Qualification of a Contract Microbiology Laboratory · Contract lab reports must provide sufficient...

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Microbiology Topics.Scott Sutton[

ABOUT THE AUTHORScott Sutton, Ph.D., is owner and operator of The Microbiology Network (www.microbiol.org), which provides services to microbiology-related user’s groups. Dr. Sutton may be reached by e-mail at [email protected].

Qualification of a Contract Microbiology Laboratory

“Microbiology Topics” discusses various topics in microbiology of practical use in validation and com-pliance. We intend this column to be a useful resource for daily work applications.

Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Please send your comments and suggestions to column coordinator Scott Sutton at [email protected] or journal coordinating editor Susan Haigney at [email protected].

KEY POINTSThe following key points are discussed in this article:

The client organization is responsible for all data and analysis that contributes to the decision to release a batch of product to the marketplace accordng to good manufacturing practice (GMP). Contract lab reports must provide sufficient infor-mation to meet regulatory expectations.Several recommendations are provided to increase the likelihood of a successful contractor-client rela-tionship. Most important of these include techni-cally competent review of the lab and the reports received—while the contract lab is working on your product the regulatory expectation is that you are responsible for all aspects of that work.There are several documents available to assist in the determination of the contract laboratory’s suit-ability for pharmaceutical work. These include 21 Code of Federal Regulation (CFR) 211 (211.22, 211.165, 211.176 and 211.194), International Orga-nization for Standardization ISO 17025, United

States Pharmacopeia chapter <1117>, and PIC/S Aide Memoire to Inspection of Pharmaceutical Quality Control Laboratories.

INTRODUCTION This article discusses the qualification of a contract microbiology-testing laboratory in the good manufac-turing practice (GMP) environment. This is a critical consideration in today’s workplace, as many companies are outsourcing technical testing activities and reduc-ing in-house capabilities. In addition, as the pool of in-house subject matter experts is reduced through layoffs, transfers, or attrition, the remaining technical experts must learn to become more efficient. Relying on outside expertise is one way to do this.

The manufacturer of record is held responsible for the quality of the medicines placed out on the US market under his name. This is irrespective of the location and corporate structure of the individual entities that might have actually manufactured the finished dosage form, tested the product for release, or stored and dis-tributed it to market. In other words, if you operate a “virtual” company that is actually composed of four or five people who supervise product acquisition, contract manufacturing, contract testing, contract distribution, etc, the corporate entity is responsible—the contractors might also carry some burden but the product belongs to the manufacturer of record. The use of services on a contract basis will become more critical as downsiz-ing becomes more intense and “virtual” companies more prevalent. There are already many small and mid-sized pharmaceutical, over-the-counter (OTC), medical device, and personal products companies that

Scott Sutton

resource for daily work applications.Reader comments, questions, and sususugggg essstititiononons

are needed to help us fulfill our obobobjejejectcc iveee forr r thththisisis column. Please send your commentntnts ananand suuuggestititionsto column coordinator Scott Suuutttttton at [email protected] or journal coordinnnatttininingg editor Susan Haigney at [email protected]

INTRODUCTIONThis article discusses the qualification of a cmmmim crobiology-testing laboratory in the good mturiririinnngn practice (GMP) environment. This is acococonnnsideration in today’s workplace, as many corarareeee outsourcing technical testing activities anHaigney at [email protected]

KEY POINTSThThThe following key points are discussedd in this article:

The clllieieientnt ooorgrgrganananizizizaatation is reespoponsnsibi le foor aall dataand annnalysis thahah t t t cooontribuutetes toto thhe dececisisioon to

arrreee outsourcing technical testing activities aninining in-house capabilities. In addition, as theiiin-house subject matter experts is reduced tlayoffs, transfers, or attrition, the remaining teexperts must learn to become more efficient. ooon oooutututsisisidedede eeexpxperee titiisese iis s s onnne waw y too ddo o ththisis.

ThThThe manufacttturrrer of reeecococordd is heeld respoonssiblrerereleaaaseee a batchhh ofofof ppprorr duuctct tto o thhe e mam rkrkettplplacaceaccccococ rdddng to gooodod manaanufufacactuuriring prractcticce (GMPMP).).CoCoCoC ntnnn raaact lab rrrrepepepepooorts mmmmussstt t prprp oovo ide suffff icccieienntn infor-rrmatitition ttto meet regulatttory expectations.Severarararal rererer commmmmennnndadd tionnns ss ararare provovovidididedee to ininincreasesesettthe liiiikekekekelilililihhhoh od oooof fff a aaa successssfsfululu contrtracacacttotor-clieennt relllaaa--tionship Most important of these include techni

qqqualalalitii y yy ofofof the mmmedddicineseses pplaaceed ouut onon tthehe USuuunder hihihis ss nnnameee. Thihiis s s iis iirrreesppecctive e ofof the lanananddd d corprpppororororate stttruuuctttturururu e of theee indndndivvviduaaal enenntimmimighghhghttt hahhahave actualllllly manufactur dedd ttthheh finisii hhhedformmmm, , , testedededd tttthehh prororoodud ct fffforororo rrreleasesese, , , ororor storerered d d tribbbbututututeeede it tooo markekekett. Innnn oooothhheere worordsdsds, if yououou o“virtual” company that is actually composedd otionshipp. Most impop rtant of these include techni-

cacacacallllllly y y y cocococompmpmpmpeteteetenenenent t tt rerereevivivivieweeww ooof ff thththe ee lalalabbb ananand d d thththe ee rererepopoportrtrtsssrerererececececeivivivivedededed ww—wwhihihihilelelele tttthehehehe cccconononontrtrtracacactt t lalalab bb isisis wwworororkikikingngng ooonnn yoyoyoururur

virtual comppany y that is actuallyy compop sed ofiffifiveveveve ppppeoeoeoeoplplplple e e e whwhwhwhoooo susususupepepepervrvrrvisisisiseee prpprprodododucucuct tt acacacquququisisisitititioioion,n,nmamamamanunununufafafafactctctctururururinininnggg,g cccconoonontrtrtrracacacacttt t tetetetestststinininggg, cccononontrtrtracacact tt dididistststrr

gxpand jv t .com JOURNAL OF VALIDATION TECHNOLOGY [AUTUMN 2010] 53

Scott Sutton.

are completely dependent on contract services for all microbiology testing services. While many of these companies would never consider being restricted to a sole supplier for a process raw material, they are will-ingly dependant on a single vendor for all microbiology-related quality functions.

