Principle and Procedure of Analytical Test Method Validation for GMP Regulated Industry

Transcription

1 Principle and Prcedure f Analytical Test Methd Validatin fr GMP Regulated Industry Regulatry Basis: FDA Quality Systems Regulatins Reference: FDA CFR - Cde f Federal Regulatins Title 21 Purpse The purpse f this guideline is t utline the cntent and apprval prcess fr analytical prcedures and t describe thse activities that shuld be carried ut t demnstrate that analytical prcedures used in GMP labratries are suitable fr their intended purpse. Scpe and Applicability This guideline applies t qualitative r quantitative analytical prcedures that are used t test finished drug prduct, in-prcess materials, excipients, raw materials, packaging materials and Active Pharmaceutical Ingredient (API), in supprt f regulatry registratin dcuments and in cleaning validatin. Technlgy Transfer is utside the scpe f this dcument. Definitins Analytical Prcedure A cntrlled dcument that describes in sufficient detail hw a specific analysis is perfrmed. Analytical Prcedure Validatin Cnfirmatin that the perfrmance characteristics f the analytical prcedure meet the requirements fr the intended applicatin. This is usually established by labratry studies. Analytical Prcedure Revalidatin Cnfirmatin that the perfrmance characteristics f the analytical prcedure cntinue t meet the requirements f the intended applicatin, fllwing changes t the specific prcedure r the synthetic rute/methd f manufacture f the test material. This is usually established by labratry studies. Validatin Prtcl A validatin prtcl is written plan r prtcl stating hw validatin, sampling and testing will be cnducted, defining rles and respnsibilities, and defining acceptance criteria. Analytical prcedure validatin prtcls may be generic r specific and their cntent will depend n the phase f develpment r marketing. Respnsibilities Analytical prcedures shuld be develped, validated and apprved by the riginating labratry. This may be within Analytical, Micrbilgy, Device r Packaging, r Quality Cntrl functins. Analytical prcedure validatin reprts shuld be written and apprved as part f the validatin prcess. Analytical prcedure revalidatin is the respnsibility f the department that will rutinely use the revalidated prcedure. Quality Assurance will apprve any lcal standard perating prcedure that cvers analytical methd validatin. QA will ensure that analytical prcedure(s) and validatin exists as required by Cpyright All rights reserved Unauthrized cpying, publishing, transmissin and distributin f any part f the cntent by electrnic means are strictly prhibited. Page 2 f 27 2

2 Principle and Prcedure f Analytical Test Methd Validatin fr GMP Regulated Industry directly linked t the methd s intended use. Methd Validatin Summary Reprt: It is recmmended t analyse the experimental results and prepare a Methd Validatin Summary f the findings. These methd validatin summaries may include but are nt limited t: The perfrmance results against criteria listed within this guideline, site SOP, r separate pre- apprved prtcl. Fr higher risk methds, at least tw reviewer signatures are recmmended t be btained fr the Methd Validatin Summary t be apprved. It is suggested that at a minimum ne signatry shuld be a member f the Site Quality Team. This shuld be an independent reviewer, nt invlved in the validatin activities fr that test methd, in rder t avid the ptential fr cnflict f interest. The authr shuld be respnsible fr determining that all data are accurately transcribed int the Methd Validatin Summary. The reviewing/ apprvers shuld be respnsible fr Technical crrectness and cmpleteness, Regulatry Cmpliance Practices, Cmpliance Registratin, Cmpliance with written site requirements, SOPs; Authrizatin t implement. Review f changes t methds and their impact n ther quality systems (e.g. prcess validatin, etc) Review f deviatins and failures during the methd validatin and their impact n the cnclusins, if any. Test Raw Data r Reference t Raw Data. Reference t methd develpment data (e.g rbustness) if nt referenced in a prtcl. Validatin f Pharmacpeial Methds: Pharmacpeial methds included in a specific fficial mngraph are generally cnsidered as validated. Hwever, the suitability f cmpendial analytical prcedures must be verified under actual cnditins f use. It is recmmended t demnstrate absence f interference with the cmpendial methd, thus specificity (if applicable) shuld be assessed. Intermediate precisin and stability f the sample slutin shuld als be investigated using the cmpendial methd fr the specific API. Demnstratin f the applicability f the methd fr use in the analysis f the specific prduct/material shuld be accmplished by the analysis f the material using the pharmacpeial methd. System suitability requirements f the methd shuld be met, and fr raw materials the results shuld cnfrm t the expected result fr that grade f material. Cpyright All rights reserved Unauthrized cpying, publishing, transmissin and distributin f any part f the cntent by electrnic means are strictly prhibited. Page 6 f 27 6

