A very common question asked bymanufacturers, suppliers and contractlaboratories is: “what should be on acertificate of analysis?” Let’s start fromthe beginning by defining a “certificateof analysis” or “CofA.”Alas, that modern mainstay of elec-

tronic information, Wikipedia, is silenton the topic. A Google search, howev-er, turns up hundreds of examples ofactual certificates but surprisingly fewdefinitions. A useful starting point

might be an online bank glossary,which states: “Certificate of Analysis:A document usually issued by aninspection firm attesting to the qualityor purity of exported commodities.The document is often required eitherby the importer or by government reg-ulation in the importing country.”According to a Pharmaceutical Vali-

dation Blog, “…the Certificate ofAnalysis of a Drug or Formulationgives the exact details about its qualityand compliance to specifications and isa document relating specifically to theresult of testing a representative sam-ple drawn from the specific batch or lotof material it is purported to repre-sent.” The CofAis the documented evi-dence of the quality control testing car-ried out on the drug or formulation. Inshort, a CofA is a piece of paper thatcertifies something. Since it’s a certifi-cate of analysis, that is what it certifies,an analysis.Turning to the dietary supplement

GMP regulations is not overly helpful,as FDA stated in the preamble to thefinal rule that itwoulddecline to defineCofAs. Although a parenthetical com-ment in the preamble, which lacks theforce of law, notes a CofA is a docu-ment, provided by the supplier of a

component prior to or upon receipt ofthe component that documents certaincharacteristics and attributes of thecomponent.” Section 111.75 titled“What must you do to determinewhether specifications are met?” saysyoumust test or examine everything tosee whether or not specifications aremet, but the final rule also says you canrely on a CofA in lieu of testing orexamination. Despite the lack of a fulldefinition Section 111.75(a)(2)(ii)(B)does require that a CofA include sever-al features: a description of the test orexamination method(s) used; limits ofthe test or examinations; and actualresults of the tests or examinations.Now, imagine you are a manufac-

turer and are required to have specifi-cations and test results, but you do nothave a lab. That is where the CofAbecomes important. If you want tobuy that low cost raw material buthave to show the FDA that it meetsyour high standards, then you need toget a CofA that proves your standardswere met. No lab, no CofA, FDA canshut you down.Keep inmind aCofAmay playmany

roles and the GMP standards requirethat manufacturers set and test againstspecifications for pretty much every-thing from raw materials (includingbottles, labels, the cotton used in thebottles, colorants, the excipients anddietary ingredients) to outgoing fin-ished products.Also remembering thatthe GMP applies to manufacturers andnot to farmers or raw material suppli-ers, the question “what should be on acertificate of analysis?” should bedirected inward rather than outward.Section 111.70 of the GMP, “What

specifications must you establish?”tells you (111.70 (b)) that for each com-ponent you use in themanufacture of adietary supplement, you must estab-lish component specifications as fol-lows: (1) You must establish an identi-ty specification (remember a CofAalone will not work for identity); (2)You must establish component specifi-cations that are necessary to ensurethat specifications for the purity,strength and composition of dietary

30 • www.nutraceuticalsworld.com Nutraceuticals World • November 2008

QUALITY FOCUS

Certificates ofAnalysisWhat is that pieceof paper andwhat role does itplay in GMPcompliance?

By Paula Brown

Paula Brown, Director of the Natural HealthProduct Research Group (NRG) at BCIT,directs a multi-disciplinary research facilityprovidingfundamental investigationsonprod-uct quality, safety and efficacy. In establishingNRG, Ms. Brown has created the capacity tosupport industry through the entire continu-um, from grower to manufacturer, ensuringproduct integrity ismaintained. Anactivevol-unteer, she is a founding member of the NHPResearchSocietyofCanada, anon-profit groupdedicated to supporting and promoting scien-tifically rigorous research and education onNHPs. Ms. Brown is also General Referee forthe AOAC Dietary Supplements MethodsCommittee. She can be reached BCIT, 3700Willingdon Avenue, Burnaby, BC, Canada,V5G 3H2; E-mail: pbrown@bcit.ca; Website:www.bcit.ca/appliedresearch.

supplements manufactured using thecomponents are met; and (3) You mustestablish limits on those types of con-tamination that may adulterate or maylead to adulteration of the finished batchof the dietary supplement to ensure thequality of the dietary supplement. So toanswer the question, “What should beon a CofA?” The answer is that the CofAshould demonstrate all the specifica-tions have been met.While there are certainly industry stan-

dards that may be covered by a genericCofA, remember the information on thatpiece of paper has to certify your specifi-cations for quality have been met. If youchoose to accept somebody else’s specifi-cations as yours, then be prepared for thepossibility that a change of suppliercould mean the CofA they provide is dif-ferent. If that’s the case, you have justchanged your specifications (whetheryou wanted to or not) and you’re going

to have to go back through ALL yourGMP paperwork, including your masterbatch records, and make changes toreflect that change. You’re better off com-municating to your supplier your specifi-cations. If theywon’t cooperate or cannotmeet these specifications, I suggest youfind another supplier.There are several major pieces of

information thatmust be on everyCofA:the specifications and their acceptancecriteria, the names of the tests used foreach specification, and the results ofthose tests. (Remember too that the bur-den is on the manufacturer to demon-strate the tests used have to be scientifi-cally valid.) This information must beprovided for each batch or lot number.CofAs with no batch or lot numbers,with the same photocopier stripes as thelast seven certificates, or with the exactsame numerical test result values to foursignificant figures, are not acceptable.

