Explanations and Unresolved Issues Pertaining to the Development of the Nuclear Pharmacy Compounding...

Vol 42 No 5 SeptemberOctober 2002 Journal of the American Pharmaceutical Association 789

COMMENTARY

Explanations and UnresolvedIssues Pertaining to theDevelopment of the NuclearPharmacy CompoundingGuidelinesJoseph C Hung Samuel C Augustine Kenneth T Cheng Richard L GreenWade M Hopkins David L Laven Brigette R Nelson Neil A Petry James A Ponto Timothy M Quinton and Dennis P Swanson

The Nuclear Pharmacy Compounding Guidelines wereapproved by the Board of Trustees of the AmericanPharmaceutical Association (APhA) in September 2001 and pub-lished by APhA in November 2001 This set of guidelines (seewwwaphanetorgnuclear_compoundingpdf) is the first nation-ally recognized document that provides realistic and practical

compounding guidance for nuclear pharmacy practice The Food and Drug Administration Modernization Act

(FDAMA) enacted in late 1997 protects a pharmacistrsquos profession-al prerogative to compound drug products however the provisionsof the pharmacy compounding section of the act (ie section 127 ofFDAMA which added section 503A to the Federal Food Drug andCosmetic Act [FDampC Act]) do not apply to radiopharmaceuticals1

The decision not to include radiopharmaceuticals was related to thecomplexities specifically associated with compounding radiophar-maceuticals as well as the time constraint that Congress placed onthe development and approval of the section 127 language2

Nuclear pharmacy compounding like traditional pharmacycompounding is an integral part of pharmacy practice and is

Objectives To provide background information related to the development of the Nuclear Pharmacy Compounding Guidelines to dis-

cuss regulatory complexities related to radiopharmaceutical compounding practice and to summarize the gaps in the current com-

pounding regulations for radiopharmaceuticals Data Sources The Guidelines closely follow the provisions of section 503A of the

Federal Food Drug and Cosmetic Act (FDampC Act) the monographs and chapters related to pharmacy compounding in the United States

Pharmacopeia (USP) and the recommended guidelines published by the American Society of Health-System Pharmacists Summary

The Food and Drug Administration Modernization Act (FDAMA) of 1997 established parameters under which the compounding of drug

products is appropriate and lawful but these criteria expressly do not apply to radiopharmaceuticals The Nuclear Pharmacy

Compounding Practice Committee a group of nuclear pharmacists convened by the American Pharmaceutical Association developed

the Nuclear Pharmacy Compounding Guidelines to establish a set of principles and guidelines for good radiopharmaceutical com-

pounding practice The intent of the new document is to provide guidance on radiopharmaceutical compounding practices that have

evolved over the last 2 decades and to place them in an appropriate regulatory framework in accordance with previous enforcement poli-

cies and guidelines issued by the US Food and Drug Administration (FDA) regarding the exemption of certain pharmacy practices from

enforcement of adulteration misbranding and new drug requirements Conclusion The Nuclear Pharmacy Compounding Guidelines

recently released by APhA is the first official document that provides realistic and practical compounding guidance for nuclear pharma-

cists Even though the United States Court of Appeals for the Ninth Circuit recently ruled section 503A of the FDampC Act to be invalid in

its entirety and the Supreme Court upheld that ruling the compliance policy guides issued by FDA in March 1992 and revised in May

2002 maintain guiding principles on pharmacy compounding similar to those stated in section 503A of the FDampC Act The Nuclear

Pharmacy Compounding Practice Committee is optimistic that the practical information contained in the Guidelines will assist state

boards of pharmacy FDA and the United States Pharmacopeial Convention in setting appropriate standards for nuclear pharmacy com-

pounding practice that will ensure the continued availability of high-quality compounded radiopharmaceuticals at reasonable cost

J Am Pharm Assoc 200242789ndash98

Received February 12 2002 and accepted for publication July 23 2002

Authorsrsquo affiliations are listed on pages 797ndash8

Correspondence Joseph C Hung PhD BCNP FAPhA NuclearMedicine Department of Radiology Mayo Clinic 200 First Street SWRochester MN 55905-0001 Fax 507-266-4461 E-mail jhungmayoedu

essential to the provision of high-quality cost-effective patientcare However neither federal drug laws nor the United StatesPharmacopeia (USP) includes specific requirements or standardsfor compounding radiopharmaceuticals or for the strength qualityand purity of most compounded radiopharmaceuticals used in rou-tine clinical practice today

To proactively develop a set of professional compoundingguidelines for nuclear pharmacy the APhA Academy ofPharmacy Practice and Management (APhAndashAPPM) Section onNuclear Pharmacy Practice formed the Nuclear PharmacyCompounding Practice Committee in early 1998 The group con-sisted of nuclear pharmacists from academic institutions commer-cial nuclear pharmacies and independent nuclear pharmacies Theapproved guidelines represent the end product of a nearly 4-yeareffort by the committee

This was not the first time that the Section had developed suchguidelines In 1993 APhA distributed a document on the com-pounding of radiopharmaceuticals for positron emission tomogra-phy (PET)3 That earlier endeavor served as the basis for com-pounding guidance as stated in the USP4 as well as the current reg-ulation of these PET agents under FDAMA5

The purpose of developing the Nuclear PharmacyCompounding Guidelines was not to rewrite the various nuclearpharmacy practice acts or model state board regulations Ratherthe intent was to propose principles and standards for nuclear phar-macy practice based on the related regulations (ie section 503Aof the FDampC Act)1 as well as the recommended guidelines pub-lished in the USP and by the American Society of Health-SystemPharmacists (ASHP)6ndash9 The intent of the Guidelines is to providenuclear pharmacists with information on minimum good com-pounding practices for radiopharmaceuticals and to assist stateboards of pharmacy the US Food and Drug Administration(FDA) and the United States Pharmacopeial Convention in devel-oping new regulatory guidance pertaining to the compounding ofradiopharmaceuticals

