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Out of Specification

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1 Purpose and scope

This SOP describes a consistent and controlled procedure for investigating sample test results
which are Out of Specification (OOS), including documentation of the event, communication
with the client, and oversight of the initial investigation at external test houses.

This SOP applies to investigation of OOS results for all GMP testing.
This SOP applies to products tested against an approved specification, including Raw Material
and Release testing.
Where analysis is sub contracted, the quality agreement will specify the requirements for an
acceptable OOS procedure.

1.1 Limitations
This procedure does not apply to excursions identified during environmental monitoring or in-
process testing.

2 Definitions
OOS Out of Specification

3 Responsibilities
3.1 Operator generating/observing the OOS.

3.1.1 Responsible for reporting the OOS.

3.2 Caseworker (assigned by QM)

3.2.1 Responsible for investigating and handling OOS according to SOP.

3.3 Quality Manager

3.3.1 Oversight of Phase I Investigations and Phase II Production Investigations conducted at

external test houses/Company, to ensure that adequate detail is included and coordination of
appropriate investigation personnel and strategies.

3.3.2 Coordination with external test houses and Production of any retesting and/or
resampling.

3.3.3 Construction of any retesting or investigative testing protocols and coordination of

client approval prior to implementation.

3.4 Qualified Person

3.4.1 QP shall be involved in the OOS investigation for all GMP activities.

3.4.2 Fully consider all of the information prior to making decisions to the final disposition of
the batch. Releasing a batch where OOS results have been invalidated should come only after a
full investigation has shown that the OOS result does not reflect the quality of the batch.
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3.5 Production Manager

3.5.1 Participation in the Phase II Production Investigation, including review of sampling

information, equipment, batch records and other variables which may contribute to an out of
specification result.

3.6 Project Management

3.6.1 Communication with the customer on the out of specification investigation, including
outcome of root cause investigation and re-testing strategy.

4 Safety
NA

5 Equipment
NA

6 Reagents
NA

7 Calibration
NA

8 Sample preparation
NA
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9 Procedure

Notification of an OOS
from Test House/Diatec
Compa
ny
Result Invalid.
Test House /Diatec
Compa Lab error identified Retest performed OOS
performsny and new results Closed
Phase I Investigation reported.
No lab error identified

Phase II Investigation
initiated at Diatec
Compa
ny

Hypothesis testing.
Malfunction Root cause not Retesting according to
Investigation identified retest protocol.
Clinet Notification

Root cause identified

Retest according to
Sampling or other non- Yes
protocol and report all
process related error?
results.

No

Determine Batch
Disposition

Quality Review of
Investigation and
identification of
corrective action

Report Result and Close

OOS

Figure 1: Process Flow

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9.1 Procedural definitions and responsibilities

9.1.1 An Out of Specification (OOS) is a test result that does not comply with the
predetermined acceptance criteria which have been established in official compendia and/or by
company documentation (i.e. Raw Material Specification or Release testing, etc).

9.1.2 There are two phases of investigation that may be performed when an Out of
Specification result is obtained.

9.2 Phase I Laboratory Investigation

9.2.1 This is an investigation performed to determine whether there has been an error at the
laboratory during performance of the assay which has caused the OOS result.
Testing has been performed ether at Company or at external test house (for sub-contracted QC
testing). Phase I Laboratory Investigation must be overseen by Company Quality.

9.2.2 Phase I Investigations should be restricted to a review of data, equipment and analysis
only. There should be no re-measurement, or re-analysis performed.

9.2.3 The laboratory investigation should consider, but not be limited to, the following
factors:
 The correct methodology was used
 Calculations were performed correctly
 Correct samples were tested
 Sample integrity was maintained
 All equipment used in testing was within calibration date
 Appropriate standards were used
 System suitability conditions were met before and during analysis
 Correct and clean containers/materials was used
 Media and reagents used were prepared correctly
 The correct specification was applied
 The analyst was trained on the method
 Raw data does not contain any anomalies, i.e. suspect peaks
 Consideration of any other factors that could have influenced the result

9.2.4 If the Phase I Investigation is able to attribute the result to laboratory or equipment
error, then the result is invalid. Quality must ensure that the original result is not reported, and
the assay re-performed appropriately.

9.2.5 If the Phase I Investigation is not able to identify a laboratory error, the result is valid,
and the Out of Specification Investigation must proceed to a Phase II Production Investigation.

9.3 Phase II Production Investigation

9.3.1 This is an investigation conducted at Company, with input from the test house (if
applicable), raw material suppliers, and other contributors as applicable, to determine whether
there was a possible production root cause to the result obtained.
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9.3.2 On completion of this investigation, if a root cause can clearly be attributed to sampling
errors, the assay may be retested, according to a retesting protocol approved by Company
Quality and Customer.
 The retesting protocol should include details of the samples to be retested, how many
times, and who will perform the assay.
 The retesting protocol must clearly define the Pass/Fail criteria, along with clearly defined
responsibilities for the investigation.
 The retesting protocol is written by Quality and must be approved by the Customer prior to
implementation.
 Once the retesting protocol has been executed, all results, together with the initial OOS
result must be reported.

9.3.3 If the Production Investigation is able to determine a root cause which involves how the
batch was manufactured, the result is valid, and the OOS result must be reported.

