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Environmental monitoring

 

Here you will find answers to the following questions:

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

Aim

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 grade. This can result in optimisation of cleaning and disinfection measures. Trend analyses unveil tendencies and enable early changes to processes. In addition to microbiological investigations, the particle load is checked in sterile areas.

Responsibilities

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.

Carrying out

Monitoring is carried out in several stages. The procedure is based on procedural instructions which establish the monitoring process. 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

11.E.1 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.

Figure 11.E-2 Content of the sampling plan

Sampling plan

  • Sampling point (related to the location and function)
  • Number of samples
  • Frequency of sampling
  • Sampling method (for quantitative or qualitative determinations)
  • Size sample
  • Auxiliary liquids (dilutions, rinsing agents, neutralisers, etc.)
  • Factors with possible impact on incubation results
  • Operating conditions/at rest

The plan contains various details, which are listed in figure 11.E-2. 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. 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.

11.E.2 Establishment of limits and frequencies

The limits for clean rooms can be taken from the "Supplementary guidelines for the manufacture of sterile drugs" (Annex 1 of the EU GMP Guideline, see chapter C.3). 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 (see figure 11.E-3 and figure 11.E-4). 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.

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, immediate remedial action is taken, such as modification of the disinfecting procedure. This is to be established in advance (see figure 11.E-5).

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 Guideline. The frequency of sampling should also be fixed for non-sterile production areas (see figure 11.E-6).

Figure 11.E-3 Limits of cleanliness grades A-G

G

Own definition

Particle load

n.d.

n.d.

n.d.

n.d.

Microbiological load

n.d.

n.d.

(300)

n.d.

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

F

n.d.

n.d.

3,500,000

20,000

500

200

150

n.d.

E

n.d.

n.d.

3,500,000

20,000

200

100

100

n.d.

D

Annex 1 EU GMP Guideline

3,500,000

20,000

n.d.

n.d.

200

100

50

n.d.

C

350,000

2,000

3,500,000

20,000

100

50

25

n.d.

B

3,500

0

350,000

2,000

10

5

5

5

A

3,500

0

3,500

0

<1

<1

<1

<1

cleanliness grade

 

0.5 mm

5 mm

0.5 mm

5 mm

Air [CFU/m3]

Settling plate
(90 mm) [CFU/4 hours]

Contact plate
(55 mm) [CFU/plate]

Gloves (5 fingers)

(at rest)

 

(in operation)

 

(in operation)

     

Figure 11.E-4 Categorisation of the cleanliness grades

 

Assignment of the cleanliness grades to production areas

A

Sterile preparations
aseptic processing and filling

B

Sterile preparations
surrounding area in sterile rooms of A

C

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

D

Sterile preparations
preparation of solution (subsequent sterilisation) with additional measures to minimise contamination, e.g. closed containers
Non-sterile products
inhalation preparations

E

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

F

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

G

Surrounding area of F

Figure 11.E-5 Alert and action values

Limits and consequences when exceeded

Alert level:

Modification of the sampling plan

Action level:

Immediate action

Figure 11.E-6 Frequencies

G

Own definition

yearly

yearly

Personnel

-

-

-

F

half-yearly
to yearly
(depending on
risk to product)

quarterly to
yearly

yearly

-

-

E

quarterly to half-
yearly
(depending on
risk to product)

quarterly to
yearly

yearly

-

-

D

Annex 1 EU GMP Guideline

Room "in operation":
monthly

monthly

not defined

not defined

not defined

C

Room "in operation": daily to fortnightly (depending on
exposition of the product)

Room "at rest": weekly, if no measurement could be carried out in the operated room within a week (not used)

Table, wall, floor:
weekly to monthly
(depending on use)

not defined

not defined

not defined

A, B

Batch-based at the end of production or during use, if this does not result in an increased risk through measurement

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

Batch-based at end of production

monthly

monthly

   

Air
microbes

Surfaces

Hand

Forearm

Hood/
face mask

11.E.2.1 Methods

Direct contact test

Direct contact tests are usually used for surfaces, with the help of RODAC plates (corresponding to 25 cm2 area). 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.

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 Guideline. 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 or 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.

11.E.3 Investigation areas

The possible influencing factors that come into question for contamination are investigated.

Figure 11.E-7 Investigation areas

Investigation areas

  • Surfaces
  • Air
  • Cleansing agent and disinfectant
  • Personnel
  • Utilities

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.

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.H Heating Ventilation Air Conditioning (HVAC).)

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 Guideline, 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.

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.

Utilities

Utilities are e.g. water and process gases (e.g. nitrogen, product contact compressed air). These must be reviewed regularly.

11.E.4 Evaluation

Report

An evaluation is compiled after receipt of all individual measurement values. It is summarised in a report. This report should contain the following information (see figure 11.E-8).

Figure 11.E-8 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

Trend analyses

Trend analyses should also be carried out as part of monitoring (EU GMP Guideline). These make it possible to identify deviations from the regular status and tendencies 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.

Measures when limit is exceeded

If a limit is exceeded, microbial identification should be carried out. 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.H.4 Principles for the design and planning of  air conditioning ventilation systems.)

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 are all tested. Alert and action limits are set, as well as measures to be taken if they are exceeded. The monitoring methods must be described accurately.



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