What is OOS (Out of Specification)?

During the course of a drug or drug product’s development and as the product is nearing
completion, it needs to be tested to ensure that it performs as expected, within the specified limits
as mentioned in the compendia, drug master file, or drug application. When it does not and falls
outside the specified limits, it is said to be OOS or out of specification. If this happens often, it is
an indication of the manufacturing and analytical procedures not being in control. It can lead to
frequent customer complaints and the rejection of commercial batches. As a result, the
pharmaceutical business will face a heavy inventory loss. It may also compromise the safety of
patients and their handlers. Therefore, any incident of OOS result occurrence must be
investigated and the root cause addressed.

Typically, the specified limits are detailed in documents such as the compendia, drug master file,
or drug application. This happens right at the product design stage after the product has been
conceptualized and the details of the nature of the product, its goals, and the raw materials to be
used are specified. The testing criteria are also laid down at this stage, explaining how the
product should be tested and who will be testing it.
 From the time of design to the time of manufacturing, the design undergoes several
changes. Due to these changes or due to process errors, deviations may be introduced at
the time of manufacturing too, this can cause Out of Specification. Some of the common
factors of Out of Specification (OOS) include:
 Deviations during the product manufacturing process
 Errors during testing due to incorrect procedure
 Errors caused by malfunctioning analytical equipment
 Therefore, to understand whether the error is due to the product not conforming to the
specifications or other factors, a root cause analysis must be performed to identify the
true cause. The OOS causes can be classified as
 Assignable: When the error is identified.
 Non-assignable: When the error is not identified.

On observing an OOS result, a laboratory preliminary investigation (Phase-I) is recommended to

identify the assignable cause. Based on the findings, further investigations will be conducted. If
no error was found, then too, the batch may need a QA to be performed.
These decisions are communicated by the QC team to the designated personnel on OOS being
reported, who will be responsible for classifying the OOS as the assignable or non-assignable
cause.
Out-of-Specification (OOS)
Glossary

Out-of-Specification (OOS) is a critical term frequently used in the field of life sciences, particularly in
pharmaceutical, biotechnology, and other regulated industries. This glossary provides an in-depth
understanding of OOS, its significance, causes, investigation processes, and regulatory implications
within the context of life sciences.

Definition and Significance of Out-of-Specification (OOS)

Out-of-Specification (OOS) refers to a result or observation that falls outside the predetermined
acceptance criteria or specifications established for a particular process, product, or material in the life
sciences industry. These acceptance criteria are defined quality standards used to ensure the safety,
efficacy, and reliability of pharmaceuticals, biologics, medical devices, and other life science products.

The significance of OOS findings lies in their potential impact on patient safety, product quality, and
regulatory compliance. Identifying and appropriately addressing OOS results are crucial steps in
maintaining the integrity of products, ensuring patient well-being, and complying with stringent
regulatory requirements.

Causes of Out-of-Specification (OOS)

1. Analytical Errors
OOS results can arise due to analytical errors associated with the methods, instruments, or techniques
used during testing. Issues such as inadequate method validation, instrument malfunctions, improper
sample preparation, or human errors can introduce variability and inaccuracies, leading to OOS findings.

2. Sampling Errors
Errors related to sampling, such as improper sample collection, handling, or preparation, can contribute to
OOS situations. Inadequate sampling techniques, insufficient sample quantities, contamination during
sampling, or improper sample storage conditions can all impact the reliability and accuracy of test results.

3. Environmental Factors
Variations in environmental conditions, such as temperature, humidity, or light exposure, can affect the
stability and integrity of life science products. These factors may lead to degradation, alteration, or loss of
potency, resulting in OOS results.

4. Manufacturing Process Deviations

Deviations or inadequacies in the manufacturing process can give rise to OOS findings. Factors such as
equipment malfunctions, operator errors, deviations from standard operating procedures, or inadequate
process controls can all contribute to products falling outside the specified criteria.

5. Raw Material Issues

Poor quality or variations in the raw materials used during the manufacturing of life science products can
cause OOS situations. Contaminated or substandard raw materials can introduce impurities, alter product
attributes, or compromise the final product's quality, leading to non-compliance with specifications.
Investigation Processes for Out-of-Specification (OOS) Results
1. Documentation and Data Collection
When an OOS result is identified, a thorough investigation begins by documenting all relevant details,
including sample information, test procedures, environmental conditions, and any other factors that may
have influenced the result. Comprehensive data collection is crucial for subsequent analysis and
investigation.

2. Root Cause Analysis

Root cause analysis is conducted to identify the underlying reason(s) for the OOS result. It involves a
systematic examination of all possible factors, including analytical methods, instruments, samples,
manufacturing processes, and raw materials, to determine the primary cause(s) contributing to the OOS
situation.