Drafts of the Guidelines were posted on The Nuclear PharmacyWeb site (httpnuclearpharmacyuamsedu) and distributed to vari-ous organizations (eg FDA USP National Association of Boardsof Pharmacy state boards of pharmacy Council on Radionuclidesand Radiopharmaceuticals Inc [CORAR]) with requests for com-ments and suggestions Comments received were considered by theNuclear Pharmacy Compounding Practice Committee and incorpo-rated into the final guidelines as appropriate

Objectives

The purpose of the present article is to provide backgroundinformation relating to the development of the Nuclear PharmacyCompounding Guidelines to discuss issues related to the currentstate of radiopharmaceutical compounding and to summarize anygaps that exist in the current compounding regulations with regardto radiopharmaceuticals Certain sections of the Guidelines appear

as footnotes in this article to place into context the issues dis-cussed Headings throughout the text address specific regulatoryissues related to radiopharmaceutical compounding

FDA Enforcement Policy Guidance

From June 2000 through August 2001 the Nuclear PharmacyCompounding Practice Committee received several pieces of cor-respondence from FDArsquos Pharmacy Compounding SteeringCommittee (PCSC) concerning the draft guidelines principallywith regard to FDArsquos ldquoenforcement discretionrdquo on the practice ofradiopharmaceutical compounding While PCSC indicated that thedraft guidelines closely followed the provisions of section 503A ofthe FDampC Act1 current law does not exempt compounded radio-pharmaceuticals from three provisions of the FDampC Act section501(a)(2)(B)mdashadulteration (concerning the current good manu-facturing practice [CGMP] requirements)10 section 502(f)(1)mdashmisbranding (concerning the labeling of drugs with adequatedirections for use)11 and section 505mdashnew drug provisions (con-cerning the approval of drugs and requirements for New DrugApplications [NDA] and Abbreviated New Drug Applications[ANDA])12 On that basis PCSC suggested that all references toany exemption from the above three statutory requirements withregard to radiopharmaceuticals be removed from item 6a of theGeneral Provisions section of the Nuclear PharmacyCompounding Guidelines

To help readers better understand this confusing issue the fol-lowing discussion is divided into subsections

Section 503A of the FDampC ActSection 503A of the FDampC Act stipulates that drug products

that are compounded by a pharmacist or physician for an identifiedindividual patient pursuant to a valid prescription order and thatconform to other requirements listed in section 503A are exempt-ed from the FDampC Actrsquos adulteration misbranding and new drugprovisions110ndash12

COMMENTARY Nuclear Pharmacy Compounding

790 Journal of the American Pharmaceutical Association SeptemberOctober 2002 Vol 42 No 5

aWhen a radiopharmaceutical is compounded by a nuclear pharmacistbased on a valid prescription while engaging in compounding activitieswhich are in conformance with the normal practice of pharmacy as gov-erned by the board of pharmacy which licenses the practice site and asstated in Section 510(g)(1) of the FFDCA (FDA 1998f) that compound-ed radiopharmaceutical has historically been exempted by FDA enforce-ment policy guidelines (FDA 1984 1992) from enforcement of at leastthree provisions of the FFDCA ie adulteration [eg CGMP require-ments as stated in Section 501(a)(2)(B)] (FDA 1998b) misbranding [eglabeling of drugs with adequate directions for use as stipulated in Section502(f)(1)](FDA 1998c) and the new drug provisions [ie NDA orANDA regulation as described in Section 505] (FDA 1998e) Theenforcement policy guidance for compounded radiopharmaceuticals iscurrently being reviewed by the FDA In that guidance the FDA mayaddress and clarify situations where FDA could exercise its enforcementdiscretion for the aforementioned three statutory requirements (LanaOgram FDA written communication August 2001)

Before FDAMA was enacted federal drug law could have beenstrictly interpreted as requiring a pharmacist to obtain a new drugapproval and to comply with the statutory requirements related toadulteration misbranding and NDAANDA10ndash 12 for all com-pounded prescription drugs The NDAANDA process requiredfor manufacturing and marketing drug products is not amenable topharmacy compounding in terms of cost document submissionand timeliness Additionally the enormous complexity and highcosts associated with meeting CGMP requirements13 intended forlarge-scale manufacturing would almost certainly end small-scalepharmacy compounding practice

Recognizing the importance of pharmacy compounding topatient care FDA has traditionally allowed pharmacy compound-ing activities practiced in compliance with state law to proceedunder its enforcement discretion guidance Nevertheless FDAcontended that it retained the authority to regulate pharmacy com-pounding vis-agrave-vis the statutory requirements described above atany time it chooses to do so Hence many pharmacists were uncer-tain as to the legality of compounding FDAMA finally establishedrules that clarify and formalize federal drug compounding practiceregulation1

Exemption From Adulteration Misbrandingand New Drug Provisions for CompoundedRadiopharmaceuticals

Because section 503A of the FDampC Act expressly does notapply to radiopharmaceuticals1 these drugs are not eligible for theabove three statutory exemptions provided by the federallaws10ndash12 To ensure clinical access to individual compoundedradiopharmaceuticals the Nuclear Pharmacy CompoundingPractice Committee believes that FDA should continue itsenforcement discretion policy with regard to radiopharmaceuti-cals thereby permitting nuclear pharmacists to compound radio-pharmaceuticals without requiring compliance with strict FDampCAct requirements regarding adulteration misbranding and newdrug provisions10ndash12 As a result item 6 of the General Provisionssection of the Nuclear Pharmacy Compounding Guidelines isintended to reflect the current regulatory enforcement situation andto suggest a reasonable framework for developing future regula-tion of the compounding of radiopharmaceuticals

Invalidation of Section 503A of the FDampCAct

After section 503A of the FDampC Act went into effect onNovember 21 19981 several compounding pharmacies joinedtogether and initiated a lawsuit challenging the solicitation andadvertising provisions of section 503A These pharmacies arguedthat these subsections violated the First Amendmentrsquos guarantee offree speech14 The United States District Court for the District ofNevada ruled in the pharmacistsrsquo favor FDA appealed to theUnited States Court of Appeals for the Ninth Circuit On February