The trend for a manufacturer to become dependent on a single test lab will not change as there are excellent business reasons to consolidate all testing volume to a single traceable location. How can the client be assured that the lab is qualified for these markets, rather than, for example, the food or clinical markets? This is not an easy task, especially as the company may not have any in-house expertise in microbiology. How can you tell a “good” lab from a “bad” lab in terms of testing for US Food and Drug Administration (non-food) regulated industries? Fortunately, there are guidance and infor-mational resources available. These same documents provide an invaluable resource for the contract lab to prepare for work in this area.

RECOMMENDATIONS FOR A SUCCESSFUL CONTRACT LAB EXPERIENCEThere are a variety of guidance documents to assist in this qualification effort. However, in my experi-ence as a consultant, I have noticed several common problems in the contract lab-client relationship that should be addressed. Also recommended are recent articles (1, 2) for a good basic review. In addition, I would also urge the following principles as guidance to a successful relationship:

Never trust a stranger with your moneyBring along someone who knows what is going onThere is no such thing as a free lunch Don’t try to fix a computer with a hammerNever test the temperature of the swimming pool with both feetIf it isn’t written down, it didn’t happen“Our people are the best!”“Our lab is the best because we operate under GLP, not just GMP”“What we have here is a failure to communicate...”“You don’t call, you don’t write, we don’t see you in years...”

These principles are briefly discussed as follows.

Never Trust A Stranger With Your MoneySeveral warning letters have been issued by FDA on the topic of use of contract labs. It has become an unfortu-nate practice for many manufacturing facilities to use contract labs as they would internal quality control

(QC) microbiology labs, except without the quality control measures in place. While it is tempting to rely on the contract lab’s quality assurance unit (QAU), the responsibility for the quality of the data never leaves the client. If the quality of the data from the contract lab is called into question, it is your products and your company’s reputation that will suffer in a recall. Always qualify the lab and perform ongoing full data reviews of all their work as it is completed.

Bring Along Someone Who Knows What Is Going OnAuditing a contract lab is a technical exercise as well as a quality activity. This article discusses different regulatory guidance documents that will help in point-ing out the important aspects of the microbiology lab. However, this is no substitute for having a subject matter expert along for the audit. The technical audit is at least as important as the GMP audit. It is best by far to have a balanced audit team. An important word of caution: An expert in another technical discipline does not have the appropriate background to serve as a subject matter expert in an unfamiliar area.

There Is No Such Thing As A Free Lunch While onsite at the contract lab, it will be tempting to develop friendships with your opposite numbers at the site, especially if the audit goes for several days. This natural tendency is not a bad thing, but it must not be allowed to influence the audit findings. Be careful about accepting lunch dates or other friendly overtures that might compromise your judgment and affect your eventual audit report. Everyone has to eat lunch, but be aware of the potential danger.

It will be important to develop a relationship with the lab and its contact person or people, but working with a contractor who is a friend makes it more diffi-cult to fire the lab, make demands of them, or to come down on them when needed. Do not let personal feelings cause you to compromise your responsibility to your company.

Don’t Try To Fix A Computer With A HammerThere are many different types of microbiology labs. Some specialize in environmental microbiological test-ing (as in toxic waste, not as in aseptic clean rooms), agricultural microbiology labs, food labs, etc. While they may try to make the argument that microbiology is all the same (it is, pretty much), they will not have the systems in place to handle medical device regulations

ood lab from a bad lab in terms of testing forand Drug Administration (non-food) regulated

es? Fortunately, there are guidance and infor-rral resources available. These same documentntnttsss san invaluable resource for the contract lalalaab bbb tofor work in this area.

regulatototory guidance documents that will help in point-innng g g ououout thththe e e imimi portant aspects of the microbiology lab.HoHH wewewever, thihihisss isisis nnno substitute for having a subject matterexpeeert alonngn fororor ttthehehe audit. The technical audit is at leastas important as the GMGMGMP audit. It is best by far to havea balanced audittt ttteaeam. An important word of caution:AAnA expert in aaanothththererer technical discipline does not have

MMENDATIONS FOR A SUCCESSFULLRACT LAB EXPERIENCEre a variety of guidance documents to assist qualificatatioon effort. However, in my experi-a consuultatantnt, I haavevee nnnototiccicededed ssseeeveeeral commomomon nn

ms in ththee coontntract laaab-client rrrelalalatiiionoo shippp ttthahahat tt

AAn expert in aanoththere technical discipline does not havetthe appropriatte e babackc ground to serve as a subject matter expeertrt in n ana unfnfamamiliar area.

There Is No SuSuch Thing As A Free LunchWhile ono site at ththee cocontntraracttct lllababab,, ititi wwwillilll bbbe tttemememptinggg toooded velolop p frfriei ndshhipps wiwitht your opppposite numumumbebebersr at tttheee

be adddrdresessesed. Alsso recommeeendddededed are rrreeecenenent (1,, 22)) for a gogoood baaasic revieeew.w.w. IInIn aaaddddddiitioioion,alllsososo urge the fofofolllowowowing prprinininncicicicippples aaas ss guuuuiddddaanana ce

cessful relationshhhiiip:veeerrr trtrtrust a aa stststrararanger wwwwitth hhh yourrrr mmmmononono eyng g g allono g sososomememeoono e whwhwhwhoooo kkknk owwws s s s whwhwhwhaat is gogogogoinnnng onre is no suchh thing as a free lunch

siitet , esespeecic alallyly iff tthe auaudiditt goggoes fooor severrralalal daaaysss. Thhhissnanatut raral tendndenncycy is not a a baabad thhhinnng, bbbutuut iitt mmmussts nnnoootbebee aaallll oowo ed to ininnfllueueencncnce thhhee aaaua ditt t findndddininngs. Be cccac rererer fufuufulabouttt accepting luluunchhh dadadatetetes or othhher ffff iiriendly overtttures thhhat migigight comomomprpp omissse ee yourrr jjjjudududu gmenenennt and d d d afafafaffefefefect youououur eveveventuuaal audddititit repe orrrt.t.t. EEvE eryooonnne hasss to eaaaat ttt luuuunnncn h, bbbututututbe aware of thhe potential dangerre is no such thingg as a free lunch

n’t tt trtrtry yy tototo fffixixix aaa cccomomompupupuputeteteter rr r wiwiwiwithhthth aaaa hhhhamamamammemememerrrrveeerr r teteteststst ttthehehe tttememempepeperararatutututurererere oooofff f ththththe eee swswswswimimimimmimimimingngngng pppoooooooolll l

be aware of the pop tential dangger.ItItIt wwwillll bebebe iiimpmpmpororortatatanttt ttto oo dedeedevevevevelolololop p pp a aa a rerererelallalatitittiononnonshshshshipipipip wwwwitititith h hh

thththe ee lalalabbb ananand dd itititsss cococontntntacacact tt pepepersrsrsonononon oooorrrr pepepepeopopopplelelele, bubububuttt t wowowoworkrkrkkininininggg g


Microbiology Topics.

or pharmaceutical GMPs. If they argue that it doesn’t matter, all indecision should be resolved and you should immediately leave. Their science might be excellent, but you will be responsible for the quality of the work. If the documentation will not pass inspection, it is of limited use in a recall investigation. The microbiology lab is a tool—use the correct one.

