Environmental Monitoring for Non-sterile Manufacturing Areas
Settle plate Exposure in Non-sterile Manufacturing area
This is under DRAFT
It has been a great debate to identify and set requirements for what is not stated clearly in various regulatory guidelines. As it becomes difficult at times to identify and select the correct requirement which are scientifically valid, suffices the purpose of GMPs; the insufficient regulatory guidance becomes a point of debate between visiting auditors and the auditee who intends to protect their systems and policies for which sometimes rationality becomes questionable.
Out of few missing links in these regulatory guidances, Environment Monitoring for non-sterile areas is one such. Neither the Indian Schedule-M nor the ICH Q7 or 21 CFR 211 clearly gives the requirements for Environment Monitoring for solid-oral dosage manufacturing. The sources of guidance with respect to environment monitoring frequencies are very limited with respect to solid oral - dosage facility. Because of this lack of defined standards or guidelines, viable monitoring programs in nonsterile pharmaceutical manufacturing facilities range from comprehensive programs, paralleling those of aseptic operations, to nonexistent.
No standards currently exist for establishing a viable environmental monitoring program for nonsterile pharmaceutical manufacturing operations. In the pharmaceutical industry, current guidelines or standards do not exist for establishing a viable environmental monitoring program in a nonsterile drug manufacturing operation. As a result, inconsistent practices abound, and in some cases, monitoring is not being conducted at all.
So the question continues, what should be the requirements, procedure and policies for environment monitoring for non-sterile process area ?
Environmental Monitoring describes the microbiological testing undertaken in order to detect changing trends of microbial counts and micro-flora growth within cleanroom or controlled environments. The results obtained provide information about the physical construction of the room, the performance of the Heating, Ventilation, and Air-Conditioning (HVAC) system, personnel cleanliness, gowning practices, the equipment, and cleaning operations.
However for the purpose of identifying environment monitoring requirement for non-sterile manufacturing operations, the manufacturing areas are categorised as (a) solid-oral dosage forms manufacturing, (b) APIs powder processing area, (c) Liquid orals, (d) Saampling / dispensing area and other areas where raw materials are exposed or where teh chances of microbial conamination exists (this is to be defined by the user).
As mentioned above, the purpose of EM is to ensure effectiveness of the HVAC system and various other measures taken to prevent contamination (in this discussion contamination is referred to Microbial contamination).
The questions are:
what should be the requirements for EM for these areas,
what should be the frequency for monitoring and
how to set the measurement frequency or its validation criteria.
REQUIREMENTS FOR ENVIRONMENT MONITORING:
To identify the requirements for environment monitoring there should be a balance between using resources efficiently so that a meaningful picture can be obtained. A viable environmental monitoring program should provide sufficient information to show that the manufacturing environment is operating at an adequate level of microbiological control. This requirement applies to non-sterile products. Although the required state of control will vary depending on the product being manufactured, the requirement is universal across all pharmaceutical manufacturing. The ideal porgam will be based upon
Table 1 shows the minimum attributes of a well-established microbial EM program.
Locations for microbiological monitoring
DETERMINING THE FREQUENCY OF MONITORING
In developing an adequate environmental monitoring programme, sources of guidance with respect to monitoring frequencies are very limited and the monitoring frequencies specified within the United States Pharmacopoeia (USP) <1116> may not be suitable for all facilities. Some guidance can be obtained from the International Organization for Standardization’s (ISO) standards: principally ISO 14644 and ISO 14698. However, these do not always fit with regulatory guidance documents because they apply to controlled environments across a range of industries other than pharmaceuticals, where standards can be higher. The best answer to identify the frequency for EM is by using the concept of risk assessment to decide how often to monitor different types of areas.
When establishing an environmental control programme, the frequency of monitoring different controlled areas can be determined based on ‘criticality factors’ relevant to each specific area.
What are Criticality Factors ?
The establishment of a criticality scheme on which to base monitoring frequencies is designed to target monitoring of critical process steps. Therefore, the final formulation process would receive more monitoring than an early manufacturing stage with a relatively closed process.
The criticality factor means assigning a monitoring frequency based on the risk assessment of each critical area. The risk assessment relates to the potential product impact from any risk. For example, an area of open processing at an ambient temperature, a long exposure time, and the presence of water, would constitute a high risk and would attract a higher risk rating. In contrast, an area of closed processing, in a cold area, would carry a substantially lower risk and associated risk rating.
Using a range of 1 to 6, with ‘1’ being the most critical and ‘6’ the least critical, a score of 1 would be assigned to an aseptic filling operation; a score of 2 to final formulation, a score of 3 to open processing, and so on. Each user must adapt such a scheme to his or her particular area and defend it by way of supportable rationale. An example of monitoring frequencies under such a scheme can be seen in Figure 1, and an example of its application is seen in Figure 2.
Each controlled area would be evaluated against set criteria and, with the use of a series of guiding questions, the monitoring frequency would be determined. Decision criteria include considerations in two category areas: areas of higher weighting and areas of higher monitoring frequency. Examples of these categories follow:
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.
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.
Once the monitoring frequency for each controlled area is determined, it should be reviewed at regular intervals. This review may invoke changes to a room’s status, and hence, its monitoring frequency, or to changes for different sample types within the room. For example, it may be that after reviewing data for one year, surface samples produce higher results than air samples for a series of rooms. In this event, the microbiologist may opt to vary the frequency of monitoring and take surface samples more often than air samples. There would also be an increased focus on cleaning and disinfection practices, and their frequencies, based on such data (Sandle, 2004b).
When both types of monitoring are producing low level counts, the balance of risk would be towards air samples. This is because air samples are direct indicators of the quality of the process and assign a level of control to the process, whereas surface samples are indicators of cleaning and disinfection. If the results of surface samples are generally satisfactory, as indicated by trend analysis, then either the number of samples or the frequency at which they are taken can be reduced. If subsequent data showed an increase in counts, the monitoring frequency could easily be restored. Indeed, all types of monitoring frequencies may increase as part of an investigation, as appropriate. Therefore, the criticality factor approach not only sets the requirement for a room, it can also be used to vary the sample types within a room (Ljungqvist and Reinmuller, 1996).
You define the frequency yourself, as long as you know and can assure that your remain in control of the your system, and the activities and processes you perform in the monitored zone.
Nowadays everything is automated so you set data acquisition to an interval which your PLC and network can sustain (you do not want to flood your bandwidth). For an EMS you can set for instance: pressure 1s , temperature 10s, humidity 10min and particles 30min.
Bibilogrphy:
1. Journal of Institute of Validation Technology, January 2006, Volume 10, Number 2
2. Developing a viable environmental monitoring program for non-sterile pharmaceutical operations. Pharmaceutical Technology, March 2003
3. Implementation of Microbial Environmental Monitoring Program for Non-Aseptic Pharmaceutical Processes, Pharmaceutical Review