04 Steps to Investigate Out of Specification (OOS) Result

Step 1: Understanding assignable cause in out of specification investigation

Before conducting an out of specification investigation, you should understand assignable causes and whether an assignable cause has resulted in the out of specification event.

Test results, whether in or out of specification, obtained under the following assignable causes must be invalidated, and the test should be repeated.

– Sample: the original sample was not representative or was insufficient in quantity.

– Method/Documentation: the directions for the test method or Standard Operating Procedure (SOP) were unclear, resulting in incorrect test execution.

– Analyst Error: examples include, but are not restricted to, incorrect weight of sample used, sample or sample solution spills, dilution errors, or improper test procedure; and

– Instrument/Mechanical/System Malfunction: examples include, but are not restricted to, interfering electrical surges or spikes, the pump stops pumping, or the injector stops injecting.

If the Initial Investigation determines a readily apparent assignable cause, the initial out of specification result is invalidated.

Category 1 and 2 out of specification events are mostly to be attributed to these assignable causes.

Step2: Conduct initial out of specification investigation

The exact cause of an out of specification event can be difficult to determine with certainty, and it is unrealistic to expect that analyst errors will always be documented.

Nevertheless, an initial laboratory investigation must include more than a simple repeat or retest.

Simply retesting as a strategy raises three problems:

– It is a regulatory requirement to investigate before any retests are conducted.

– It may imply a lack of control. The laboratory is not concerned about the causes of possible failures, and therefore, these conditions may recur on retest.

– It may lead to the discarding of the original result without invalidation

Therefore, a laboratory must predetermine its course of action in an out of specification event.

This should be done using a combination of standard operating procedures supported by an OOS investigation form.

This approach minimizes errors and subjective decisions and ensures the investigation is thorough and fully documented.

The initial investigation includes, but is not limited to, examinations of the following:

– Analytical records (raw data/laboratory notebooks),

– Analytical procedures used,

– Formula and Calculations used,

– Equipment or Instruments used,

– Sample preparations, storage and handling,

– Testing environment, and

– Analyst error

You are right if some of the initial investigational areas above look like the assignable causes in step 1.

That’s because the objective of an initial investigation is to ascertain if an assignable cause is readily apparent that might be attributed to an out of specification result.

In that case (an assignable cause is found without a doubt), declare the original out-of-specification result invalid and repeat the test to replace the invalidated result.

Step 3: Conduct a formal out of specification investigation and measurements

If the out of specification result cannot be invalidated by the initial investigation, or if there are multiple OOS events, you should initiate a full-scale formal inquiry involving management, QA and QC personnel.

Multiple OOS results would indicate that the cause of the problem is most likely to be either Category 3 or 4 events.

Right now, you should extend the investigation beyond the laboratory to the production area.

The batch record and any batch processing deviations should be reviewed to formally identify the source of the deviation from specification.

If you do not have sufficient original samples on hand, you must decide to resample at this point of the investigation.

The formal investigation is conducted to identify process—or non-process-related errors.

Ultimately, QA management will review the investigation, draw conclusions, and propose corrective actions.

Some requirements for formal out of specification investigation

Formal investigations extending the laboratory (Category 3 or 4) must follow an outline or protocol with particular corrective action.

The investigation team must follow the steps bellow:

1. State the reason for the investigation

2. Summation of the process sequences that may have caused the problem

3. Outline corrective actions necessary to save the batch and prevent similar recurrence

4. List other batches and products possibly affected, the result of an investigation of these batches and products, and any action. Specifically:

– Examine other batches of product made by the errant employee or machine

– Examine products produced by the errant process or operation

5. Preserve the comments and signatures of all production and quality control personnel who conducted the investigation and any reprocessed material after additional testing.

The outcome of the formal out of specification investigation leads you to one of the following considerations:

– If an assignable cause is identified due to the formal investigation, you can invalidate the initial OOS result. The original testing is repeated to generate valid results; or

– If no assignable cause is identified as a result of formal investigation, the investigation team must evaluate the need for raising an Alert.

Where a sufficient sample is available, you should initiate a retest of the same sample under a retest protocol.

Step 4a: Repeating the test (when an assignable cause is identified)

When an assignable cause is identified by the results of either the initial or formal out of specification investigation and measurements, the original OOS result is invalidated.

In this case, you should repeat all the invalidated tests. The result will replace only the original invalidated results.

If the assignable cause was not due to the sample preparation, the original sample preparation(s) shall be used for this testing.

A single analysis replaces a single initial out of specification result.

For example, an assignable cause has been identified for one of the ten results from a Content Uniformity test or one of the six results from a dissolution test.

The original single result is invalidated.

To replace the single invalidated result, you should test one additional dosage unit for the content uniformity test or perform a dissolution test using one dosage unit.

Step 4b: Conduct a retest (when no assignable cause is identified)

You should conduct a retest under a carefully designed retest protocol based on the specific problem identified, the product history, the method, and the batch.

You must delineate the number of retests to be performed.

The retest actions resulting from an OOS investigation follow some important rules.

– A retest is defined as additional testing on the same sample (from the same bottle of tablets or capsules and the same drum or mixer). Retesting is acceptable only after the investigation has commenced and only if retesting is appropriate to investigate the OOS event.

– If you have enough samples available, the retest protocol must be executed using the same sample set that was the source of the original out-of-specification result.

– You should adopt the rule that a minimum of three (3) retests is required for all types of samples, except a minimum of five (5) retests is required for formulated products (i.e., In-Process and finished product samples).

– A Control sample may be used to verify the accuracy of the analyses. The retest protocol must specify acceptance criteria for the control sample.

– Consider assigning an analyst other than the one who performed the original test to perform retesting.

– You cannot continue retesting indefinitely. The retest protocol should nominate the number of retests required.

At the conclusion of retesting, a decision should be made to either accept or reject the batch.

Additional retesting should not be conducted to ‘test the product for compliance’. 

FDA guidance on retesting as a result of out of specification investigation

– A retest is acceptable if reviewing the analyst’s work indicates an analyst’s error (Category 1).

In this case, limited retesting is required, and the retest result may replace the original result.

– A retest is acceptable if the investigation is inconclusive as to whether the OOS is category 1 or 2, as the laboratory needs to determine whether the OOS result is an outlier or a reason to reject the batch.

– Retest results should be used to supplement initial results in Category 2.

– Resampling is appropriate where provided for by an official monograph, such as sterility testing, content uniformity, and dissolution testing.

– Resampling is acceptable in the limited circumstances in which an OOS Investigation suggests that the original sample is unrepresentative.

Evidence, not mere suspicion, must support a resample designed to rule out preparation error in the first sample.

(Ref: FDA inspection Guide, Pharmaceutical Quality Control Labs (7/93))