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Risk assessment on Environmental monitoring: a CDMO perspective

 Vaishnavi Babu (Quality Excellence Team – Kemwell Biopharma)

Over the past decade, environmental monitoring (EM) program has become critical factor, refined, moving from random sampling to testing each imaginary grid in the cleanrooms of aseptic cGMP manufacturing sites. Globally, the EM program gives relevant information to document that all manufacturing steps were realized in an environment in a coherent, validated state of control. The results obtained from the EM program provide information about the physical construction of the room, the performance of Heating, Ventilation, and Air-Conditioning (HVAC) system, personnel cleanliness, gowning practices, the equipment and its cleaning operations. Rick Friedman from FDA suggests handling of these datas from EM program in the form of computerized trending for recognition pattern will be more effective and efficient to analyse the variation and risk involved periodically. Currently, the domain focuses on risk assessment which is an important cGMP in relation to microbial intervention, and the use of risk assessment tools to determine the most appropriate methods for environmental monitoring.

At present, risk based approaches involves various methods namely Failure Mode and Effects Analysis (FMEA), Fault Tree Analysis (FTA), and Hazard Analysis and Critical Control Points (HACCP), 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. These approaches recognise a risk, rate the level of the risk, and then set out a plan to minimize, control, and monitor the risk. However, FMEA permits practicable management of risk-reducing actions or measures with the help of risk priority number (RPN). In FMEA, the risk components are considered to quantify the risk of a specific failure and its effect. The risk priority number RPN functions as quantification of the risk and it is calculated by multiplying the severity SEV, occurrence OCC and detectability DET values.

Risk assessment on Environmental monitoring

All the assessment activity directly relates to the area under microbial risk at aseptic manufacturing of biologics, before that we must understand the fundamental science, that a CFU (colony forming unit) is not the same as a bacterial cell. A CFU (colony forming unit) is a collection of bacterial cells. The CFU becomes visible to the naked eye when there are sufficient microbial cells present in the biomass mound (generally in the range of 107 – 108 cells). The CFU is at best an estimate of the numbers of cells present originally. This estimate becomes even more imprecise at low numbers of CFU per plate. Based on the microbial risk in the particular area, the frequency of sampling is designated as daily at High risk, weekly at medium risk and monthly at low risk.

There has been recent spate of observation by FDA on biologics (manufacturing of biologics) citing failure to identify or investigate “objectionable organisms” in the aseptic process of EM program. Hence, it is more important to identify the microbial excursions and follow up with trending pattern to monitor consistently in the facility at least periodically, to allow for recognition of a problem in the cleaning program or recognition of a facility issue. The level of identification should be sufficient to meet trending needs, since many regulatory agencies worldwide expect regular information to the species level.

This can be mitigated by setting an individual assessment, which can be involved in various cases, addressed by Tim Sandle. Once the activity is taken place, the risk can be evaluated using numerical risk assessment approach. Table 1 provides a brief account on derivation of individual estimation of risk to the product, based on the quantification as per set criteria (the risk is categorized as low, medium and high)as well as based on the scoring and its application, the product / batch of the product is released. 

If the score is <0.03, then very safe to release the batch, >0.03 and <0.09 medium risk is expected, further assessment to release the batch is expected.

If the score is >0.09  the batch should be rejected / justified before release of the batch

Table 1: Estimation on risk to product based on Individual assessment at critical areas and operations

Individual assessment


Applies to

Settle Plate Count

Contamination rate (%) = Settle plate count X (Area of product/Area of petri dish) X (Time of product exposed/Time of settle plate exposed) X 100

The point-

of-fill, under the Grade A zone


Finger plate

Score = Microbial count X Location X Method of

intervention X Duration of operation


Grade A operations, such as filtration connection, vessel to filling machine connection and  the filling activity

Surface Sample

Score = Microbial count X proximity of critical area X

Ease of dispersion of micro-organisms X

Effectiveness of control measure

Filling and filtration activities

Air Sample

Score = Airborne microbial count (cfu/m3) X deposition velocity of microorganisms from air (cm/s) X area of product exposed (cm3) X time of exposure (s)

Air sampling at grade A


The rational approach on the risk assessment provides a complete pattern of the rigorous and defensible system which will satisfy regulatory expectations and to aid the user in assessing the risk of problematic environmental monitoring situations or results. Furthermore, risk assessments should be based on sound science in relation to biocontamination control at sterile manufacturing sites. The contribution of such effective evaluation on each risk and critical factors, indirectly affirms and assures that the sterile drugs, which reaches the patient is safe and secure, hence, these aspects would promote developing contract manufacturing organizations in the commercial production of biomolecules and biosimilars successfully.



  • Sandle T (2019) Biocontamination Control for Pharmaceuticals and Healthcare, Chapter-16 Risk Assessment and Investigation for Environmental Monitoring, Academic Press, 261-285
  • Whyte W and Eaton T (2004) Microbiological Contamination Models for Use in Risk Assessment during Pharmaceutical Production, European Journal of Parenteral and Pharmaceutical Sciences, 9(1):11-15.
  • Sandle T (2003) The Use of a Risk Assessment in the Pharmaceutical Industry – the Application of FMEA to a Sterility Testing Isolator: a Case Study, European Journal of Parenteral and Pharmaceutical Sciences, 8(2): 43-49.
  • Zimmermann H F and Hentschel N (2011) Proposal on How To Conduct a Biologics Process Failure Mode and Effect Analysis (FMEA) as Risk Assessment Tool. PDA Journal of Pharmaceutical Science and Technology 65: 506-512.
  • USP  <1227>  Validation of Microbial Recovery from Pharmacopeial Articles.


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