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1. Has the MHRA produced any guidance?
Out of specification investigations (194Kb)1 k: I, l& F P( b6 J/ w! t
http://www.mhra.gov.uk/home/grou ... urces/con100182.pdf
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2. Why is there a need to conduct an investigation of an OOS test result if the decision has been taken to reject the batch?
A phase 1 investigation should always be conducted in order to try and establish an assignable cause and determine whether any other batches may be affected. In determining the assignable and root cause of the problem appropriate corrective and preventative actions can be undertaken.
________________________________________6 u u" [' S$ ^$ O8 H: I2 X
3. Who should investigate OOS?
Both the manufacturers and the laboratories should be involved in the investigation.
________________________________________" K+ T4 j5 _) ?9 N, s r+ z8 M
4. How is an out of trend result handled?
Results that are out-of-trend (OOT) should be handled similarly to OOS investigations.
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5. Is it acceptable for a contract laboratory (contract acceptor) to use the contract givers’ procedure when handling OOS results?0 r/ i4 B" S Y$ ~
There is an expectation that contract acceptors should follow their own procedures and that these should be flexible enough to accommodate the needs of the contract giver. 1 F' T9 @* x5 s" O
It is assumed that the contract giver has assessed the contract acceptor’s procedure for handling of out of specification results and has agreed it as being suitable for their intended purpose. Any issues should have been discussed prior to conducting any analysis.|! [( ~4 Q) z8 p p2 r
________________________________________
6. How is a meaningful OOS investigation conducted?6 X; g8 n( Y: v7 e% U/ q; K) X* W3 ?, J
A meaningful OOS investigation should be thorough, timely, unbiased, well-documented, and scientifically defensible.
________________________________________
7. At what point should a manufacturing investigation be initiated?
This should be initiated as part of the phase II investigation and as a result of the phase 1 investigation not revealing a conclusive laboratory error or the error remains unclear with no assignable cause.
________________________________________2 {8 z8 y/ `9 G' e5 d+ u1 L. M& w
8. What should be done if unexpected results are obtained and there is no obvious explanation?3 c \! G" d( O! o5 N# d6 E+ ^- s
These are also referred to as aberrant/anomalous. Preliminary laboratory investigation should occur and they should be handled similarly to OOS investigations. 7 R; x, N% h4 Y: D( |, f
________________________________________* T2 U+ k& l7 z2 Q1 x
9. Under what circumstances could test results become invalid?
If there is clear evidence of a determinant error. Or where the system suitability/method validity checks fail.
________________________________________8 k; C! M( f1 _; v+ h2 s
10. What should be done in the case where part way through testing the analyst realises there is an error?
If there is clear evidence of the error and it can be corrected without compromising the results or the validity of the method; for example a dilution error 20 ml volumetric flask used instead of a 25 ml volumetric then it should be handled as a deviation and the results are still valid. If there is any doubt as to the impact of the error whICH could mean the results may not be accurate, for example sample spillage then the testing should be stopped and the issue handled as a deviation to explain what happened.
________________________________________
11. When should the analyst inform the supervisor that they have an OOS results?& k. w1 I, G' q" r
In the first instance, the analyst will be responsible for the preliminary laboratory investigation. This will involve them checking their work and confirming that there is no obvious error prior to informing their supervisor and initiating a phase 1 investigation. This should be done within a timely manner, preferably on the day of generating the results. N4 ~/ g1 e5 i" D
________________________________________
12. What should be done when the phase 1 investigation does not reveal an assignable cause or evidence of error remains unclear?1 u9 e/ X, l5 w0 F& }2 H
A phase II investigation is initiated, which will involve communication between the laboratory and the manufacturer/contract giver. The decision to undertake any further testing should be agreed and approved within a pre defined testing plan. : s1 h8 ~. ?" W. z1 e
________________________________________- r+ p5 q z5 _. Z' d- j
13. How many repeat tests should be conducted?, y7 b( Z7 n- f. @
The minimum number of retests should be documented within the procedure and be based upon scientifically sound principles. Any statistical review with regards to %RSD and repeatability should relate to the values obtained during method validation, ie accuracy, precision and intermediate precision. The number of retests should be statistically valid.
