1. OBJECTIVE This SOP defines procedures to be followed when an Out of Specification (OOS) result is detected on any analytical laboratory test performed on samples of raw materials, in-process materials, bulk products and finished products. It describes responsibilities of laboratory personnel, the laboratory phases of the inesti!ation (Initial "aboratory #eiew, #eiew, $ull "aboratory Inesti!ation) includin! additional testin!%e&periments that may be needed, when to e&pand the inesti!ation outside the laboratory, retestin! re'uirements if the inesti!ation is inconclusie and the final ealuation of all test results by . These procedures may also be used for out-of-trend inesti!ations *inimally, for raw materials OOS results, the laboratory inesti!ation aspects of this SOP will be followed. $urther inesti!ation may be performed at the supplier. $or OOS inesti!ations of process water produced by in-plant water systems, the laboratory inesti!ation aspects of this SOP will be followed. $or packa!in! components testin!, the principles of this SOP can be used as appropriate in the inesti!ation. 2. SCOPE This procedure applies to all analytical testin! on samples of raw materials, in-process materials, bulk products and finished products, includin! the followin! #elease testin! of raw materials, in-process materials, bulk products and finished products. Testin! of product from preiously released%distributed product lots. +onfirmatory, on-!oin! and accelerated stability testin! to support market launch. o Testin! associated with consumer complaints. o Testin! performed as part of process deiation inesti!ation s. Process alidation testin!. nalytical testin! on clinical %consumer trial materials intended for human%animal use. nalytical testin! for physical attributes such as iscosity, particle sie and specific !raity, althou !h certain steps in the inesti!ational aspects of the procedure may not be applicable in eery case, depe depend ndin! in! on the the type type of test test,, samp sample le prep prepar arat atio ion, n, etc. etc. $or $or e&am e&l ple, e, ther there e ma may y be no intermediate standard%sample preparations to ealuate as part of the inesti!ation. It does not apply to *aterials used in or manufactured solely for laboratory ealuation (e.!., ealuations for #/ purposes on materials not used for human%animal e&posure). "aboratory testin! performed by human ealuation (e.!., color, shape, form). 0hile a laboratory-related inesti!ation is not re'uired (i.e., limited to documentin! the OOS in the system), a manufacturin! inesti!ation will be initiated and documented. In-line or on-line analytical testin! that is used in con1unction with process controls to proide continuous data for release purposes. OOS microbiolo!ical results. This is coered by a separate SOP. #/ testin! where specification limits hae not been established, althou!h the principles of this SOP can be used, as appropriate, to ealuate for possible analytical or manufacturin! issues when data is considered aberrant%une&pected. In the case of a known stability OOS trend in #/, and the studies are continued to collect additional data for modelin!.
3. GLOSSARY Signature
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Aty#i%a& $r Out $' Tren" (OOT) $r Aty#i%a& Re*u&t*+ result, which is within specification, but different from those usually obtained i.e., does not fit the normal distribution of results. In case where in-house + limits are more strin!ent then those mentioned in #e!istration /ossier, a result out side the in-house limits but within the re!istered limit would be considered as typical #esult. Such results re'uire some ealuation as to their si!nificance. Out $' S#e%i'i%ati$n (OOS) Re*u&t*+ #esults that fall outside the established specifications or acceptance criteria. n OOS result must be thorou!hly inesti!ated in an attempt to determine an assi!nable cause. Reana&y*i*+ - nalysis of retained sample preparations - #epeatin! some part of testin! e.!. - #e-measurement, - #e-in1ection - #e-dilution of sample and standard preparations - $urther e&traction. Rete*t+ - 3ew preparation analysis of a portion of ori!inal sample - Part of full scale OOS inesti!ation Re*a,#&e+ +ollectin! and testin! a new sample of the same lot of material or product, proided ori!inal sample is found to be non-representatie%contaminated or confirmation of batch failure La-$rat$ry err$r+ nalytical or laboratory error can be instrument, enironment or operator related e.!., in1ection % instrument failure % mistake in followin! the method of analysis, wron! sample preparation, wron! reference standard used, transcription or calculation mistake etc. . RESPO/SIBILITIES 4.5 *ana!er uality 6nsurin! that there are specific site procedures and systems to comply with this SOP #eiew of report and final decision as to the disposition and use of the result. 6nsurin! that all releant persons in + hae appropriate trainin!. #esponsible for batch related decisions when an OOS or OOT result has not been inalidated throu!h laboratory inesti!ation. 4.7 -
*ana!er uality +ontrol +onduct an ob1ectie and timely inesti!ation once an OOS result has been identified /ecide on the inesti!ation that must be performed in the laboratory where OOT results are identified, /etermine the e&tent and depth of any OOS and OOT inesti!ation. 6nsure that all OOS OOT are reported, documented and inesti!ated as per laid down procedures. 6nsure that +P recommended are implemented. Signature
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*aintain records of OOS%OOT. Trainin! of nalysts.
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ssistant *ana!er + Timely assessment of OOS results and immediate initiation of inesti!ation. Prompt reiew of data to ascertain if the results may be attributed to laboratory error, or whether the results could indicate problems in manufacturin! process. There should be no preconceied assumptions as to the cause of the OOS results. llocate a uni'ue number to the OOS report as OOS%9999%se'uence number.
