Environmental Monitoring (EM) programs for pharmaceutical manufacturing are

evolving to a risk-based approach. The use of sampling data for the identification
and mitigation of risk becomes a critical element in this process. No longer is it
enough to utilize data for reactive excursion reporting. Before exploring this
concept in detail, it is important to get a good understanding of what environmental
monitoring is at its core.
Environmental monitoring is the sampling of controlled environments for non-
viable and viable air particulates as well as surface viables. It allows for
assessment of effectiveness of cleaning/disinfection, identification of trends and it
can help facilitate early detection of potential problems.
Environmental monitoring describes the microbiological testing undertaken in
order to detect changing trends of microbial count and microflora within
cleanroom or controlled environments. The results obtained provide information
about the physical construction of the room, the performance of the HVAC system,
personnel cleanliness, gowning practices, the equipment and cleaning operations.
There are different types of Environmental Monitoring. Viable monitoring is the
testing for the detection and enumeration of bacteria, yeast and mold. It includes
the monitoring of personnel, air and area surfaces for microbial contamination.
Non-viable monitoring is a reference for particle counts measured by a laser
counter. The methods used for microbiological monitoring include: passive air
sampling (settle plates), active air sampling (air sampler), surface sampling
(contact plates and swabs) and personnel sampling (finger plates/plates of gowns).
The purpose of microbiological environmental monitoring is to provide
information on microbiological quality of the environment and to identify any
potential contamination hazards. Following data analysis and trending, this
information can be used to determine the microbial flora of the environment and to
set action and alert limits based on historical data.
The implementation of an effective environmental monitoring program should
involve a well-defined and documented sampling plan and associated standard
operating procedure (SOP).  The SOP should be periodically reviewed and revised
if necessary.
The key factors to be considered and documented within the environmental
monitoring SOP should include :
 Sample locations
 Monitoring frequency
 Sampling technique
 Timing (during operation or “at rest”)
 Action and alert limits
 Investigative and corrective actions to be taken when limits are
exceeded
When selecting sampling locations for an environmental program, consideration
should be given to the design of the area and to the process.
According to the FDA Guidance for Industry, Sterile Drug Products Produced by
Aseptic Processing-cGMP, Section A.11, monitoring locations that present the
highest potential contamination risk to the product should be included in the
monitoring program. Monitoring locations should be selected by assessing the
critical activities taking place and the flow of personnel in the processing area to
determine the most potentially high-risk contamination locations.
Until recently, when establishing a microbiological monitoring program, sample
locations were often randomly selected using the grid approach for non-viable
particulates as outlined in ISO 14644 series Cleanrooms and associated controlled
environments.  As per Cleanroom Management in Pharmaceuticals and Healthcare,
p4233, this method involves applying a grid over the cleanroom plans and
selecting sample sites at equal distances in each zone. This method of selection is
inherently random and does not involve identifying locations which pose the
greatest microbiological risk to the product.
Environmental monitoring programs have become more advanced with the
progression from random sampling approaches to the use of risk assessment tools
to determine sample locations and monitoring frequency. Regulatory expectations
regarding the use of risk assessment principles when establishing an environmental
monitoring program have also become more stringent. Eudralex, Volume 4, EU
GMP, Annex 1; Manufacture of Sterile Medicinal Products, Section 84 states:
“Clean rooms and clean air devices should be routinely monitored in operation and
the monitoring locations based on a formal risk analysis study and the results
obtained during the classification of rooms and/or clean air devices”.
Application of Quality Risk Management tools and approaches into your EM
Program design and throughout the product lifecycle should include:
 Understanding your products and processes
 Understanding your microbial contamination risks
 Ensuring that proper risk mitigations are in place to help
prevent contaminations
 Ensuring that EM sample sites selection and sampling
frequencies reflect this understanding and are properly
established to best detect potential contamination