6 2001 the court of appeals delivered its opinion agreeing withthe ruling of the district court14 However the appeals court wentfurther declaring section 503A to be invalid in its entirety14

FDA petitioned the US Supreme Court for writ of certiorariand on February 26 2002 the Court heard oral arguments in theappeal15 On April 29 2002 the Supreme Court upheld the deci-sion of the court of appeals in affirming that the advertising banwas unconstitutional and that section 503A should be struck downin its entirety15 Since the Supreme Court did not rule on the issuerelated to the advertising and promotion of compounded drugproducts and did not remand the decision to the circuit court15

section 503A in its entirety is now considered to be invalid

CPG 460200 and 1984 Nuclear PharmacyGuideline

At the time FDAMA was enacted two FDA enforcement poli-cies were in place the 1992 Compliance Policy Guide (CPG) onPharmacy Compounding (CPG 713216 later renumbered as460200) Manufacture Distribution and Promotion ofAdulterated Misbranded or Unapproved New Drugs for HumanUse by State-Licensed Pharmacies and the Nuclear PharmacyGuideline Criteria for Determining when to Register as a DrugEstablishment issued by FDA in 1984 (1984 Nuclear PharmacyGuideline)1617 After the US Supreme Court upheld the decisionof the court of appeals in the pharmacy compounding case15 FDAissued a guidance for FDA staff and industry titled Sec 460200Pharmacy Compounding on June 7 2002 to address certainldquoambiguousrdquo issues related to pharmacy compounding that arosefollowing the decision by the Supreme Court18 Overall the ldquonewrdquoguidance is very similar to 1992 CPG 4602001618 and it providesguidelines for drug compounders as well as FDA staff as to whatactivities the agency will consider in exercising its enforcementdiscretion with regard to pharmacy compounding practice18

Neither the 1992 version nor the 2002 version of CPG 460200includes specific guidance on nuclear pharmacy1618 The primaryfocus of either version of the CPG 460200 is on nonradioactivedrugs rather than radiopharmaceuticals and as such the 1992 and2002 versions of CPG 460200 specifically state that one mustrefer to FDA guidelines and other CPGs for interpretation or clar-ification of FDArsquos position concerning nuclear pharmacyissues1618 Because the 1984 Nuclear Pharmacy Guideline isdirectly related to nuclear pharmacy operations including radio-pharmaceutical compounding17 the Nuclear PharmacyCompounding Practice Committee contends that this documentshould be the primary legal reference for issues associated withradiopharmaceutical compounding

The 1984 Nuclear Pharmacy Guideline indicates that if theoperational activities of a nuclear pharmacy are consistent withsection 510(g)(1) of the FDampC Act19 then that nuclear pharmacyis not required to register as a drug establishment17 Therefore if anuclear pharmacy is not considered a drug establishment itappears reasonable to assume that it should be exempted from

Nuclear Pharmacy Compounding COMMENTARY


compliance with federal adulteration misbranding and new drugprovisions10ndash 12

Accordingly it would also seem logical to surmise that a radio-pharmaceutical that is compounded pursuant to a valid prescrip-tion by a nuclear pharmacist engaging in compounding activitiesthat are in conformance with the normal practice of pharmacy aslicensed and governed by the state board of pharmacy should beexempted from compliance with at least the three aforementionedstatutory provisions10ndash12

In actuality however the current drug laws simply offer nostatutory exemptions for compounded radiopharmaceuticals Eventhough the 1984 Nuclear Pharmacy Guideline implies that com-pounded radiopharmaceuticals are not subject to the adulterationmisbranding or new drug provisions it actually provides only fordiscretionary enforcement of these requirements The NuclearPharmacy Compounding Guidelines used the above-referenceddocuments as a springboard to further refine the definitions ofgood compounding practice as they exist in todayrsquos practice arena

FDA Working GroupNew Radiopharmaceutical Guidance

Without statutory exemptions from adulteration misbrandingand new drug provisions10ndash12 or a discretionary enforcement policybeing observed by FDA the potential exists that nuclear pharmacycompounding practice will cease due to the imposition and overen-forcement of regulations not intended for the practice That in turnwould certainly pose a serious threat to proper and necessary carefor certain groups of patients which is dependent on the readyavailability of cost-effective compounded radiopharmaceuticals

The Nuclear Pharmacy Compounding Practice Committeemembers were pleased to learn that FDA recently established aworking group to develop a new guidance on the compoundingof radiopharmaceuticals (PCSC personal communicationAugust 13 2001) Currently FDA is reexamining CPG46020016 and the 1984 Nuclear Pharmacy Guideline17 in light ofFDAMA in the development of the new guidance on the com-pounding of radiopharmaceuticals According to FDA thisworking group includes pharmacists and nuclear pharmacistsand the new guidance will be published in the Federal Registerwith a request for comments from the public (PCSC personalcommunication August 13 2001) Until new guidance is issuedFDA will continue to rely on these two documents to ldquoregulaterdquonuclear pharmacy compounding practice (PCSC personal com-munication June 26 1999)

Until FDA issues the new guidance to address and clarify thesituations in which it may exercise its authority to enforce the threestatutory requirements as they apply to compounded radiopharma-ceuticals the Nuclear Pharmacy Compounding PracticeCommittee feels that FDA should continue to follow its existing1984 Nuclear Pharmacy Guideline17 This course of action wouldallow nuclear pharmacists to continue providing proper patientcare It would also show that FDA is being reasonable in its

approach to regulating professional practice and sensitive to theneeds of patients and health care providers

Compounded Radiopharmaceuticalsand PET Drugs

ldquoRadiopharmaceutical or radioactive drugrdquo as defined in the1997 FDAMA20 and reiterated in the Nuclear PharmacyCompounding Guidelines includes any nonradioactive reagent kitor radionuclide generator intended for use in the preparation of anysuch drug product Hence nonradioactive reagent kits as well asthe corresponding final radiolabeled products are covered by theNuclear Pharmacy Compounding Practice Committeersquos guidelines

