How to identify Out-of-Trend Results in Stability Studies?

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How to identify Out-of-Trend Results in Stability Studies?,8348,8430,Z-QCM_n.html

An article in PharmTech from June 2013 (by Trajkovic-Jolevska et. al) deals with the methods to identify Out-of-Trend (OOT) results in ongoing stability studies.

With regard to stability studies, it is important to make the difference between Out-of-Specification (OOS) and Out-of-Trend (OOT). Both the pharmaceutical industry and authorities often misuse these two terms.

The article defines OOT results as those results which don’t follow the expected trend, either in comparison with other stability batches or compared to previous results collected during a stability study. OOT results aren’t necessarily OOS, but they don’t look like a typical data point.
Although OOT results are a serious problem, neither the scientific literature nor regulatory guidelines fully address them.

The aim of the study described in this Pharmtech article by Trajkovic-Jolevska et. al was to perform a statistical evaluation of the statistical methods used in the identification of OOS results.

The authors of this article present 4 statistical methods for the identification of OOT results:
•The regression control-chart-method
•The by-time-point method
•The slope-control-chart method
•The z-score method

The conclusion of this article is the statement that there is a tremendous need for a regulatory Guideline on OOT results in stability studies. This is exactly the next objective of ECA’s QC working group: an SOP on the handling of OOT results. On 22-23 October 2014, the OOT Forum in Prague will present the Draft of ECA’s SOP on OOT results.

The complete article can be found with the title “Methods for Identifying Out-of-Trend Results in Ongoing Stability Data”.


Different Storage Conditions and Stability Characteristics for Generics and Innovator Product: Is that allowed?

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Different Storage Conditions and Stability Characteristics for Generics and Innovator Product: Is that allowed?

It may happen – in the development of generic medicinal products – that the in-use stability properties or the storage conditions deviate from those of the innovator product. The question whether this is basically allowed or only allowed with restrictions in the context of the application for authorisation of a generic product has been answered by the EMA and put on its updated Q&As webpage. The answer to the following two questions was published as supplement to the Q&As:

  • “Is it allowed that the in-use stability of one product deviates from other authorised products (e.g. regarding storage time, storage conditions)?
  • Is it allowed that the storage condition of one product deviates from other authorised products (e.g. storage in refrigerator versus storage at temperatures not exceeding 25°C)?”

The EMA clearly states in the answer to both questions “each product will be assessed on its own merits”. At the same time, the EMA takes into consideration whether differences in in-use stability and/or storage conditions potentially could lead to detrimental medication errors (wrong dosing). In such a case, the EMA cannot accept the differences and will delay the treatment of the application until the problem has been solved. In its answer, the EMA refers to a position paper of the CHMP which discusses medication errors caused by differences between generics and innovator products. This position paper is dated 30 May 2013 and its title is “Position paper on potential medication errors in the context of benefit-risk balance and risk minimisation measures“. The different in-use stability and storage conditions aren’t explicitly addressed in the document. That’s the reason why the EMA felt compelled to clarify those questions in the Q&As.

Authorisation of Generic Drugs in the USA: Requirements on APIs Stability Data for US Drug Master Files

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Authorisation of Generic Drugs in the USA: Requirements on APIs Stability Data for US Drug Master Files
According to the new Generic Drug User Fee Act (GDUFA) for the marketing authorisation of generic drugs in the USA, the Drug Master File (Type II) for APIs must undergo a completeness assessment (see our GMP News from 11 October 2012). The approach is described in the Draft Guidance for Industry entitled “Initial Completeness Assessment for Type II API DMFs under GDUFA” from October 2012.

Which information about the stability of the API contained in a generic drug is required in a Drug Master File submitted for a marketing authorisation application? The answers to this question can be found in a Q&A document published by the FDA on 26 August 2013 entitled “Guidance for Industry; ANDAs: Stability Testing of Drug Substances and Products; Questions and Answers“. This Q&A document refers to the “Guidance for Industry; ANDAs: Stability Testing of Drug Substances and Products” which was released 2 months before and tackles a range of outstanding issues with regard to stability data of APIs and finished products for the marketing authorisation application of generic products.

The statements laid down in the Q&A document regarding the stability data of the API required in a DMF are explicit: in addition to the stability protocol and commitments, data demonstrating the beginning of stability studies have to be provided. The initial and one additional time point for the accelerated studies and long-term studies are sufficient. Yet, the DMF holder should provide amending data to keep the DMF as up-to-date as possible. This is the only way to ensure the successful completeness assessment by the reviewer in the Office of Generic Drugs (OGD) of the FDA. Furthermore, stability data from production scale batches are also accepted. Three production batches are necessary. The data must come from 6 months of accelerated data and long-term data covering the proposed retest period.

The Q&A document contains a range of other interesting clarifications like for example a concrete explanation of the term “small scale” with regard to the various dosage forms.