[Stability Testing related News – vol.11]

◆  Scientific guideline:Guideline on stability testing for applications for variations to a marketing authorisation, adopted (09-Apr-14 ECA)

This draft guideline is scheduled to go into effect this October. It states how many lot and how many months is needed for stability testing for applications for variations to a marketing authorisation.

Comments were also received for this guidline.

◆ When to use Mean Kinetic Temperature Calculation (MKT)? (07-May-14 ECA)

The British Medicines Authority MHRA is performing GMP and GDP Inspections on a risk based strategy. Based on the experience the MHRA answers frequently asked questions. One very interesting Q&A refers to Mean Kinetic Temperature Calculations (MKT). Mean kinetic temperature is a simplified way of expressing the overall effect of temperature fluctuations during storage or transit of perishable goods. The MKT is widely used in the pharmaceutical industry. According to Pharmacopeia definition the MKT “is defined as the single calculated temperature at which the total amount of degradation over a particular period is equal to the sum of the individual degradations that would occur at various temperatures.”

According to MHRA: “Mean Kinetic Temperature (MKT) should not be used to compensate for poor temperature control of storage (or transportation) facilities. It may be applied in situations where control is good but where occasional excursions may be encountered. (J. Taylor. ‘Recommendations on the Control and Monitoring of Storage and Transportation Temperatures of Medicinal Products’ The Pharmaceutical Journal (vol 267) July 2001).

It is not possible to obtain a meaningful MKT value from daily readings of simple max / min thermometers as temperature fluctuation is not a linear function. It is noted that some data loggers and building management systems are capable of recording multiple temperature readings over a time period and some offer the function of calculating the MKT over a given time period.

Temperature deviations usually fall into one of two categories: A ‘spike’ deviation where local conditions vary in such a way as the temperature suddenly deviates from and quickly recovers to within the required range and a ‘plateau’ deviation where the temperature lays outside of the range for an extended time period prior to eventual recovery. These two deviations can have differing effect of the product.

It is unlikely that the wholesale authorisation holder will have sufficient data in his possession to assess the potential impact on a specific product of these deviations. In the event of a temperature deviation, the wholesale authorisation holder should seek advice from the marketing authorisation holder of the medicinal item in question.

If the wholesale authorisation holder is able to provide the marketing authorisation holder with details of MKT that the product has been subjected to whilst in his care as well as the times and extent of the temperature deviation, this may assist the marketing authorisation holder in formulating his advice to the wholesale authorisation holder.”

◆ Validation – Revision of Annex 15: Industry’s “problems” – Results of an ECA Industry Survey (21-May-14 ECA)

With the publication of a draft on the revision of Annex 15 at the beginning of February 2014 movement was brought into the GMP requirements on validation and qualification – also in Europe. We have known about changes – especially concerning the topic of process validation – by means of the new FDA Process Validation Guidance from the USA since the beginning of 2011. But the changes which might result from revision of Annex 15 should not be underestimated either. The European Compliance Academy (ECA) has carried out a survey to determine how industry assesses these possible changes and the uncertainties that exist concerning the revision draft. 

A total of 116 persons participated in the survey.  Below are some of the questions and feedback.

1. Question 1: “Ongoing validation strategy” which, according to the draft, should be described in the validation master plan. The question was whether more explanation was needed on this term. More than half of those (51.3%) answering this question answered in the affirmative. About 1/3 (34.5%) did not need further explanation. 10 persons answering “yes” substantiated their answer. Some of the responses were: A prepared format including a table of contents; some general conditions on the level of detail expected would be useful; specify minimum requirements; more details; is that revalidation or “traditional” trending? – Where does an annual product quality report end and where does an ongoing validation strategy start? It is not clear as to whether the term relates to a future change control and revalidation strategy or whether it relates in part, or in full, to ongoing process verification. More clarification concerning acceptability is necessary since everybody uses the term of “ongoing validation strategy” in a different way. An extension to verifications is required with the exception of legacy systems. A further comment suggested that Annex 15 should require an SOP for the “ongoing validation strategy”.

2. Question 3: 57.7% of the participants who answered on how the new requirement that Factory and Site Acceptance Tests become a request in how equipment qualification is judged said they would only use it on new complex equipment. 19.7% would use it for all new equipment. 18.3% considered it to be a very good idea and only 4.2% of those participants answering said that the tests were not required.

3.Question 6: Regarding question on how to judge the fact that 3 validation batches are still mentioned, 39.1% answered that more explanation was needed. 30.4% are glad that this is the case. About 14.5% of the persons answering the question stated that they wished one batch were sufficient. The percentage of persons who would prefer that the 3 validation batches were not mentioned any more in order to prevent confusion is about equal (15.9%).

4.Question 10: “Do you appreciate the fact that the “Verification of Transportation” and “Validation of Packaging” chapters are now part of Annex 15?” was answered by 79.9% with “yes” and by 9.2% with “no”. The answer is not clear yet for 13.8%.

5. Question 13: The penultimate question was about the wish for more conformity with FDA Process Validation Guidance. 60.9% answered “yes”, 20.3% answered “no” and for 18.8% it is not clear yet. Some of the comments of the participants answering “yes” were: more details on stages 1, 2 and 3; necessity for a statistical approach – 3 batches are not sufficient; it would be very nice to have one single guideline covering US and EU requirements (or two identical ones). With regard to world-wide distribution, in addition to harmonisation with the FDA, one comment wants harmonisation with KFDA, Japan, Anvisa etc. (to avoid an extra workload on validation activities). The traditional and the hybrid approach should be dropped completely; more clarity with respect to expectations concerning statistics and terminology (stages 1-3) would significantly simplify harmonisation; I would like to see more conformity.

Conclusion

The participants in the survey have a surprisingly positive opinion of the draft of Annex 15. 57.2% of participants considered the document to be very good or good. Another 31.7% said the draft was “satisfactory”. This is somewhat surprising since the desire for more “clarity” and for further explanations/examples was expressed rather often by the participants in the survey. This concerned the following points in particular:

◆ Japan and Korea to join PIC/S (19-May-14 PIC/S)

The PIC/S Committee, meeting in Rome (Italy) on 15-16 May 2014, has invited Japan and Korea to join PIC/S as of 1st July 2014. Japan will become the 45th PIC/S Participating Authority and will be represented by the Pharmaceutical & Food Safety Bureau of the Ministry of Health, Labour & Welfare (MHLW), the Pharmaceutical and Medical Devices Agency (PMDA) and the GMP Inspectorates of Japan’s Prefectures. Korea’s Ministry of Food and Drug Safety (MFDS) will become the 46th PIC/S Participating Authority. Both Japan and Korea applied for PIC/S membership on 9 March 2012 and 10 April 2012, respectively.