Investigating Out of Trend Results (OOT s) Dr. Pradeep Nagalkar Head Quality Control (Bio. & Chem.) Haffkine Bio-Pharma. Corp. Ltd.

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1 Dr. Pradeep Nagalkar Head Quality Control (Bio. & Chem.) Haffkine Bio-Pharma. Corp. Ltd., Mumbai

2 - We will be discussing - 1. What is OOT & OOS Examples of OOT & OOS Regulatory issues - 4. Method for detection of OOT - 5. Types of OOT - 6. Documentation / SOP Consideration Investigation - 8. Depth of investigation - 9. Conclusion

3 What is OOS and OOT OOS (Out Of Specification) is a comparison of one result verses a predetermined specification criteria while OOT (Out Of Trend) is a comparison of many historical data values verses time. OOS investigations focus on determining the truth about that one value while OOT investigation focus on understanding non-random changes.

4 What is OOS and OOT Example : The specification limit for assay is : % w/w of label claim 1. For a particular batch, the result obtained 94.2%w/w This result is out of specifications and is called OOS. An investigation is required. Root Cause Analysis (RCA) is required for OOS investigation. Once a root cause is identified, corrective and preventive measures need to be taken. 2. The result obtained 95.8 w/w. Although the results are well within the specifications, we should compare the result with the previous batches trend. If found the average value of the trend w/w then this batch result (95.8 w/w) is called Out Of Trend (OOT). A through understanding and control of the process is required.

5 OOS regulatory issues have been well understood and documented in the literature. However, OOT issues, for product stability, raw materials, in-process and finished product, data identification and investigation are less understood, but rapidly gaining regulatory interest. Though FDA s draft guidance indicates that much of the guidance presented for OOS can be used to examine OOT results, there is no clearly established legal or regulatory basis for requiring the consideration of data that is within specification but does not follow expected trend.

6 Methodology [3 sigma approach] A minimum of batches data shall be compiled for fixing the Trend range. Results that shall be obtained from the 25 batches tabulated, average value, minimum and maximum values are noted. Standard deviation will be calculated for these 25 batches. Excel spread sheet shall be used for Standard deviation calculation. Standard deviation will be multiplied by 3 to get the 3 sigma (3 )) value. Maximum limit will be arrived by adding the 3 1 value to the Average value of 25 batches. Minimum limit will be arrived by subtracting the 3 1 value from the Average value of 25 batches. Minimum value may come in negative also at times.

7 The maximum and minimum limits in above steps shall be taken as the Trend range for upper and lower limits. Any value that shall be out of this range will be considered as Out of Trend (OOT) value or Outlier value. Wherever specification has only Not more than, then only Maximum limit for trend can be considered. Minimum limit should be excluded. Wherever specification has only Not less than, then only Minimum limit for trend can be considered. Maximum limit should be excluded. Wherever specification has range then both the Maximum and Minimum limits for trend should be considered.

8 Methods of Identifying OOT Results 1. 3 sigma approach : Advantages: One advantage of this approach is that as long as the assumptions are met, the rate of false positives can be set when one calculates the limits. Disadvantage: The products with limited data, the appropriate limits may be difficult to determine. This can lead to wrongly centered, too narrow or too wide OOT limits. 2. Regression-Control-Chart Method: Advantage: Suitable for identification of the present OOT results in case where is no historical stability data. Disadvantage: The main disadvantage of this method is the necessity of having results for each time point due to the fact that the construction of the regression line was based on gradually adding the values in each subsequent time point.

9 Methods of Identifying OOT Results 3. The by-time-point Method: Advantages: The main advantage is that the absence of having a result in any time point did not affect the analysis of the previous or next point result. Disadvantage: A large history of data is preferred for proper use of this method. 4. Slope-Control-Chart Method: Advantage: Any small change in the value of the tested attribute from point to point is precisely recorded in the slope value of each time point. Disadvantage: If the test of the attribute were omitted in any time point for various reasons, the limits of that time point may not be appropriate. Dr.Pradeep Nagalkar / March 2015

10 There are mainly three types of OOT alerts: 1. An Analytical Alerts is observed when a single result is aberrant but with in specification limit ( i.e. outside normal analytical or sampling variation and normal change over time). 2. A Process Control Alerts occurs when a succession of data points shows an atypical pattern that was possibly caused by changes to the laboratory or manufacturing process. These data points might originate from the same stability study or from multiple studies assayed within a reasonably close time. Despite the deviating trends, no pending potential OOS situation occurs.

11 There are mainly three types of OOT alerts : 3. A Compliance Alert defines a case in which an OOT result suggests the potential or likelihood for OOS results to occur before the expiration date within the same stability study (or for other studies) on the same product.

12 SOP for OOT : Considerations An investigation's depth may depend on the nature of the data, the product history and characteristics being measured, the potential risk to product quality, and the potentially related safety or efficacy implications. A review of the OOT alert procedures' performance might coincide with the annual product review. When preparing an SOP for handling OOT test results, it is prudent to consider risks to product quality when determining the company's assessment of OOT test results. The depth of an investigation and the corrective measures taken may depend on the potential or implied risk to product quality.

