Procedure to investigate out of specification (OOS) test result for pharmaceutical production

1.0	PURPOSE To lay down a procedure for Investigation of Out-Of-Specification (OOS) Test results for Pharmaceutical Product.
2.0	SCOPE This procedure is applicable to results of chemicals and instrumental analysis of drug product including in process/core /bulk/ raw material for the manufacture of drug product except the test for dissolution and particle size determination. OOS is also applicable to test result of stability studies.
3.0	RESPONSIBILITY  Concern Analyst/ Chemist (QC) Head QA To allot a unique alphanumeric identification code to the OOS. Head QC To conduct investigation for OOS.
4.0	ACCOUNTABILITY Head QC To forward the OOS after Laboratory investigation (if found Valid) to head QA for extended / failure investigation.
5.0	PROCEDURE
5.1 5.2 5.2.1 5.2.1.1 5.2.2 5.2.2.1 5.3 5.3.1 5.3.2 5.3.3 5.4 5.4.1 5.5 5.5.1 5.5.2 5.5.3 5.6 5.6.1 5.6.2 5.6.3 5.6.4 5.6.5 5.6.6 5.6.7 5.6.8 5.6.9 5.6.10 5.6.11 5.6.12 5.6.13 5.6.14 5.6.15 5.6.16 5.6.17 5.6.18 5.6.19 5.6.20 5.6.21 5.6.22	Definition: The term OOS test results includes all test results that fall outside the specification or acceptance  criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer  Specifications.  Causes of OOS test results:   Assignable causes: Laboratory error during analysis, error in sampling, handling and storage of sample. Non Assignable causes:         In such cases, additional data must be generated to assess whether the initial atypical (not typical) result is a St     statical outlier.         Numbering of OOS:  .1    QA shall allocate the numbering of OOS.as per the following pattern:         In the report no. of out of specification, 1st,2 nd, & 3rd Character stand for “ OOS’. The fourth Character ‘/’ is a forward slash. the 5th & 6th character represent the last two digit of the year. the 7th character ‘/’ are again a forward slash. the 8th, 9th, 10th character ‘001’ are a sequential number. for ex. for first out of specification no is given as OOS/12/001.    5.  Entries of OOS shall be made in Register as per Annexure- II.         OOS (Laboratory investigations) shall be concluded within 3 working days from the date of generation of OOS.  Identifying assessing & investigating OOS test results:         The investigation should be thorough, timely, unbiased, well documented & scientifically defensible. 5      Responsibility of the analyst: 1      When an unexpected or suspected result is obtained, test preparation shall be retained& the analyst shall inform the QC head regarding the same. .2     There is no need for a formal laboratory investigation in situations like instrument failure, power failure, in- complete transfer of a sample, spilling of sample solutions etc. 3      If no obvious explanations exist, the analyst shall retain the test preparations and   inform the results to supervisor/ Head QC. 5.6   Responsibility of Head QC: 1      Investigation by Head- QC shall include but not limited to following: 2      Discuss the test method with the analyst; confirm analyst knowledge of and performance of the correct procedure. 3      Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify anomalous or suspect information.       Verify that the calculations used to convert raw data values into a final test result are scientifically sound, appropriate and correct; also determine if unauthorized or unvalidated changes have been made to automated calculation methods.         Confirm the performance of the instruments. Determine that appropriated reference standard, solvents, reagents and other solutions were used and that they met quality control specifications. Evaluate the performance of the test method to ensure that it is performing according to the standard expected based on method validation data and historical data. Head QC shall co ordinate with Head QA for OOS log in, allocation of OOS number and issuance of OOS laboratory investigation format Annexure –I. Head QC shall assess the data generated from the investigation to identify the probable cause. Head-QC shall evaluate the performance of the test method to ensure that it is performing according to the standard expected based on the method validation data and historical data.  Head QC shall then get the test repeated by the same analyst from: The retained sample solutions (hereafter referred as “Solution A”) or The original sample.  Retesting from the “solution A” shall be performed only once. If an assignable cause is found and the test result of the repeat analysis of “solution A” is within specification, report this result & consider the OOS test result as invalid. The OOS shall close with justification. If the test result of the repeat analysis of “solution A” is out of specification, then the test has to be repeated thrice on the original sample by an analyst other than the one who performed the original Example: Initial OOS Results: 97.8%                            Retest thrice by a different analyst    Example 1 Example  2 Example 3 Retest results 1% 99.20 98.0 98.3 Retest results 2% 99.50 98.1 98.5 Retest results 3% 99.90 98.2 99.0 Average % 99.53 98.1 98.6 Std Deviation (SD) 0.35 0.1 0.36 3SD 1.05 0.3 1.08 Avg.- 3 SD% 98.48 97.8 97.52 Avg. + 3 SD% 100.59 98.4 99.68 Result *Passes **Fails **Fails Acceptance Criteria: 98.0% to 102.0% *OOS-Invalid, Report average values; Close the OOS. **OOS-Valid; Re-Sample. If the test results of all the 3 determinations are within the specification and,  a) If average±3SD values are within the Specification, then report the average value & consider the OOS test result as invalid. The OOS shall be closed with justification. b) If average±3SD values are out of specification, then consider the OOS test result test valid. Re-sample & Re-testing on the re sampled sample has to be performed.  If at least one of the three test results is out of specification, resample & retest.  In case test solution (Solution A) is not stable or required quantity is not available for repeated analysis, the testing may be performed on original sample.  Re-sampling is performed only when it is concluded from the assessment that the original sample was sampled improperly and therefore not representative of the batch (widely varied results original sample not stored properly.  After testing the re-sampled sample- a) If the result is within the specification, then the OOS test result is invalid the result of re-sample tested is to be reported. The OOS shall be closed with justification. b) If the result is out of specification, then the Head QC or the deputy shall forward  the Laboratory,      Investigation report along with a summary to Head QA for   extended investigation. c) For identification and conformance of hypothetical cause of OOS, solutions can be re-tested as part of an     Investigation where a transient equipment/instrument malfunction is suspected. Concluding the investigation :   5.13.1        If an assignable cause is identified for OOS result:   5.13.1.1     a) Details of assignable cause.   5.13.1.2     b) Corrective action to be taken.   5.13.1.3     c) Batch is released or rejected(with justification)                     d) Preventive action to be taken for future. 5.13.2       If no assignable cause is identified for OOS results, an extended investigation shall be concluded to determine what caused the OOS as per the SOP “out of  specification: failure investigation”.
6.0	REFERENCES      C GMPs guideline