Never Test The Temperature Of The Swimming Pool With Both FeetThe microbiology contract lab may become a critical asset. You would never allow a critical process step to be dependent on a sole supplier, but many companies will only qualify one contract lab to provide testing. This makes sense if the lab does not change, and can always accept your samples in a timely fashion. It will not make sense if the lab itself transfers ownership or if it becomes very popular. A laboratory will be loath to turn business away. They will be motivated to accept all incoming work and may hire “temps” to perform your studies or try to cram too much work into the workday in times of excess testing. Always have at least two labs qualified and know how they track labor resources.

If It Isn’t Written Down, It Didn’t HappenMany contract labs send out reports that are woefully inadequate. 21 CFR 211.194 clearly states the minimum expectations for laboratory records. These requirements are further discussed and developed for the microbiol-ogy lab in the current version of United States Pharma-copeia (USP) chapter <1117> (3). Despite these clear expectations, many labs prepare reports that are little more than an executive summary of the test method and the results. This is appropriate for a Certificate of Analysis, not a lab report. Given the status of the contract lab as an extension of the company’s QC unit, lab reports are subject to the same QAU review require-ments as any other testing conducted in support of product release. Insist that all relevant lab records are provided. At a minimum, this proactive documentation should allow confirmation of all critical aspects of the test, and confirmation of all calculations (i.e., round-ing, averaging, log10 unit manipulations, most prob-able number [MPN], etc.). There are contract labs that provide complete GMP documentation—they will most likely be more expensive than the low end of the field.

“Our People Are The Best!”Team spirit is a wonderful thing, but numbers are bet-ter. Learn how the contract facility tracts resources and if you agree that this is a suitable measure. A starting

point might be the current USP <1117> (3) discussion on laboratory resources that urges trending of three aspects of lab resource adequacy. The first is the amount of time the sample, once received, remains in queue before the initiation of the test. The second measure is the amount of time between the final benchwork performed on the test and the release of the report. The final is the number of investigations performed on tests. Increases in these metrics might indicate a labora-tory that is insufficiently resourced either in number of people, availability of other resources, or adequacy of lab leadership. These measures should be available during the audit and can be invaluable in determining how the lab plans to meet your testing needs.

“Our Lab Is The Best Because We Operate Under GLP, Not Just GMP“This type of statement from the sales department of the contract facility should raise concerns. This openly stated belief strongly suggests that the facility is not familiar with current pharmaceutical requirements. The 21 CFR 210 and 211 requirements clearly call for GMP studies (see 21 CFR 210.3(b)(12) and 21 CFR 211.160) as Kuwahara’s (4) recent review article discusses. Secondly, this might indicate that the facility does not keep up with changes in regulatory expectations as the “supe-riority” of good laboratory practices (GLPs) over the perceived difficult and cost of GMPs was a popular position years ago. This belief has been largely sup-planted with the current thinking based on readings of the CFR. Make sure that you pay particular attention to the “quality” side of the audit if the microbiology lab is proud of their GLP compliance.

“What We Have Here Is A Failure To Communicate...”Making sure that all instructions and procedures are clearly documented is critical for both parties. The emphasis on this point is one of the particular strengths of ISO 17025 certification for both members of the relationship. From the client side, it prevents the lab from performing tests that are not reviewed by the client on material that is inappropriate to test. From the contract lab side, positive documentation of test requests provides the evidence that the specific test was contracted for that specific material (even if priorities have changed for the client). Phone call communica-tion is excellent for maintaining the personal rapport so important to the successful business relationship, but the record of the exchange is dependent on the party’s memories. It should be part of the base contract that

This makes sense if the lab does not change, aaandnn canalways accept your samples in a timely fasasashihihiononon. IIIt tt wiwiwillnot make sense if the lab itself transfeersrsrs ooownww ererershippp ooor r r ifififit becomes very popular. A laboratototoryryry wwwill bbeb loaththth toturn business away. They will be mmmotivated to accept allincoming work and may hire “tempmm s”s”s” to perform yourstudies or try to cram too much workkk intttooo the workdaaayyy

“Our Lab Is The Best Because We OpeUnder GLP, Not Just GMP“TTThT is type of statement from the sales departthe ee e cccoc ntract facility should raise concerns. Thistststataa ed belief strongly suggests that the facilitfafafamimmm liar with current pharmaceutical requiremestudies or try to cram too much workk intoo the workdayy

in times of excess testing. Always haveve aatt least two labssqualified and know how they track labbor resosourrceces.

Ifff It Isn’t Written Down, It Diddn’t HappenMaMaMany cooontrtrtracactt laalabsbsbs ssseenend dd out repoportrts ththat are wwoeo fully innnadddequaaateee. 21 CFR R R 21111.11 11194 cleaarlrlyy ststatatess the mmini imimum

faaammmiliar with current pharmaceutical requireme212121 CFR 210 and 211 requirements clearly call fssstudies (see 21 CFR 210.3(b)(12) and 21 CFR 21Kuwahara’s (4) recent review article discusses. Sthis might indicate that the facility does not wwwiththth ccchahahangngngesees iin nn reeegugulalalatoryrry expecctatitionons s asas thrrriooorittty”yy of gooddd laaaboratttororory yy ppractiicees (GLPLPs)s

exxexpepp ccctatiiionnns for laboooratttooory y y recoordrds.. TThesse rer quuiiremmenntstare fuff rrtrthhherr r discusseddd aaanddd dedevevelolopepedd ffor ththee mimicrobioiol-ogy lalalalab bb iiin the cururrurrerereenntntn versssis onnn oooff UUnU ited SStatt tetees PPhP arma-copeia ((((USUSUSPPPP)))) hhchapter <111777> (((3)3)3). Despite ttthheh se clearexexexexpepepepectatioioioionssss, manynyyy labababbs preppparrre ee repooortrr s thtt at aaarerr littltltleeemomomomorererer thaaan nnn anaana execucucucutitititivevevev summmamamary of f thththe ee test mmethooodddand the results This is appropriate for a Certificate

pppercrcrceiee veeed d d difficcculllt annd d d cosst oof GMGMPsPs wwaas a pppositionn yyyeeaears aaagooo. TTThihhis bbelil eff hasas bbeeenn largppplananananted wiwiwiwitththt theee curururrrerererennnt thinkkkinini gg g bababased onono rrreattthe CFCFCCFRRRR. Make sure ttthat you pay particulall r ato thehehehe “qualalalitititi y”yyy side e e ofoo theeee aaaaudududit if thththe e mimm crobobobioioiois pppprorororouuudu of thththeir GLLLP compmpmpmplililiaana ce.

