PP eople entering orbecoming familiar with thepharmaceutical industry,including the productionof drugs and vaccines

through biotechnology, quicklyencounter a set of regulatoryrequirements known as “GoodManufacturing Practices” (GMPs).For companies, following GMPs isessential to getting new productsapproved by regulatory agencies andfor producing drug products thathave the required safety, identity,strength (or potency), purity, andquality. For individuals — at alllevels — adhering to GMPrequirements and principles iscritical so that every action anddecision contributes to productsthat meet the expectations ofpatients, healthcare professionals,and regulatory agencies.

So just what are GMPs anyway?They are the requirements thatmanufacturers of regulated health-care products must follow so thatthe products they make have thesafety, identity, strength (orpotency), purity, and quality thatthey purport or are represented tohave. Expanding upon the definitiongives us a richer understanding.

GMPs are the requirements . . . Inmost countries, GMPs have a legalaspect: They can be part of anation’s food and drug law (as theyare in Canada) or regulations thathave been issued by a regulatory

agency (as in the United States).These requirements are enforced byregulatory officials who evaluatecompliance through on-siteinspections, review of documents,and random testing of products. Forexample, the Canadian HealthProducts and Food BranchInspectorate (HPFBI), Britain’sMedicines Control Agency (MCA),and the US Food and DrugAdministration (FDA) conductinspections of manufacturingcompanies in their respectivecountries and in most cases,companies in other countries thatexport into their countries.

One aspect of GMP that isdifferent from other types ofregulation is that not all therequirements that need to befollowed are clearly written in theregulations or in supplementalguidance documents that regulatoryagencies frequently issue. The FDAexpects many things that aren’tspecifically stated in its regulations.The FDA does state, however, thatits “Current Good ManufacturingPractices” or cGMPs (sometimeswritten CGMP) are the “minimumrequirements” (1), and that whatdefines a manufacturing practice ascurrent and good is being “feasibleand valuable in assuring drugquality”(2). In other words, theFDA expects companies to use thesystems and practices that providethe best control over a process orproduct or information used to

make a decision about a process orproduct. These evolvingexpectations make understandingand implementing GMPs a dynamicactivity that needs continual review.

That manufacturers . . . Anyoneinvolved in pharmaceuticalproduction — including theproduction of clinical trial materials— is subject to GMPs. The USFDA defines covered groups asthose working in “manufacture,processing, packing, holding,including packaging and labelingoperations, testing, and qualitycontrol”(1). The Canadian GMPsapply to the “fabrication, packaging,labeling, distribution, testing, andwholesaling” of drugs (3). Forcompanies that use contractors formanufacturing or testing, GMPsapply to both the contractor and,ultimately, the company that has itsname on the label.

So So What What Are GMPAre GMPs,s, AnAnywywaay?y?by James L. Vesper

PHOTODISC (WWW.PHOTODISC.COM)

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Of regulated healthcare productsmust follow . . . The specific productsthat must be manufactured underGMP vary, but most countriesinclude at least prescription andover-the-counter medicines, bloodand blood-derived products,vaccines, antitoxins, and activepharmaceutical ingredients that aremarketed, sold, or distributed.

Have the safety, identity, strength,purity, and quality . . . These are thecharacteristics (SISPQ) of a GMP-compliant product:

Safety. The product is free fromunknown side effects when used asdirected.

Identity. The product is what thelabel and labeling describe it to be.All personnel, equipment, actions,and decisions involved in itsproduction are identified anddocumented so that the process canbe reconstructed from the records.

Strength (or potency). Theproduct delivers what its label claimsthroughout the product’s shelf life.

Purity. The product is free frommicrobial, chemical, and physicalcontamination.

Quality. The product meetsregulatory requirements wherever itis sold, and it can be madeconsistently, time after time.

If a product does not possess theabove characteristics or is notproduced or tested according toGMP, the product is consideredadulterated and not fit for use.

EVOLUTION OF TODAY’S GMPS

GMPs didn’t occur overnight orsimply appear as regulatoryrequirements. They are based onquality principles and business

practices that have evolved overtime.

From the 1900s to the 1950s,the quality of a product wasdetermined mainly by testing it todetermine whether it metspecifications. No one was reallysure that something was acceptableuntil all the test results came in.

From the 1950s to the 1970s,quality gurus like Edward Demingand Joseph M. Juran (whose workwas initially ignored in their nativeUnited States) were convinced thatindustries could save money andmaterials if companies used practicessuch as statistical process control

and continual improvement. Theidea of building quality into theproduct began to take hold. Thisexpanded to designing quality infrom the very beginning, soprocesses could produce productsthat met the predetermined needs ofcustomers. GMPs were formalizedin the 1960s and 1970s with thisphilosophy in mind.