3 Principle and Prcedure f Analytical Test Methd Validatin fr GMP Regulated Industry Methds may be gruped fr this evaluatin, such as in the abve table t set priritizatin fr the team. During this evaluatin phase, a number f cntributing factrs tend t determine impact t quality. Dwnstream effects may als need t be cnsidered. Fr example, nce the material is islated, tested, and discharged frm the equipment, ne may have t reprcess/ rewrk material because f ptentially inaccurate data frm the earlier IPC test methd. The use f what-if scenaris can assist in the risk analysis. Fr example, cnsider the fllwing: Stage in the API Prcess: Where des this test methd s result lie within the verall quality cntrl r assurance strategy in prducing a quality API? Critical Quality Attribute: Can analytical data gleaned frm this early stage f the step highlight where an impurity r its precursr is frming? Critical Quality Parameter: Culd the prcess step be adjusted within allwable parameters t marginalize r purge unwanted impurities befre islatin? Evaluatin Cnclusins and Crrective Actins: Fr thse test methds, which are identified as higher risk (e.g. See Table 1), ne can review the existing validatin dcumentatin (if any) assciated with the methd. Dcumentatin cntent and accessibility f the raw data shuld be cnsidered rather than specific validatin dcuments when assessing legacy methds and their existing validatin. Sites shuld leverage existing dcumentatin thrugh remediatin and reference (when pssible), t address validatin deficiencies. System Suitability Testing Per ICH Q7A, the degree f analytical validatin perfrmed shuld reflect the purpse f the analysis and the stage f the API prductin prcess. Material, In-Prcess Cntrl and Early Intermediate Material Tests. System Suitability is a predetermined set f tests and applied methd requirements that are used t determine if an analytical methd is perfrming within its validated parameters and is acceptable fr its intended use. The methd validatin exercise may include statistical interpretatin f data t prvide adequate justificatin fr reduced System Suitability Testing (SST) and numbers f standard and sample injectins. Suggested System Suitability recmmendatins are established in Appendix 1 fr different types f API In-Prcess testing. Recmmended SST Data: System suitability criteria frm cmpendial general chapter methds may be used fr sme test methds but shuld be evaluated against the intended use f the test methd as t applicability. Reslutin can be calculated between the majr cmpnent and an internal standard, the majr cmpnent and an expected impurity fund in the reference standard, tw impurity peaks in the reference standard (reslutin material), r tw peaks that are the mst difficult t separate (ften referred t as the critical pair ). Since reslutin is the primary criterin fr specificity and rbustness, it serves as a rigrus parameter fr suitability. If there is n critical pair t establish a reslutin criterin, a retentin time windw may be 11 Cpyright All rights reserved Unauthrized cpying, publishing, transmissin and distributin f any part f the cntent by electrnic means are strictly prhibited. Page 11 f 27

4 Principle and Prcedure f Analytical Test Methd Validatin fr GMP Regulated Industry Accuracy is imprtant when a specific value is needed. Fr example, in the case when a methd is used t mnitr an impurity that is nt reduced in dwnstream prcessing r if a minimum titer r amunt is required (e.g. specific mlar rati) r if the assay is used t calculate the amunt f catalyst needed t drive a reactin t cmpletin. Accuracy may be established acrss the specified range f the analytical prcedure. Accuracy may be assessed using a minimum f 9 determinatins ver a minimum f 3 cncentratin levels cvering the specified range (e.g. 3 cncentratins /3 replicates each f the ttal analytical prcedure). Accuracy can be reprted as percent recvery by the assay f knwn added amunt f analyte in the sample r as the difference between the mean and the accepted true value tgether with the cnfidence intervals. Accuracy may be established by ne f the fllwing: Applicatin f the analytical prcedure t an analyte f knwn purity (e.g., a reference material r stck standard) and demnstratin that the expected true value is btained. Accuracy shuld be determined acrss the range. This can be accmplished by spiking the analyte f interest with a knwn amunt f cncentratin f the analyte material. In cases where specified impurities/degradatin prducts are nt available a surrgate material such as a cmpund with similar structure r API may be used t demnstrate accuracy. In these cases, a ratinale fr the use f a surrgate shuld be given. Knwn amunts f impurities r degradatin prducts may be added t the prcess slutin. The spiking prcedure shuld include the high and lw extremes f the range plus an intermediate value. Recmmended Accuracy Data: Percent recvery is calculated fr each reprtable value as defined in the methd. The average percent recvery may be calculated at each level and cmpared t the acceptance criteria. Recmmended Accuracy Criteria: Several factrs can be cnsidered when selecting criteria: The intended purpse f the test and the expected specificatin range are imprtant parameters. See Tables belw fr recmmended acceptance criteria. Statistical Basis fr Acceptance Criteria fr bth Accuracy and Precisin: The fllwing recmmended criteria in the Tables are derived t insure that the methd can supprt its intended purpse, which is release f prduct against specificatins. Fr impurity methds, the accuracy f the impurity determinatin can be either determined cncurrently with the methd precisin recvery f spiked impurities r by spiking the impurity int a sample at apprximately the Quantitatin Limit (QL), 100% and 120% f the specificatin limit. The verall % RSD f results frm multiple ccasins shuld meet the recmmended criteria. Fr impurities, the fllwing tables may be used as guidance fr setting acceptance criteria that is als based n the specificatin. These recmmended acceptance criteria are based n what can typically be achieved by an impurities methd, including thse that are Area% methds. Table 1: Recmmended Criteria fr Precisin and Accuracy Higher Risk Test Methd Impurity Determinatins Impurity Spike Precisin Accuracy 15 Cpyright All rights reserved Unauthrized cpying, publishing, transmissin and distributin f any part f the cntent by electrnic means are strictly prhibited. Page 15 f 27

