Verification of Compendial Procedu. -- Horacio Pappa, David Porter,and Karen Russo

Horacio Pappa, PhD,* IS a senlor scientist, D a v i d Porter, PhD, is a dirxtor, and Karen Russo, PhD, IS

an associate director, all in the Department of Standards Development at the US Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852- 1790, tel. 301 -81 6.831 9, hpBusp.org.

Ta whom all correspondence should be addressed.

C alibration, validation, and traceability are central components of metrology (1-3). The process of validating a new analytical

procedure for compendial urage is addressed in US Phamacopeia (USP) General Chapter {I 225) "Validation of Compendial Proceduresm* (4).

Even though a USP procedure is fully vali- dated, one inay not have assurance that the pro- cedure is snitable for use with a specific ingre- dient or product, in a specific laboratory, with specific laboratory personnel, equipment, and reagents. The latter falls within the area termed verj;fication, whereby analysts demonstrate that a validated procedure to be used for the first time with a particular product will yield accept- able results using a given laboratory's equip- ment, personnel, and reagents. Therefore, the purposc of the proposed General Chapter (1226) "Verification of Compendial Procedures'" (5) is to provide guidance about the verifica- tion process.

USP developed this chapter in response to industry's requests to provide illstructions for verifying compendial procedures. The authors note that verification is not mandatory unless an enforcing body adopts it by reference, it is referenced in a specific USP monograph, or it is adopted by a specific manufacturer in stan- dard operating procedures subject to current good manufacturing practices (CGMPs) regu- lations (see also General Chapters, USP Gen- eral Notices).

A compendia1 procedure is considered vali- dated if it is published as official text in USP-National Formulary (NF), in a supple- ment, or a s an Interim Revision Announcement in Pharrnacopeial Forum (PFj. Therefore, users of such procedures are not required to perform validation studies. But, they muss demonstrate that the use of the official procedure is suitable given the actual conditions of use. This require- ment is established by the US Food and Drug Administration's CGMPs, which state "The snit- ability of all testing merhods used shall be ver-

ified under actual conditions of use" (6). The suitability of a cornpendial procedure

may be an issue for an article under test for sev- eral reasons (e.g., different impurity profiIes from different routes of synthesis, composition of formulations, or interference from excipi- ents). General Chapters already exist in the USP on rhe general topic. For example, various Gen- eral Chapters for microbiological testing de- scribe apprnaches that will ensure the article to be tested is suitable for use with the validated procedure. Similarly, many USP monographs have sections devoted TO establishing the suit- ability of chromatographic systems.

If multiple laboratories are expected to use the cornpendial procedure with essentially the same conditions of actual usage, then one lab- oratory may perform the verification. With ap- propriate verification of adequate robustness, other locations may use the verified procedure. Some factors that must be considered when as- certaining usage conditions are:

article to he tested; laboratories to be used; equipment to be used; personnet - reagents.

Verification process It is assumed that personnel involved in the ver- ification process possess appropriate experi- ence, knowledge, and training to execute a ver- ification properly. A critical step in the verification process is the preparation of a doc- ument describing:

procedures to be verified; number and identity of lots or batches of ar- ticles that will be used (note that the verifi- cation may need to be repeated for different types of articles); analytical performance characteristics to be

7 h e proposal to replaoe "Methods" in the title with "Procedures" was made in Pharmacopeial Forum 31 (2) and will become official in USP29 (Suppl. 1).

Inside USP

evaluated, along w i t h a spzi i t ic, i t io l~

of the acceptable range of results ex- pressed in terms of acceptable accu- racy, precision, or linearity parame- ters; justification of any deviations from the recommendations in General Chapter (1226). A critical part of the process is to pre-

establish acceptance criteria for the veri- fication attributes being tested. These cri- teria vary with the intended use of the procedure. Upon completion of sample analysis, laboratory personnel should compare the data obtained with the pre- established acceptance criteria. l%e ensu- ing documentation shorsld include a sim- mary of analytical data, a comparison of the data with acceptance criteria, and a conclusion about the suitability of the d- idated pmcedure under actual usage cnn- ditions. If the data meet the acceptance criteria, it may be assumed that the com- pendial procedure will perform as in- tended under actual usage conditions.

