[Stability Testing related News – vol.13]

◆  Handling of OOS Results in Europe (27-Aug-14 ECA)

For some time now, information about the handling of OOS results has been put on the website of the MHRA. There, you can find a Guidance document entitled “Out of Specification Investigations”. This document was updated last year to add microbiological aspects.

It is easier to understand than the FDA Guideline on the same topic. The different Flow Charts are also helpful.

A definition of all terms – both Out-of-Specification (OOS) Results and Out of Trend (OOT) Results – is provided at the beginning as well as atypical / aberrant / anomalous results. A definition of the term “Reportable Result” is also provided as follows: “is the final analytical result. This result is appropriately defined in the written approved test method and derived from one full execution of that method, starting from the original sample.”

Regarding averaging, it is explicitly said that it “must be specified by the test method”. Moreover, the 95% Confidence Limit must be taken into consideration when averaging is used.

Retesting may be performed if no assignable cause can be found to explain a deviating result. Retesting should be performed on the original sample not on a different sample. Regarding the number of retests required, the MHRA refers to other publications suggesting 5, 7 or 9 retests. Retest results shouldn’t be averaged with the original results which triggered the OOS investigation.

Like in the FDA Guidance, an outlier test solely can’t be considered as sufficient to justify the rejection of data.

Also the aspect of OOS and OOT results for stability testing is addressed.

For quite a long time, Germany has been using the ZLG Aide Memoire (Zentralstelle der Lander fur Gesundheitsschutz bei Arzneimitteln und Medizinprodukten) on the monitoring of manufacturers of medicinal products; section 6.8 also addresses the handling of OOS results. With regard to retesting, the Aide Memoire defines that the number of retests should be set in advance in an SOP based on sound scientific judgement and should be statistically valid.

The ZLG Aide Memoire also states that averaging is allowed: the average value must correspond to the specification, but single results must not. However, it is a condition that acceptance criteria should be defined for the variability of the single values and that these provisions are described in an SOP.

You can find more information in the MHRA Guidance Document Out-of-Specification Investigations here as well as in the ZLG Aide Memoire on the monitoring of manufacturers of medicinal products.

◆  What is the difference between OOS / OOE / OOT? (10-Sep-14 ECA)

The terms OOS, OOE and OOT always emerge in connection with the handling of deviating analysis results. But what are their definitions?

For some time, ECA’s Quality Control Working Group has published a SOP on the handling of OOS results and is currently planning the elaboration of a SOP on OOE and OOT. The OOS SOP respectively the draft of the OOT SOP contains the following definitions for the three terms:

Out-of-Specification (OOS) Results
A result that falls outside established acceptance criteria which have been established in official compendia and/or by company documentation.

Out-of-Expectation (OOE) Results
An atypical, aberrant or anomalous result within a series of results obtained over a short period of time is an OOE result. An OOE result is a result that meets specifications, but is outside the expected variability of the analytical procedure.

Out of Trend (OOT) Results
A time dependent result which falls outside a prediction interval or fails a statistical process control criterion.

A trend is a sequence of temporal procedures, e.g. for the manufacture of different batches of a product. There are two types of trends:
In one case, no trend is expected, e.g. in production or when analysing process data where everyone expects that they are under statistical control.

In the other case, a trend is expected. One typical example for that is stability testing where one expects that the content of the API reduces over the storage period, or that the quantity of impurities increases over time.

There is a fundamental difference between these two types of OOT results: indeed, in the second situation the dispersion increases over time.

The new Chapter 5 of the EU GMP Guide – coming into force on 1st October 2014 – requires that in future certain data have to be recorded so that trends can be recognized and assessed.

PS: At the OOT Forum organised by ECA’s QC Working Group from 22 -23 October 2014 in Prague, Czech Republic, ECA’s draft SOP on OOE and OOT results will be presented.

◆  If a Facility stores Medicinal Products for more than 36 Hours GDP will apply (17-Sep-14 ECA)  

Since the EU Good Distribution Practice (GDP) Guide has been revised, a number of questions regarding its interpretation have been raised. One of these questions relates to storage facilities and so called distribution hubs. In the past, many facilities which have been involved in the supply chain were not managed under GDP and didn’t posses a licence for their activities.

The British Medicines Authority MHRA published a press release on 18 August 2014 to explain what they consider to be a facility which must be licensed and which needs to implement the GDP requirements. According to the MHRA: “The GDP Inspectorate is raising awareness of the impact of the new regulations to those parties that are either directly or indirectly affected and any freight consolidator or freight forwarder either in the air, sea or road transport sector that is either holding ambient medicinal products on site for more than 36 hours or has cold room facilities will require a Wholesale Distribution Authorisation WDA(H) in order to comply with the Human Medicines Regulations 2012 [SI 2012/1916] (as amended) and with the Falsified Medicines Directive 2011/62/EU.”