Lab Investigations  >  OOS (Out of Specification)

OOS (Out of Specification)

out of specification
out of specification

One of the important aspects of drug and drug product development is providing specifications that must be conformed to for the product to be considered acceptable for its intended use. According to the definition by the International Conference on Harmonization (ICH), specifications refer to “a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described.” This is a critical quality standard where the manufacturers propose and justify the conditions that form the basis for the approval by regulatory authorities.

The specifications are detailed during the product design stage, clearly defining the objectives the product is expected to achieve using specific components, containers, closures, in-process materials, and finished products.

To ensure that the product conforms to the specifications, laboratory testing is mandated by regulatory bodies such as CGMP (§§ 211.160 and 211.165). It ensures that not only does the product perform as required but all components and other aspects mentioned above meet the specifications criterion.

When the results of the laboratory test show the product values to be outside the specifications or acceptance criteria, it is said to be Out-of-Specification or OOS. Further action needs to be taken to prevent its rejection or receiving a warning letter from the FDA based on a root cause analysis.


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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.

Origin of OOS

Statistically speaking, nearly five percent of lots and tests are likely to fall outside the accepted limits, even if the product does not deviate from specifications. Often, manufacturers also apply retesting procedures and averages incorrectly. This could be due to a lack of skills in the application of statistical methods or an attempt to prevent discarding lots for unethical reasons. This results in repeated testing of lots till a sample is shown to be conforming to the specification range. One passing result is considered enough to accept the lot. This approach is called ‘testing into compliance’.

The turning point in the history of Out of Specification (OOS) came in 1993 when Barr Laboratories lost a lawsuit and prompted FDA to interpret the rules differently. FDA had initiated a regulatory lawsuit against the company, asking it to recall millions of its tablets and other drug products for not meeting quality requirements. Called the ‘Barr Decision’, This was a precedent-setting decision, which allowed FDA to recall products that did not meet the quality requirements and did not conform to the FDA Guidance on Investigating OOS Results.

The FDA Guidance tries to address the common misunderstanding of important statistical principles and requires an investigation to be conducted before testing a replicate sample.

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FDA's Latest Guidance for OOS Results

FDA regulation (§ 211.192) requires an investigation to be conducted every time there is an OOS test result. The investigation should aim to identify the root cause of the OOS result, which could be an aberration of the measurement or the manufacturing process. Even in case of a rejected batch due to Out of Specification (OOS) result, it should be investigated to understand if other batches of the same drug product or other products are also similarly affected. Despite a batch being rejected, the investigation is necessary. Further, the investigation, conclusions, and follow-up need to be documented (§ 211.192).

  • For the investigation to be meaningful, it should be:
  • Thorough
  • Timely
  • Unbiased
  • Well-documented
  • Scientifically sound

The investigation is conducted in two parts. The first part is Phase I, when it is determined whether the correct methodology was followed as per STP, calibrated instruments were used, the analysts trained, and so on. If the Out of Specification (OOS) is a result of a laboratory error, the analysis should be repeated as defined in the SOP. This includes–Min NLT 6 replicates by two different analysts, one by the original analyst followed by an experienced analyst.

If the OOS is not because of a Laboratory error, then a full-scale, Phase-II investigation is recommended. In this Phase, all critical aspects of the operations, including manufacturing, packaging, sampling/re-sampling, and so on should also be included in the SOP definitions.

If Phase-I reveals an assignable cause, a repeat analysis as established in the SOP should be conducted. In case of no assignable cause being identified, the QA should recommend further investigation/batch disposition.

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Phase I: Laboratory Investigation to Identify and Assess OOS Test Results

In Phase-I, the accuracy of laboratory data should be assessed before test preparations are discarded. This helps eliminate possible laboratory errors or instrument malfunctions as the cause of OOS. If no meaningful errors are identified in the analytical method used to arrive at the data, a full-scale out-of-spec investigation should be initiated. In the case of contract laboratories, the manufacturing company’s quality control unit (QCU) should be informed of the data, findings, and supporting documentation by the laboratory so that they can then initiate the full-scale OOS investigation.

