Out of Specification Investigation in Pharmaceuticals | Complete Guide

For the purposes of manufacturing pharmaceuticals and controlling quality of pharmaceutical products, it is imperative that products conform to pre-defined product specifications; as nonconforming product specifications could negatively affect the health and safety of patients as well as create non-compliance from a regulatory perspective. Occasionally, products that were manufactured fail to conform to their respective acceptance criteria. When this occurs, the test results are classified as Out of Specification (OOS) test results.

OOS test results are considered to be significant quality events requiring immediate attention, a thorough investigation and documented resolution. Regulatory bodies such as the US FDA and WHO have specific expectations regarding the manner in which OOS test results are to be addressed using Good Manufacturing Practices.

The purpose of this article is to provide a complete understanding of OOS investigations, e.g., types of investigations, phases of investigations, root cause analysis for investigations and overall best practices for the performance of OOS investigations.

What Does OOS Result Mean?

An OOS Result will occur when a lab testing result does not meet the established criteria for acceptance as established in the according to the following:

• Pharmacopoeial criteria
• Product specifications
• Regulatory papers

Some examples of an OOS Result:

• Test results not in the accepted range of acceptable
• Impurity levels above acceptable specifications
• Inability to meet dissolution criteria

OOS Results will result from the testing of:

• Raw material
• In-process testing
• Finished goods testing
• Stability study

All OOS results must be thoroughly investigated, including investigation on the cause and impact of the OOS Result.

Importance of Performing OOS Investigation

It is very important to handle this type of result because they can:

• Ensure a good product quality for GxP and be safe for consumer
• Identify issues that can occur with manufacturing or laboratory analysis
• Prevent the release of a defective product
• Provide subject matter support for regulatory compliance
• Increase understanding of the process

Not properly investigating an OOS Result can lead to many regulatory actions such as warning letters or product recalls.

Types of OOS Results

There are two types of OOS results:

1. True OOS

True OOS results indicate that the product does not meet specifications. The reason for a true OOS result may be due to one of the following:
- Manufacturing errors
- Degradation of the product
- Incorrect formulation
- Variability in the manufacturing process
True OOS results can typically lead to rejection of the batch or reprocessing it.

2. Invalid OOS

Invalid OOS results are the result of laboratory errors or external factors. An invalid OOS result may be caused by one (or more) of the following:
- Analytical errors
- Malfunctioning instrument
- Contamination of the sample
- Errors in calculation
Once a true OOS result has been identified, the laboratory must perform an extensive investigation to determine if the actual reason for the OOS result is valid.

Phases of OOS Investigation

The investigation of "out of specification" (OOS) results is a structured multi-phase process.

Phase I: Laboratory Investigation

The initial goal of the investigation is to determine whether an OOS result was caused by something that occurred in the laboratory.
Phase One Activities include:

• Reviewing the analytical procedures used
• Verifying the calibration and performance of any instruments used
• Verifying calculations and data entries performed during testing
• Examining the sample preparation steps used in testing
• Interviewing the analyst

Upon completion of Phase One, if an assignable cause is determined (for example: calculation error), the test result may be declared invalidated and re-testing may occur. If no laboratory error is found, the investigation proceeds to Phase Two.

Phase II: Full Scale Investigation

The goal of the full-scale investigation is to identify any potential non-conformances related to the manufacture or process of the product.
The investigation should include the following areas of consideration:

• Batch manufacturing records.
• Process parameters and deviations.
• Quality of raw materials.
• Performance of equipment.
• Environmental conditions.

The goal of the full scale investigation is to determine if the OOS result is an indication of a quality issue with the manufactured product.

Phase III: Additional Testing (if applicable)

Additional testing may be performed in some situations in support of the investigation.
Examples of additional testing may include:

• Re-testing of the original sample.
• Testing of retained samples.
• Stability testing.

All re-testing must be justified scientifically and documented accurately.

Unjustified re-testing for the purpose of generating passing results (the act of "testing into compliance" as it is called) will NOT be tolerated.

Root Cause Analysis in OOS Investigation

The most important step of an OOS investigation is the identification of root cause.
The more common root causes of OOS results can be broken down into:

• Analytical errors
• Equipment failure
• Variation of raw materials
• Deviations from process
• Environmental conditions

Tools used to perform root cause analysis are:

• Fishbone (or Ishikawa) diagram
• 5 Whys technique
• Trend analysis

Performing an adequate root cause analysis will allow for appropriate corrective actions and preventative controls to be implemented.

Regulatory Expectations for OOS Investigation

The FDA has provided regulatory guidelines for how OOS results should be handled during the course of investigation. These guidelines state:

• OOS investigations should be done in a timely and thorough manner.
• Investigations should be supported by scientific rationale.
• Proper records should be maintained.
• Data manipulation will not be tolerated.