Over the past decade, environmental monitoring has become more sophisticated in
moving from random sampling, using an imaginary grid over the room and testing
in each grid, to the current focus on risk assessment and the use of risk assessment
tools to determine the most appropriate methods for environmental monitoring.
 Determining the Frequency of Monitoring: Using the concept of risk
assessment to decide how often to monitor different types of
cleanrooms
 Risk Assessment Tools: Applying risk assessment tools to establish
methods for environmental monitoring
 Numerical Approaches: Considering a numerical approach to assess
risk data using a case study of an aseptic filling operation
Once the status for each room has been selected, a risk assessment procedure is
required to determine locations for environmental monitoring. Such risk-based
approaches are recommended in ISO 14698 and regulatory authorities are
increasingly asking drug manufacturers about this subject. Risk-based approaches
include Failure Mode and Effects Analysis (FMEA), Fault Tree Analysis (FTA),
and Hazard Analysis and Critical Control Points (HACCP), all of which employ a
scoring approach. Other approaches include: Failure Mode, Effects, and Criticality
Analysis (FMECA);Hazard Operability Analysis (HAZOP);Quantitative
Microbiological Risk Assessment (QMRA);Modular Process Risk Model
(MPRM);System Risk Analysis (SRA);Method for Limitation of Risks; and Risk
Profiling.
Next, developing the EM Risk Management Planning is critical.
Risk Management Planning includes:
  Determine Team/Members – cross functional (Micro, QA, MFGing,
Facilities, Engineering)
 Select Facilitator – not bias to activity
 Define Scope of Risk Activities for EM Program assessment
 Determine the Risk Management Tools to be used
 Determine Scoring to be used – company procedure may already exist
 Determine Communication of Risk Plan
 Who needs to be communicated to, when, how often, how much
detail?
 Impact to Regulatory Filings
 Costs

Assessing the root causes of Microbial Contamination are key. Giving Higher
Weighting to – ‘dirtier 'activity performed in a room adjacent to a clean activity,
even if the clean activity represents later processing; areas that have a higher level
of personnel transit (given that people are the main microbiological contamination
source). This may include corridors and changing rooms. Give consideration to:
 Routes of transfer
 Areas that receive in-coming goods
 Component preparation activities and sites
 Duration of activity (such as a lower criticality for a 30-minute
process compared to a six-hour operation)
 Having Higher Monitoring Frequencies for –
 Warm or ambient areas as opposed to cold rooms
 Areas with water or sinks as opposed to dry, ambient areas
 Open processing or open plant assembly compared to processing that
is open momentarily or to closed processing (where product risk
exposure time is examined)
 Final formulation, purification, secondary packaging, product filling,
etc.
The next step is to review data and commence risk assessment. Once all of the
planning, brainstorming and walk-throughs of the areas have been completed, you
can begin the process of doing the risk assessment. Quality risk management
should include systematic processes designed to coordinate, facilitate and improve
science-based decision-making with respect to risk. Possible steps used to initiate
and plan a quality risk management process might include the following:
 Define the problem and/or risk question, including pertinent
assumptions identifying the potential for risk
 Assemble background information and/or data on the potential hazard,
harm or human health impact relevant to the risk assessment
 Identify a leader and critical resources
 Specify a timeline, deliverables and appropriate level of decision-
making for the risk management process
Implementation follows this process. The next step involves deciding which
contamination sources need to be controlled and the level of control required.
Critical levels and the most appropriate sampling methods to monitor the
contamination hazard or their control should then be determined. The
environmental monitoring program should be established with “alert” and “action”
limits and determination of appropriate corrective actions when deviations occur.
The effectiveness of the environmental monitoring program should be monitored
by trending of resultant data and reassessment of hazards when necessary. The risk
assessment method should be fully documented to detail the steps and justify the
rationale taken to select the monitoring locations. Key to the success of this
activity is ensuring that a multi-disciplinary team is involved in the process with
‘buy in’ from the senior management team.
Using a risk based approach when establishing an environmental monitoring
program drives a continual review of trends and a periodic re-assessment of the
program. This will contribute greatly to demonstrating control of the
manufacturing environment and ensure that the EM program meets with regulatory
requirements and expectations. Examples of questions you should be asking are:
 How are you currently assessing the location of your sampling point
locations as part of your current environmental program?
 What risk-based tools have you used for sampling location selection?
 How frequently are your locations being monitored when in use and
not in use?
 What are your current environmental trends telling you?
Once the risk assessment is completed and implemented, any relevant SOPs and
training needs to be updated to ensure the end users are on board with the changes.
The use of risk assessment approaches is an important current Good Manufacturing
Practice (cGMP) topic in microbiological environmental monitoring. The
microbiologist must consider each aspect of the environment and decide what level
of monitoring best suits his or her system, and then must justify the techniques
used and the locations selected. The approach adopted should be detailed in a
written rationale and approved by senior management. After this, a rigorous and
defensible system will be in place to satisfy regulatory expectations, and to aid the
user in assessing the risk of problematic environmental monitoring situations or
results.