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Phase II: Full-Scale OOS Investigation

When the initial assessment establishes that laboratory error is not responsible for the Out of Specification (OOS) result and that the test results are accurate, a full-scale, Phase-II OOS investigation should be conducted. The investigation should conform to a predefined procedure and include a review of the production process and/or additional laboratory work. The aim is to determine the root cause of the OOS result and initiate corrective and preventative action (CAPA).

    Some of the steps involved in the investigation include:

  • A review of production and sampling procedures
  • Additional laboratory testing
  • Evaluation of the impact of OOS result(s) on batches that have been distributed already.

How to Handle Out of Specification (OOS) Results?

oos result handling

Once the investigation is complete and the results available, the QCU should evaluate it, determine the quality of the batch, and make a decision about its release using the SOPs as its guideline.

Even if a batch is rejected, further tests should be performed to identify the cause of the failure. This will help take corrective and preventive action to avoid similar OOS results in the future.

Interpretation of the investigation results is a critical aspect of OOS investigation. A batch need with an OOS result need not be rejected outright but needs the findings to be investigated further. The findings of the initial and subsequent investigations should be analyzed and the batch evaluated before deciding on releasing or rejecting the batch (§ 211.165).

Where a cause has been identified and the result invalidated, the quality of the batch should not be assessed based on that result. However, a discrete test result may be invalidated only on observing and documenting a test event that is considered a reasonably sure cause of the OOS result.

Where the cause of the OOS result is identified as a factor that affects the batch quality, the result may be used to evaluate the batch or lot quality. A confirmed OOS result is a clear indication of not meeting the established standards or specifications. This is sufficient ground to reject the batch (§ 211.165(f)).

If the OOS cause is confirmed, the OOS investigation transforms into a batch failure investigation that must encompass other batches or products with possible association with the specific failure (§ 211.192).

If the cause is inconclusive, the QCU might want to release the batch. But this decision should be made only after a thorough investigation proving the OOS result is not a reflection of the quality of the batch. It is better to err on the side of caution.

oos result handling

Drawbacks in Manual Out of Specification Tracing

manual out of specification drawbacks
manual out of specification drawbacks

Traditionally, Out of Specification (OOS) tracing was done using manual procedures. Even in modern times, businesses may continue to use manual processes or use legacy systems for OOS investigations. Considering the number of dependencies associated with OOS testing, this can be quite a challenging task and likely to be fraught with risks of errors and missing out on key indicators.

It also involves much paperwork. When the QA team initiates the investigations, it will have to manually note down the findings. This will be reviewed by the reviewer, who will have to go through all the steps again and recommend the next step, which could be to conduct a fresh investigation into the causes of Out of Specification (OOS).

The reviewer’s findings maybe forwarded to an analyst, who will also receive a sample for further investigation. The steps of testing will have to be repeated and the findings recorded manually. All these leave ample scope to introduce human error and noncompliance.

There have been cases of the production team sending a batch of raw materials or finished goods for production or sale even before the investigation has been completed. This can cause problems during the audit process when all the investigation documents of OOS will be required to be shared with the auditor. It may be deemed noncompliance with FDA regulations.

What is Out of Specification (OOS) Investigation?

A drug or a drug product is part of treatment therapy and aims to alleviate the illness in some form or the other – either as a direct treatment, as a mitigative solution, or for diagnosing the disease. It can be intrusive, inserted in the body, consumed as a drug, etc., or an application or connected to the surface of the body. In all of these situations, it is essential for the product to perform as expected. Any anomaly can cause a life-threatening or injurious repercussion. To mitigate this risk, regulatory bodies introduce checks and balances to enhance the safety of using these products. It has been realized that risk mitigation must begin right from the word go – right from the design stage. Not only the end purpose but also the input materials have an impact on the safety and performance of these products. Therefore, design controls need to be put in place to ensure that the end product is aligned with the vision set forth while designing.

At every stage from design to development and manufacturing, the product needs to be tested for its performance as well as conformance to the specifications established at the beginning. Any variance, referred to as Out-of-Specification, needs to be investigated.

But OOS may be due to lab conditions or a genuine problem. Therefore, it needs to be investigated thoroughly to see whether there is an assignable cause or if it is true. To establish that, manufacturers need to find out whether an entire batch is at variation, only the sample, or whether there is no variation but a faulty test is throwing up a deviation.