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+ nalyst rchiin! accurate laboratory testin! results Should be aware of potential problems that could occur durin! the testin! process and should watch for problems that could create OOS results. Immediate reportin! to respectie ssistant *ana!er of an OOS % OOT result. Preseration of sample, solutions, standards and !lassware for reanalysis, if re'uired.
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*ana!er uality ssurance #eiew of SOP Trendin! of OOS OOT durin! nnual Product #eiew.
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GE/ERAL I/VESTIGATIO/AL PRI/CIPLES ll OOS or OOT results must be thorou!hly inesti!ated and documented to determine an assi!nable root cause accordin! to established laboratory procedures, which must comply with the re'uirements of the releant !roup 'uality standard.
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+onfirmed OOS results must tri!!er a cross-functional failure inesti!ation.
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+orrectie and preentie actions (+P) must be taken to preent reoccurrence of OOS or OOT test results.
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ll OOS results, both alid and inalid must be tracked and trended.
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ll analysts must be trained on the handlin! of OOS and OOT results process prior to commencin! their 1ob.
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#esults are allowed to be inalidated only if a laboratory or samplin! error can be assi!ned. Inalidated results must not be used to determine the final reportable result for the test.
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n inesti!ation must be initiated no later than 7 business days after the OOS or OOT occurs. It must be completed within =< business days, or a written rationale must be proided.
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Preious occurrences of the problem (historical data) and other batches or products possibly affected must be taken into consideration. ppropriate +P must be defined as part of the inesti!ation?s conclusion and implemented.
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lert limits are important criteria that need to be established for specific analytical Signature
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methods for assessin! trends. :.5=
0hen compendial tests are performed which describe calculation, interpretation and handlin! of test results, that compendial procedure must be followed.
. .1 ;.5.5
PROCEDRE Re#$rting OOSOOT te*t re*u&t* The analyst when come across with an OOS%OOT result will immediately inform + 6&ecutie or ssistant *ana!er + or *ana!er + and presere the sample and standard preparations. The analyst will report this eent by fillin! Out of Specification%Out of Trend #eport $orm (nne&ure A 5, P#T - ).
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.2 Ine*tigati$n Inesti!ation will be carried out in two phases ;.7.5 Initial "aboratory Inesti!ation ;.7.7 $ull Scale OOS Inesti!ation .2.1 Initia& La-$rat$ry Ine*tigati$n ;.7.5.5 The first step of inesti!ation will be Initial "aboratory Inesti!ation. Once an OOS or OOT result has been identified, the data must be initially assessed by the 'uality control mana!er or desi!nate, prior to initiatin! full scale laboratory inesti!ation, takin! into consideration the followin! aspects in detail nalyst?s e&perience Samplin! method stora!e of sample Testin! *ethod followed #eference Standards used 6'uipment used condition #ea!ents used and alidity 6nironmental conditions "ast batches run on same set of e'uipment Browth Promotion Test results 3e!atie controls results +alculations accuracy Transcription accuracy #eanalysis results, if aailable ;.7.5.7 Initial assessment on OOS results related to printed te&t % color % font style sie % packa!in! % labelin! will be limited to sample stora!e and specification % standards used. In case no error is detected, the report will be submitted to *ana!er + who may allow for re-samplin! testin! and will take final decision based on the results so obtained.
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;.7.5.8 Initial assessment on OOS results related to appearance of material, packa!in! labelin! of containers would be limited to sample stora!e and specification used. In case no error is detected, the report will be submitted to *ana!er + who may allow for re-samplin! testin! and will take final decision based on the results so obtained keepin! in iew the criticality and e&tent of non-compliance and its probable impact on product processin! % 'uality of end product. ;.7.5.4 In case, OOS results obtained related to physical appearance of the semi % finished batch, the ssistant *ana!er + prior to initiatin! initial assessment will stop further processin! and put the batch on 2O"/, inform *ana!er + for the final decision. ;.7.5.: /urin! initial assessment, if a clear error is found with the calculations or transcription and after correction results found within the specification limits, no further inesti!ation or assessment will be re'uired. ssistant *ana!er +, in this case will inalidate the OOS results and submit the report to *ana!er +. ;.7.5.; /urin! initial assessment, if any other laboratory error is identified, *+%+6 will /ocument this error on the OOS%OOT $orm, Inalidate the ori!inal OOS result rran!e fresh analysis of that control test /eelop +P and document on OOS%OOT $orm #e-ealuate the results, and Submit the report to *ana!er +. The repeated test data and results will be attached with the OOS%OOT form. ;.7.5.< If no laboratory error is identified durin! initial assessment ssistant *ana!er + will immediately initiate $ull-Scale OOS Inesti!ation in order to find out the possible cause, within =7 business days from the reportin! date of OOS%OOT results .2.2