If the analytical data do not compare

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NIA Specificity ! "Reproduced w~th permlsslon from the US Pharrnacopela Abbrev~at~ons: HPLC-GC IS high-performance liqu~d chromatography-gas chromatography. NIA 1s not appl~cable TLC IS th~n-layer chromatography

favorably with the prc-established ac- propriate), which may include rectify- ceptance criteria, one should try to de- ing training deficiencies or contacting termine the sources of the deviations USP personnet for craxification of the and initiate corrective action (when ap- procedure. Any corrective actions should

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be indicated in a revised verification ap- proval document. The final document and its components should contain the initial unacceptable resuIts.

Despite repeated attempts to perform the procedure and obtain acceptable re- sults, the results may demonstrate that the procedure is not suitable for appli- cation under specific usage conditions. In such a case, it may be necessary to modify the official compendial proce- dure (in which casc, suggestions for im- provement should be submitted to USP), develop and validate an alterna- tive procedure, change the matrix to ovcrcome potential interferences, or make other changes.

Tf an alternative procedure Is validated, the new procedure and supporting vali- dation data can be submitted to USP for consideration as part of a flexible mono- graph. Flcxible monographs allow alter- native tests, procedures, and acceptance criteria to account for control of quality attributes that may differ between arti- cles of the samc cornpcndial name. If a compendial procedure is deemed unsuit- able after consultation with USP scien- tists, the11 the final verification document should summarize the steps to dernon- strate suitability of the new procedure and to describe the final action taken in dc- veloping the alternative procedure.

The characteristics chosen for use in the verification prOCESS typically are de- rived from those used in validation stud- ies. %ble I1 in General Chapter (1225) providcs a listing of the performance characteristics that should be assessed based in different analytical categories. Caregory 1 encompasses procedures in- tended to quantify major components of drug substances in finished dosage forms. Category J l covers procedures in- tended for use as either quantitative or limit testing for impurities. Category IIT refers to procedures such as dissolution intended to assess dosage-form per- formance. Category lY includes identi- fication procedures. All thc characteris- tics in Table 11 are not required for procedure verification.

Table I in proposed General Chapter (1226) lists the data elements that should be evaluated for procedure verification

for drug substances and excipients (sec Table I).

Table IT in proposed General Chapter (1 226) lists the data elements that should be evaluated for procedureveritication for do~age forms (see Tahle 11). The number of tests for the verification of procedures for use with drug products is larger for several categories hecause of the increased conlplmity of drug products, in compar- ison with drug substances and excipients.

Additional performance characteris-

tics may be appropriate for verification purposes, For ex;anple, if a pharmaceu- tical manufacturer wants to make delib- erate modifications in a procedure in terms of analyst, equipment, reagent, or environmental condition, then robust- ness studies are appropriate. Definitions for robl~mess are listed in General Chap- ter (1225). In particular cases, the stabil- ity of the sample preparation should be investigated because different matrices can affect the stability of the solution.

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Status of the new chapter After General Chapter (1226) was pub- lished in PF, USP received numerous comments horn pharmaceutical man- ufacturers and regulators. As specified in the briefing, the deadline was July 15, 2005. USP deferred this deadline in an- ticipation of discussions at the USP An- nual Scientific Meeting in September 2005. A summary of the comments and USP responses follows.

Some respondents indicated that by including elements of validation in the verification process, USP is calling into question one key principle (and advan- tage) of a compendia1 procedure: it is robust and validated. It should be un- derstood that the proposed chapter is not focused on challenging the validity of the procedure per se, but rather the suitability of the analyticid system (i.e., a matrix of factors such as the article to be tested, the laboratories to be used, the equipment to be used, the person- nel involved, and reagents used, etc.).