Therefore, the first stage of investigation is to eliminate the possibility of a laboratory error. It should be performed before discarding the test samples and reagents to validate the original data.

  • Factors that can cause Out of Specification (OOS) results in a laboratory include:
  • Incorrect handling of the sample
  • Use of wrong reagents
  • Equipment not calibrated
  • Sample not incubated for the correct time and temperature
  • Possible contamination of sample
  • Incorrect reading of the result
  • Not reporting to the correct units of measurement

The solutions and reagents should be retained till a second person has verified all data and that they meet the defined acceptance criteria.

  • Some of the factors to be considered during an Out of Specification (OOS) investigation include
  • Analyzing historical data to capture past trends and errors due to assay, equipment, environment, or analyst.
  • Whether the test methodology is as per the SOP
  • That the test was conducted by a trained analyst
  • Other tests conducted on the same day as the test are reviewed by the same analyst or the same tests being conducted by different analysts.
  • Factoring in any other OOS results obtained on the batch of material being tested
  • Ensuring that the analyst understands the procedure
  • Ensuring the correct samples(s) were tested

If the error is not laboratory-based, then further investigations should be conducted to identify the root cause across all operations. All laboratory investigations must be documented and trends identified and monitored.

  • A typical OOS investigation process covers the following:
  • oos investigation process

  • Definition of the problem or event
  • Examining trends and history
  • Risk assessment to understand the impact of the Out of Specification (OOS) on the final product
  • Prevent a recurrence of the problem
  • Identify the root cause through a thorough analysis
  • Initiate CAPA to take corrective action and prevent future recurrence

Corrective and preventative actions are the consequences of the investigation and describe the actions taken which are designed to lead to an improvement of process and environmental quality.

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Requirements for Out of Specification investigations

The regulatory bodies such as the cGMP and FDA lay down certain requirements that are essential for all drug and device manufacturing companies to comply with. Some of these include:

oos establishing specification

Establishing specifications, standards, sampling plans, test procedures, and other laboratory control mechanisms (§ 211.160).

oos investigation written records

A written record of the investigation should be maintained and must include details about the investigations conducted, the conclusions, and the follow-up action taken. Root cause analysis and CAPA form an essential part of this requirement.

out of specification analysis method

For some analytical methods, system suitability requirements must be met. For instance, chromatographic systems require reference standard solutions to be injected at periodic intervals throughout the chromatographic runs to measure drift, noise, and repeatability. In case the system is not functioning properly as per the reference standard responses, then it is essential to identify the data collected during the suspect time period and not used it in the future. The reason for the malfunction should be determined and corrected, if possible, before taking a decision on whether to use any data before the suspect period.

out of specification for cgmp regulation

According to the CGMP regulations, statistically valid quality control criteria must be determined and include appropriate acceptance and/or rejection levels (§ 211.165(d)).

oos lab invetigation

Investigations to be conducted every time an Out of Specification (OOS) test result is obtained (§ 211.192).

oos instruments

CGMP regulations § 211.160 (b)(4) require the analyst to use only those instruments that meet the established performance specifications and are properly calibrated.

out of specifiaction deviation

Setting a threshold for deviation from acceptance limits among the replicates must also be established. In case of an unexpected variation in replicate determinations, remedial action must be triggered, as required by § 211.160(b)(4).

oos approved drug

For products that are the subject of approved full and abbreviated new drug applications, in case of any failure of a distributed batch to meet any of the specifications established in an application (21 CFR 314.81(b)(1)(ii)), a field alert report (FAR) of information must be submitted within 3 working days.

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I’ve been using ComplianceQuest (CQ) for about 9 months and am extremely pleased with the product, the implementation team and ongoing support. I selected CQ for a number of reasons. Functionality and a simple user interface were key requirements. CQ has all the functionality needed in support of a global QMS. Implementation includes; Document control, change order, personnel training, NC/CAPA, equipment management, supplier management, audit management, and customer complaints all on a single platform. As a small biologics company it was critical to find a single solution to meet our GMP quality system requirements. We wanted a cloud-based system, that would be quick to implement, that could be expanded globally and in other languages, all for a reasonable price. The user interface – it is exactly what I was hoping for. I constantly hear the staff saying, “I love CQ, it’s so straightforward to use”.

