Question about environmental monitoring
The question arises whether it would be possible to completely dispense with temperature monitoring if, for example, an extended stability test at 50°C could prove that the product remains stable even at these temperatures. It can be assumed that these temperatures will never be reached. This could be supported by data from previous years.
Would you give this approach a chance from a regulatory point of view or must we prove at any time that stability data up to 50°C have not been exceeded?“
We have given two detailed answers to our customers, which will certainly provide food for thought for further decision-making within the company.
The opinion of a GMP inspector can be read as follows:
"In principle, I could imagine the proposed course of action. The existing regulatory requirements for active substances (GMP and GDP) offer on the one hand the possibility of a risk-based approach, but on the other hand also a monitoring/recording of storage temperatures is described.“
(Sources without claim to completeness: EU-GMP Guide Part II: 7.40, 10.10, 11.50; EU-GDP for active substances: 2.2 [1.vii)], 4.5, 5.1, 6.7)
"If these requirements are deviated from, it shall be justified that the chosen procedure is at least equivalent. I believe it is imperative to coordinate with the competent supervisory authority. However, the question arises whether this is the only active substance stored in the described warehouse (i.e. "dedicated") or whether it is a warehouse in which other, not so robust active substances are also stored that require other, narrower storage conditions. In the case of a storage of different, mostly also changing active substances, the discussion as to whether one of them is still stable at 50°C or more and whether a monitoring system can be dispensed with would be futile. In such a case, the specifications for the product with the lowest stability are decisive. Here, the presence of a monitoring system would offer greater security and flexibility."
A GxP-experienced auditor and consultant adds further aspects to the question:
"In connection with the question of whether and to what extent storage conditions must be monitored and recorded, it is also relevant how the active substance concerned is labelled with regard to storage conditions. Based on the customer's information, I assume that an ICH stability study was conducted for climate zone II, i.e. long term data (25/60) and accelerated data (40/75) are available that show no significant change.
If, on the basis of these data, the active substance concerned does not bear information on the storage conditions on the label, specific storage conditions need not be defined either. Accordingly, neither monitoring nor records are required - there are no limits that could be exceeded or undercut and would require action. The records would then be purely "decorative in nature".
If, on the other hand, the active substance concerned is labelled with storage conditions (e.g. not above 25°C or not above 30°C or even not above 40°C), then it must be ensured that these storage conditions are also adhered to. Monitoring and storage of the relevant records are mandatory.
Another aspect to be considered is whether the responsibility for the active ingredient lies entirely with the customer or whether it is, for example, a contract manufacturer or similar who stores on behalf of his customer. If it is then contractually agreed with this customer that a certain storage temperature must be maintained. Monitoring and recording are mandatory too.
Now for a brief example of the case where the active ingredient is actually labelled with a storage condition, let's say "do not store above 40°C". Let us also assume that this active ingredient is the only temperature-sensitive substance in stock (important point). Then there is still the question of the extent of monitoring and recording required. In other words, is comprehensive computer-aided monitoring required or are a few calibrated min/max thermometers that are read regularly sufficient? The existing historical monitoring data can be used very well for this decision. Perhaps it will then become apparent that the temperature of 40°C is only exceeded on a few days a year and always only at the highest shelf level. In the future, storage locations for the active ingredient could only be assigned to the lower storage levels and these storage locations could then also be monitored using calibrated min/max thermometers and handwritten form records. (Why should I monitor an entire warehouse, if the active ingredient only occupies two square metres of storage space?)
Finally, on the question of whether monitoring, which is fundamentally necessary, may be discontinued at some point when it has been seen for many years that a certain limit value will never be reached. In my opinion, this depends on the distance between the defined storage condition and the maximum temperature reached. So, again, assuming a storage condition of maximum 40°C is defined. If the long-term monitoring shows that the maximum summer temperatures in the warehouse are nowhere above 30°C and never above 30°C, then I see very good chances of justifying on a risk basis that monitoring will no longer be necessary in the future. If, on the other hand, the measured maximum values are 39.7°C, it will hardly be possible - risk analysis or not - to justify this.
Depending on the scenario, it is therefore possible to justify very well on a risk basis whether, and if so to what extent, monitoring is necessary.“
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