________________________________________
14. What should be done if after retesting there is a combination of OOS results and pass results?
All results should be reported unless there is clear evidence of a determinant error or an assignable cause that could invalidate any of the results.
* q& I+ {: B7 m7 y0 d( u
________________________________________
15. What should happen if the OOS investigations are inconclusive?3 T+ }* G6 F6 v) `
The certifying qualified person should fully consider all of the information prior to making any decisions as to the final disposition of the batch. Any decision to release a batch where OOS results have not been invalidated should come only after a full investigation has shown that the OOS result does not reflect the quality of the batch. In making such a decision quality assurance and the Qualified Person should always err on the side of caution.
________________________________________. |& ~& h' p. V0 l
16. When is it acceptable to average test results?
Where averaging of separate tests is appropriately specified by the test method, a single averaged result can be reported as the final test result. The validity of averaging depends upon the sample and its purpose. Using averages in the case of microbiological assay can provide more accurate results because of the innate variability of the microbiological test system. For example the kinetic scan of individual wells or endotoxin data from a number of consecutive measurements or with HPLC consecutive replicate injections from the same preparation where the determination is considered one test one result.9 w- `+ U8 E$ r$ w$ ]9 [
________________________________________9 `% T9 V) ^- J1 Z1 c7 l4 I
17. When is it not acceptable to average test results?
Averaging cannot be used in cases when testing is intended to measure variability within the product, such as powder blend/mixture uniformity or dosage form content uniformity. In the context of additional testing performed during an OOS investigation, averaging the result(s) of the original test that prompted the investigation and additional retest or resample results obtained during the OOS investigation is not appropriate because it hides variability among the individual results.
________________________________________% h6 D7 M0 d2 L+ {6 S; ?
18. At what stage should retesting occur?
Retesting occurs at phase II of the investigation. The initial hypothesis testing can involve re-measurement of the original preparation or working solutions, however retesting is when the original sample or composite sample is used to perform analysis. Hypothesis testing and retesting are part of the phase II investigation. Only if the original sample is depleted or compromised should a new sample be used.
________________________________________
19. At what stage should re-sampling occur?& J7 \7 O( m! k+ b7 y: j# w
Re-sampling at phase II of the investigation should only occur if the original sample is depleted or compromised and the same method should be used. If the investigation determines that there were errors with the initial sampling method only then should a new accurate sampling method be developed, qualified and documented.
________________________________________1 ^$ e% m6 k% r
20. When is it appropriate to use outlier tests?
Statistical analysis for Outlier test results can be as part of the investigation and analysis. However for validated chemical tests with relatively small variance and that the sample was considered homogeneous it cannot be used to justify the rejection of data.
1. Has the MHRA produced any guidance?+ E7 |% o0 u. ~; W- e
Out of specificationinvestigations (194Kb)
- s2 G) b7 y R' h/ c+ {
1. MHRA有相关指南吗？
答：见Out of specification investigations(194Kb)
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2. Why is there a need to conduct an investigation of an OOS test resultif the decision has been taken to reject the batch?2 c7 `$ t6 w, v! R4 B9 f; S
Aphase 1 investigation should always be conducted in order to try and establishan assignable cause and determine whether any other batches may be affected. Indetermining the assignable and root cause of the problem appropriate correctiveand preventative actions can be undertaken.
2. 如果已决定拒绝该批了为什么还需要进行OOS调查？3 N% M8 z( Q/ v7 H; G4 X
2 O) N F: Y8 D9 H; @0 O* j; y8 Y
答：为了尝试和确定一个明确的原因并决定是否有其他批次受到影响，阶段1调查总应进行。在确定了问题明确的和根本的原因后应进行纠错和预防措施。
3. Who should investigate OOS?
Boththe manufacturers and the laboratories should be involved in the investigation.