5 Principle and Prcedure f Analytical Test Methd Validatin fr GMP Regulated Industry In sme cases the instrument itself is the limiting factr fr the analysis regardless f the sample. An example f this is an LOD test using an analytical balance. In this case a discussin f the quantitatin limit may be cnstructed in the validatin dcumentatin based n the calibratin tlerance f the equipment rather than analysis f actual samples. The actual limit f quantitatin wuld still be presented in numerical terms relevant t the assay methd based n the discussin. Anther example f this may be fr KF titratin assays where the ability f the instrument t deliver a minimum amunt f titrant wuld be the limiting factr. It is recmmended that experiments t determine this minimum amunt f sample shuld be cnducted fr the specific instrument mdel if this apprach is taken. The experiment(s) culd then be referred t in any validatin that utilizes the same mdel f equipment. Based n the Standard Deviatin f the Respnse and the Slpe The quantitatin limit (QL) may be expressed as: QL = 10 σ/ S where, σ= the deviatin f the respnse; S = the slpe f the calibratin curve. The slpe S may be estimated frm the calibratin curve f the analyte. The estimate f σ is carried ut in a variety f ways including: Based n the Standard Deviatin f the Blank: Analyzing an apprpriate number f blank samples and calculating the standard deviatin f these respnses and perfrm measurement f the magnitude f analytical backgrund respnse. Based n the Calibratin Curve: A specific calibratin curve shuld be studied using samples cntaining an analyte in the range f the QL. The residual standard deviatin f a regressin line r the standard deviatin f y-intercepts f regressin lines may be used as the standard deviatin. In all cases, the quantitatin limit can be subsequently validated by the analysis f a suitable number f samples knwn t be near r prepared at the quantitatin limit r reprting level. Tw pssible appraches include: A) Three replicate preparatins f a spiked sample are prepared at the quantitatin level r reprting level and analyzed. Calculate the % recvery. Calculate the average f the replicates and % RSD. B) Alternatively, accuracy r repeatability experiments at r near the quantitatin limit r reprting level can be used fr this determinatin. Recmmended QL Data: The quantitatin limit and the methd used fr determining the quantitatin limit shuld be presented. Fr validatin f the actual quantitatin limit r reprting level: Fr case (A) it is suggested t reprt the average f replicates, % recvery and RSD. Fr case (B) it is suggested t reprt the accuracy r repeatability f replicate experiments cnducted at r near the reprting level. The quantitatin limit shuld be expressed as the amunt actually measured, as well as the crrespnding percentage f the target analyte cncentratin. If applicable, representative chrmatgrams can be presented at an expansin that allws visual inspectin f the signal vs. nise and integratins that impact quantitatin. 19 Cpyright All rights reserved Unauthrized cpying, publishing, transmissin and distributin f any part f the cntent by electrnic means are strictly prhibited. Page 19 f 27

6 Principle and Prcedure f Analytical Test Methd Validatin fr GMP Regulated Industry Figure: Parameters that can be used fr test methd rbustness: 24 Cpyright All rights reserved Unauthrized cpying, publishing, transmissin and distributin f any part f the cntent by electrnic means are strictly prhibited. Page 24 f 27

7 Principle and Prcedure f Analytical Test Methd Validatin fr GMP Regulated Industry Recmmended Rbustness Criteria: Changes within the test range whether allwed explicitly r implicitly by the assay shuld nt exceed the previusly defined validatin parameters fr accuracy, precisin r specificity. This may be accmplished by evaluatin f system suitability parameters that are relevant t the change. Fr example, rbustness fr limits tests shuld cnfirm that variatins still cause a pass/fail decisin t be unaffected by the change. Multiple preparatins belw and abve the specificatin can be used t demnstrate the ability f the methd t reliably distinguish passing and failing results. Increased rbustness testing during develpment may prvide additinal supprt fr an abbreviated System Suitability Testing (SST). If rbustness testing is nt adequately perfrmed and dcumented during develpment and/ r validatin, there is mre f a reliance n detailed SST, which shuld be included during the run. A full SST at the beginning f a campaign culd be perfrmed, and then repeated peridically thrughut the campaign. As a wrking practice, sme sites allw 24 hurs validity between SST and running a sample (prvided n majr changes in instrument perating cnditins have been perfrmed within the time perid). This allws the labratry t analyze a series f samples within that 24 hur perid withut repeating the SST and prvides the advantage f allwing a quicker sample turn arund in cases where analysis f many samples may be required ver a shrt time perid (e.g. when mnitring residual slvent by hurly sampling during drying). The chice f taking this apprach shuld be carefully weighed with the risk f implicating a large amunt f data if a system suitability failure were t ccur. 27 Cpyright All rights reserved Unauthrized cpying, publishing, transmissin and distributin f any part f the cntent by electrnic means are strictly prhibited. Page 27 f 27