Learn from the Good. GMPs alsoarose from best-of-industrypractices. For example, in 1884, onemanufacturer (still a major companytoday) stated in its price list that“each lot of drug is EXAMINEDBY ASSAY before manufacture. Wemake no extra charge on thisaccount as we consider it ourhighest duty to know ourpreparations to be of uniform andfull strength” [all emphasis inoriginal] (4). It also tested rawmaterials (botanicals like roots andbark) when they arrived so that thecompany could be assured it wasgetting what it paid for. Finalproduct and incoming testing are

now standard elements of GMPsystems.

In the United States, an“Inspection Manual” of May 1945listed items that agency inspectorsshould examine when theyconducted comprehensive druginspections. The list includedrecords, tests, and adequacy offacilities and equipment. Thisguideline was expanded in 1955 tomore than 10 pages with details ofthe methods and controls that wereto be examined. Many things listedin the 1955 guide are found inGMPs today.

The industry was also trying toset standards for manufacturingcontrol during that period. ThePharmaceutical Manufacturer’sAssociation (now thePharmaceutical Research andManufacturers Association,PhRMA) published a document in1961, “General Principles ofQuality in the Drug Industry,” thatestablished guidelines for theindustry. This document includedmany of the items found in theFDA’s inspection manuals; latercGMP regulations also parallel thisindustry document.

Learn from the Bad. Contrasted tothose best practices were badpractices, some of which werehighlighted in 1962 US Senatehearings examining the poormanufacturing practices found atsome companies. Lack of trainingand inadequate manufacturingfacilities, equipment, and processcontrols were mentioned. Onespeaker (the Secretary of Health,Education, and Welfare) contrastedthe mandated regulation andtraining of pharmacists with the lackof regulation and training of thosemaking and testing drugs (5).

Tragedies that showed the criticalneed for practices to ensure thatproducts had the five GMPcharacteristics of SISPQ wereanother force that shaped GMPsover the years. In England, while adraft was being circulated in 1972of what would become the BritishGMPs (Rules and Guidance forPharmaceutical Manufacturers andDistributors, still known as the

GGMMPPSS are the requirements that manufacturersof regulated healthcare products must follow sothat the products they produce have the safety,identity, strength (or potency), purity, and qualitythat they purport or are represented to have.

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“Orange Book” because of thecolor of its cover), five people diedas the result of microbiallycontaminated intravenous fluids.The government study on theincident, known as the ClothierReport, found that a combination of“simple carelessness [and] poormanagement” contributed to thetragedy (6). In the United States inthe mid-1970s, a similar problemwith intravenous bottles that werecontaminated after being terminallysterilized was the impetus for asepticprocessing validation.

The ICH Q7A GMPrequirements for activepharmaceutical ingredients includethe need to identify clearly theproducer of a product, in partbecause of the deaths of nearly 100children in Haiti in 1996 due to acontaminated solvent, the specificorigin of which was in question.GMP requirements are reactions toprevent industry problems fromhappening again. We need to learnfrom the past in order not to repeatits tragedies.

ESSENTIALS OF GMPIt is useful to read through theGMPs of different countries (orregions) to see how they approachcreating products that have SISPQ.The Canadian (3) and European (7)GMPs and the ICH Q7A (8) GMPsare much more similar to each otherthan they are to the US cGMPs (1).The Canadian, EU, and ICHdocuments also have an importantopening section on qualitymanagement and its role in creatingGMP-compliant products.

Similarities among therequirements are much strongerthan the differences. The essence ofGMP can be summarized into sevenelements:

1. Protect the product fromcontamination.

2. Prevent mix-ups.3. Know what you are to do

before you do it.

4. Document what reallyoccurred.

5. Strive for consistency andcontrol.

6. Have an independent groupmake the final decisions.

7. Solve problems, learn frommistakes, monitor, and continuallyimprove.

Expanding these essentials andwhat they involve allows us to seesome of the well-recognizedconcepts of GMP.

Protect the product fromcontamination. Of the sevenessentials, this is the most critical. Aproduct that contains unwantedcross contamination (from otherproducts), microbes (molds orbacteria), particulates (metalshavings or dirt), physical objects(bolts or pens), or other chemicals(sanitizing agents or pesticides) cancause serious or fatal injuries.

Prevent mix-ups. Ensuring that thedrug product, the label, andlabeling are all in agreement is onlypart of this essential. All rawmaterials, intermediates, equipment,and processing steps must beidentified so that one canimmediately determine anything’sidentity and status. Examples ofstatus include clean or dirty (forequipment or facilities) andapproved, quarantined, rejected, orreleased (for materials or products).