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3. 谁应调查OOS？4 G V$ U$ H7 |' Z; F
+ `6 Z9 p& E6 G; X1 T
答：制造商和实验室应参与调查。
4. How is an out of trend result handled?' z$ `( x0 y2 T; w+ r9 S1 f* W( i
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Resultsthat are out-of-trend (OOT) should be handled similarly to OOS investigations.
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4. 如何处理超趋势（OOT）结果？- R2 v/ Z( Q! K5 L. \" u( t! W2 M
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答：OOT结果的处理与OOS调查相似。
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5. Is it acceptable for a contract laboratory (contract acceptor) to use thecontract givers’ procedure when handling OOS results?
5. 在处理OOS结果时合同实验（合同的接受方）使用合同提供方的程序是否可以接受？
Thereis an expectation that contract acceptors should follow their own proceduresand that these should be flexible enough to accommodate the needs of the contractgiver.
It isassumed that the contract giver has assessed the contract acceptor’s procedurefor handling of out of specification results and has agreed it as beingsuitable for their intended purpose. Any issues should have been discussedprior to conducting any analysis.3 V& x% G" r0 p7 T# [! p& V) H
答：我们期望合同接受方应执行自己的程序，并且这些应足够的灵活以适应合同提供方的需求。
+ v( k* X7 S( o) I2 k
这里假设合同提供者已评估了合同接受方处理OOS结果的程序并同意其适合于特定的目的，在进行任何分析前任何问题应已经过讨论。$ e2 i9 k! G! H3 I6 A
6. How is a meaningful OOS investigation conducted?
2 `/ L7 b. f' }$ f7 ?
Ameaningful OOS investigation should be thorough, timely, unbiased,well-documented, and scientifically defensible.
3 I( o8 Y$ U6 j6 J' x- m! m( K
6. 如何进行有意义的OOS调查？# B4 y/ P. e8 T. l4 s
答：有意义的OOS调查应是彻底的、及时的、公正的、证据充分的且是科学上可支持的。
7. At what point should a manufacturing investigation be initiated?5 w1 W, j$ X B; C$ K9 Q
Thisshould be initiated as part of the phase II investigation and as a result ofthe phase 1 investigation not revealing a conclusive laboratory error or theerror remains unclear with no assignable cause.% D& U/ I0 z( o O: M9 i! [9 A
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7. 生产调查应该在哪点开始？6 Z2 _, C5 L; p$ \
答：生产调查应该作为阶段II调查的一部分，并且阶段I调查的结果不能表明决定性的实验室错误或仍然有错误不明且无指定原因。
4 N& q1 H/ Q" u. h S* h& K
8. What should be done if unexpected results are obtained and there is noobvious explanation?
Theseare also referred to as aberrant/anomalous. Preliminary laboratoryinvestigation should occur and they should be handled similarly to OOSinvestigations.+ n4 o" g3 n9 |+ L5 A% L
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8. 如果得到了非预期结果且无明显解释时应该如何做？* }" B" l& u4 d, ^9 C9 ?6 M
答：这些同样被称作为异常的情况，初步的实验室调查应进行，且与OOS调查的处理相似。9 p$ Y0 Q0 `* c3 L) }
0 O1 w$ [5 q8 d/ _& i0 j
9. Under what circumstances could test results become invalid?
Ifthere is clear evidence of a determinant error. Or where the systemsuitability/method validity checks fail.