Other respondents suggested that the

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, cea wlrn perrnlssron rrom rne us rnarrnacopela. Abbrwiations: HPLC-GC is high-performance liquid chromatography-gas chromatography. NIA is not applicable. TLC is thin-layer chromatography

range of results that will be considered for the first time will have no way of acceptable represents knowledge typi- knowing in advance what results would cally avahble only to the group that pa- be acceptable4ther than those defined formed the original validation. Thus, a by the specification range. USP believes laboratory testing a compendia1 article that acceptance criteria verification

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should be selected according to a risk-based approach according to the in-tended use of the procedure and justi-fied in the verification protocol.

Another respondent stated concernrelated to the issueof "grandfathering"because numerous official procedureshave been in place for years and havebeen used without being subjected toformal verification procedures. Somerespondents asked that a provision beadded indicating that the intent of theproposed chapter is to provide guidancefor verifying the suitability of newlyadopted proceduresand not for retroac-tive application to those being per-formed successfully. USP agrees withthis concern and will provide publicstatement to support itsprospectiveuse.

Some respondents suggested that anorganization performing a verificationexerciseshouldhavethe freedomto doc-ument its process in a defensible man-ner.These pharmaceutical manufactur-ers were concerned that words like"typically" and "may" sometimes arereinterpreted, particularly in regulatorycontexts, as "must." Further, these re-spondents suggestedthat submission ofinformation associatedwith the resolu-tion of verification issues should be atthe discretion of the pharmaceuticalmanufacturer that was performing theverification activities.Asa variation onthese observations, some respondentsnoted that contract laboratoriesperformnumerous procedures for different ma-terials submitted by client companies.In an outsourcingcontext,it maybeverydifficult to verify the suitability of thecompendial procedure for a largenum-ber of articles. USP generally supportsthese observations and notes (as statedabove) that the proposed chapter doesnot specifya requirement exceptunderthe circumstances noted. Manufactur-ers may use all,none, or part of the pro-posed chapter, when finalized, at theirdiscretion.

Finally,some respondents suggestedthat it is inappropriate to combine drugsubstances and excipients in the sametable because the types and require-ments of procedures for these two verydifferent articlescan vary broadly. USP

notes this point and will attempt to clar-ify the distinction as the proposed chap-ter moves to finalization.

ConclusionProcedures published as officialtext inthe USP-NF are considered validated.Therefore, the user of an officialproce-dure does not haveto perform a fullval-idation study. But, CGMPs require thedemonstration that a compendial pro-cedure can be used successfully for agiven article, a processknown as verifi-cation. USP'sproposed new general in-formation chapter (1226)"Verificationof Compendial Procedures"is intendedto fill the gap in the proper usage ofcompendial procedures by outlining aprocess for verifyingtheir suitability.

A newversion of (1226) is scheduledto appear in the May-June issue of PF.USP is amenable to the receipt of com-ments about chapters and monographsthat are in development or are official.USP encourages industry and others toreview the chapter and submit com-ments. Finalization of the proposedchapter is the General Chapters ExpertCommittee's responsibility.

Referencesl. W. May et al., Definitions of Terms and

Modes Usedat NIST for Value-Assignmentof Reference Materials for Chemical Mea-surements (National Institute of Standardsand Technology [NISTJ, Gaithersburg,MD, Jan. 2000).

2. D.L. Duewer et al., An Approachto theMetrologicallySound TraceableAssessmentof the Chemical Purity of OrganicReferenceMaterials (NIST, Gaithersburg, MD, Sept.2004).

3. EURACHEM/CITAC Guide. QuantifyingUncertainty in Analytical Measurement.S.L.R. Elllison, M. Rosslein, and A.Williams, Eds. 2d ed. (NIST, Gaithersburg,MD, April, 2000).

4. Pharm. Forum. 31 (2),549 (2005).

5. General Information Chapter (1226) "Ver-

ification of Compendial Procedures,"Pharm. Forum. 31 (2),555-558 (2005).

6. 21 CFR 211.194(a)(2). PT

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