Radiopharmaceutical and compounded PET drugs are the onlytwo drug categories excluded from the ldquosanctuary listrdquo of the phar-macy compounding law as stated in section 503A of the FDampCAct1

Although PET drugs precisely fit the statutory definition of aradiopharmaceutical or radioactive drug the Nuclear PharmacyCompounding Practice Committee decided to exclude ldquocom-pounded PET drugrdquo from the definition of ldquoradiopharmaceuticalor radioactive drugrdquo stated in the Guidelines The main reason forthis exclusion is that section 121 of FDAMA provides a separateand distinct regulatory framework for PET drug products includ-ing compounded PET drugs5 However there are several contro-versial issues related to the law concerning compounding of PETdrug products17 When the rule sunsets 2 years after the date onwhich FDA establishes the requirements compounded PET drugswill likely be subject to the same type of regulation (eg CGMPNDAANDA) that FDA currently applies to drug manufacturingand marketing activity5

While the application of the ldquomanufacturingrdquo requirements ofsection 121 of FDAMA to the compounding of PET drugs is per-plexing one may wonder whether following this precedent FDAwill eventually place compounded radiopharmaceuticals under thesame regulatory framework making them subject to the adulter-ation misbranding and new drug provisions of the FDampC Act521

Compounding ofRadiopharmaceuticals

Preparation According to ManufacturerrsquosInstructions

According to the definition stated in section 503A of the FDampCAct the term ldquocompoundingrdquo does not include mixing reconsti-tuting or other such acts performed in accordance with directionscontained in approved product labeling provided by manufacturersand other directions consistent with that labeling1 Thus a drugproduct prepared via a process that is the same as that stated onFDA-approved labeling is not considered to be compounded

Conversely a drug product prepared via processes or proce-



COMMENTARY Nuclear Pharmacy Compo

dures that deviate even slightly from those described in a packageinsert would be considered a compounded product Using this def-inition of compounding the vast majority of the nearly 20 millionradiopharmaceutical patient doses dispensed annually by nuclearpharmacists would be considered compounded drug products22

Deficiencies of Package Inserts forRadiopharmaceuticals

Within the field of nuclear pharmacy it is common to find thata package insert contains inadequate information to permit thereconstitution and quality control (QC) of the radiopharmaceuti-cal The five categories of deficiencies identified by the NuclearPharmacy Compounding Practice Committee in the package insertinstructions for the preparation of radiopharmaceuticals are absentor incomplete directions (eg QC procedure23) restrictive direc-tions (eg specific needle sizes24 particular QC techniques25)inconsistent directions (eg conflicting expiration times26 differ-ing reconstituted volumes for preparing the same radiopharmaceu-tical24) impractical directions (eg unsafe particle number withregard to certain particulate radiopharmaceuticals27 unrealistical-ly low activity limits for reconstituting various cold kits28) andvague directions (eg can29 recommend28 should30)

The poor quality of package insert instructions supports thenotion that strictly adhering to manufacturerrsquos directions is notalways the best way to ensure quality patient care radiationsafety or timely provision of radiopharmaceutical dosesBecause of the aforementioned deficiencies it is difficult andsometimes impossible to prepare a radiopharmaceutical by fol-lowing the directions exactly as stated in the package insertUnfortunately manufacturers are not interested in either revis-ing or augmenting the information contained in the packageinserts because of the huge expense and extensive paperworktypically involved in gaining FDA approval for a revised insertThis situation creates a dilemma for nuclear pharmacists

The Nuclear Pharmacy Compounding Practice Committee is ofthe opinion that the manufacturerrsquos instructions should be viewedas guidance rather than required procedure A nuclear pharmacistshould have the professional prerogative to use alternative meth-ods to prepare radiopharmaceuticals provided those procedureshave been proven to provide equivalent or better results and thathe or she does not engage in activities that fall outside the normalpractice of nuclear pharmacy These beliefs of the NuclearPharmacy Compounding Practice Committee are reflected in item3 of the General Provisions section of the Guidelinesb

Strictly speaking any radiopharmaceutical that is not preparedin accordance with the manufacturerrsquos instructions could be clas-sified as a compounded radiopharmaceutical However as impliedabove deviations in procedure when preparing radiopharmaceuti-cals are by and large caused by deficiencies in package insertdirections that make it impossible for nuclear pharmacists toadhere to manufacturerrsquos instructions

Copycat DrugsCompounded drug products are not required to meet the adul-

teration misbranding and new drug provisions specified in sec-tion 503A of the FDampC Act The section does place severalrestrictions on compounding practice1 and will not be subjected toFDArsquos enforcement action as per CPG 4602001618 providedsuch drug products are compounded in accordance with state lawand traditional compounding activity (eg extemporaneouslycompounding reasonable quantities of human drugs upon receiptof a valid prescription from a licensed practitioner for an individ-ually identified patient) However section 503A and CPG 460200nonetheless place several restrictions on the pharmacy compound-ing practice11618

One restriction is that a pharmacist cannot copy any commer-cially available drug product on a regular basis or in inordinateamounts1 The main intent here is to limit the scope of compound-ing in order to prevent small-scale manufacturing under the guiseof compounding However this copycat limitation does not applyto a drug product that may be similar to the commercially availabledrug when the change made to the drug product produces a ldquosig-nificant differencerdquo in the care of the patient1 For example theremoval of a dye from a commercially available drug product fora particular patient who is allergic to the dye may be presumed tomake a significant difference in that patientrsquos care Thus com-pounding the above drug product without dye is not only permis-sible under current federal drug law but becomes a professionalresponsibility for both the compounding pharmacist and the pre-scribing physician

ldquoDeviationsrdquo From the ManufacturerrsquosInstructions in the Preparation ofRadiopharmaceuticalsb