Good Manufacturing Practices (GMP) require an investigation of all quality-related issues that arise throughout the manufacturing process.

Typically, inspections will include an OOS investigation, which is used to assess the overall effectiveness of an organization's quality systems.

Common Mistakes in OOS Investigations

OOS results represent data that is not within specification limits (out of specification). Many pharmaceutical organizations experience issues related to OOS results due to issues during the investigation process.

Mistakes that are frequently made that may lead to regulatory observations or loss of credibility include:

• Incorrect root cause analysis
• Too many or unwarranted retests
• Poor documentation
• Delays in the OOS investigation process
• Ignoring OOS result trends

Best Practices for a Successful OOS Investigation

1. Follow a Standard Procedure

The correct procedure for conducting an Out Of Specification (OOS) investigation will have an established SOP to serve as guidance.
The SOP will contain:

• Steps to conduct the OOS investigation
• Roles and responsibilities
• Documentation requirements

2. Act Promptly

OOS investigations should begin immediately when identified.
Delays in the initiation of the OOS investigation may result in:

• Loss of critical data
• Greater potential for product release

3. Maintain Data Integrity

Data must be fully compliant with ALCOA+ principles.
This will ensure that the data is:

• Accurately captured
• Not subject to data manipulation
• Able to provide full traceability

4. Avoid Testing into Compliance

Retesting should only take place if there is adequate scientific justification to conduct the retest. Conducting repeat testing to obtain acceptable values is a significant violation of compliance.

5. Use Scientific Justification

Conclusions drawn in an OOS investigation must be supported by data and scientific reasoning. Assumptions and unsupported conclusions are not acceptable.

6. Implement CAPA

Based on the investigation, the appropriate corrective and preventive actions (CAPA) must be implemented.
Implementation of CAPA will:

• Remove root cause
• Prevent recurrence

7. Personnel Training

Providing appropriate training to analysts and quality staff will provide them an understanding of OOS procedures and regulatory expectations.

Role of Trending in OOS Management

Using trends to analyze OOS data allows companies to identify common themes and areas of possible risk.
Examining OOS trends over time helps a company to:

• Find Trends
• Identify Weaknesses in Processes
• Create Preventive Actions

In addition, trending is an important component of Continuous Improvement.

Documentation Requirements for OOS Investigations

It is essential that all documents associated with any OOS investigation are complete.
They should contain at a minimum:

• Original OOS result
• Details of Investigation
• Root Cause Analysis
• Retesting Data (if applicable)
• Final Conclusion
• Corrective and Preventive Actions

Well written OOS investigation documentation provides evidence of compliance for regulatory audits.

Impact of OOS on Product Quality

OOS results can have serious consequences:
- product Lot Rejection
- Product Lot Recall
- Product Lot Production Delays
- Product Lot Increased Costs
- Product Lot Increased Regulatory scrutiny.
By having a good OOS management system, each of the above consequences can minimize their effect on product quality and consistency.

OOS (Out-of-Specifications) investigations are an important part of any Pharmaceutical Quality System. These investigations are performed to investigate and resolve any deviations from a predetermined specification.

Using a systemized approach to determine the root cause through sound scientific analysis along with good documentation practices allows a Pharmaceutical Company to effectively manage OOS results and comply with all regulatory requirements.

An effective OOS investigation process is critical in maintaining product quality and supporting the overall quality management process; thus providing increased patient safety and greater confidence from the Regulatory (FDA) agencies.

Frequently Asked Questions (FAQs) on OOS Investigation

Q1. What is an OOS result?

Answer: An out-of-specification (OOS) result is defined as a test result that is outside of the acceptable criteria for that test.

Q2. What are the phases of OOS investigation?

Answer: The investigation of OOS results has three phases: laboratory investigation, full investigation and additional testing.

Q3. What is true OOS?

Answer: True OOS refers to an actual failure of the product that can be attributed to a problem in either manufacturing or the product itself.

Q4. What is invalid OOS?

Answer: Invalid OOS refers to out-of-specification test results caused by laboratory error.

Q5. Which guidelines cover OOS investigations?

Answer: There are two primary sets of guidelines that govern OOS investigations: Good Manufacturing Practices (GMP) and the guidelines provided by the Food and Drug Administration (FDA).

Q6. What is testing into compliance?

Answer: Testing into Compliance refers to the unjustified retesting of samples in order to obtain acceptable results.

Q7. Why is root cause analysis important?

Answer: The root cause analysis process is critical because it provides a means of identifying the actual cause of an OOS result, which is important for preventing future occurrences.

Q8. What happens after OOS investigation?

Answer: After completing an investigation of an OOS result, appropriate CAPA (corrective and preventive actions) should be implemented and the disposition of the product should be determined.