The implementation team has met all my expectations. The CQ product ‘out of the box’ meets the majority of my requirements. With some minor configurations we have developed QMS workflows that are highly efficient and robust. A risk-based validation plan also allowed us to move quickly through the foundational functions; Controlled Documents, Change Order, and Personnel. The implementation team offer many industry best practices as solutions to questions and are also highly competent in listening to your requirements and doing whatever is necessary to fulfill them. Customer Support is incredibly timely in their responsiveness; addressing most questions or concerns within 24-48 hours, meanwhile communicating along the way. We are extremely happy with our selection and highly recommend ComplianceQuest.

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How ComplianceQuest is Superlative for OOS Investigation Success?

ComplianceQuest is a cloud-based, end-to-end workflow management solution that integrates quality, safety, clinical trial, product design, and lab investigation solutions on one platform. This helps pharmaceutical and medical device manufacturers improve the quality and safety of their products while enhancing compliance.

The CQ Product Design Management Solution helps companies implement a comprehensive design development process to mitigate product risks by providing complete visibility at every stage of the product lifecycle. The solution provides manufacturers with 100% traceability over design controls, establishing specifications, facilitating review at every stage to capture deviations, and minimizing the risk of Out of Specification (OOS). A unified repository for all design documentation and advanced collaboration tools lets engineering and quality teams to work together and improve conformance and compliance.

The Design Development solution embeds product risk management, essential for OOS investigation, helping identify and document product-related risks and link them to specific parts or requirements. The Design Control solution also features solutions for storing design history files and complete design-related documents that help QA teams to ensure that the project is progressing as expected, and meeting specifications.

CQ’s Lab Investigation solution automates the investigations process, ensuring a systematic, efficient, and comprehensive approach. It facilitates collaboration and guided workflows that empower QC and QA teams to identify the assignable or root cause of every Out of Specification (OOS) test result, and then act on it while staying compliant due to thorough documentation. Laboratory teams can initiate a Phase-II investigation whenever necessary, conduct a full production review, then escalate to a CAPA if needed to ensure high-quality products. Built-in checklists help QA and QC conduct comprehensive investigations consistently and identify the correct assignable or root cause every time.

OOS Lab Investigation features

The pre-built workflows simplify the process for QC and QA teams. It is also possible to create customizable checklists to guide investigators during lab investigations and even production reviews to make sure no step is missed.

Documents and investigation records are easily accessible online, from anywhere, anytime, with sufficient security. Built-in collaboration tools make it easy to communicate and share progress and allow QC and QA analysts and manufacturing investigators to conduct comprehensive full-scale investigations.

By automating the investigation process, the solution also makes Out of Specification (OOS) investigations time and cost-effective. It is aligned with regulatory standards such as GLP, ISO, and FDA, speeding up the investigation process and automating the document management for reporting and compliance purposes.

As not all OOS result requires a full-scale investigation or a Non-Conformance record, lab supervisors and QAs can escalate Phase-I investigations to a full-scale Phase-II investigation based on need and specify whether a production review is required. Indicating if a Field Alert Assessment or Customer Notification is required and directly launching Non-Conformance at the end of an investigation are also possible.

The solution is integrated into the 5 Why Root Cause analysis solution, helping teams collaborate on identifying the true root cause. Once the cause has been identified, CAPA and management review are just a button click away. All the current and historical data are within easy access to help make informed decisions on the correct action to be taken to prevent future recurrences.

Automatic notifications and action requests allow lab supervisors to assign actions to the members of the investigation team and track the progress effortlessly.

The key features of the CQ Lab Investigation Solution include:

  • Phased Investigation

    Lab supervisors and QA can escalate from phase 1 to phase 2 or close the investigation based on findings.

  • Integrated

    Can launch NCs and actions directly from the investigation record and link records together.

  • Automated Alerts and Notifications

    Automatic notifications and action requests to people involved in the investigation.