The Nuclear Pharmacy Compounding Practice Committee feelsthat the definition of nuclear pharmacy compounding should notapply to a radiopharmaceutical prepared via deviation(s) frommanufacturerrsquos instructions as long as the radiopharmaceuticalmaintains the same quality and purity as that produced by adher-ence to the manufacturerrsquos directions Therefore if a radiophar-maceutical is not prepared in accordance with the manufacturerrsquosdirections we maintain that it should not be considered a



bNuclear pharmacy compounding does not include mixing reconsti-tuting or other such acts that are performed in accordance or consistentwith the directions contained in approved labeling or other manufacturerdirections consistent with that labeling Nuclear pharmacy compoundingalso does not include any deviation(s) from the directions contained in theapproved product labeling or other manufacturer directions consistentwith that labeling which result in a final radioactive drug product that isof the same quality and purity as that produced with adherence to theproduct labeling The nuclear pharmacist should use hisher professionaljudgement scientific knowledge literature evidence etc as the basis toperform any deviation(s) from the manufacturerrsquos recommended prepa-ration process and the final product should be checked by the appropri-ate quality control process as described in the Quality Control section orother reliable source(s)

compounded drug product as long as its quality and purity are thesame as those drugs produced in compliance with the preparationinstructions as provided by the manufacturer

The committeersquos view with regard to the use of an alternativemethod for the preparation of a radiopharmaceutical is in line withthe policy adopted by USP The General Notices section of theUSP indicates that the existence of an official test method in theUSP does not preclude the use of a validated alternative method31

However when a difference appears or in the event of dispute theUSP method is the referee method31

Examples of CompoundedRadiopharmaceuticals

Clearly when a radiopharmaceutical is not commercially avail-able a nuclear pharmacist is allowed to compound that particularradioactive drug for an individual patient based on a prescriptionorder and medical need (ie items 2c and 10d of the GeneralProvisions section of the Nuclear Pharmacy CompoundingGuidelines) Examples of such compounded radiopharmaceuticalsare technetium-99m (99mTc)-labeled human serum albumin and99mTc(V)-labeled succimer

In certain circumstances a nuclear pharmacist may be requiredto compound a radiopharmaceutical that is only slightly differentfrom an FDA-approved radiopharmaceutical that is commerciallyavailable (ie item 11e of the General Provisions section of theNuclear Pharmacy Compounding Guidelines) Again the prepa-ration of this compounded radioactive drug is permissible onlywhen it is done for the legitimate medical needs of an individualidentified patientc Examples of this type of compounded radio-pharmaceutical include 99mTc-labeled macro-aggregated albumin(99mTc-MAA) with a reduced number of particlesdose for apatient with severe pulmonary hypertension and 99mTc-labeled sul-fur colloid with a smaller particle size for lymphoscintigraphy

It is sometimes necessary to change an inactive ingredientbecause of the potential for sensitivity or allergic reaction in certain

patientse (for example 99mTc-labeled mebrofenin prepared from aCholetec reagent kit [Bracco Diagnostics] contains propylparabena preservative to which some patients are allergic)

A particular patient may require a specific dosage form that can-not be prepared using a commercially available drug producte

Examples of this include a sodium iodide 131I capsule compound-ed for a patient who requires a dosage or capsule size that is notavailable from the manufacturer and a sodium iodide 123I solutioncompounded for a pediatric patient since it is often difficult foryounger patients to swallow the commercially available radioac-tive iodine capsule(s)

Kit SplittingKit splitting or vial fractionation is a process that is generally

applied to reagent kits Kit splitting is usually accomplished whenthe lyophilized contents of a vial are reconstituted with physiolog-ical saline and the resulting solution is divided and transferred to anumber of new vials and stored under frozen conditions for anextended period of time

This practice has usually been carried out during drug shortagesor for economic reasons and is typically similar to partial vialusage or multiple dosage dispensing from a single-use vial both ofwhich are common practice in hospital pharmacies Howevermanufacturers (CORAR personal communication June 18 2002)and others caution that kit splitting can have a significant adverseeffect on sterility drug content uniformity and stability especial-ly for products that must be manipulated and stored in a specialenvironment such as low moisture or inert gas conditions3233

The Nuclear Pharmacy Compounding Practice Committeespent a great deal of time discussing this difficult issue Kit split-ting is clearly a practice that deviates from package insert direc-tions One interpretation was that when done carefully with veri-fication of sterility radiochemical purity (RCP) etc kit splittingshould not be considered compounding as long as the final prod-uctrsquos quality and purity are the same as those produced in compli-ance with the manufacturerrsquos preparation instructions A secondinterpretation was that kit splitting should be considered com-pounding of limited quantities of drug in anticipation of receivingprescription orders A third take was that this practice should beconsidered manufacturing because repackaging is typically con-sidered a manufacturing activity

Because of the lack of consensus the committee decided not toaddress kit splitting in the text of the Nuclear PharmacyCompounding Guidelines However given the recurring shortagesof certain reagent kits and radiopharmaceuticals in recent years kitsplitting may be a viable option for prolonging the availability ofradioactive drugs to meet patientsrsquo needs If this practice is under-taken it is important for the nuclear pharmacist to ensure that anadequate amount of any active ingredient is maintained in thesmaller dosage forms so that the quality of the nuclear medicineprocedure is not compromised and the final product complies withall applicable standards of quality and purity It is also critical for



cBased on the existence of a practitionerndashpatientndashpharmacist relation-ship and the presentation of an unsolicited and valid prescription order ora notation approved by the prescribing practitioner which states that acompounded product is necessary for an identified individual patient anuclear pharmacist may compound radiopharmaceuticals in a nuclearpharmacy a nuclear medicine laboratory or a federal facility

dThe nuclear pharmacist may compound a radiopharmaceutical thathas been previously approved by the FDA but is no longer commerciallyavailable [does not include a radiopharmaceutical that has been withdrawnor removed from the market because such drug product or component(s)of such drug product has been found to be unsafe or not effective]

eThe nuclear pharmacist does not compound regularly or in inordinateamounts (as defined by the FDA andor state board of pharmacy) anyradiopharmaceuticals that are essentially copies of a commercially avail-able drug product However the term ldquoessentially a copy of a commer-cially available drug productrdquo does not apply to a drug product in whichthere is a change made for an identified individual patient which pro-duces for that patient a significant difference as determined by the pre-scribing practitioner between the compounded drug and the comparablecommercially available drug product

the nuclear pharmacist to base any kit splitting practice on his orher professional judgment and knowledge and to ensure that sucha practice is in compliance with the applicable law