9 Y) d; R9 K8 [' e6 @4 ?4 z' Q6 K
9. 在什么情况下检测结果变为无效？
答：如果有检测错误的明确证据，或系统适用性/方法验证失败。
8 f2 x/ l( t# |+ T# L
10. What should be done in the case where part way through testing theanalyst realises there is an error?
Ifthere is clear evidence of the error and it can be corrected withoutcompromising the results or the validity of the method; for example a dilutionerror 20 ml volumetric flask used instead of a 25 ml volumetric then it shouldbe handled as a deviation and the results are still valid. If there is anydoubt as to the impact of the error which could mean the results may not beaccurate, for example sample spillage then the testing should be stopped andthe issue handled as a deviation to explain what happened.; d5 W% F# K8 K" U \3 B
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10. 如果检测进行了一部分时分析员意识到存在错误，这种情况如何做？
答：如果有错误的明确证据，可以在结果或方法有效性未妥协时进行校正；比如：稀释用的量瓶误以25ml代替了20ml了，那么可以作为偏差进行处理，结果仍然有效。如果有任何对错误的影响可能导致意味着结果不能准确的怀疑，如：样品溢出，那么检测应停止，问题作为偏差处理以解释发生了什么情况。* l% `% _5 y, o1 s
* d& Z: t! @4 I# S2 i& f5 ^
11. When should the analyst inform the supervisor that they have an OOSresults?/ l, b0 o5 \% j: S0 d8 w4 A
b1 e" b* |( F8 U0 K2 e# ^
In thefirst instance, the analyst will be responsible for the preliminary laboratoryinvestigation. This will involve them checking their work and confirming thatthere is no obvious error prior to informing their supervisor and initiating aphase 1 investigation. This should be done within a timely manner, preferablyon the day of generating the results.4 P, G' l1 l0 o
11. 什么时候分析员应通知主管他们得到了OOS结果？
在第1个例子中，分析员应负责初步的实验室调查。这些包括他们检查他们的工作并确定在通知其主管前无明显错误，并开始阶段1调查，这些应及时进行，最好是在结果产生的当天进行。
1 z! S% J& V. r6 U
12. What should be done when the phase 1 investigation does not reveal anassignable cause or evidence of error remains unclear?
Aphase II investigation is initiated, which will involve communication betweenthe laboratory and the manufacturer/contract giver. The decision to undertakeany further testing should be agreed and approved within a pre defined testingplan.
12. 当阶段1调查不能提示指定原因或错误的证据仍然不清时应如何做？
7 x+ ^- m" `: x/ [( G8 n& F; r" p
答：应进行阶段II调查，包括实验室和制造商/合同提供者之间的交流，进行任何进一步的检测的决定应经过同意并在预定的检测计划内批准。
13. How many repeat tests should be conducted?' n8 T5 N5 j: z* r- l- k2 p
Theminimum number of retests should be documented within the procedure and bebased upon scientifically sound principles. Any statistical review with regardsto %RSD and repeatability should relate to the values obtained during methodvalidation, ie accuracy, precision and intermediate precision. The number ofretests should be statistically valid.
13. 应进行多少次重复检验？% ~9 S% U& n" X* m3 M
答：复验的最小次数应在程序中以文件形式规定且以合理的科学原则为基础。任何统计学的审核有关的RSD%和重复性应与方法验证（即：准确性、精密度和中间精密度）得到的数值相关，复验的次数应在统计学上有效。
14. What should be done if after retesting there is a combination of OOSresults and pass results?) F( q; J- u8 y- l* ^6 j
: [3 K1 Q" [- l! Z* m
Allresults should be reported unless there is clear evidence of a determinanterror or an assignable cause that could invalidate any of the results.: h# U2 L. K% p: n' s5 d( `5 r
14. 如果复验后有OOS结果也有通过的结果则应如何做？" y D1 ~6 r% ]$ U: b2 U% i; G
答：所有结果应报告，除非有检测错误的明确证据或者有可以导致任何结果无效的指定原因。) e7 B- R( y7 b- k0 l
15. What should happen if the OOS investigations are inconclusive?! r! j- B9 m" P( [5 t
0 t3 B1 j( c8 _7 q. d/ [
Thecertifying qualified person should fully consider all of the information priorto making any decisions as to the final disposition of the batch. Any decisionto release a batch where OOS results have not been invalidated should come onlyafter a full investigation has shown that the OOS result does not reflect thequality of the batch. In making such a decision quality assurance and theQualified Person should always err on the side of caution.' ]! Q# ]& e7 N
15. 如果OOS调查没有结果应该怎么办？/ M* M! I! U" ~8 b
答：具有资质的质量受权人在做出任何有关最终对该批处理的决定前应全面考虑，任何对于OOS结果尚未无效批的放行决定应仅仅在全面调查已表明OOS结果不影响该批质量的情况下才能进行，在做出这样的决定时质量保证和质量受权人应格外小心。! I& t- W7 i/ m- D7 i9 ~6 Y