and the results. This is appprp oppriate for a Certificateofofofof AAAAnanananalylylylysisisisis,s,s,s, nnnnotototot aaaa llllabababa rrrrepepeporoorort.t.t. GiGiGiveveven nn thththe ee stststatatatusuu ooof ff thththeeecocococontntntntrarararactctctct llllabababab aaaas anananan eeeextxtxtxtenenenensisisisionononon ooofff thththeee cococompmpmpananany’y’y’sss QCQCQC uuunininit,t,t,

“W“W“W“Whahahahat tt t WeWeWeWe HHHHavavavave e e e HeHeHeHerereere IIIs s s A AA FaFaFailililururure ee ToToToTo CCCComomomommumumumunininin cacacacatetetete...”””


Scott Sutton.

only work authorized in writing can be initiated and that work can only be halted by authorization in writ-ing. This agreement avoids potentially acrimonious misunderstandings later.

“You Don’t Call, You Don’t Write, We Don’t See You In Years...”Maintaining a contract lab relationship is an ongo-ing process. Laboratories change owners, especially in this time of economic flux (5). The lab should be physically audited on a regular basis with an eye to the technical execution of their tasks, not just the quality aspect. This is especially true for the microbiology lab, as it is frequently a target of the new corporate bean-counters in an acquisition. Set up an audit schedule for lab recertification that includes regular, full technical, and quality evaluations. “Phone audits” or “Survey audits” are not sufficient.

REGULATORY DOCUMENTS OF USE The following regulatory documents address the con-tract microbiology laboratory.

21 CFR 211The first place to look for regulatory expectations is 21 CFR. We will first look on the drug side in Section 211. 21 CFR 211.22(a) states:

“There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-pro-cess materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.”

Because this approval or rejection is one of the fun-dament purposes of the QC microbiology lab (either in-house or contracted out), it is clear that the manufac-turer’s QAU is responsible for the quality of those data. This includes, of course, not only finished product but also raw materials and components (see 21 CFR 211.84) and in-process bioburden (6).

The majority of laboratory guidance is provided in 21 CFR 211 Subpart I - Laboratory Controls (7). Initially, there is a requirement that “...establishment of any speci-fications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other

laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit.” If there is no microbiology group in the client’s organization, where does this leave the drafting of specifications? The cli-ent must assume this responsibility, but the design of the test is a shared obligation with the client holding the whip hand.

A recent situation I heard of included a ridiculously weak sterility test (1 unit, 1 medium/incubation con-dition). The lab was criticized—they definitely knew better—until they pulled out a pair of memos from the file. The first memo contained a formal notification to the client that the sterility test as designed was unsuit-able. The second memo was from the client telling the lab that the client wanted the test done in a particular way and that is what they were being paid for—the lab was to do as they were told. This pair of memos shifted the role of the microbiology lab from a consultant—an “expert” who had responsibility to guide the client—to the role of a contractor who was doing as the client instructed. There is a lesson in this story for both the client and the testing lab.

21 CFR 211.165 discusses testing and release. The following is a particularly interesting section that talks about accuracy, sensitivity, etc.:

“(e) The accuracy, sensitivity, specificity, and repro-ducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with 211.194(a)(2). “

We have always pretended that this does not really apply to microbiology, but we will later be discussing ISO 17025 where it is becoming clear that this willful avoidance is drawing to a close. The use of USP com-pendial tests may allow some leeway here (8), but this only works if the test is performed exactly as described by the USP or other cited reference. How many labs perform the test in precisely the same manner or have validated deviations from the compendial text?

The records for the testing are of critical importance in determining if the test was done correctly, and the lab can find a good deal of guidance in the CFR. 21 CFR 211.194 describes minimal records for all tests. The microbiology lab should add proactive documentation for all measurements that may have a significant effect on the outcome of the test. For example, if using pour plates and the method specifies that the agar tempera-ture be 45-48oC (to prevent solidification if too cool, or thermal injury to the cells if the molten agar was too hot), does the data sheet provide a means to record this

s in an acquisition. Set up an audit schedule for rtification that includes regular, full technical,ality evaluations. “Phone audits” or “Survey yyyare not sufficient.

LATORY DOCUMENTS OF USEowing regulatory documents address the con----

able. TTThheh second memo was from the client telling thelalaab b b thththaata ttthehehe ccclient wanted the test done in a particularwaww y aana d thththatatat iiis ss whww at they were being paid for—the labwas to do aasa thehehey yy weww re told. This pair of memos shiftedthe role of the microbobbioioiology lab from a consultant—an“expert” who hadadad rese ponsibility to guide the client—tothththe role of a ccoc ntntntraaactor who was doing as the clientowing regulatory documents address the con

crobiology laboratory.

211place too llooook for regulatory expectations is 21

e will fiirsrst t loooko on thhheee drddrugugug ssididideee ininin Section 2221111 . 211.22(2(aa) sstatatetes:

the role of a ccontntraractor who was doing as the clientiinstructed. Theherere iis a lesson in this story for both theclientnt andnd the ttesestting lab.

211 CCFRFR 221111.11656 discusses testing and release. Thefollowing is a particularly interesting section that talksabouut aaccuracy, sesensititivivitity,y, eeetctctc :.:

“(ee) TThehe accuracacy,, seensitivity, spppeecificity,y,y, aaandndnd reproroo-e shaall bbee aa qquala ityy cccontrol unnnit ttthahahattt shalalll hahahaveveveonsisibibility andd auuthohority to apppprprprooovee e ororor rrrejejejecececttt alaalll ennntsss, drug proddud ctctc cooontainererere s,s,s,s, ccclosuuurerrr s,,, iinnn-n ppprp o-teriiai ls, packaging mattte iiri llal, labeling, and ddd dddrug, , , ananand dd the auauauthththority totototo rrreveveve iew prprprprodddducuu tionnn recccoro ds

e e ttht ata no erererrorororrsr havvveee e ococooccccurredededed oooor,rr if errororoorsrsrs hhhave d hthat they have been fully investigatedd The

duducibibilityy of f tet st mmetthohodsds eempm loyyyeddd byy ttthhhe fffirii mmm shhhalllll bebe eesttaablishheded aandnd docummennentet d. Suuuchhh vvvalaalididatattioioionnn aaanddd dodoocuuummem ntatioon nn mamaay y y be aacccccccooomo plllisheheheed d d d in accorrrrdaaaannncn eee ewiiiththth 22211.194(a)((2)22 . “““