Other Restrictions Under Section 503A ofthe FDampC Act and CPG 460200

Withdrawn or Removed Drug Products

Since section 503A of the FDampC Act and the 1992 and 2002versions of CPG 460200 do not apply to radiopharmaceuti-cals11618 FDA has no statutory responsibility to include radio-pharmaceuticals on its list of unsafe or ineffective drug productsNonetheless any drugs included on this list probably should not beused as components when compounding radiopharmaceuticalsItem 9f of the General Provisions section of the Nuclear PharmacyCompounding Guidelines reflects this reasoning

Demonstrably Difficult to Compound Drug ProductSection 503A of the FDampC Act indicates that a pharmacist can-

not compound a drug product if the difficulty of the compoundingprocess may potentially compromise the safety or effectiveness ofthat drug product1 Since the sectionrsquos provisions do not apply toradiopharmaceuticals1 the Demonstrably Difficult to CompoundDrug Product list issued by FDA does not include a listing of suchradiopharmaceuticals Additionally the criteria used by FDA toidentify drugs that present demonstrable difficulties in compound-ing may be too subjective or restrictive Furthermore the 1992 and2002 versions of CPG 460200 do not list the aforementionedrestriction as one of the pharmacy acts that may ldquotriggerrdquo FDArsquosenforcement action although the list of ldquoinappropriaterdquo acts asstated in the 1992 and 2002 CPG 460200 is not exhaustive andother acts may be considered by FDA on a case-by-case base1618

As a result the Nuclear Pharmacy Compounding PracticeCommittee decided not to include the phrase ldquodemonstrably diffi-cult to compound drug productrdquo in the text of the NuclearPharmacy Comopunding Guidelines

Pharmacy Compounding Memorandum ofUnderstanding

The intent of the memorandum of understanding (MOU)between the state and FDA as described in section 503A of theFDampC Act is to provide guidance concerning the distribution ofinordinate quantities of compounded drug products outside thestate in which the compounding pharmacy is located1 As stated inthe previous sections compounded radiopharmaceuticals are notcovered by the MOU regarding interstate distribution since theprovisions of section 503A are not applicable to radiopharmaceu-

ticals In addition neither the 1992 nor the 2002 CPG 460200addresses the MOU issue As such the MOU item is not includedin the Nuclear Pharmacy Compounding Guidelines

Advertising and PromotionSection 503A of the FDampC Act prohibits pharmacists from

advertising or promoting the drugs they compound1 Those phar-macists are however permitted to advertise or promote their com-pounding service Some pharmacists have argued that these regu-lations violate the First Amendmentrsquos guarantee of free speech Inits decision on a lawsuit brought by Western States Medical Centerof Nevada against FDA the United States Court of Appeals for theNinth Circuit ruled in a statement dated February 6 2001 that notonly are points (a) and (c) of section 503A in violation of the FirstAmendment but further that section 503A in its entirety isinvalid since as determined by the court points (a) and (c) of sec-tion 503A may not be severed from the rest of the provisions insection 503A14 As stated earlier in this article the Supreme Courthas affirmed the decision made by the court of appeals Howeverthe Supreme Court failed to address whether pharmacy com-pounding was legal before FDAMA15 Therefore the only rulingwith regard to section 503A is the one issued by the court ofappeals in which the court declared the advertising ban in section503A to be unconstitutional and that it could not be severed fromthe rest of section 503A As such the court concluded that section503A of the FDampC Act was invalid in its entirety

The Nuclear Pharmacy Compounding Practice Committeechose not to include this restriction within the Nuclear PharmacyCompounding Guidelines This decision was based not only onsection 503Arsquos inapplicability to radiopharmaceuticals but also onthe fact that the issue of advertising and promotion with regard topharmacy compounding is not mentioned in CPG 46020011618

ACARA (As Clean As ReasonablyAchievable)

Since the majority of radiopharmaceuticals are administeredintravenously and all package inserts for parenteral radiopharma-ceuticals require the use of aseptic technique during preparation itseems reasonable to stipulate that radiopharmaceutical compound-ing practice be performed in a clean and controlled environment(eg an M35 [Class 100] laminar flow hood located in a cleanroom) More than 25 years of history have proven that nuclearpharmacy practice yields incredibly safe products problems asso-ciated with lack of sterility and pyrogenicity have been exceeding-ly rare Although theoretical improvements could be made if allradiopharmaceuticals were compounded in a clean and controlledarea the value could be negative based on the law of diminishingreturns and decreased use because of increased costs

USP 1191 ldquoStability Considerations in Dispensing Practicerdquostates that ldquobecause of potential unobservable problems with respectto sterility and chemical stability all extemporaneous parenteralpreparations should be used within 24 hours unless data are avail-



fThe nuclear pharmacist does not compound a radiopharmaceuticalusing as a component a drug product that appears on a list published bythe FDA in the Federal Register of drug products that have been with-drawn or removed from the market because such drug products or compo-nents of such drug products have been found to be unsafe or not effective

able to support longer storagerdquo7 Therefore the Nuclear PharmacyCompounding Practice Committee believes that the practice ofcompounding parenteral radiopharmaceuticals outside of a laminarflow hood or a clean room can be further justified by the short expi-ration times (typically hours) of virtually all radiopharmaceuticals

However if compounding certain radiopharmaceuticals posesgreater than usual potential risk for patients (eg drug productscompounded from nonsterile ingredients or compounded with non-sterile components containers or equipment or if ldquoopen systemrdquotransfer or nonsealed reservoirs are used in the compounding pro-cess) the committee suggests that nuclear pharmacists refer to USP12068 and an article titled ldquoASHP Guidelines on Quality Assurancefor Pharmacy-Prepared Sterile Productsrdquo published in the AmericanJournal of Health-System Pharmacy9 for further guidance

