POINT OF VIEW: CHANGES IN THE CHAPTER ON TESTING NON-STERILE DOSAGE FORMS
Supplement 6.71 to the European Pharmacopoeia (EP) was published on 1 October 2009 and implemented as of 1 April 2010. This version of the EP contains the first revision of the chapters on the testing of non-sterile dosage forms and the acceptance criteria proposed for them (testing: chapters 2.6.12., 2.6.13., 2.6.31. and acceptance criteria: chapters 5.1.4., 5.1.8.). Hence these new requirements are binding for us. In this report I would like to provide an overview and make some comments on the most important changes to the respective chapters from my point of view. A summary of these revisions can be found in the following table.
The most important change concerns the removal of the old test methods and acceptance criteria in each of the three chapters. The chapters on the test of non-sterile dosage forms have been harmonised among the three most important pharmacopoeias (European, EP; American USP, Japanese, JP). As a result, both methods - the former and the harmonised one - were valid for the time being on the date of implementation on 1 January 2009. After the first revision only the harmonised methods are officially valid. What exactly does this mean for our laboratories? Since April 2010 we are supposed to test all of our nonsterile dosage forms using harmonised methods. If these are not implemented yet there has to be a validation demonstrating the equivalence of both methods. In the last years, we have repeatedly discussed various possibilities for such validation. Nevertheless, most colleagues have implemented the harmonised methods in their laboratories.
Only a few have considered keeping the old methods and developing a general validation between the old and the harmonised method instead. Personally, I do not consider this to be the ideal method (or at most a possible interim solution) since the harmonised methods have the great advantage of being valid for all large product markets world-wide. For this reason, there should be considerably fewer discussions during inspections or audits since the same methods and levels are now valid for all countries. Only 18 months have passed since the first official publication of the harmonised methods and implementation thereof or implementation of the first revision. This is a relatively short period for carrying out a suitability test with the harmonised method for all dosage forms. Certainly, the harmonised methods were known of earlier. Therefore, we had some more time at our disposal. Normally, this should have enabled us to carry out the work in due time.
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The first revision of the two chapters on test methods (2.6.12. and 2.6.13.) brought along another change: the explicit mention of a negative control during routine testing. Generally, I consider these negative controls to be very useful. They can be of great value during an OOS/OOE investigation. For example, if there is a contamination of the buffer and the testing of the sample shows growth. In such a case, the negative control can be used to demonstrate that the buffer was the cause for microbial growth. Hence, it is in the interest of the manufacturer to also carry out negative controls. However, I do not think that it is necessary to list them in a pharmacopoeia.
Some small and partly insignificant changes have been carried out in chapter 2.6.13. (see table). But elimination of the test of the indicative growth properties of Xylose, Lysine, Desoxycholate agar (XLD) for Escherichia coli is very useful, since they could not be shown at all when the test was carried out correctly. If an inoculum of <100 CFU E. coli was put on a plate, it was possible to find a few colony forming units (CFU) only in some rare cases. It has long been known that XLD shows the indicative properties only at a very high E. coli load. All established instruction manuals of the known medium producers state that at least 105 E. coli have to be inoculated to show the indicative properties of XLD.
The text on the test for Clostridium was rephrased for better comprehensibility. A small - but not totally unimportant - change is the longer incubation time for the tests selective step from the initial 48 hours to 48-72 hours. Even if it is often asserted that these flexible hours should simplify work in the laboratories, it must now be decided whether the suitability test has to be controlled again.
The formulations of the culture media in chapter 2.6.13. did not change. It would certainly have been inconvenient if they had been adapted. In general, the formulations of the culture media show good microbial growth. Nevertheless, my experience with the actual EP composition of the EEB Enterobacteriaceae Enrichment Broth (EEB or Broth Mossel) is unsatisfactory. It could be demonstrated that using this EEB results in worse growth of Escherichia coli than using other EEB products. Another point of great importance is the swift cooling down of the EEB after heating (as described in the EP). In my opinion, there are nevertheless better formulations than the actual ones in the EP.
The old acceptance criteria have been removed from chapter 5.1.4. Consequently the harmonised ones are valid, which I appreciate principally. The dosage form is defined in a much clearer way, therefore a product can be placed more easily in one of the groups listed. Surely, the greatest challenge of this chapter is the interpretation of objectionable germs. Chapter 5.1.4. states explicitly that we can not concentrate only on the micro-organisms listed in chapter 2.6.13. but that we also have to consider other - potentially objectionable micro-organisms. This topic has bothered us a lot during the last few years, especially when we talked to our American colleagues. There the pharmaceutical industry is obliged by law2 to keep products free from objectionable germs. In my opinion, this topic will accompany us throughout the next few years. What or rather who are the objectionable germs? In which product is one germ objectionable and the other not? Who is the group of patients and how is it defined? According to chapter 5.1.4. EP we should have an idea of the micro-organisms found by means of a risk-based assessment. Does this mean in practice that we need such an assessment on each germ found in the product? This would be a great challenge!
Finally the acceptance criteria for herbal drugs were removed from chapter 5.1.4. and a new chapter 5.1.8. was drawn up, which describes these products in a much more clear and detailed way. This is also valid for the test methods for which the new chapter 2.6.31. has been published in Supplement 6.8 of the EP. This is a useful addition to the two chapters 2.6.12. and 2.6.13. on herbal drugs.
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7/8 May 2024
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In summary, it can be stated that the first revision of the chapters on the testing of non-sterile dosage forms does not provide any major surprises. This revision was planned primarily to remove the old methods from the text. Luckily, it has taken advantage of the possibility to make small corrections which simplify work in the laboratories. From my point of view, the greatest challenges are the definitions and the assessment of objectionable micro-organisms within the scope of non-sterile products. Let's wait and see what we hear and read about this topic in the near future.
Author:
Dr Marcel Goverde
... took a doctoral degree in biology at the University of Basle. Over seven years, he headed four release and development laboratories in a pharmaceutical company in Basle. Mr Goverde is currently a freelancer and working as a consultant and training representative.
Source:
1 Chapter 2.6.12.has been published again in Supplement 6.8 of the EP. In this version Aspergillus niger was substituted by Aspergillus brasiliensis.
2 21 CFR Ch. I, § 211.113 Control of microbiological contamination and § 211.165 Testing and release for distribution.
