[Stability Testing related News – vol.43]

◆ Comprehensive FDA Warning Letter Analysis – Stability Testing on the Rise (14-Aug-19 ECA)

The analysis of the FDA Warning Letters of the last 9 months (October 2018 to June 2019) contains some interesting findings regarding the frequency of certain deficiencies discovered in the inspected API facilities. First of all, it is noticeable that the number of Warning Letters (69) published in the above-mentioned period is already quite high compared to FY 2018 (=fiscal year/October 2017 to September 2018) and will probably exceed the number of Warning Letters published in FY 2018 (89). Surprisingly, the distribution of Warning Letters between pharmaceutical and API production sites differs considerably, as does the distribution of Warning Letters among the countries in which the sites are located.

Stability Testing (21 CFR 211.166) cited in 17 Waterning Letters for FY 2019 (October 2018 to June 2019).

More detailed Analysis can be found in ECA Academy News.

◆ Track & Trace: Still ongoing issues (11-Sep-19 ECA)

For roughly half a year now, manufacturers have only been allowed to enter medical products (which are subject to verification) into the market if they bear the new safety features; this includes the 2D code. So far, however, this has hardly worked out anywhere: many issues arose, the project has not been properly adapted EU-wide and discontentment is spreading amongst pharmacists.

Ongoing issues

• In Germany, where everything had been tested extensively beforehand, there are issues concerning the accessibility of the database. There are frequent error messages, and as of right now, the original purpose of protecting the supply chain from falsifications cannot be fulfilled. In case of a temporary failure in the system at the time of administration, pharmacists are instructed to dispense a medical product and perform the verification and decommissioning manually as soon as the error has been eliminated (to that end, the serial number and product code must be noted down, or the 2D code must be photographed). This, however, proved to be anything but practical.
• In France, pharmacies have only just been connected to the system.
• It may occur that a scanner cannot read a 2D code even though it works smoothly when scanning other medicinal products. Despite apparently correctly printed, the 2D code is not or not fully legible.
• There were cases where the information from the conventional bar code and the 2D code did not match (e.g. regarding the package content). This may lead to recalls on wholesale level.
• The system appears to be overstrained with large data sets when uploading large data volumes into the database (e.g. when uploading large batch-sizes of a serialised drug).

Conclusion: right now, these issues and deviations are “accepted”, i.a. because there is a need of these medicinal products. However, the pharmacist’s daily routine is made considerably more difficult since error messages necessitate time-consuming communication (i.a. with SecurPharm and the drug manufacturers) and documentation, amongst other things.

◆ New Ph. Eur. chapter on statistical process control (SPC) planned (18-Sep-19 EMA)

Process controls have become customary in pharmaceutical processes. The aim is to monitor a process and improve it if possible. With changes to the FDA’s Process Validation Guideline and Annex 15 of the EU GMP Guidelines, this process monitoring has also gained more regulatory importance as a part of the product validation lifecycle (Ongoing/Continued Process Verification). Statistical process control (SPC) is viewed as one option to implement Ongoing/Continued Process Verification. PharmEuropa, the publication medium of the European Directorate for the Quality of Medicines and Healthcare (EDQM), has now published a new draft chapter (5.28) about SPC for the European Pharmacopoeia.

New draft chapter 5.28 of the European Pharmacopoeia
This chapter particularly covers multivariate statistical process control (MSPC). To start with, however, the “classic” univariate SPC is being explained. In univariate SPC, a single parameter is being monitored with a control chart. The article describes how this control card is to be set up. The advantage of this kind of control cards is the relatively simple mathematics behind them.

Multivariate Statistical Process Control (MSPC)
In contrast, multivariate statistical process control can be used to monitor several, even correlating, parameters. This enables its use in the application of process analytical technologies (PAT), continuous manufacturing (CM) or real time release testing (RTRT). In principle, various univariate SPC control cards could also be used for different parameters; however, those parameters should not be correlating. If they do, an MSPC would be the better choice. The development, application and theoretical background of MSPC are outlined in the draft chapter. However, the mathematics behind MSPC is much more complicated than that behind univariate SPC.

Comments on the draft chapter are to be submitted by the end of September.