It is not a simple task to adequately manage both aseptic tech-nique and radiation safety when compounding radiopharmaceuti-cals In fact nuclear pharmacists typically have to make some com-promise between the two considerations in order to complete thepreparation of a radiopharmaceutical This has led us to adopt thestandard of ACARA (as clean as reasonably achievable) as a com-panion to ALARA (as low as reasonably achievable) the commonstandard for radiation protection34 To clarify the requirements forACARA three additional criteria were added to the definition ofACARA in the Definitions section of the Nuclear PharmacyCompounding Guidelines These three new criteria for ACARA aresimilar to the conditions set for ALARA in the Definitions sectionof Part 352 of Title 10 of the Code of Federal Regulations34

Other Minor Issues Related to NuclearPharmacy Compounding Practices

Patented Radiopharmaceuticals

As indicated in section 503A of the FDampC Act exemptionsfrom the adulteration misbranding and new drug requirementsgranted to compounded pharmaceuticals do not apply to com-pounded drugs that are essentially copies of commercially avail-able drug products when those drugs are compounded on a regu-lar basis or in inordinate amounts1 In addition the recently issuedCPG 460200 indicates that FDA would seriously considerenforcement action against any pharmacy conducting the afore-mentioned activity18 These restrictions suggest that copying com-mercially available drugs for economic reasons is permissible aslong as it is not done regularly or in inordinate amounts TheNuclear Pharmacy Compounding Practice Committee believesthat any patented drug product including radiopharmaceuticalsshould receive more protection due to the research and develop-ment efforts involved as well as the cost invested by the pharma-ceutical manufacturer in acquiring the patent As a result theCommitteersquos Guidelines place more stringent requirements on thecompounding of patented radioactive drugs

As stated in item 12g of the General Provisions section of theNuclear Pharmacy Compounding Guidelines a nuclear pharma-

cist is allowed to compound a patented radiopharmaceutical onlywhen it cannot be readily obtained from a commercial source andprovided it is to be used to meet the urgent medical need(s) of anidentified individual patient

One may argue that copying a patented drug is no different fromphotocopying an article from a scientific journal for onersquos ownuse and thus that a nuclear pharmacist should be permitted tocopy a patented radiopharmaceutical for in-house patient useHowever as long as the patient is charged for the compoundedpatented radiopharmaceutical that money exchange will be in vio-lation of copyright or patent law However were the compound-ing of a patented radiopharmaceutical to be performed in an emer-gency to meet the medical needs of an identified individual patientthe Nuclear Pharmacy Compounding Practice Committee does notbelieve that the pharmaceutical company that owns the patentrights of the radiopharmaceutical would pursue any legal chal-lenge concerning the nuclear pharmacistrsquos actions

Sources of Compounding Drug ComponentsUsing an alternative high-quality source of compounding drug

components as stated in item 4 of the Bulk Drug Substanceh anditem 3 of the Excipienti subsections of the Nuclear PharmacyCompounding Guidelines is not specifically identified in section503A of the FDampC Act or in the 1992 and 2002 versions of CPG46020011618 Section 503A does mention that the bulk drug sub-stances and any other drug substances used in compounding a drugproduct must also comply with standards as stated in the USPchapter on pharmacy compounding (ie USP 795)16

According to USP 795 a USP- or a National Formulary-gradesubstance is the preferred source of substances for compoundingall other drug preparations6 If such a product is not availablehowever then the use of a high quality substance (ie analyticalreagent- certified American Chemical Society- or FoodChemicals Codes-grade) substance is acceptable6

Radiochemical Purity TestingWith regard to compounded radiopharmaceuticals that are sim-

ilar to radiopharmaceuticals prepared in accordance with manu-facturerrsquos directions (eg 99mTc-MAA with a reduced particlenumber) USP radiopharmaceutical monographs and packageinserts may provide adequate information for completion of the



gThe nuclear pharmacist should not compound any patented radio-pharmaceutical unless it is not reasonably available to meet the urgentmedical need(s) of an identified individual patient This is allowed onlywhen the patented radiopharmaceutical cannot be readily obtained froma commercial source and the prescriber shall be informed that a radio-pharmaceutical will be compounded to replace the commercial product

hA high quality source of chemical substance such as a substancewhich is an analytical reagent (AR) a substance which has been certi-fied by the American Chemical Society (ACS) or a substance which islisted as Food Chemicals Codes (FCC) grade

iA high quality source of chemical substance such as a substancewhich is an AR a substance which has been certified by the ACS or asubstance which is listed as FCC grade

required RCP testing However if the RCP testing information asstated in a USP monograph or package insert is inadequate orinappropriate nuclear pharmacists can refer to the AlternativeRadiochemical Purity Testing Procedures for the CompoundedRadiopharmaceuticals Approved from 1988ndash1997 which waspublished by APhA in 199835 or they can use their professionaljudgment in selecting a suitable RCP testing method from the lit-eraturej

Bacterial Endotoxin Limit for IntrathecallyAdministered Radiopharmaceuticals

Because intrathecally administered radiopharmaceuticalsbypass the bloodndashbrain barrier and enter the brain directly via thecerebrospinal fluid the bacterial endotoxin limit for this type ofradiopharmaceutical is considerably lower than that for intra-venously administered radiopharmaceuticals37 As a result theNuclear Pharmacy Compounding Guidelines suggest that bacteri-al endotoxin testing at a sensitivity appropriate for intrathecaladministration should be performed by qualified personnel or thatin lieu of this testing the dose volume should be limited to no morethan 8 of the maximum intravenous dose volume in conjunctionwith meticulous aseptic technique in the compounding of theradiopharmaceutical for this use

Conclusion

The exclusion of radiopharmaceuticals from section 503A of theFDampC Act places the practice of compounding radiopharmaceuti-cals by nuclear pharmacists in a state of regulatory limbo Becausecompounded radiopharmaceuticals are ineligible for the statutoryexemptions from the adulteration misbranding and new drug pro-visions of the FDampC Act provided by section 503A1 and are notspecifically addressed in the 1992 and 2002 versions of CPG460200 nuclear pharmacists must continue to rely on FDArsquosenforcement discretion as described in its 1984 Nuclear PharmacyGuideline If FDA revises its enforcement compliance policies toeliminate this discretion for radiopharmaceutical compounding

such activities would by default be viewed as manufacturing Thiswould place the compounding of radiopharmaceuticals in the samepredicament as the compounding of PET drug products521