9.3.4 If required during the Production Investigation, hypothesis testing, re-analysis and re-
sampling may be performed to help elucidate a root cause. This investigative testing must be
performed according to a protocol approved by Company Quality and Customer. Investigative
testing protocol should include details of the samples to be tested, how many times, and who
will perform the testing.

9.4 In case of an Out of Specification incident

9.4.1 When an Out of Specification result is obtained at an external subcontractor, they will
notify Quality, according to timelines and communication pathways defined in the Technical
Agreement/Quality Agreement.

9.4.2 If an Out of Specification result is obtained by Company, Production Manager, Quality

Manager and Qualified Person must be alerted immediately.

9.4.3 The data must be checked for errors by an independent operator.

9.4.4 A note should be added in the raw data recordings to detail that an OOS has occurred.
All relevant solutions, material or original containers from which reagents or samples taken
must be retained under suitable conditions. If errors are evident, the operator should
document the circumstances without delay. An operator should not continue with a test for
which an OOS seems likely.

9.4.5 An Out of Specification Investigation must be raised by the operator generating /

observing the OOS.
Use “Out of Specification Report”.
Fill inn required information:
 Reported by
 Date Occurred
 Customer
 Project no
 Batch no
 Product no/name
 Assay
 Sample ID (original QC sample of final product, re-sampled, reference sample etc)
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 Description – Provide as much information as possible on the specifics of the OOS Result,
including lot numbers, sample identification numbers, assay details, timelines, document
references, etc. The description should be brief, yet clear enough to be understood by any
member of staff.
 Specification not achieved.

Hand the OOS Report to Quality, who will assign a OOS Report no and a caseworker. (OOSXXX,
Where: OOS = Out of Specification and XXX = the next sequential number)

9.4.6 Quality will maintain a level of oversight of the initial Phase I Investigation performed at
the laboratory, ensuring that all factors listed in Phase 1 laboratory Investigation are
investigated appropriately and that the investigation proceeds in a timely manner.

For external testing: At this stage, all documentation generated should be according to the
procedure for Investigation of Out of Specification Results at the external Test house, and be
the responsibility of the test house.

If a laboratory error is identified, the external test house/Company will proceed with closing the
OOS investigation and re-testing/re-calculating the data, ensuring that the OOS result is
invalidated and not reported.

9.4.7 If the Phase I Investigation is not able to attribute a root cause, the investigation must
proceed to a Phase II Investigation.

9.4.8 Ownership of the OOS Investigation will remain with Quality throughout the lifecycle of
the investigation and reporting. However Project Management must be notified immediately
upon notification of a valid OOS result from the external Test house.

9.4.9 Project Management is responsible for communicating the OOS event to the customer
and ensuring that any investigations follow up corrective actions, retest strategies and/or batch
disposition is appropriately communicated to the customer in a timely manner.

9.4.10 Phase I investigation performed at external Test house will be summarised. Any relevant
documentation such as investigation reports, test result sheets, equipment data print outs, etc.
should be attached to the OOS Record and referred to in this section.

9.4.11 The Phase II Investigation stage should detail all investigations performed.
 Hypothesis Testing: Should not include another preparation from original sample. Must be
approved by Quality prior to initiating. Result may not be used to replace an OOS result,
only used to confirm or reject a probable cause.
 Retesting: Performed on original sample.
 Averaging: Averaging of the results of the original test and retesting/resampling must not
be done. This hides variability among the individual results.
 Resampling: If insufficient quantity of original sample remains, suspecting not truly
representative sample or documented error in preparation, discuss with Quality and
Production Manager for resampling.
 Outlier test: An outlier may result from a deviation from prescribed test methods, or it may
be the result of variability in the sample. It should never be assumed that the reason for an
outlier is error in the testing procedure, rather than inherent variability in the sample being
tested.
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9.4.12 When a root cause is identified, a clear, concise root cause statement is detailed in the
Root Cause Stage of the OOS Report.

9.4.13 The Batch Disposition Stage is completed by Quality, and should clearly detail the
disposition of the affected batch dependent upon the root cause and/or validity of the OOS
Result obtained. The Batch Disposition statement should also consider the disposition of any
other batches that may be impacted by the root cause identified. If no laboratory or calculation
errors are identified in Phase I or II Investigation, there is no scientific basis for invalidating
original OOS result in favor of passing retest results. All results must be reported and should be
considered in batch release decisions. The decision to reject cannot be reversed as a result of
further testing.

9.4.14 Any corrective actions are listed and the numbers clearly referenced.

9.4.15 Details of Customer Notification is recorded in the Client Notification Stage.

This is completed by Project Management and should include references to dates, methods of
communication, response and any other information to provide a timeline of events, and to
provide assurance that affected customers are aware of all aspects of an OOS Investigation and
its outcomes.

9.4.16 When all previous stages are complete, Quality will review the OOS Report and added
documentation and detail the approval in the Approval Stage of the OOS Report.

9.4.17 Once all stages are complete, the OOS Record may be closed by Quality Manager.

9.4.18 Quality will maintain a list of all Out of Specification Investigations, including date raised,
date closed and outcome.

10 Quality Control
NA

11 References
Out of Specification Report
Guidance for Industry - Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical
Production. (October 2006)
U.S. Department of Health and Human Services.
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)