Welcome to our USP 1116 questions and answers blog, where Particle Measuring Systems answers commonly asked questions pertaining to the USP 1116 guidance.
What guidance is there for non-sterile facilities in regards to CRR (aseptic processing)?
It is important to note that <1116> is a “general information” chapter, and as such, it “provides information and recommendations for environments where the risk of microbial contamination is controlled through aseptic processing.”
The scope of this chapter has been narrowed to apply to the following products manufactured in an aseptic processing environment:
- Pharmaceutical sterile products
- Bulk sterile drug substances
- Sterile intermediates
- Excipients
- Some Medical Devices
In addition, types of environments covered in <1116> are:
- Conventional clean rooms with unidirectional flow
- Blow/fill/seal machines
- Restricted Access Barrier Systems (RABS)
- Isolators
How are alert and action limits set for ISO 5?
These limits must be set based on your data for a given period of time. If, for example, you monitor daily, you should re-evaluate your alert and action levels based on your facility data and alert, and action levels should be evaluated (and re-set if necessary) based on real time data.
Why is the limit for ISO 5 less than 1 CFU?
In an ISO 5 cleanroom with the absence of any adverse trends, a single result above an action level should trigger an evaluation and be the impetus for determining whether remedial measures are appropriate.
Check out the BioCapt® Single-Use 100 LPM Microbial Monitor for your Grade A/ISO 5 cleanroom.
EU GMP Annex I has quality action levels and USP <1116> has CRR. Which do we follow? Will they ever align? Have 483s been issued for not having both?
USP <1116> is an informative chapter, not mandatory, unlike the EU GMP. USP <1116> is also written by FDA inspectors (not EU), and does not necessarily apply to companies that produce exclusively in Europe. However, EU-based companies should take an interest in USP <1116> and all regulatory documents that can serve to better their manufacturing practices. The release date should also be considered. USP <1116> is a relatively new release when compared to the EU GMP Annex 1 and FDA guidelines, and can help companies prepare for the future. Regulatory documents should not serve inspectors, but instead provide an avenue for process improvement and understanding.
Is the new way of trending (instead of using CFU) applicable to low bioburden control facilities that produce drug substances? That is, facilities that do not have fill finish and no drug product manufacturing takes place?
The scope of USP <1116> has been narrowed to apply to the following products manufactured in an aseptic processing environment: 1) Pharmaceutical sterile products, 2) Bulk sterile drug substances, 3) Sterile intermediates, 4) Excipients, 5) Some Medical Devices. USP <1115> describes a risk-based approach to bioburden control and EM for non-sterile industries.
Where does the excursion of greater than 15 CFU (from USP <1116>) come from? If the CRR recovery is zero, is there a recommended percentage calculation based on USP?
Even if contamination recovery rates (CRRs) are adopted as a way to analyze microbial contamination, <1116> emphasizes that for an ISO 5 cleanroom, any excursion of >15 CFU should also be investigated. This is because excursions beyond approximately 15 CFU recovered from a single sample, whether originating from an airborne, surface or personnel source, should happen very infrequently in aseptic processing environments. However, for such occurrences, they may be indicative of a significant loss of control, particularly when they occur within the ISO 5 critical zone in close proximity to product and components. Therefore, any excursion >15 CFU should be the subject of a careful and thorough investigation.
If the new USP uses a percentage of positive culture, will this parameter be affected by a small sampling size? The number of culture/sampling may be less than 50 in a small institute. What is the recommended number of samples?
USP <1116> defines the contamination recovery rate as the percentage of plates that show any microbial recovery irrespective of the number of CFU. This would be affected by the sample size but no recommendation is given.
Are risk assessments the same as contamination probability calculations?
A risk assessment is used to determine which areas within your cleanroom or sterile environment that pose the greatest risk to product based on the environment (material and personnel flow) and based on the product (open system/closed system, etc.). Sampling detection methods for EM are then implemented based on the areas of greatest risk. See PIC/S Annex 1:
“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.”
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