You cannot accept just any old piece ofpaper. Under final Section 111.75(a), amanufacturer may rely upon a CofAfrom its supplier of a component, pro-vided that certain criteria are met, in-cluding the following: (1) The firm firstqualifies the supplier by establishing thereliability of the supplier’s certificate ofanalysis through confirmation of theresults of the supplier’s tests or exami-nations; (2) the certificate of analysisincludes a description of the test orexamination method(s) used, limits ofthe test or examinations, and actualresults of the tests or examinations; (3)the firm maintains documentation ofhow it qualified the supplier; (4) the firmperiodically reconfirms the supplier’scertificate of analysis; and (5) the firm’squality control personnel review andapprove the documentation setting forththe basis for qualification (and requalifi-cation) of any supplier.

Nutraceuticals World • November 2008 www.nutraceuticalsworld.com • 31

QUALITY FOCUS

32 • www.nutraceuticalsworld.com Nutraceuticals World • November 2008

QUALITY FOCUS

Basic Anatomy of a CofAHaving nowdiscussed both the broad

requirements (specifications, tests, testresults, batch numbers) that should beon every CofA, and remembering thereare different types of CofA (incomingdietary supplement components, fin-ished products, reference materials,etc.), we can move on to the CofA tem-plate. According to the bloggers cited atthe beginning of this column, a basictemplate includes a header, a body, cer-tification and compliance statementsand a footer. (See Table 1.)The header should have the term

“Certificate of Analysis”; the name,address, and phone number of the com-pany providing the certificate, as well asthose of the manufacturer for whom thecertificate is intended; the name of thematerial or formula being certified; andthe category into which it fits (dietary

component, dietary ingredient, in-process control, finished product).The body of a CofA should include

the lot/batch number to which the cer-tificate applies, the date of manufac-ture or production of the materialbeing certified, the product code ornumber, the expiration date (if there isone), the recommended re-evaluationdate (if required) and a stability state-ment (if required). Within the body isthe heart of the CofA, the analysis sec-tion. It should include the name of thespecification, the acceptance criteriafor determining whether or not thespecification has been met, the nameof the test(s) used with references andthe test results along with test methodtolerances. The results section containsthe data and/or observation. Wordslike “passes” or “complies” are notrecommended, as they are not clear

and do not describe the observa-tion/data that lead to such a determi-nation. Any substance that is testedagainst specifications laid out in apharmacopeial or other compendialmonograph must list all tests from themonograph and the results.The certification and compliance

statements section provides an affirma-tive statement that the material com-plies with the intended specification(e.g. a pharmacopeial standard or thespecifications laid out in a master batchrecord for the product) along with a ref-erence to the specification (e.g. USP34/NF 28, In-House Specification#XXXX for Finished Product #YYYY). Ifthe reference is an in-house specifica-tion, this should be noted, and a copy ofthe written specification, with the asso-ciated tests, should be a part of the man-ufacturer’s GMP paperwork.Finally, the last part of a CofA is the

footer, which includes the name andtitle of the analyst(s) who performedthe analysis/analyses, the name of theperson who approves or authorizes thefindings presented in the certificate,their respective original signatures andthe date of approval. The footer shouldalso include the page number and thetotal number of pages associated withthe CofA and various significant dates,such as the date of manufacture, theexpiration date (if applicable), theanalysis date(s) and the batch releasedate for the certified material.While this discussion has focused pri-

marily on incoming components,including dietary ingredients, recall thatSec.111.35(g) requires testing of eachbatch of finished product when possible(and justification for not testing whennot possible). FDA has made it clear inthe preamble that the manufacturer cantest, examine, rely on a certificate ofanalysis (other than to verify the identi-ty of dietary ingredients), or, in the caseof a specification that is exempted fromperiodic testing of a finished batch, relyon other information that ensures thatsuch an exempted product specificationis met. NW

References furnished upon request.

Table 1ITEMSTHAT BELONG ONA CofA:

• “Certificate of Analysis”• Name/address/phone number of supplier and manufacturer• Name of raw material/finished product• Category: (component, ingredient, in-process, finished product)• Lot/Batch number• Date of manufacture (of material being certified)• Product Code or Number• Expiration date of certified material (if applicable)• Re-evaluation date (if applicable)• Stability statement (if required), e.g. store at -80°K•Test name(s)—note may include physical descriptions, chemical tests for contami-nants as well as desirable characteristics—chemicals like caffeine will require only afew specs and tests, botanicals and extracts will require more•Test reference(s), e.g. USP 28/NF 34•Test results—actual values as well as the pass/fail designation• Acceptance Criteria—usually something along the lines of “not less than x, or notmore than y”• Certification of compliance—something like “this material complies with the speci-fications set forth in XXXX (e.g. USP 34/NF 28, In-House Specification) for the man-ufacture of Finished Product QQQQ as described in Master Batch RecordVVVV”• Printed name(s) and signature(s) of analysts• Printed name and signature of Approver• Page number and total pages, e.g. page 1 of 5• Date of manufacture of the material being certified• Expiration date (if applicable)• Analysis date(s)• Batch release date for the certified material