Blog

Out of Trend (OOT) Results in Stability Study

Standard Operating Procedure (SOP) for Handling of Out of Trend (OOT) results during Stability Study of Drug Product.

Out of Trend (OOT) Result

1.0   OBJECTIVE :

    • To lay down a procedure for handling of Out of Trend (OOT) encountered during analysis and during stability study of Drug Product.

2.0   SCOPE :

    • This SOP is applicable to all the Out of Trend (OOT) results, which are obtained during analysis of Stability samples and finished products.
    • This SOP is not applicable for incomplete analysis (due to malfunction of equipments) where results are not derived and in case no conclusive reference data is available e.g. during validation studies.
    • SOP is not applicable swab analysis and other in process control tests.

3.0   RESPONSIBILITY :

    • Officer / Executive, QC:
    • For identification and reporting of possible Out of Trend (OOT) stability result to the Supervisor or Head QC and compilation of results.
    • Head, QC: 
    • To initiate the laboratory investigation on Out of Trend (OOT) test results and forwarding laboratory investigation report to Quality Assurance for final disposition.
    • Head, QA / designee: Investigation of results, monitoring of cross-functional investigation and compliance to the procedure.

4.0   DEFINITION (S)

    • Out of Trend (OOT): is defined as a result that does not follow the expected trend, either in comparison with other batches or with respect to previous results collected.
    • It may also be defined as a result or sequence of results that are within specification limits but are unexpected.

5.0   PROCEDURE FOR HANDLING OF OUT OF TREND(OOT) RESULTS :

  • Type of Out of Trend (OOT) Results:

    • Out of Trend (OOT) results shall be classified into three categories:
    • Analytical alert:
    • When a single result is aberrant but within specification limits. e.g. OOT assay value.
    • Process control alert:
    • A succession of stability data points or successive batches finished product showing an atypical pattern.
    • e.g. 1 M, 2 M and 3 M results of Accelerated stability studies of Product X batch No. 1 showing consistent OOT results or 1 M of Product X batch no. 2 showing similar Out of Trend (OOT) results.
    • Compliance alert:
    • When a particular stability study or release results may not meet specification limits (OOS) during the expiration period or shelf life or with regulatory specification of the same product or due to unusual trend the a batch or lot of finished.
    • Any result, which is not falling in trend and to be consider as Out of Trend (OOT) are described in Annexure III (Out of Trend Results Evaluation Guidance for Related Substance/ Assay/ Impurities).
    • In degradation products or impurities or related substance, occurrence of any additional peak during any stage of analysis shall be considered as an Out of Trend (OOT).

  • Investigation of Out of Trend (OOT) results :

    • The basic investigation emphasis of Out of Trend (OOT) results shall be like the methodology adopted in case of out of specification results.
    • Out of Trend (OOT) result shall be treated as an alert to initiate further investigations.
    • Laboratory Investigation
      • The investigation shall involve laboratory investigation to evaluated occurrence of laboratory failure.
    • The analyst shall inform the result to the supervisor.

    • The supervisor shall investigate the results under following points as per Annexure – I.

      1. Method / AnalystOut of Trend (OOT) Results
      2. Glassware
      3. Analysis
      4. Chemical / Reagents / Standards
      5. Instrument / Equipment
      6. Others
    • If assignable cause is identified during laboratory investigation the analyst shall re analyse the aliquot of the initial sample preparation and report the results. The previous result shall be invalidated.
    • In absence of any conclusive laboratory investigation, investigate the manufacturing details e.g. Batch records, changes in equipment or critical equipment malfunction / breakdown, personnel or operator changes, deviation records in manufacturing or packaging procedures, change in input material (both raw and packaging).
    • If required, the investigation may even be directed towards verification of analytical data for raw and packaging material.
    • In case of conclusive shop floor investigation, acknowledge and re sampling and reanalysis may be done as per requirement.
    • If assignable cause for Out of Trend (OOT) test results are not identified reanalysis shall be done on the same sample by Analyst-2 in duplicate.
    • When all the results found within trend, the mean of same shall be reported.
    • If the results found similar with the initial analysis then the initial results shall be reported and investigation shall be closed.
    • In case the manufacturing and laboratory investigations are inconclusive, inform R&D (both formulation and/ or analytical section) for remedial actions.
    • Based on the remedial actions suggested by R&D, take corrective and preventive actions.