We hhhavaa e alalalwawaways preeetett ndedddd tttthahh t thhhisiii doeeees s s s nonononot realalallylylylyapaapply toto micccrororobibiologggy,y,y, bbbut wwwe will lllaaater bbbe e ee diiiiscsccscussiiingngngngISO 17025 whhere it is becoming clear that thhis willfuld, that they y have been fully y investiggated. The

cooontntntrororol ll unununititit ssshahahallllll bbbe e ee rerererespspspspononononsisisisiblbbb e ee e fofofofor rr r apapapapprprprprovovovovininining g gg ingngng dddrururugg g prprprodododucucuctststs mmmmaanananufufufufacacacactutututurererereddd,d pppprorororocecececesssssss edededed,

ISO 17025 where it is becomingg clear that this willfulavavavoioioidadadanccce e e isisis dddrararawiwiwingngng ttto oo a aa clcllclososososeee.e. ThThThThe ee e ususuuse eee ofoffof UUUUSPSPSPSP cccomomomom-pepependndndiaiaial tetetestststsss mamamayyy alalallololow ww sososomemememe llleeeeeeeewawawawayyy heheheherererere ((((8)8)8)8), bubububuttt ththththisisisis



critical test parameter, and how do you monitor it? Stan-dard records listing in 211.194 include the following:

Description of sampleStatement of method used—validation of test and demonstration of method suitabilityWeight or measure of sample Complete record of all data derived during the testRecord of all calculations performed during the testStatement of the test results and how they compare with expectationsInitials or signatures of all personnel involved with the testInitials or signature of a reviewer (competent to recognize errors)Complete records of any modifications to the test methodComplete records of any testing or standardization of standards, reagents, etc.Complete records of equipment calibration and maintenanceComplete records of stability testing.

This is a basic list that is expanded in USP chapter <1117>. I would want to draw your attention to the fact that the “responsible party” is to maintain docu-mentation of all raw data. Several contract facilities are now charging extra for this “service” of providing the client’s data to him. The form and extent of informa-tion provided in the test reports should be established early in the relationship, preferably before going to the expense of the qualifying audit.

ISO 17025In many respects ISO 17025 accreditation is a com-plement to the GMPs. Where the GMP grew out of responses to problems (9) and regulations meant to prevent further problems, the ISO 17025 was cre-ated out of whole cloth to provide a framework for a laboratory’s quality system. While it is certainly true that a quality system without science is pretty useless to a lab (doesn’t really matter what you do, just so that you document it well), science without a quality system resembles a university lab—great stuff going on (maybe) but substandard record keeping that would make it impossible to continue the work if the researcher left. Both competent science and a solid Quality system are required for our field and for ISO 17025 accreditation.

The thrust of ISO 17025 is to develop a complete laboratory system that drives the lab’s quality manage-ment system to completeness, while requiring identi-

fication of specific technical requirements for that lab that must be met. I know most readers are skeptical of another quality document to allow ISO certifica-tion of labs, but bear in mind that FDA microbiology labs, Health Canada microbiology labs, and many governmental labs in Western Europe and the Pan-Asia region are accredited to this standard (10). It is a reasonable position to expect a contract testing lab to be ISO 17025 accredited.

ISO 17025 provides much more detail in some areas where the documents overlap than is present in the GMPs. Some of these areas include test result reporting, measurement of uncertainty of test results (a sincerely frightening idea for microbiology once we become seri-ous about it), and significant detail on what exactly is meant by “proficiency.”

The strength of the program comes with the actual accreditation—this involves inspection and test-ing against the standards by a neutral third party. While this is, undoubtedly, a nerve-racking experi-ence (especially the first time), accreditation pro-vides a concrete and objective demonstration of the lab’s caliber. The requirements are along the fol-lowing topics:

Management requirementsOrganization. A clear description and operation of the laboratory organization, both as an entity and as part of a larger organization (if appro-priate). Demonstration of impartiality is also expected.Quality system. Requirements for a written qual-ity manual are detailed, its components described and a requirement all in the lab are familiar with it.Document control. The lab must maintain control over “quality” documents in terms of approval and issue, changes, revision control, etc.Review of requests, tenders and contracts. These requirements are to ensure the sales force does not oversell the lab’s capacities; does everyone under-stand what the client wants and if it is possible? Subcontracting of tests and calibrations. This sec-tion deals with what happens if some work needs to be subcontracted and requires the customer to be informed. The lab remains responsible for the subcontractor’s performance. These subcontrac-tors shall also be certified ISO 17025.Purchasing services and supplies. The lab keeps records, approves vendors, and employs quaran-tine and release system for incoming materials to ensure nothing is used until released.

Complete records of any modifications to ttthe test methodComplete records of any testing ororor ssstatatandnn aara dizazazatititionononof standards, reagents, etc.Complete records of equipmmment calibration and maintenanceComplete records of stability testststingg.g

ous about it), and significant detail on what emeant by “proficiency.”

The strength of the program comes with thaaaca creditation—this involves inspection aing gg g aaagainst the standards by a neutral thirWWhWhW ile this is, undoubtedly, a nerve-rackingnenennce (especially the first time), accreditatiComplete records of stability teststingg.

This is a basic list that is expanded iin USSPP chahaptp erPPP<1117>. I would want to draw your aattteentiion to ththe efafafact that the “responsible party” is to maintain docu-memementatiooon ofofof aallll rrrawawaw dddattta.aa Severaall ccontntrract faccililitities arennonowww chaarggging extraaa fororor ttthihh s “serrvivicee” ofof pprovvidid ngng the

ennnce (especially the first time), accreditativivivides a concrete and objective demonstratiolllab’s caliber. The requirements are alonglowing topics:

Management requirementsOrOrOrgagaganinin zazatitit onoon. A AA ccleaeaear r descriipttioionn anand d opof the laboooraaatory orororgagagannizationon, bothh aas a

clcliiientntnt’s dddattta to him. TTThhhe ffform m aandd eextetentnt of innfoormrmaa-tionnn prrrovvviddded in theee teeest rerr poportrts shshouldld bbe esestatablisheheddearly y yy inn tttheee relatioioioonsnsnsshhhip, pppprefefeeraaablblbly beforeee gooio nngn to the expense fffof ttthhhe qqualifying audiiittt.

