EU GMP Annex 1, which regulates the manufacturing, control and release of sterile pharmaceutical products, is undergoing some substantial changes, as the current 2020 draft suggests. These will directly affect manufacturers in North America insofar as their exports to Europe are concerned, and probably leave a mark at home as well. The FDA’s equivalent guidance “Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice” dates back to 2004 and is likely to incorporate many of the new principles and provisions when it is next reviewed.
A broader scope than before
Annex 1’s new title “Manufacture of Sterile Products” (not specifically medicinal products, like the previous version) hints at its much broader scope. This is expounded at the beginning: “The manufacture of sterile products covers a wide range of sterile product types (active substance, sterile excipient, primary packaging material and finished dosage form), packed sizes (single unit to multiple units), processes (from highly automated systems to manual processes) and technologies (e.g. biotechnology, classical small molecule manufacturing and closed systems).”
Quality Risk Management (QRM) will also carry greater weight. Manufacturers of sterile products will have to devise environmental monitoring programs and procedures based on QRM to ensure that microbial, particulate and pyrogen contamination is prevented in the final product. QRM should cover the entire chain, from the facility’s design to its equipment and processes, then on to the implementation of suitable procedures, and finally to monitoring systems. QRM is also seen as the basis for justifying any necessary deviation from the specified requirements. Alternative approaches should be supported by rationales and risk assessment that serve to meet the intent of Annex 1.
Preventing equipment-borne contamination
An increased emphasis is on preventing the spread of contaminants through equipment. We at MilliporeSigma have added an H13 HEPA filter option to our portable MAS-100 NT® microbial air sampler to address the risk that contaminants in the instrument’s interior may be carried over when it is moved from a lower to a higher grade cleanroom. In our tests, the retention efficiency of the filter proved to be nearly 100% for particle sizes down to 0.3 μm, with this near-total efficiency being maintained over a simulated one-year typical usage. In air visualization studies (smoke tests) the instrument also showed no disturbance of unidirectional air flow, an Annex 1 requirement that must be demonstrated and qualified across the whole of a Grade A zone. Furthermore, we measured to what degree removing the inner packaging material (including the desiccant bag) of our ICR media plates, which can be used with the MAS-100 NT®, would release particles. The number of detected 0.5 μm sized particles averaged less than 1% of the limit set in ISO 14644-14 for an ISO 5 cleanroom environment, and none of the 30 runs reached 10% of that limit.
More and continuous monitoring
Annex 1 also states that viable air monitoring in a Grade A zone should be undertaken continuously (e.g. by air sampling or settle plates) over the course of critical processing, including aseptic equipment assembly and filling operations. What does continuous monitoring mean in practical terms? According to the definition in the PDA Technical Report No. 13.2 (2020) “that a state of control is maintained during processing and that any aberrant events are detected. Frequency of monitoring is determined by a risk assessment.” Depending on the risk assessment, the monitoring frequency can by quite high which, in turn, calls for care that more frequent manual handling activities do not themselves lead to greater contamination risks. Annex 1’s new requirement to use a combination of methods for microbial monitoring (e.g. settle plates, active air, glove print, and surface sampling) amplifies this point.
The need for less manual activity
To support customers in minimizing their manual activities to perform environmental monitoring, we at MilliporeSigma conducted studies to determine how our MAS-100 NT® microbial air sampler and ICR settle plates can be teamed up to further reduce manual handling. In general, agar plates are prone to drying when used in active air monitoring. However, our tests with the MAS-100 NT® revealed that the ICR settle plates were able to sample an extended air volume of up to 4000 liters without impacting microbial growth and thus the quality of results, thus allowing longer and/or more comprehensive active air sampling before being replaced. Another way to reduce manual handling is to make use of the MAS-100 NT® air sampler’s ability to perform sequential air sampling, whereby the air is sampled at certain intervals over a pre-determined period of time onto a single plate rather than onto several consecutive plates as in conventional air sampling. This reduces the frequency of plate replacement and thus the risk of contamination this may cause. Our study showed that sequential sampling and conventional sampling led to comparable colony counts, suggesting that the sequential method may be preferable for manufacturing processes over a longer period of time.
Contact us to receive detailed information on the studies mentioned in the article. SigmaAldrich.com/em-pharma-info
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