  • Recording of Out of Trend (OOT) Investigation :

    • Where Out of Trend (OOT) results are observed, it should be inform Supervisor/ Head-QC for the same.
    • Head QC or designee shall raise a requisition to QA for issuance of copy of “Out of Trend Investigation Form” (Annexure-I).
    • QA shall assign the Out of Trend (OOT) number as per the format OOT/XX/YYY
      • Where,
      • OOT stands for Out-of-Trend.
      • XX   stands for current year. e. g. 20 for 2020, 21 for 2021
      • YYY   stands for serial number of the form. e.g. 001, 002, 003…….etc.
      • e.g. First OOT form in the year 2020 shall be numbered as OOT/20/001
    • Issuance details shall be recorded in Annexure-II “Out of Trend Form Issuance Register”.
    • After completion of each stage, the form shall be submitted to QA.

6.0   REFERENCE (S) – Out of Trend (OOT)

    • Identification of Out-of-Trend Stability Results,” Pharm. Technol. 27 (4), 38–52 (2003).
    • Guidance for Industry, Q1E Evaluation of Stability Data

7.0   ANNEXURE (S) – Out of Trend (OOT)

Annexure – I   : Investigation Form

Form No. : Issued by (Sign/ Date) :
Issued to (Name) : Date :

 

Product                      :
Batch No. / A.R No.  :
Stage/ Station                        :
Previous Occurrence of OOT : Yes/ No (If yes, mention details) OOT No. :
Test: Results:     Limit:
Analyzed by: Date: Reference:

LABORATORY INVESTIGATION

S. No. Checklist Observation(Yes / No / NA)
Method / Analyst
1 Analyst trained in the particular test?  Correct sample used for the analysis?

2

 Correct Analytical Method used for the analysis?

3

 Analytical Method adequate and followed properly?

4

 Evident from the discussion that the analyst has understood Analytical Method and the Operation SOP of the equipment / Instrument?

5

 Evident that the correct techniques were used by the analyst to perform the test?

6

 Evident that the suitability requirements of the analytical method were all met?

7

 Analyst calculated the results correctly as mentioned in Analytical Method?

8

 Analyst calculated the results using correct potency of the standard?

9

 Any similar occurrence with the analyst earlier?

10

 Any similar history with the product / material?

Glassware

1

 Proper glassware used for analysis?

2

 Proper volumes of pipettes used for analysis?

3

 Any obvious evidence of glassware contamination? (Visual)

4

 Evidence or probability of the glassware was not washed or dried properly?

5

 Glassware used for analysis properly and legibly labeled?

6

 Any evidence that the sample was not stored properly?

7

 Dilutions made in sample / standard preparation as per Analytical Method?

8

 Environmental conditions (temperature, humidity, light) during analysis appropriate?

9

 Instrument related problems if any noticed?

10

 Is the chromatographic pattern matching with previous analysis?

11

 Is the processing method followed correctly?

12

 Are there any samples analysed for the same test together with this failing sample?

13

 If Yes (for the above question), then is there any implication for the results obtained for those samples?

Chemicals / Reagents / Standards

1

 Reagents / chemicals used of recommended grade and prepared as per the analytical method?

2

 Correct standard used for analysis?

3

 Standards, reagents used properly stored?

4

 Any evidence that the standards, reagents were not properly labeled?

5

 Standards, reagents used within their expiration dates?

6

 Evidence that the standards, reagents have degraded?

7

 Evidence that the reagents, standards or other materials used for test were contaminated?

8

 Working standards standardized as per the Analytical method?

Instrument / Equipment

1 Equipment / Instrument used for analysis in calibrated state?

2

 Any evidence of malfunction of the relevant equipment?

3

 Preventive Maintenance Programme of the equipment performed as per schedule?