13 SOP for OOT : Considerations How to set alert limits :SOPs may identify scientifically sound approaches to determine procedures with associated limits for the identification of each type of OOT alert for stability test attributes such as assay and degradation products. Once an approach is identified, some potential topics to be included in the SOP are data requirements, personnel responsible for setting the limits, and methods used to detect each type of OOT alert.

14 SOP for OOT : Considerations How to set alert limits: For new products, available stability data will be limited. Established products often will have sufficient historical data. The method for detecting OOT results may vary depending on the type of OOT alert. Ideally, a method for each OOT should be specified. How to use limits : The SOP may contain a section about how OOT alert limits are applied and which personnel will be responsible for comparing new stability results with the OOT alert criteria and timeliness of the review.

15 SOP for OOT : Considerations Investigation : Investigation requirements could include personnel responsibilities with defined timelines, documentation requirements, and proper internal notification requirements. The investigation's depth required for each OOT alert will depend on potential risks to product quality. The SOP should not be overly prescriptive because the steps taken to investigate OOT results will depend on the nature of the initial finding and the investigation findings.

16 SOP for OOT : Considerations Investigation : Nonetheless, SOPs should provide basic criteria for conducting the investigations. Moreover, the steps taken to investigate OOT results should be scientifically defensible, and the rationale for the investigation's depth should be documented. Although an OOT result usually will be investigated as soon as possible after it is identified, it also can be addressed more broadly during the annual product review. The notification requirements and the department responsible for performing the annual product reviews also could be included.

17 SOP for OOT : Considerations Depth of Investigation : If an analytical alert is observed, a laboratory investigation may be performed. If the laboratory investigation is inconclusive, then the supervisor may take no further action at that time and monitor subsequent time points closely. A review of results for related or correlated test attributes also can facilitate the investigation. Depending on the product, history, and nature of the analytical alert data, the company may decide to investigate whether a manufacturing error occurred in cases in which a laboratory error is not conclusive.

18 SOP for OOT : Considerations Investigation : More data (i.e., the next stability test point) may be needed to indicate whether the result is part of a longterm trend (process control alert) or just an isolated result. If subsequent results within the study and across other studies are not out of trend, then the initial analytical alert result may be an isolated incident that requires no further investigation.

19 SOP for OOT : Considerations Investigation : A process control alert may indicate unexpected changes in product or assay performance. A stability study with an unusual trend may reveal that a characteristic's stability profile changed, whereas multiple analytical alerts may suggest that the measurement process is no longer in control.

20 SOP for OOT : Considerations Investigation : When a process control alert is evident, the investigation will often begin with an assessment of the effect of potential changes to the laboratory process (e.g., changes in instrument, column, integration technique, or standard). It also may extend to the manufacturing process (e.g., looking for changes in materials, personnel, equipment, and procedures).

21 SOP for OOT : Considerations Investigation : A compliance alert identifies a situation in which a particular study (or several related studies) may not meet specification limits during the expiration period, one may need to conduct a thorough investigation. In general, this investigation begins with the laboratory process and expands to the manufacturing process if no conclusive laboratory root cause is identified. The manufacturing investigation might include other batches (from the same or related products) that may be associated with this predicted failure to identify whether the discrepancy is isolated or systematic.

22 SOP for OOT : Considerations Investigation : The investigation also could assess whether more analytical testing, an investigation into the manufacturing process, a product recall, or shorter dating is required. An investigation of a compliance alert aims for the early detection of potentially failing product and the identification of possible causes. If a root cause is determined, then appropriate action should be taken such as the identification of potential preventative actions.

23 SOP for OOT : Considerations Periodic review of limits : SOPs may specify a periodic review process for OOT alert limits. The frequency of the review and the personnel responsible for completing it may be addressed in the SOPs. This assessment can involve identifying a previous result that was once within trend but is now an OOT result. Or, it may find that a previous OOT result is now within trend. It is natural that earlier conclusions be revised in light of new information because developing OOT alert criteria is an active and continuing process.

24 Conclusion : Identifying OOT results is a growing interest for FDA and vaccine Industry point of view. Despite this, very little has been discussed in the scientific literature or in regulatory guidance on this topic. The vaccine industry still lacks having a proper guideline for the identification of OOT results among results. As a result, industry is not harmonized in the way they conduct OOT analysis. The method to determine an OOT should not be too complex. However, some-thing too simplistic may not be sensitive enough to identify a true OOT or may give a high rate of false signals.

25 Conclusion : Challenges: What statistical approach should be used for OOT assessment, What minimum data to be used, What data to be used for updating the limits, How is an OOT result is confirmed, What action to be taken if an OOT result is confirmed, How are OOT investigation incorporated in APR

26 Thank you

1 of 9 2/7/ :53 PM. Identification of Out-of-Trend Stability Results, Part II PhRMA CMC Statistics, Stability Expert Teams

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