IIISI O O O O 17020202025555In many respects ISO 17025 accreditation is a com

annnd d d as paaart of aa lllaaargeger oro gaaninizazatitioon (ipriaiaiateee). DDDemomomonsnsnsttr tatioion off impmparartit alityexpepepepecccted.QuQQuQuality sy ttstem. Requirementtts for a w iirittttity mamamaanununun al arereree detaiiiileleleled,d,d, its comomompopoponenttts s s dddaaana d a reeequirememement t alalala l ininin the lababab aare famamamiiiitIn many y resppects ISO 17025 accreditation is a com-

plplpplememememenenenent t t t totototo tttthehehehe GGGGMPMPMPMPs.s.s.s. WhWhWWherereree e thththe e e GMGMGMP PP grgrgrewewew oooututut ooofff rerereespspspspononononsesesesesss s totototo ppprorooroblblblblemememems sss (9(9(9(9)))) anananddd rereregugugulalalatititionononsss mememeanananttt tototo

it.DoDoDoDocucuucumememementntntnt cccconononontrtrttrolollol.. ThThThThe ee lalalabbb mumumuststst mmmaiaiaintntntaiaa nnovovovoverererer “““ququququalalalalitititity”y”y”y ddddococococumumumumenenentststs iiinn n tetetermrmrms ss ofofof aa


Scott Sutton.

Service to the client. The lab is to provide good service, communicate with the client.Complaints. The lab is to have a complaint reso-lution policy. These and the corrective actions are to be trended.Control of nonconforming testing and/or calibra-tion work. The lab has procedures in place for work that does not conform to its own procedures or the client requirements. Corrective action is implemented.Corrective action. This section is fairly large with discussions of cause analysis, implementation, and monitoring of corrective actions, and finally a determination of additional audits are required.Preventive action. The lab is to have a program in place to look for needed improvements and potential problems to be corrected. This infor-mation might come from a robust program of trend analysis.Control of records. This section describes the need for procedures for control (“identification, collection, indexing, access, filing, storage, main-tenance and disposal”) of quality and technical records. This section also provides basic data recording information. Internal audits. The lab is required to have com-plete internal audits, generally on an annual cycle. Management reviews. ISO 17025 also requires periodic, scheduled management reviews that cover the quality program and consider audit reports (e.g., internal, client and external body), corrective and preventative actions, proficiency test results, changes in volume or type of work, client feedback, complaints, resources, QC activi-ties and staff training.

Technical requirementsGeneral.Personnel. The standard requires the workers to have training, education, experience, and proficiency suitable to their job function (also see discussion of USP <1117>). There will be a formalized method to determine if a technician is qualified for a particular activity and how to determine what training is required. Any tem-porary workers will operate under this system. There will be job descriptions for technical and key support people.Accommodation and environmental conditions. The laboratory will have appropriate facilities in terms of the following:✦ Lighting

✦ Environmental conditions (monitored and appropriate)

✦ Sufficient separation between incompatible (“clean” and “dirty”) activities

✦ Controlled access to the lab✦ Measures of good housekeeping will be

collected. Test and calibration methods and method vali-dation. The lab must use appropriate methods and be able to cite the relevant reference for the method using appropriate, calibrated equipment. There is guidance on how to select these methods.Equipment. The lab must have sufficient equip-ment, of appropriate accuracy to perform the work. This equipment must be on a calibrated condition and operated by qualified and trained personnel. Records of all activities shall be kept.Measurement traceability. This section deals specifically with activities associated with cali-bration, testing and reference standards and the expectations associated with these activities. Sampling. The laboratory is expected to have sampling plans for testing and calibration, and these are to be in a defined procedure.Handling of test and calibration items. The lab is expected to have procedures for the transporta-tion, receipt, handling, protection, storage, reten-tion of test and calibration items, along with the identification of these items to prevent confusion. There shall also be procedures to accept items for testing, and to stable storageAssuring the quality of test and calibration results. The lab shall have QC procedures for monitoring the validity of test results and calibrations, and these results shall be in a format to allow detec-tion of trends.Reporting the results. The results shall be reported accurately, clearly, unambiguously and objectively and include all information requested by the cli-ent and necessary for the interpretation of the test or calibration results. If relevant, deviations shall be reported. If opinions are included, the lab will document the basis on which the opinions and interpretations are made.

USP <1117>Another regulatory document specifically aimed at laboratory operations is the USP informational chapter <1117> “Microbiological Best Laboratory Practices.” USPchapter <1117> is organized on operational lines, with different sections devoted to the following:

eventive action. The lab is to have a program place to look for needed improvements and

otential problems to be corrected. This infor-rration might come from a robust program ofofofofend analysis.ontrol of records. This section describes ttttheheheeeed for procedures for control (“identification,,,,

woww rk. This equipment must be on a calibratedcondndnditititioi n and operated by qualified and trainedpersrsrsonononnenenel.l.l. Records of all activities shall be kept.Meaasa uremememenenent traceability. This section dealsspecifically wititithh h activities associated with cali-bration, tesesestititingn and reference standards and theexpectatatationsnn aaassociated with these activities.eed for procedures for control ( identification,,,

llection, indexing, access, filing, storage, main-nance and disposal”) of quality and technicalcords. This section also provides basic data cording ininfformation.ternal aaududitts.s The lababab iiiss rereequququiririrededed ttto have cccomomom-ete inteternrnalal auudits, geeenerally onnn ananan aaannual cycycycle.e.e.

expectaationsns associated with these activities. Samplingng. ThThe laboratory is expected to havesampmplingg ppllans for testing and calibration, and ththese arare e tto be in a defined procedure.Handling of test and calibration items. The lab isexexpected ttoo haaveve pprorocececedududurerees fofof rr thththe tttraaansporrrta---titionn, , receipptt, hhanndling, proteeectttion, stototorararagegege, reteeennn-

anaggemementnt revviewsws. ISO 17002555 alalalssso reqeqequuuirereress eriododiic, schedudulledd mmmanagemmmennnt rrrevevevieieiewsww ttthahhatt ovevever the qualititty prpp oogogram anananand dd d conssssidddeeere aaaauuudu itports (e.g., internalll, clilillienttt and external bbbbody), rrrrrrececectitt ve aaandndnd pppreveeentnnn atatattivii e acccctitititionnnns,ss prooofiff ciiienee cyststst resesultsss, ,, chchchananangess inininin vvvvooolummme ee e orororor tttype ofofofo wwwwork,ient feedbackk complaints resources QC activi

ttionn of f testt aandd ccallibibraraation iiiteems, aaalooong g g wiwiwith tttheeeiidentiifificaatitioon of thesse e itttems to preeeveveve tnt connnfufufusiononon. TThere shhalaa l aalsososo be prprprocococo edurrresss tooo o aaaca cept iteeeemsmsms forororottet sting, andndd to stststabababllle storageAsAsAssuringngng ttthehh quaaalill ty of ff teteteestststs and ccccalaa ibraaaatitititionononon resullltstststs. ThThe labbb shshshala l haaaveveve QQQC ppproooceduuureees forrrr mmmmononononitorininingg g g the validid ty of test results and calibrations andient feedback, complp aints, resources, QC activi-

esss aaandndnd ssstatataffffff tttrararaininininining.g.gg.hnininicacacal ll rererequququiririremememenenentststss

the validityy of test results and calibrations, andthththesesese ee rereresususultltltsss shshshalalall ll bebebe iiiin nnn aaaa fofooformrmrmrmatatatat tttoooo alalalallolololow w w w deededeteteteteccc-cctititiononon ooof f f trtrtrenenendsdsds.