3. Repeat Testing and Retesting

To validate the OOS result and rule out potential errors, repeat testing or retesting of the sample is often
performed. This ensures the accuracy and reliability of the initial result and helps identify potential issues
that may have occurred during the initial testing process.

4. Out-of-Trend (OOT) Analysis

In cases where the OOS result cannot be explained or attributed to a specific cause, an Out-of-Trend
(OOT) analysis is conducted. This involves reviewing historical data, trends, and patterns associated with
similar products or processes to identify any underlying issues that may have contributed to the OOS
finding.

5. Corrective and Preventive Actions (CAPA)

Once the root cause of the OOS result is determined, appropriate corrective and preventive actions are
implemented. These actions may include process improvements, equipment calibration, staff training,
adjustments to manufacturing procedures, or modifications to raw material sourcing to mitigate the risk of
future OOS situations.

Regulatory Implications of Out-of-Specification (OOS) Findings

In the life sciences industry, OOS findings have significant regulatory implications. Regulatory
authorities, such as the Food and Drug Administration (FDA) in the United States or the European
Medicines Agency (EMA) in Europe, require timely reporting and appropriate handling of OOS results.
Non-compliance with regulatory requirements related to OOS situations can result in regulatory actions,
product recalls, fines, or legal consequences for the responsible entities.

To ensure compliance, companies in the life sciences industry are required to establish robust quality
management systems, including thorough documentation, data integrity measures, proper investigation
processes, and adherence to Good Manufacturing Practices (GMP) and other regulatory guidelines.

Summary
Out-of-Specification (OOS) findings in the life sciences industry signify results falling outside the defined
acceptance criteria or specifications. Recognizing and appropriately addressing OOS results are crucial to
maintain the quality and safety of life science products and comply with stringent regulatory
requirements. Thorough investigation processes, including root cause analysis, repeat testing, and OOT
analysis, facilitate the identification of underlying causes and the implementation of corrective and
preventive actions. Compliance with regulatory reporting and handling procedures is essential to ensure
regulatory compliance and maintain the trust and safety of patients and consumers.
Handling Out of Specification (OOS) and Out of Trend (OOT) is of utmost importance to Pharma sector.
Pharma companies should be aware of these two terms exhaustively. They need to perform stability tests
at regular intervals to find the status of the samples of raw materials, in-process materials, bulk products,
and finished products.

Definition of OOS and OOT

Out of specification (OOS) is defined as a result that falls outside the predetermined specifications or
established acceptance criteria set by the manufacturer and/or the laboratory. In simple terms, the result of
a stability test conducted by a Quality Analyst (QA) should always adhere to the previously established
specifications or criteria. The Quality Control (QC) declares the result as OOS if it doesn’t comply or
agree with the given test result criteria. Similarly, out of trend (OOT) is defined as a result that falls
outside the trend. QC compares the result of the current test with a set of previous results to check with
the on-going trend.

Finding OOS and OOT

The pharma company’s standard operating procedures (SOPs) will layout steps for carrying out
investigation in case an OOT or OOS is traced. In the case of OOS, the Quality Control (QC) personnel
will directly report for any of the sample test results going out of the predetermined specifications.
However, there are three methods to find OOT. The QC can find if the sample’s test result has gone Out
Of Trend (OOT) by
1. a) finding the average of previous readings,
2. b) 3 sigma approach, and
3. c) checking the high and low range of the previous results.

Issues with Manual Process Followed for Tracing OOS and OOT
The process of finding Out of Specification (OOS) and Out of Trend (OOT) through manual procedures
is quite a herculean task. It involves a lot of paperwork. The test will be first conducted by a QA and
manually noted down. Then, the reviewer receives the test result and goes through all the steps again to
suggest the next step. He may raise investigation to find the reason for OOS or OOT. Another analyst
may finally receive the sample for investigation purposes. This analyst also must repeat all the steps of
testing and note down everything manually. Thus, leaving a lot of scope for transcriptional errors and
compliance issues.
Further, in some companies, the production team may send a batch of raw materials or finished goods for
production or sale even before completing the investigation for an OOS or OOT. This can lead to serious
problems when an auditor requests for all the investigation documents of OOS or OOT. The auditor can
question the reason for taking the next step without stringently complying with the FDA regulations.

CaliberLIMS for Effortless Tracing of OOS and OOT

Laboratory Information Management System (LIMS) is a software that helps in overcoming all these
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Therefore, he can avoid the tedious manual result recording process. LIMS also makes it easy for the
reviewer to go through the pre-validated testing processes and suggest for investigation in case of OOS or
OOT. Sometimes, the analyst also gets direct intimation about OOS or OOT. Thus, helping the analyst to
take the necessary steps without wasting time and effort.
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