8 s1 \# i/ Z4 Y y
16. When is it acceptable to average test results?
Whereaveraging of separate tests is appropriately specified by the test method, asingle averaged result can be reported as the final test result. The validityof averaging depends upon the sample and its purpose. Using averages in thecase of microbiological assay can provide more accurate results because of theinnate variability of the microbiological test system. For example the kineticscan of individual wells or endotoxin data from a number of consecutivemeasurements or with HPLC consecutive replicate injections from the samepreparation where the determination is considered one test one result.1 M( n+ @( U1 A' m/ W
答：什么时候可以接受平均检测结果？
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答：检测方法中如果对各次检测结果取平均值给出了适合的规定，一个平均结果可以报告为最终检测结果。平均值的有效性取决于样品及其目的，因为微生物学检测系统的先天变异性，在微生物学含量测定时使用平均值可以提供更准确的结果。比如单个培养皿的动态扫描或一系列连续测定的内毒素数据或同一溶液的HPLC连续进样，这些被认为一个检测一个结果。
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17. When is it not acceptable to average test results?
% ^* Y0 ?: u( F
Averagingcannot be used in cases when testing is intended to measure variability withinthe product, such as powder blend/mixture uniformity or dosage form contentuniformity. In the context of additional testing performed during an OOSinvestigation, averaging the result(s) of the original test that prompted theinvestigation and additional retest or resample results obtained during the OOSinvestigation is not appropriate because it hides variabilityamong the individual results.
{. s+ V* R4 m% O+ U% R# ], c
17. 什么时候平均检测结果不能接受？ K, q0 h9 L" g
答：当检测是用于测定产品间的变异，如：粉末混合均一性或含量均一性时不能使用取平均值。在OOS调查过程中所进行的额外的检测，将原始结果与OOS调查过程中的额外的检测或重新取样的检测结果取平均值是不适合的，因为这会隐藏单个结果的变异性。
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18. At what stage should retesting occur?
Retestingoccurs at phase II of the investigation. The initial hypothesis testing caninvolve re-measurement of the original preparation or working solutions,however retesting is when the original sample or composite sample is used toperform analysis. Hypothesis testing and retesting are part of the phase IIinvestigation. Only if the original sample is depleted or compromised should anew sample be used.
18. 哪个阶段应进行复验？
" x5 j, }- G7 t' O1 ~- K! d
答：在阶段II调查时进行复验。起初的假设检验可以包括对原始样品溶液或工作溶液的重新测定，然而，复验是当原始样品或成分样品是用于进行分析的，假设检验和复验是阶段II调查的一部分，只有当原始样品耗尽或失效时才应使用新的样品。
19. At what stage should re-sampling occur?
Re-samplingat phase II of the investigation should only occur if the original sample isdepleted or compromised and the same method should be used. If theinvestigation determines that there were errors with the initial samplingmethod only then should a new accurate sampling method be developed, qualifiedand documented.
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19. 哪个阶段应进行重新取样？
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答：在阶段II调查时只有当原始样品耗尽或失效时才重新取样，并且使用相同的方法。如果调查确定最初取样方法有误时才应开发、确认新的准确的取样方法并且制定文件证明。/ p- K0 y2 {# Y/ t7 Z
20. When is it appropriate to use outlier tests?, U6 s- @. l7 _ L) V& {# H
6 \( `# k$ L4 h8 P6 f
Statisticalanalysis for Outlier test results can be as part of the investigation andanalysis. However for validated chemical tests with relatively small varianceand that the sample was considered homogeneous it cannot be used to justify therejection of data.
20. 什么时候使用异常测定值是适合的？
2 I2 K& m& X2 y: P& D
答：对于异常检测结果的统计分析可以作为调查和分析的一部分。然而，对于具有相对较小变异的经验证的化学检测且其样品被认为是均匀的，这不能用于拒绝数据的合理的理由。
附件：
1、MHRAOOS调查译文
2、201501MHRA数据完整性指南
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