7.0

ANNEXURES

Annexure No.	Title of Annexure	Format No.
Annexure I	LABORATORY OOS INVESTIGATION FORM	QA/010/F01-03
Annexure I	QA OOS LOG BOOK	QA/010/F02-00

8.0	ABBREVIATIONS

Abbreviations						Full Forms
SOP						Standard Operating Procedure
QA						Quality Assurance
cGMPs						Current Good Manufacturing practices
QC						Quality Control
OOS						Out of Specification
SD						Standard Deviation
9.0	DISTRIBUTION
Master Copy							Head Quality Assurance Department
Controlled office Copy No. 1							Head Quality Assurance Deptt.
Controlled office Copy No. 2							Head Quality Control Deptt.
10.0		REVISION HISTORY
S.No.			Revision No.	Effective Date	Reason for Revision			Details of Change	Authorized By (sign & Date)

                                               

Annexure I

LABORATORY OOS INVESTIGATION FORM

1.  OOS No./Date:
2.  Date of investigation:
3.  Name of the product under investigation
4.  Batch No.		5. Mfg. Date	6. Exp. Date
7.  Stage of manufacturing at which OOS is reported :
8.  Details of OOS laboratory results: (If required attached a page with details.)
9.  Name of the analyst who has reported the OOS results:
10. Check list used during laboratory investigation: (tick whichever is applicable.)
					Yes		No		Remark
a.  Laboratory investigation:
i. Error in the method of analysis.
ii. Error in specification.
iii. Error in calculation.
iv. Wrong transcription of data.
v. Use of non calibrated instruments & /or apparatus.
vi. Use of contaminated apparatus.
vii. Use of invalid / incorrect working standard.
viii. Lack of training & / or knowledge.
ix. Use of expired or old chemicals, reagents or solvents.
x. Software error.
xi. Method validation not appropriate (ruggedness missing.)
b. Repeat test on the remaining sample solution or on the original      sample by same analyst.
c. Repeat test on the original sample trice by a different analyst.
d. Error in sampling                / error in handling           / error of storage              of sample               ( Tick whichever is applicable.)
i. Sampling procedure is available.
ii. Sampling chemist is trained.
iii. Sampling area is qualified.
iv. Use of clean sampling tool & container.
v. Error in labeling details on the container to be sampled & goods         inward memo with respect to product name, manufacturer’s B. N.,      grade etc.
vi.  Error in labeling details on the container to be sampled & container  for sampled material with respect to product’s name, manufacturer's  B.N.,grade etc.
vii. Is raw material from approved vender?
e. Any other cause (give details):
Conclusion : OOS is closed   / not closed  ( tick mark whichever is applicable) :         i.  If assignable cause is identified for OOS result:    Ø Details of assignable cause : _______________________________________
Ø Corrective action to be taken (if appropriate):___________________________            ______________________________________________________________          Ø Batch is accepted or rejected or reprocessed (with justification) :            ______________________________________________________________              Ø Preventive actions to be taken for future batches :_______________________            ______________________________________________________________        If no assignable cause is identified for OOS result, review the trend of acceptable batch records.Summary of the review : _______________________________________________________________________________________________
Sign (Dept) : Date:	Quality Control :			QA :

Annexure II

QA OOS LOG BOOK

Sr. No.	Date	OOS No.	Initiated by	Details of OOS	Closure/ remarks	Head – QA Sign / Date