4

 Appropriate analytical balance used?
5 SOP adequate and the equipment operated as per SOP?
6 Instrument / equipment meeting the system suitability criteria mentioned in the analytical method?
7 Any other Observations / Comments / discussion points
Analyst (Sign / Date:) Investigator (Sign/ Date:
Summary of investigation by investigator (Based on Raw data checking / Discussion/ Previous experience, additionally mention if cause can be identified and assigned): 
Sign: Date:
Verified by Head, QC (sign / Date):
Were there any Assignable cause identified ? if yes, proposed action

(Reanalysis with final solution / stock solution of the original preparation/ from same sample by same analyst-1)
Sign: Date:
Conclusion:
Sign: Date:
QA Comments & Closure:
Sign: Date:
Assignable cause not identified from Laboratory Investigation, then summarize the proposed actions
Sign: Date:
QA Comments :
Sign: Date:
Analytical Results obtained by Analyst 2 Analyzed By/ Date Limit
Analysis –1 Analysis –2
Sign:          Date:
Conclusion: 
Sign: Date:
QA Comments & Closure:
Sign: Date:

Cross-functional investigation

Cross-functional investigation
Batch manufacturing record review:
Done By (Sign/ date)                                                                               Reviewed By (Sign/ date)
Equipment review:
Done By (Sign/ date)                                                                              Reviewed By (Sign/ date)
Manpower review:
Done By (Sign/ date)                                                                              Reviewed By (Sign/ date)
Material review:
Done By (Sign/ date)                                                                              Reviewed By (Sign/ date)
Process review:
Done By (Sign/ date)                                                                               Reviewed By (Sign/ date)
Process trendsDone By (Sign/ date)                                                                                Reviewed By (Sign/ date)
Any abnormal observation:
Observed By (Sign/ date)                                                                            Verified By (Sign/ date)
Conclusion & Closure (By Head, QA)

Evaluation by R&D

Comments of R&D:
Sign: Date:

Disposition of OOT

 Final Conclusion by Head, Quality Assurance:
Sign: Date:

Based on the evaluation inform Contract Giver, if applicable

Annexure – II : Out of Trend (OOT) Form Issuance Register

Sr. No.

 Product Name Batch No. Stage/ Time point Test Form No. Issued By Recd. By

Conclusion

Annexure – III : Out of Trend (OOT) Results Evaluation Guidance for RS/ Assay/Impurities

TEST

 LIMIT CRITERIA

EXAMPLES

Impurity / Related substances

Chromatographic purity by HPLC

(For stability – Long term condition samples only)

 

 Up to 0.10%                               (Excluding 0.10%) The result deviate by 0.06 (Absolute value) from the previous interval A value obtained as 0.090% against the value of 0.030% in the previous interval is considered as OOT
A value obtained as 0.076% against the value of 0.027% in the previous interval is not considered as OOT
Above 0.10% (Including 0.10%) and below 0.50%

 (Including 0.50%)

 The result deviate  by 0.1 (Absolute value) from the previous interval A value obtained as 0.287% against the value of 0.176% in the previous interval is considered as OOT
A value obtained as 0.296% against the value of 0.197% in the previous interval is not considered as OOT
Above 0.50% (Excluding 0.50%) and   below 1.0%

(Including 1.0%)

 The result drop by 0.15(Absolute value) from the previous interval A value obtained as 0.666% against the value of 0.511% in the previous interval is considered as OOT
A value obtained as 0.651% against the value of 0.511% in the previous interval is not considered as  OOT
Above 1.0%

(Excluding 1.0%) and below 2.0%

(Including 2.0%)

 The result drop by 0.5 (Absolute value) from the previous interval A value obtained as 1.71% against the value of 1.20% in the previous interval is considered as OOT
A value obtained as 1.64% against the value of 1.15% in the previous interval is not considered as OOT
Above 2.0%

(Excluding 2.0%)

 The result drop by 0.8 (Absolute value) from the previous interval A value obtained as 3.95% against the value of 3.14% in the previous interval is considered as OOT
A value obtained as 4.82% against the value of 4.04% in the previous interval is not considered as OOT

Assay

 (For stability – Long term condition samples only)

 All type of limits The result drop by 3% (Absolute value) from the previous interval

or

The result drop by 5% (Absolute value) from the initial value.

 A value obtained as 99.0% against the value of 102.0% in the previous interval is considered as OOT
A value obtained as 99.1% against the value of 102.0% in the previous interval is not considered as OOT

****************************************END*************************************

Janki Singh

Mrs. Janki Singh is the professional pharmaceuticals Blogger. She has already posted more than #1000 articles on varrious topics at different blogging plateforms. Contact : guideline.sop@gmail.com