  • Configurable Queues

    To configure the workflow and approval matrix queue to fit your needs and processes.

  • Formatted Printouts

    With ability to assign parent/child document structure and customize printouts of investigations as needed.

  • Reports and Dashboards

    To generate any report or dashboard they need to keep track of lab investigations and identify trends.

  • Pre-built Checklists

    Preliminary lab investigations and production reviews can be populated with pre-built and customizable checklists to guide the investigation, ensure consistency and thoroughness.

  • Field Alert Assessment

    Will automatically show in the lab investigation if the record of the OOS test result is for stability testing, reminding quality teams to send the alert if needed.

  • Embedded Risk Assessment

    Embedded in-lab investigation so that QAs can determine the risk assessment.

  • Customer Notification

    After a lab investigation (phases 1 and 2), quality teams can indicate if notifying customers is needed.

  • Impacted Material/Batches

    Can be referenced in the lab investigation record.



  • Some of the other features that support the lab investigation system include:
  • Audit management.
  • Change management
  • Management review
  • CAPA
  • Documentation management
  • Training management

Together, they make ComplianceQuest a comprehensive solution to improve design control, reduce deviations, and minimize OOS results. To know more about the CQ Lab Investigation Solution, visit https://www.compliancequest.com/lab-investigations/

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Frequently Asked Questions

  • Out-of-Specification or OOS refers to a product that does not meet the specifications defined for it. This indicates a deviation and could have occurred at any stage of the product lifecycle, needing a thorough investigation. The OOS result could also be a laboratory-based error. This should be eliminated before deciding to reject or retain a batch.

  • While this is an FDA requirement, a deviation can also be a risk for the patients and their handlers. Releasing a product with OOS can cause it to be recalled, which will prove costly for the company, affect brand image, and require going back to the drawing board to manufacture the product.

  • The purpose of the Out of Specification (OOS) investigation is to determine the true cause of the OOS result. This could be due to lab conditions or a genuine problem due to errors in manufacturing or other operations. The cause needs to be investigated to initiate CAPA to prevent future recurrence while taking corrective action for the current error.

  • Pharmaceutical manufacturing companies and contract laboratories are required to perform OOS.

  • The OOS investigation can be out-of-specification when it is thorough, timely, unbiased, scientifically defensible, and well-documented.

  • Before discarding the test solution for the out-of-specification investigation, the accuracy of the laboratory data should be established following an initial assessment. This allows any hypothesis inferring laboratory error or instrument malfunction to be tested with the same solutions.

  • If errors are identified after the initial assessment of the analytical process used to obtain the data, it should be followed by a complete failure investigation.

  • Yes, you must, to ensure that other batches of the same drug product or other products also do not have deviations. Identifying the root cause is also important to prevent its recurrence.

  • After the accuracy of the laboratory’s data has been assessed and established. This will help test the hypothesis regarding a laboratory error or instrument malfunction using the same solutions.

  • If the initial assessment shows the analytical process to be accurate and the problem is not a laboratory error, then a full-scale investigation must be initiated.

  • The analyst is primarily responsible for conducting out-of-specification investigations and ensuring accurate laboratory test results. They should be aware of the potential problems likey to occur when conducting the tests and be alert at the time of testing to identify the problems responsible for the out-of-specification results.

    CGMP 211.160(b)(4) holds the analyst responsible for ensuring that the instruments used for out-of-specifications meet the established specifications. It requires the analyst to use only properly calibrated instruments.

  • If you are facing frequent laboratory errors, you should be concerned. There are four possible reasons for frequent laboratory errors:

    • analysts not being trained adequately

    • equipment being maintained poorly,

    • equipment not being calibrated properly,

    • careless work.

  • The practices used include:

    • Retesting a portion of the original sample,

    • testing a specimen from the collection of a new sample from the batch,

    • resampling test data,

    • using outlier testing.

  • Retest is required when the investigating testing instrument malfunctions or possible integrity problems during sample handling are identified.

  • A supervisor must assess data promptly to determine whether laboratory error is responsible for the results or whether it is a manufacturing process problem. He should be objective and timely during the assessment and not have any preconceived notions about the cause of Out of Specification (OOS) results.

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