels for each class

● Based on regulatory requirements or expectations: ● Action Levels (EU GMPs, Annex 1; US Federal Standard
209E),
● Alert Levels (Historical data from monitoring program

● Issue notice if alert level is exceeded ● review past results for sample site and area,

● if two alert notices in one week, follow-up as if action level

exceeded,
● initiate failure investigation if action level exceeded

11.E.5.3 Cleansing agents and disinfectants

These must be checked regularly for microbiological contamination in order to disclose the development of resistant
strains. In accordance with Annex 1 of the EU-GMP-Guide, disinfectants used in the production of sterile drugs must be
sterile at the time of application. It is advisable to investigate samples that are taken directly at the application point, e.g.
from the dispenser system. For sterile productions, dilutions for use should be microbiologically tested once a month
and also according to the frequency with which the disinfectant is changed. Attention should be paid to an extended
incubation time, as there may be predamaged organisms.

11.E.5.4 Personnel

For the production of sterile drugs, precise specifications are made regarding personnel testing (depending on the
cleanliness grade). Clean room clothing should be changed after sampling, as agar residue from the contact plates
always sticks to the textiles and cannot be reliably removed with disinfectants. Checking the microbial count on hands
allows conclusions to be drawn about compliance with the hand hygiene regulations. When a personnel monitoring
program is set up, the aspects described in Figure 11.E-14 should be considered.

Figure 11.E-14 Personnel monitoring program

Personnel monitoring program

Develop monitoring procedures

● Gowning training and assessment ● test prior to entering aseptic facility,

● must put on new gown after sampling,

● initial training – three consecutive passing gownings

● Aseptic technique assessment ● test to assess a person’s ability to keep gown sterile,

● test prior to exit of aseptic facility

Develop monitoring tests

● Finger touch plates, Gown touch plates

Establish sampling plan

● Determine sites for sampling: ● Gowning training and assessment:

● clavicle,

● above both gloves on forearm,

● above both boots,

● fingers on both hands;

● Aseptic technique assessment:

● clavicle,

● above both gloves on forearm,

● to one side of the front closure,

● forehead,

● fingers on both hands,

● Determine frequency and time for sampling personnel and facilities,

● Describe procedures for collection and transportation of samples to laboratory,

● Describe media used, procedures and incubation parameters

Establish alert and action limits for the different sampling locations

● Based on sampling history, EU-GMP-Guide Annex 1, USP-Guidance , FDA-Guidance

11.E.5.5 Utilities

Utilities are e.g. water and process gases (e.g. nitrogen, product contact compressed air). These must be reviewed
regularly. See Chapter 5.D.6 Performance qualification (PQ) for microbiological testing of water.

11.E.6 Evaluation
11.E.6.1 Report

An evaluation is compiled after receipt of all individual measured values and summarised in a report. This report should
contain the following information (see Figure 11.E-15).

Figure 11.E-15 Report

Content of the sampling report

● Type of sample
● Test method

● Sampling method, sampling aids

● Sampling point

● Status (in operation/at rest)

● Number of persons in the room at the time of sampling (in clean rooms)

● Time of sampling

● Duration of sampling

● Test date

● Incubation conditions

● Deviations, special features

● Result

● Compiler of the report

11.E.6.2 Trend analyses

Summaries of data over periods of time should be developed, where counts over time and microorganisms isolated over
time are evaluated. Trend analyses should also be carried out as part of monitoring (EU-GMP-Guide). These make it
possible to identify deviations from the regular status and trends even before the alert and action limits are exceeded.
Numerical data for microbiological contaminations should be considered as uncertain due to the spread of measuring
values and moderate reproducibility in terms of quantification. Therefore, trending offers an additional level of certainty
in critical areas. Graphical execution is an easy way to visualise noticeable problems.

11.E.6.3 Measures when limit is exceeded

If a limit is exceeded, microbial identification should be carried out (see Chapter 12.J.8 Measures if levels are
exceeded and Chapter 12.J.9 Organism identification). The type of organism can help you draw conclusions about the
origin of the contamination, as there is a typical microbial flora for water, air and humans.

The cleansing agent and disinfectant (diluted and concentrated solution) should also always be checked for possible
contamination. In sterile areas, the daily monitoring data is taken into account at the time of batch release. That is, if the
limits have been exceeded, the batch must first be rejected and further investigations must be set up until a safe
assessment of the situation is possible.

The monitoring results can also lead to changes in the cleaning or disinfecting processes. The results of changes in
other areas (e.g. restructuring measures, defective transport devices, etc.) only become evident through monitoring,
especially in the area of the environment immediately around the actual production areas. This may mean an increase
in the number or frequency of samples carried out in future.
If the particle load is exceeded, changes to facilities, the air flow pattern and air preparation may be necessary
(see Chapter 3.G.4 Principles for the design and planning of air conditioning ventilation systems).

In case of Out of Specification results, measures to be taken should be described in an Out-of Specification (OOS)
SOP.

The investigation of OOS Results should include at least the following:

● Review laboratory analysis performed

● Perform additional analysis of product

● Review production documents

● Review maintenance documents

● Review sanitation documents

● Review physical and operational parameters

● Review personnel monitoring data

The documentation of the results of the investigation should state

● the problem

● what was reviewed

● findings

● conclusions and recommended corrective actions

Corrective action may include, but is not limited to, the following:

● Retraining of personnel involved

● increase the frequency of sampling or number of samples

● Evaluate the need for increasing the frequency of sanitization

● Perform additional media fill to revalidate the filling environment

● must demonstrate return to validated state

● if definable cause, perform one media fill

● if no definable cause, perform three media fills

All investigations and the decision made regarding the disposition of the affected product have to be documented and
should be in accordance with the written procedure on OOS results.

11.E Summary
Monitoring gives information on the actual hygienic status and thus on the success of the cleaning and disinfecting
measures.
Surfaces, personnel, air, utilities and cleansing agents and disinfectants have to be tested. Alert and action limits have
to be set, as well as measures to be taken if they are exceeded.
The monitoring methods must be described accurately.