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 investigation (Initial Laboratory Review, Full Laboratory Investigation) including
additional testing/experiments that may be needed, when to expand the investigation outside the
laboratory, retesting requirements if the investigation is inconclusive and the final evaluation of all
test results by QA.
These procedures may also be used for out-of-trend investigations
Minimally, for raw materials OOS results, the laboratory investigation aspects of this SOP will be
followed. Further investigation may be performed at the supplier.
For OOS investigations of process water produced by in-plant water systems, the laboratory
investigation aspects of this SOP will be followed.

For packaging components testing, the principles of this SOP can be used as appropriate in the
investigation.

2. SCOPE
This procedure applies to all analytical testing on samples of raw materials, in-process materials, bulk
products and finished products, including the following
 Release testing of raw materials, in-process materials, bulk products and finished products.
 Testing of product from previously released/distributed product lots.
o Confirmatory, on-going and accelerated stability testing to support market launch.
o Testing associated with consumer complaints.
 Testing performed as part of process deviation investigations.
 Process validation testing.
 Analytical testing on clinical /consumer trial materials intended for human/animal use.
Analytical testing for physical attributes such as viscosity, particle size and specific gravity, although
certain steps in the investigational aspects of the procedure may not be applicable in every case,
depending on the type of test, sample preparation, etc. For example, there may be no
intermediate standard/sample preparations to evaluate as part of the investigation.
It does not apply to:
 Materials used in or manufactured solely for laboratory evaluation (e.g., evaluations for R&D
purposes on materials not used for human/animal exposure).
 Laboratory testing performed by human evaluation (e.g., color, shape, form). While a
laboratory-related investigation is not required (i.e., limited to documenting the OOS in the
system), a manufacturing investigation will be initiated and documented.
 In-line or on-line analytical testing that is used in conjunction with process controls to provide
continuous data for release purposes.
 OOS microbiological results. This is covered by a separate SOP.
 R&D testing where specification limits have not been established, although the principles of
this SOP can be used, as appropriate, to evaluate for possible analytical or manufacturing
issues when data is considered aberrant/unexpected.
In the case of a known stability OOS trend in R&D, and the studies are continued to collect
additional data for modeling.

3. GLOSSARY
Signature Date

Written By Quality Assurance Manager (HC)

Reviewed By Quality Control Manager

Reviewed By Quality Assurance Manager (HH)

Approved By Quality Manager

 Atypical or Out of Trend (OOT) or Atypical Results:
A 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 QC limits are more stringent then those
mentioned in Registration Dossier, a result out side the in-house limits but within the registered
limit would be considered as Atypical Result. Such results require some evaluation as to their
significance.

Out of Specification (OOS) Results:

Results that fall outside the established specifications or acceptance criteria. An OOS result
must be thoroughly investigated in an attempt to determine an assignable cause.

Reanalysis:
- Analysis of retained sample preparations
- Repeating some part of testing e.g.
- Re-measurement,
- Re-injection
- Re-dilution of sample and standard preparations
- Further extraction.

Retest:
- New preparation & analysis of a portion of original sample
- Part of full scale OOS investigation

Resample:
Collecting and testing a new sample of the same lot of material or product, provided original sample
is found to be non-representative/contaminated or confirmation of batch failure

Laboratory error:
Analytical or laboratory error can be instrument, environment or operator related e.g., injection /
instrument failure / mistake in following the method of analysis, wrong sample preparation, wrong
reference standard used, transcription or calculation mistake etc.

4. RESPONSIBILITIES
4.1 Manager Quality
- Ensuring that there are specific site procedures and systems to comply with this SOP
- Review of report and final decision as to the disposition and use of the result.
- Ensuring that all relevant persons in QC have appropriate training.
- Responsible for batch related decisions when an OOS or OOT result has not been invalidated
through laboratory investigation.

4.2 Manager Quality Control

- Conduct an objective and timely investigation once an OOS result has been
identified
- Decide on the investigation that must be performed in the laboratory where OOT results are
identified,
- Determine the extent and depth of any OOS and OOT investigation.
- Ensure that all OOS & OOT are reported, documented and investigated as per
laid down procedures.
- Ensure that CAPA recommended are implemented.
Signature Date

Written By Quality Assurance Manager (HC)

Reviewed By Quality Control Manager

Reviewed By Quality Assurance Manager (HH)

Approved By Quality Manager

- Maintain records of OOS/OOT.
- Training of Analysts.

4.3 Assistant Manager QC

- Timely assessment of OOS results and immediate initiation of investigation.
- Prompt review of data to ascertain if the results may be attributed to laboratory error, or
whether the results could indicate problems in manufacturing process. There should be no
preconceived assumptions as to the cause of the OOS results.
- Allocate a unique number to the OOS report as OOS/YYYY/sequence number.

4.4 QC Analyst
- Archiving accurate laboratory testing results
- Should be aware of potential problems that could occur during the testing process
and should watch for problems that could create OOS results.
- Immediate reporting to respective Assistant Manager of an OOS / OOT result.
- Preservation of sample, solutions, standards and glassware for reanalysis, if required.

