Handling of OOS Results in Europe

 

FDA’s Guidance on Out-of-Specification Results has been seen as the state of the art regarding the handling of OOS results. In the meantime, Europe – through the British MHRA and the German ZLG – has also developed requirements on that topic. Read more here about the most important regulations of the respective guidance documents.

 

GMP News: Handling of OOS Results in Europe

http://www.gmp-compliance.org/enews_4461_Handling-of-OOS-Results-in-Europe_8360,8430,Z-QCM_n.html

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 Mémoire (Zentralstelle der Länder für 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 Mémoire 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 Mémoire 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 Mémoire on the monitoring of manufacturers of medicinal products.

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Author: DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......http://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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