Media preparation and quality controlPreparationStorageQC testing

Maintenance of microbiological culturesLaboratory equipmentLaboratory layout and operationsSample handlingMicrobiological media incubation timesTraining of personnelLaboratory resourcesDocumentationMaintenance of laboratory recordsInterpretation of assay results.

This chapter was significantly changed in the 2010 revision (3) and included completely new sections on sample handling, media incubation times, and labo-ratory resources. In addition, all other sections were modified, with major changes in the sections devoted to equipment, training, and media. This informational chapter was written to be a tutorial but can be easily converted to an audit checklist for ease of audit review. Familiarity with this chapter should be an essential part of preparation for the audit of the contract lab facility by all members of the audit team.

PIC/S Aide Memoire to Inspection of Pharmaceutical Quality Control LaboratoriesPIC/S is the acronym for both the “Pharmaceutical Inspection Convention” and the “Pharmaceutical Inspection Co-operation Scheme.” Currently there are about 30 cooperative national regulatory bodies in PIC/S, which exists “to lead the international develop-ment, implementation and maintenance of harmonized Good Manufacturing Practice (GMP) standards and quality systems of inspectorates in the field of medicinal products” (11). The interested reader is referred to an excellent review by Lyda (12).

This particular document is designed to be an inter-national aid in training inspectors and in preparing for an audit visit. As such it is an excellent prepara-tory document for looking to an audit of a contract lab. The first sections involve general considerations in a laboratory audit, followed by two appendices–one for analytical chemistry labs and the other for microbiol-ogy labs with issues specific to each. The document describes its purpose as:

“Inspections of sites involved in testing of medicinal products should be more and more specific, thorough

and conducted under normal working environment. These inspections may include a complete assessment of laboratory’s conformance with the code of GMP or they may be limited to specific methodology or aspects of the laboratory. Inspection process of a laboratory involves the assessment of laboratory functions in full operation. Consequently, PIC/S has developed the Aide Memoires, which can be considered a good tool for enhancing the understanding and performance of inspectors…”

“The purpose of this document is to provide guidance for GMP inspectors to assist in training and preparing for inspections” (11).

The full document is available on the PIC/S website (http://www.picscheme.org). The document outline is provided as follows:

Quality Assurance SystemGeneral Ensuring Suppliers QualitySelf Inspection Change ControlTrendingRisk Management

Documentation system General InformationLaboratory DocumentationData TraceabilityElectronic Documentation/Computerized Systems

Personnel General Training

Premises and Equipment PremisesEquipmentEquipment ValidationCleaning/SanitationMaintenance

Materials and SuppliesMaterialsWater/Water Systems

Sampling and SamplesSamplingSamplesPersonnel for Sampling

TestingTesting GeneralTesting of Raw MaterialsIn-Process Controls (IPC)Testing of IntermediatesTesting of Final Products

This chapter was significantly changededd iiinnn ttht e e e 2020201011revision (3) and included completelyyy nnnewewew sececectionnns ss onononsample handling, media incubatiooonn n tititimmem s,,, and laaba o-ratory resources. In addition, alalall ll other sections weremodified, with major changes in thththe e e sess ctions devotedto equipment, training, and media. TTThihh s inii formationaaalll

(http://www.picscheme.org). The document oprovided as follows:

Quality Assurance SystemGeneralEnsuring Suppliers QualitySelf Inspection Change Controlto equipment, training, and media. TThhis iinformationaal

chapter was written to be a tutorial bbutut can be easilyyconverted to an audit checklist for ease oof auudidit reeviv ew. Familiarity with this chapter should be e ann eessentiti lal parart tofofof preparation for the audit of the contract lab facility bybyby all mememembebebersrs oooff f thththe ee auauaudit teamm.

Change ControlTrendingRisk Management

Documentation systemGeneral InformationLaLaLaboboborararatotoryrr DDDococcumumumeneentationnData Traceeeabbbility

PIIPIC/C/C/S SS AAAiddde Memoioio rerere ttto Innspspece titionon offPhaararmamamaccceutical QQQuauaualiityty CConontrtrololLabobobooraaaatoooriesPIC/S SSS iiiis ttthhhhe acronym for bbboth hh ttht e “Pharmaceutical InInInInspspspspectionononon CCCConveeeentnnn ioiooon” andnn ttthe “PhPP araa macececeuticalalalIIInI spspspspectionononon CCCCooo-oppppererereratatatatiooon Scchehehemme.” CuCuCurrrentllyy thererereeeare about 30 cooperative national regulatory bodies in

ElElElececectronicc Docococummenentattionon/C/ComompuSyyystss emmms

PersononononnelGeGGeGeneralTrainininingngngn

PrPrPrPremeee iseseses and EEEqquipppmmmem ntntnt Premisesare about 30 coopep rative national regug latoryy bodies in

PIPIPPIC/C/C/C/S,SS,S, wwwwhihihihichchchch eeeexixixixisttststs ss s “to oo o lelleleadaadad ttthehehe iiintntntererernananatititionononalalal dddevvvelelelopopop-mememementntntnt, imimimimplplplplememememenenenntatatatatitititionononon aaaandndndnd mmmaiaiaintntntenenenananancecece oooff f hahaharmrmrmonononizizizededed

PremisesEqEqEqEquiuiiuipmpmpmpmenenenenttttEqEqEqEquiuiuiuipmpmpmpmenenenenttt t VaVaVaV lilililidadadadatitititiononono


Scott Sutton.

Stability TestingValidation of Test Methods

Results and Release of Test ResultsHandling of Test ResultsFailures–Out-of-Specification Test Results (OOS)Failures—Re-testing and Re-samplingTest Results Release/Analytical Reports/Certification

Supplement No.1: GMP inspection in chemical and physical-chemical laboratoriesSupplement No.2: GMP inspection in microbio-logical laboratories.

SUMMARYThere is a wide range of microbiology testing labs on the market. All are eager for your business. As the GMP manufacturer, you are responsible for the work performed by the lab on your product and for your decisions based on that work. This will not be a prob-lem if there is never a problem. However, if one of you products becomes involved in a dispute on the market or with FDA, the quality of the microbiology work involved in release of that product could become very important indeed. If the work is poor, or not able to pass GMP-style audit, the testing lab will probably express regret for the inconvenience, but you may be faced with recall or legal action.