4.5 Manager Quality Assurance

- Review of SOP
- Trending of OOS & OOT during Annual Product Review.

5. GENERAL INVESTIGATIONAL PRINCIPLES

5.1 All OOS or OOT results must be thoroughly investigated and documented to determine an
assignable root cause according to established laboratory procedures, which must comply
with the requirements of the relevant group quality standard.

5.2 Confirmed OOS results must trigger a cross-functional failure investigation.

5.3 Corrective and preventive actions (CAPA) must be taken to prevent reoccurrence of
OOS or OOT test results.

5.4 All OOS results, both valid and invalid must be tracked and trended.

5.5 All analysts must be trained on the handling of OOS and OOT results process prior
to commencing their job.

5.6 Results are allowed to be invalidated only if a laboratory or sampling error can be
assigned. Invalidated results must not be used to determine the final reportable
result for the test.

5.7 An investigation must be initiated no later than 2 business days after the OOS or
OOT occurs. It must be completed within 07 business days, or a written rationale
must be provided.

5.8 Previous occurrences of the problem (historical data) and other batches or products
possibly affected must be taken into consideration. Appropriate CAPA must be
defined as part of the investigation’s conclusion and implemented.

5.9 Alert limits are important criteria that need to be established for specific analytical
Signature Date

Written By Quality Assurance Manager (HC)

Reviewed By Quality Control Manager

Reviewed By Quality Assurance Manager (HH)

Approved By Quality Manager

 methods for assessing trends.

5.10 When compendial tests are performed which describe calculation, interpretation and
handling of test results, that compendial procedure must be followed.

6. PROCEDURE
6.1 Reporting OOS/OOT test results
6.1.1 The analyst when come across with an OOS/OOT result will immediately inform QC Executive
or Assistant Manager QC or Manager QC and preserve the sample and standard preparations.
6.1.2 The analyst will report this event by filling Out of Specification/Out of Trend Report Form
(Annexure – 1, PART - A).

6.2 Investigation
Investigation will be carried out in two phases:
6.2.1 Initial Laboratory Investigation
6.2.2 Full Scale OOS Investigation

6.2.1 Initial Laboratory Investigation

6.2.1.1 The first step of investigation will be Initial Laboratory Investigation.
Once an OOS or OOT result has been identified, the data must be initially assessed
by the quality control manager or designate, prior to initiating full scale laboratory
investigation, taking into consideration the following aspects in detail:
- Analyst’s experience
- Sampling method & storage of sample
- Testing Method followed
- Reference Standards used
- Equipment used & condition
- Reagents used and validity
- Environmental conditions
- Last batches run on same set of equipment
- Growth Promotion Test results
- Negative controls results
- Calculations accuracy
- Transcription accuracy
- Reanalysis results, if available

6.2.1.2 Initial assessment on OOS results related to printed text / color / font style & size / packaging
/ labeling will be limited to sample storage and specification / standards used. In case no
error is detected, the report will be submitted to Manager QC who may allow for re-sampling
& testing and will take final decision based on the results so obtained.

Signature Date

Written By Quality Assurance Manager (HC)

Reviewed By Quality Control Manager

Reviewed By Quality Assurance Manager (HH)

Approved By Quality Manager

6.2.1.3 Initial assessment on OOS results related to appearance of material, packaging & labeling of
containers would be limited to sample storage and specification used. In case no error is
detected, the report will be submitted to Manager QC who may allow for re-sampling &
testing and will take final decision based on the results so obtained keeping in view the
criticality and extent of non-compliance and its probable impact on product processing /
quality of end product.
6.2.1.4 In case, OOS results obtained related to physical appearance of the semi / finished batch, the
Assistant Manager QC prior to initiating initial assessment will stop further processing and put
the batch on HOLD, inform Manager QC for the final decision.
6.2.1.5 During initial assessment, if a clear error is found with the calculations or transcription and
after correction results found within the specification limits, no further investigation or
assessment will be required. Assistant Manager QC, in this case will invalidate the OOS results
and submit the report to Manager QC.
6.2.1.6 During initial assessment, if any other laboratory error is identified, AMQC/QCE will:
- Document this error on the OOS/OOT Form,
- Invalidate the original OOS result
- Arrange fresh analysis of that control test
- Develop CAPA and document on OOS/OOT Form
- Re-evaluate the results, and
- Submit the report to Manager QC. The repeated test data and results will be attached
with the OOS/OOT form.
6.2.1.7 If no laboratory error is identified during initial assessment Assistant Manager QC will
immediately initiate Full-Scale OOS Investigation in order to find out the possible cause,
within 02 business days from the reporting date of OOS/OOT results

6.2.2 Full-Scale OOS Investigation

The full scales OOS investigation will involve in parallel both:
6.2.2.1 Review of production, in case a locally manufactured product is involved
6.2.2.2 Additional laboratory testing.
The data/results will be documented on OOS/OOT Form

6.2.2.1 Review of production

The investigation will involve all other departments that could be implicated (e.g.
manufacturing, SSG, maintenance and engineering).

