Out of Specification Investigation Reports

OOS Investigation report, Descision tree and Assesment.

OOS report.doc (48.0 KB)

OOS Tree.doc (42.5 KB)

Assesment.doc (38.0 KB)

xcellent post sir…, d link whc u hav suggstd fr industrial hazards r gud., pls suggst any othr links for the same., and also pls suggst me for the analyst validation , statistical process control …

Excellent material. It will be great to add the same for process deviation, validation, maintenance failures.


Dear Mr. Durga Prasad,

Pl. clarify the below queries…

What is the minimum number of replicates required to prove initial result is failure?

Is there any regulatory requirement for minimum number of replicates?

Thanks & Regards,

C. Suresh

Honestly it is a Three replicates that Industry will look if the result is OOS or not.
3 are carried by 3 individuals taking many operator errors into consideration and also 3 is statistically accepted.
I will certainly give more information on this question soon.
I like this question and you have a valid point.
Let me do my home work and come back with a best possible reply.

It should be noted that a test might consist of a specific number of replicates to arrive at a result. For instance, an HPLC assay result may be determined by averaging the peak responses from a number of consecutive, replicate injections from the same preparation (usually 2 or 3). The assay result would be calculated using the peak response average. This determination is considered one test and one result. This is a distinct difference from the analysis of different portions from a lot, intended to determine variability within the lot, and from multiple full analyses of the same homogenous sample. The use of replicates to arrive at a single reportable result, and the specific number of replicates used, should be specified in the written, approved test method. Acceptance limits for variability among the replicates should also be specified in the method. Unexpected variation in replicate determinations should trigger remedial action as required by § 211.160(b)(4). If acceptance limits for replicate variability are not met, the test results should not be used.

[b]From FDA Guidance :

Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production[/b]

A very informative Document but, plz tell me how many companies follow the work & progress of OOS. Or is it just a document to be prepared and kept aside. U see, I work as QA Executive in KALINDI MEDICURE P.LTD. DEHRADUN.For Further discussion

Mail me at agam.prasad@gmail.com

The above attachments are being used in the companies.These are official templates.The best way of understanding is that you should know what is Out Of specification material at your company. Then what the regulatory guidance tells about such OOS materials.You should start acting by implementation of the above documents.
You have a OOS tree. Simply follow that tree.

It s exellent.
Do u have some thing like this about oot?

Thanks a lot.
I’d like to remember your help when making capa doc.

I do not have OOT document.
I shall prepare and certainly upload that very soon.

Dear All,

Please find the FDA, MHRA OOS guideline and the related approaches


FDA OOS_Guide.pdf (98.0 KB)

MHRA_OOS .pdf (190.3 KB)

MHRA OOS_Consideration.pdf (0 Bytes)

These are very good references. Thank you. In relation to the same can you provide any article / referece by regulatory for OOT.

Out of trend range shall be fixed as per 3 sigma methodology. For your reference methodology attached.


Thanks and regards

OOT methodology.doc (91.5 KB)

Excellent information on OOT.
Thanks Jayopravel.

thanxx Alot 4 such informative material …

Thanks very much for this useful template

Very good format .If you don’t mind can you please share and Completed Investigation report

Dear Sir,

I have a question regarding OOS during the repeatable analysis by two different analysts.

  1. Can we set any acceptance criteria like RSD for different type assay limits, Related Substances, residual Solvents, Moisture Content and other tests? Is there any guideline?
    Example: Assay below 80% - RSD - 3%
    Residual Solvents - RSD 15%

  2. Two analysts have been performed the test but 1 result is OOS out of 6 results during the confirmation analysis by two analysts. In this case what we can do?

  3. Can we make the OOS SOP separately for Raw Materials and Finished products? because we don’t want to put our effort more and don’t waste our time. Can we simply reject the material with out any confirmation tests after complete the primary investigation?

  4. We have used Starch material in our production batches due to urgency before complete the microbial tests, then we found that material failed to meet the specification. How we can solve this problem.

  5. I don’t want to do the confirmation tests for questionable results if i not found any assignable cause during the primary investigation. Is it possible to present these documents during the audit?

We are really facing the above said problems during our profession. Because management does not want to invest more money on that way. As a QA fellow i should not accept that but WITH OUT PROFIT NO USE FDA, GMP …etc.

Kindly supply your good feed back to survive a industry these competitive days.

Thanks in advance
Pulla Reddy Karnati.
Executive - QA

A review of the 2011 FDA Warning Letters shows that the incorrect handling of OOS results is still a hot topic in FDA inspections and inspection follow up activities (483s, etc.). In total 10 companies (6 drug product manufacturers and 4 API manufacturers) received a FDA Warning Letter relating to OOS investigations in the calendar year 2011. Here are some examples of these citations:

Failure to investigate and document out-of-specification results obtained for … .
Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed, and you failed to extend the investigation to other batches of the same drug product that may have been associated with the specific failure or discrepancy.

Your firm’s out-of-specification (OOS) investigations did not include analysis of all available data.
Inadequate or lack of an investigation of critical deviations or a failure of a batch to meet its specifications or quality standards.

Your firm has failed to conduct an investigation for numerous OOS results (e.g., for colony forming units, conductivity, assay, etc.). Many of these OOS results were not reported to your client.

Your QCU approved and released a batch of … despite an initial OOS bulk assay result. These results were later confirmed through repeat testing, but further testing of additional samples produced passing results. Your QCU released the batch even though the investigation did not identify a discernable cause.

Your QCU failed to detect multiple discrepancies in sample weights and dilution factors between the analyst’s notebook and the Calculation Sheet. As a result, incorrect data was recorded for multiple products and finished products not meeting specifications were released. Specifically, a lot of … was released and distributed even though it did not meet the established specification of … % label claim. The correct calculation would have reported a … % label claim.

Your QCU did not require a second, independent person to review the raw data, calculations and records before releasing these lots for distribution.

The inspection also found that your analyst did not record these out-of specification results in the OOS logbook as required by your SOP.

Your investigation failed to follow your procedures when your firm … initiated Phase 2 sample testing prior to completing Phase 1 of the investigation, and … only analyzed two samples as opposed to the required three samples

According to these citations, giving adequate attention to out-of-specification (OOS) results in batch release decision remained the dominant theme in 2011 in the FDA Warning Letters

My special thanks goes to Mr.Pradeep Naik who shared all info via mail.