This article has provided some pointers for qualify-ing a microbiological laboratory for GMP work. It is not intended to be comprehensive but rather provide pointers for where to look for more complete informa-tion. I would strongly urge that the audit team include at least one individual with experience in microbiology who can serve as a subject matter expert to the rest of the team.

REFERENCES1. Nims, R and Meyers, E., “Contractee Responsibilities in

Outsourced Pharmaceutical Quality Control Testing,” BioProcess International. 8(5):26-33, 2010a.

2. Nims, R and Meyers, E., “Contractor Responsibilities in Outsourced Pharmaceutical Quality Control Testing,” BioProcess International. 8(6):16-20, 2010b.

3. USP, <1117> Microbiological Best Laboratory Practices, USP 33 Reissue, Second Supplement:R-1100-R-1105, 2010.

4. Kuwahara, S., “GLP and GMP in Contract Testing of Drugs and Biologics—What’s the Difference?” J GXP Compliance 13(2):11-14, 2009.

5. Miller, J., “Contract Organizations Are the Sell of the Sea-son,” Pharm Technol. 33(4):82 – 83, 2009.

6. Sutton, S., “The Revised cGMP—21 CFR 211 (ef-fective December 8, 2008),” PMF Newsletter 14(12) http://www.microbiologyforum.org/PMFNews/PMF-News.14.12.0812.pdf

7. FDA, Title 21—Food And Drugs, Chapter I—Food And Drug Administration Department Of Health And Human Services Subchapter C—Drugs: General, Part 211 Current Good Manufacturing Practice For Finished Pharmaceu-ticals, Subpart I--Laboratory Controls, 43 Federal Register 45077, Sept. 29, 1978.

8. 211.194 Laboratory Records (a)(2): “A statement of each method used in the testing of the sample. The statement shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested. (If the method employed is in the cur-rent revision of the United States Pharmacopeia, National Formulary, Association of Official Analytical Chemists, Book of Methods, or in other recognized standard refer-ences, or is detailed in an approved new drug application and the referenced method is not modified, a statement indicating the method and reference will suffice). The suitability of all testing methods used shall be verified under actual conditions of use.”

9. Immel, BK., “A Brief History of the GMPs for Pharmaceu-ticals,” Pharm Technol July:44-52, 2001.

10. Weitzel, MLJ., “ISO/IEC 17025:2005 and Pharmaceutical Testing Laboratories,” PDA Letter 17(10):8, 2006.

11. PIC/S, PI 023-2 Aide Memoire to Inspection of Pharmaceutical Quality Control Laboratories, 2007.

12. Lyda, J., “PIC/S: Why is it Important? What is its Impact? A Perspective on the Organization “Of-By-For” Inspec-tors,” PDA Letter 18(3):1 & 17 – 23, 2007. JVT

ARTICLE ACRONYM LISTINGCFR Code of Federal RegulationsFDA US Food and Drug AdministrationGLP Good Laboratory PracticeGMP Good Manufacturing PracticeISO International Organization for StandardizationMPN Most Probable NumberOTC Over the CounterPIC/S Pharmaceutical Inspection Convention and

Pharmaceutical Inspection Co-operation Scheme

QAU Quality Assurance UnitQC Quality ControlUSP United States Pharmacopeia

a wide range of microbiology testing labs onrket. All are eager for your business. As theanufacturer, you are responsible for the work

med by the lab on your product and for youuuurrr s based on that work. This will not be a prprprprobooo -

here is never a problem. However, if one e e e ofofofofducts becomes involved in a dispute on theeee

shallll ll indicate the location of data that establish that themememe hthhododods s s usuu ed in the testing of the sample meet proper stttaana daaardrdrdss s ofofof aaaccc uracy and reliability as applied to the pprp oduct t t testededed. (I(( f the method employed is in the cur-rrrent revision of the UUUnited States Pharmacopeia, NationalFormulary, Assssssooco iai tion of Official Analytical Chemists, Book of Meeetththododods,, or in other recognized standard refer-rrducts becomes involved in a dispute on theee

or with FDA, the quality of the microbiology volved in release of that product could become portant indeed. If the work is poor, or not ableGMP-stylyle aua dit, the testing lab will probablyregret fforor thhe incoonvevveninienenencecece, bububuttt you maaayyy bebebeth reccalalll oror legegal aactttion.

Book of Meethodods,s, or in other recognized standard references, or is ddetetaiaileled in an approved new drug application anandd ththe e refereencnced method is not modified, a statement indidicating tthehe method and reference will suffice). The suitability of all testing methods used shall be verifiedunndeder actual conondititiononss ofof uuusesse ”.”

9. Immmmell, BKB ., “A BBrieef HHistory of theee GGGMPs fooor r r PhPP aaarmaccceuuu-articlele hhasas pprrovvidedd sssome poinnntererers ffofor quququaaalifffyyy-yyicrobobiiologicaal laabooraaatory for GMPMPMP wwwororrkkk. ItItIt iis ndddeddd to be commmprprprehehhensiveeee bbbutututu rathhheh r prprprp ovovovovidefffor where to lo kkok fffor more complete iii ffnforma-

wwouououldldld stronononglglgly yy urgeee tttthaaaat tt the auauauaudiiiittt teammm iiinccclull deoonenene indn ividididuaaal withhh eeeexpxpxpxpeeeriencncceee e inininin mmmicrooobbbbiolooo ogy n serve as a subject matter expert to the rest of

ticacals,”” PhPhaarm TeTechnooll Julyly:4:444-52,, 200001.101 . WWeiitzel, MMLJLJ., ““ISSO/IEC 171702225:2000555 anddd PPPhharmaaca eeeutiiicaaal

TeTeTesttting Laborrar toorieseses,”,, PDDAA A LLLeL tter 177(10000):):):) 8, 2006.r11. PIPIPIC/C/C/S, PI 023-2 AAAide MeMMemmoire to Inspectioii n of Pharmaceutiitical

Qualalalitii y Contntntrororol ll Laboraaatott ries, 20202007070 . 12112. Lyda,, J., “PPPICCC/S/S/S: Whhhy y y isisis it Impopoportant??? WWWhatttt iiiis sss ittttsss Impaaactctctt? ???

A Perspecti e on the Organi ation “Of B For” Inspecn serve as a subjej ct matter expep rt to the rest of m.

A Perspective on the Orgganization Of-Byy-For Inspec-cctototorsrsr ,” PDPDPDAAA LeLeLettttttererer 181818(33):):111 & && 17171717 ––– 22223,3,3,3, 222200000000777. r JVJVTTT

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