The review of production must consist of timely, thorough, and well documented
investigation including, for example:
•Master Manufacturing Document (MMD) evaluation
• Equipment (Validation, Qualification, Calibration)
• Personnel training evaluation
• Risk management evaluation
• Deviations & complaints systems

If this part of the OOS investigation confirms the OOS result and is successful in identifying its root
cause, the OOS investigation may be terminated and the investigation report written.

If no deviation is identified, possible causes of laboratory errors will be investigated in detail by

means of consistency with results of other analyses, retests, and if required and justified, re-
sampling.
Signature Date

Written By Quality Assurance Manager (HC)

Reviewed By Quality Control Manager

Reviewed By Quality Assurance Manager (HH)

Approved By Quality Manager

6.2.2.2 Additional Laboratory Testing
Retesting
Two different analysts will carryout retesting, among these one will be the original analyst
who reported OOS while other will be assigned by Assistant Manager QC. The dates of
analysis may or may not be same.

Re-Sampling & Testing

Manager QC will allow re-sampling only if:
a. Original sample is not sufficient to perform the target test (retest).
b. Sampling error is detected during initial assessment
c. Original sample found/suspected contaminated
d. Retest results are to be re-confirmed, if found within limits.

Re-sampling will be carried out by one analyst as per normal sampling plan or as approved by
Manager QC and recorded in the respective logbook

The additional laboratory testing can lead to 3 outcomes:

o A laboratory error is clearly identified: the error is documented, the result invalidated
and the retest result will replace the original test result;

o The retest result confirms the OOS or OOT: the original test result is reported as such
and the retest results will be documented and filed;

o The retest result does not confirm the OOS or OOT but no laboratory or sampling error
is identified: all test results, both passing and suspect, will be reported in the
investigation report

Report on Full OOS Investigation will be completed and submitted within 20 business days
from the date of initiation. Any exception will be notified, justified and authorized by
Manager Quality.

6.2.3 Reporting and Evaluating Testing Results

The analytical data reporting and evaluation will be done using averaging or outlier
tests dependent of the sample and its purpose. However, all investigation results
will be taken into consideration for evaluation and the final disposition decision.

6.2.3.1 In the case of microbiological tests, averaging is a practice dependent of the application, but
where used it will be documented in the analytical procedure and justified.

6.2.3.2 In the case of physical and chemical tests, averaging is more limited:

o Where averaging of separate test results is appropriately specified by the

test method, an averaged result will be reported as the final test result
(reportable result). It will be documented in the analytical procedure.

o Averaging is not permitted in the following situations:

when analysing different portions from a lot (separate samples) intended to
determine variability within a lot (e.g. blend uniformity, content uniformity); or
if the investigation indicates sample non-homogeneity,
Signature Date

Written By Quality Assurance Manager (HC)

Reviewed By Quality Control Manager

Reviewed By Quality Assurance Manager (HH)

Approved By Quality Manager

 for results obtained from multiple full analysis of the same homogeneous
sample,

- when one or more of the results are OOS and others are within specifications,
even if the difference between those results is within the defined specification of
a distribution range.

- between the initial OOS result and results obtained from retest or re-sampling.

For biological assays with high variability, an outlier test may be an appropriate tool
to identify extreme results. For chemical assays, such tests may be used in an
auxiliary fashion to evaluate the significance, but should not be used to invalidate
suspect results.

6.3 CONCLUDING THE INVESTIGATION

To conclude the investigation, the results will be evaluated, the batch quality will
be determined, and release decision will be made by the Quality Manager.

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 quality alert, describing the issue
will be sent to the region

6.4 INVESTIGATION REPORT

Completed OOS/OOT form and results of the investigation, as well as conclusion, will be
documented and approved by Quality Manager, and be considered during 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-000/0.

8. DISTRIBUTION
Total number of copies to be prepared = 03

Recipient’s Title Recipient s Name Copy#

Manager Quality Control 01

Assistant Manager QC 02
QC Executive 03

Signature Date

Written By Quality Assurance Manager (HC)

Reviewed By Quality Control Manager

Reviewed By Quality Assurance Manager (HH)

Approved By Quality Manager

9. ANNEXURE
Following Annexure are attached with this SOP
Annexure – 1 OOS/OOT Report Form

10 HISTORY

Version No. Effective Date Reason for Revision Change Control No.
First Issue
Second Issue

11 NEXT REVIEW STATUS (to be filled when Review Date is due)

Review Reviewed by SOP complies with the New Validity Approved by

Date Due MQA latest GQS & Regulatory Date Manager Quality
(Checklist Ref & Requirements
date) (Yes/No)
02/04/2015

Review Date = Valid up to that date

Signature Date

Written By Quality Assurance Manager (HC)

Reviewed By Quality Control Manager

Reviewed By Quality Assurance Manager (HH)

Approved By Quality Manager