Know what to do before you do it.Documentation systems are used toproduce and control functionaldocuments that tell how to dosomething (master formulae,procedures, methods, protocols) orhelp in making decisions(specifications). Reviews andapprovals by subject-matter experts,management, and the quality unithelp ensure that the content iscorrect and complete. Training —on the procedures, processes, and inGMPs — enables people at all levelsto perform their responsibilitiesconsistent with GMP expectations.

Document what really occurred.Carefully prepared records allow fora rapid and reliable re-creation of anevent, action, or decision.Recordkeeping standards andpractices need to ensure that the

records are complete, permanent,and accurate. If electronic recordsand signatures are used to meetGMP requirements, they must becreated and stored so they arereliable and trustworthy. Recordretention systems ensure thatdocuments and records are readilyavailable to those who need them,including regulatory inspectors.(Batch manufacturing records are ahybrid: They tell what to do and alsoare used to collect information abouthow the batch was actually made.)

Strive for consistency and control.This requirement is achieved inthree phases. First, define what is tobe controlled: Identify criticalprocessing parameters,specifications, and functionalrequirements. Next, demonstratethat adequate control can beachieved through installationqualification, operation qualification,performance qualification, andprocess validation. Finally, usecalibration, preventive maintenance,and change control systems tomaintain control. Change controlensures that the approvedcharacteristics of the drug aremaintained. More simply, it helpsprevent unwanted surprises. Changecontrol is the most complicatedelement in a pharmaceutical orbiotech company’s quality system.

Have an independent group makethe final decisions. A philosophy thatruns throughout GMP is the role ofthe quality control unit (also referredto as quality assurance or simply as“quality”). This doesn’t mean that itis solely responsible for producinghigh-quality products; every grouphas a role to play. Instead, the qualitycontrol unit must be given theauthority and responsibility to do itsjob effectively. The quality controlunit must also approve procedures,specifications, and protocols that areused in GMP areas. The unitconducts internal quality andcompliance audits and certifiesvendors and third-party contractors.Although the quality control unit candelegate some of its responsibilities(analytical testing on incomingmaterials and finished products, forexample) it must make often difficult

decisions about approving orrejecting materials and final products.

Solve problems, learn from mistakes,monitor, and continually improve. Allquality systems — ISO 9000, TotalQuality Management, Six Sigma,GMP — have a common component:They include ways to continuallyimprove. Monitoring products andprocesses gives assurance that all iswell — or can give early warnings ofpotential problems. Looking broadlyat the pharmaceutical industry andcompanies both large and small, thisis the element that is most in need ofstrengthening.

We can now see how the sevenessentials of GMPs and SISPQ arerelated: To create products that havethe GMP characteristics of safety,identity, strength, purity, andquality, companies and individualsneed to fully adopt the sevenessentials of GMP. Each companydefines how it accomplishes theessentials for its particular productsand in its unique circumstancesthrough policies and procedures.

Establishing a GMP system in apharmaceutical company takes timeand resources. Making sure everyaction and decision is consistentwith GMP takes the continual,enthusiastic dedication of everyonewithin the company, even when ittakes a little longer or whenshortcuts are appealing. We haveGMPs for regulatory and legalreasons, but their real importance isin protecting the health andconfidence of those using theproducts we help make.

REFERENCES1 Food and Drugs Scope. Code of

Federal Regulations, Part 210.1a, Title 21,www.fda.gov/cder/dmpq/cgmpregs.htm.

2 Preamble to Final Rule (21 CFR Parts210 and 211), Docket 75N—0339,Comment #17. Available at www.fda.gov/cder/dmpq/preamble.txt.

3 Available at www.hc-sc.gc.ca/hpb-dgps/therapeut/htmleng/guidmain.html#GMP.

4 Kahn, EJ, Jr. All in a Century: TheFirst 100 Years of Eli Lilly and Company. Eli Lilly and Company, 1976; p 73.

5 House Committee on Interstate andForeign Commerce, 87th Congress, 2ndSession, pp 62–63.

6 Report of the committee appointed toinquire into the circumstances, includingproduction, which led to the use of thecontaminated infusion fluids in the DevonSection of Plymouth General Hospital.Chairman: C.M. Clothier, Esq. Ondon: HerMajesty’s Stationery Office, July 1972, p. 18.

7 Available at dg3.eudra.org/F2/eudralex/vol-4/home.htm.

8 Available at www.ich.org/pdfich/Q7Astep4.pdf. ��

James L. Vesper is president ofLearningPlus (www.learningplus.com),Rochester, NY, and executive producerof pharma programs for LearnWright(www.learnwright.com). In bothorganizations, he uses his 22 years inthe pharmaceutical industry indeveloping and presenting GMP-relatedtraining programs for pharmaceuticaland biotech companies in NorthAmerica, Europe, and Asia. He can be reached at jvesper@learningplus.com or 585-442-0170.