4u&&5S%a&e OOS Ine*tigati$n The full scales OOS inesti!ation will inole in parallel both ;.7.7.5 #eiew of production, in case a locally manufactured product is inoled ;.7.7.7 dditional laboratory testin!. The data%results will be documented on OOS%OOT $orm
.2.2.1Reie! $' #r$"u%ti$n The inesti!ation will inole all other departments that could be implicated (e.!. manufacturin!, SSB, maintenance and en!ineerin!). The reiew of production must consist of timely, thorou!h, and well documented inesti!ation includin!, for e&le C*aster *anufacturin! /ocument (**/) ealuation C 6'uipment (Dalidation, ualification, +alibration) C Personnel trainin! ealuation C #isk mana!ement ealuation C /eiations complaints systems If this part of the OOS inesti!ation confirms the OOS result and is successful in identifyin! its root cause, the OOS inesti!ation may be terminated and the inesti!ation report written. If no deiation is identified, possible causes of laboratory errors will be inesti!ated in detail by means of consistency with results of other analyses, retests, and if re'uired and 1ustified, resamplin!. Signature
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.2.2.2A""iti$na& La-$rat$ry Te*ting Rete*ting Two different analysts will carryout retestin!, amon! these one will be the ori!inal analyst who reported OOS while other will be assi!ned by ssistant *ana!er +. The dates of analysis may or may not be same. Re5Sa,#&ing 6 Te*ting *ana!er + will allow re-samplin! only if a. Ori!inal sample is not sufficient to perform the tar!et test (retest). b. Samplin! error is detected durin! initial assessment c. Ori!inal sample found%suspected contaminated d. #etest results are to be re-confirmed, if found within limits. #e-samplin! will be carried out by one analyst as per normal samplin! plan or as approed by *ana!er + and recorded in the respectie lo!book The additional laboratory testin! can lead to 8 outcomes o laboratory error is clearly identified the error is documented, the result inalidated and the retest result will replace the ori!inal test resultE o The retest result confirms the OOS or OOT the ori!inal test result is reported as such and the retest results will be documented and filedE o The retest result does not confirm the OOS or OOT but no laboratory or samplin! error is identified all test results, both passin! and suspect, will be reported in the inesti!ation report #eport on $ull OOS Inesti!ation will be completed and submitted within 7= business days from the date of initiation. ny e&ception will be notified, 1ustified and authoried by *ana!er uality. .2.3
Re#$rting an" Ea&uating Te*ting Re*u&t* The analytical data reportin! and ealuation will be done usin! aera!in! or outlier tests dependent of the sample and its purpose. 2oweer, all inesti!ation results will be taken into consideration for ealuation and the final disposition decision.
;.7.8.5 In the case of microbiolo!ical tests, aera!in! is a practice dependent of the application, but where used it will be documented in the analytical procedure and 1ustified. ;.7.8.7 In the case of physical and chemical tests, aera!in! is more limited o
0here aera!in! of separate test results is appropriately specified by the test method, an aera!ed result will be reported as the final test result (reportable result). It will be documented in the analytical procedure.
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era!in! is not permitted in the followin! situations when analysin! different portions from a lot (separate samples) intended to determine ariability within a lot (e.!. blend uniformity, content uniformity)E or if the inesti!ation indicates sample non-homo!eneity, Signature
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for results obtained from multiple full analysis of the same homo!eneous sample,
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when one or more of the results are OOS and others are within specifications, een if the difference between those results is within the defined specification of a distribution ran!e. between the initial OOS result and results obtained from retest or re-samplin!.
$or biolo!ical assays with hi!h ariability, an outlier test may be an appropriate tool to identify e&treme results. $or chemical assays, such tests may be used in an au&iliary fashion to ealuate the si!nificance, but should not be used to inalidate suspect results.
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CO/CLDI/G T7E I/VESTIGATIO/ To conclude the inesti!ation, the results will be ealuated, the batch 'uality will be determined, and release decision will be made by the uality *ana!er. In case of confirmed OOS for a product already on the market or for a risk that could affect other batches or products already on the market, a 'uality alert, describin! the issue will be sent to the re!ion
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I/VESTIGATIO/ REPORT +ompleted OOS%OOT form and results of the inesti!ation, as well as conclusion, will be documented and approed by uality *ana!er, and be considered durin! the batch release process.
7.
TRAINING Training on this SOP will be provided to all concerned as mentioned in the Annexure – 2 and as illustrated in training material TM-QA-!"
8.
DISTRIBUTION Total number o# copies to be prepared $ % &ecipient's Title
&ecipient s (ame
)op*+
Manager Qualit* )ontrol Assistant Manager Q) Q) xecutive
, 2 % Signature
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9.
ANNEXURE .ollowing Annexure are attached with this SOP Annexure – , OOS!OOT &eport .orm
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HISTORY
Version No. .irst /ssue Second /ssue
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Effeci!e D"e
Re"son for Re!ision
#$"n%e #onro& No.
NEXT REVIE' STATUS 0to be #illed when &eview 1ate is due
&eview 1ate 1ue
&eviewed b* MQA 0)hec3list &e# 4 date
SOP complies with the latest 5QS 4 &egulator* &e6uirements 07es!(o
(ew 8alidit* 1ate
Approved b* Manager Qualit*
2!9!2,:
Review Date = Valid up to that date
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