Either underregulating (ie excluding radiopharmaceuticalsfrom section 503A of the FDampC Act) or overregulating (ieapplying CGMP and NDAANDA requirements to compoundedpharmaceuticals) the practice of radiopharmaceutical compound-ing will only serve to escalate the cost of compounded radiophar-maceuticals and force many nuclear pharmacists out of the prac-tice of compounding These alternatives are clearly inconsistentwith the general publicrsquos welfare or benefit To ensure the contin-ued availability of compounded radiopharmaceuticals at reason-able cost and to maintain adequate quality of those drug productsit is imperative that current federal law be revised to provide astatutory exemption for compounded radiopharmaceuticals

Until the federal compounding regulation for radiopharmaceu-ticals is changed the availability of the Nuclear PharmacyCompounding Guidelines will assist state boards of pharmacy inappropriately evaluating and regulating nuclear pharmacy com-pounding practices The realistic and practical compounding prin-ciples and procedures provided in the Nuclear PharmacyCompounding Guidelines are also offered as a blueprint for FDAto follow in developing new radiopharmaceutical guidance

Joseph C Hung PhD BCNP FAPhA is chair Nuclear PharmacyCompounding Practice Committee American Pharmaceutical AssociationAcademy of Pharmacy Practice and Management (APhAndashAPPM) Section onNuclear Pharmacy Practice director Nuclear Pharmacy Laboratories andPET Radiochemistry Facility Nuclear Medicine Department of RadiologyMayo Clinic and professor of pharmacy and professor of radiology MayoMedical School Rochester Minn Samuel C Augustine PharmD BCNPFAPhA is associate professor Department of Pharmacy Practice College ofPharmacy Department of Pathology and Microbiology College of MedicineUniversity of Nebraska Medical Center and director Nebraska DrugInformation Network Omaha Neb Kenneth T Cheng PhD BCNP FAPhA isassociate professor and director Nuclear Pharmacy Program Department ofPharmaceutical Sciences College of Pharmacy Medical University of SouthCarolina Charleston SC Richard L Green RPh BCNP is adjunct associateprofessor of bionucleonics College of Pharmacy and Health Sciences ButlerUniversity Indianapolis Ind and program managerndashpharmacy practiceQuality amp Regulatory Department Syncor International CorporationWoodland Hills Calif Wade M Hopkins BCNP is pharmacy managerSyncor International Corporation Houston Tex David L Laven NPh CRPhFASHP FAPhA is owner Gammascan Consultants Longwood Fla BrigetteR Nelson MS PharmD BCNP is staff nuclear pharmacist RegulatorySupport Central Pharmacy Services Inc Jacksonville Fla Neil A Petry MSBCNP FAPhA is assistant professor of radiology and directorRadiopharmacy and Nuclear Medicine Laboratory Duke University MedicalCenter Durham NC James A Ponto MS BCNP FAPhA is chief nuclearpharmacist and professor (clinical) Division of Nuclear MedicineDepartment of Radiology University of Iowa Hospitals and Clinics Iowa CityIowa Timothy M Quinton PharmD MS BCNP FAPhA is presidentRadiopharmacy Inc Evansville Ind Dennis P Swanson MS BCNP FAPhAis professor of pharmacy and therapeutics School of Pharmacy Universityof Pittsburgh and director Research Conduct and Compliance OfficeUniversity of Pittsburgh Pittsburgh Pa

None of the authors of this article or members of their immediate familieshave conflicts of interest or financial interests (ie grants [pending orreceived] employment gifts stock holdings or options honoraria consul-tancies expert testimony patents and royalties) with regard to anyproduct or service mentioned in this article with the following exceptionsHung supervises radiopharmaceutical compounding services at theNuclear Pharmacy Laboratories of Mayo Clinic and serves as chairAPhAndashAPPM Section on Nuclear Pharmacy Practice Augustine served asmember at large APhAndashAPPM Section on Nuclear Pharmacy Practice and



jThe radiochemical purity (RCP) of compounded radiopharmaceuticalsshould be monitored before administration to patients The nuclear phar-macist must select an appropriate RCP testing method based on literatureevidence scientific data and hisher professional judgement etc In theabsence of USP or equivalent standards radiochemical purity specifica-tions should be established a priori based on scientific data and soundrationale Appropriate and acceptable RCP value of the final compound-ed radiopharmaceutical should be confirmed using an established andorvalidated procedure In any event clear easy-to-follow descriptions oftest methods should be readily available to all nuclear pharmacy staff

While both the USP radiopharmaceutical monographs and manufac-turerrsquos package inserts provide standard methods for testing RCP RCPtesting procedures that may be more adaptable to a nuclear pharmacy set-ting can be found in the Alternative Radiochemical Purity TestingProcedures for the Compounded Radiopharmaceuticals Approved from1988ndash1997 which was published by the APhA (Section on NuclearPharmacy Practice 1998) or in the appropriate literature

serves as a member of the Expert Committee on Parenteral ProductsmdashCompounding and Preparation General Policies and RequirementsDivision United States Pharmacopeial Convention (USP) Cheng providesdrug compounding services as director of the Nuclear Pharmacy Divisionof the Department of Pharmaceutical Sciences at the Medical University ofSouth Carolina and served as chair APhAndashAPPM Section on NuclearPharmacy Practice 1999ndash2000 Nelson served as member-at-largeAPhAndashAPPM Section on Nuclear Pharmacy Practice 1999ndash2000 Petrysupervises and performs radiopharmaceutical compounding services atthe Radiopharmacy and Nuclear Medicine Laboratory of the DukeUniversity Medical Center and served as chair APhAndashAPPM Section onNuclear Pharmacy Practice 2000ndash2001 Ponto served as a consultant forthe Office of Compliance US Food and Drug Administration (FDA) 2000performs radiopharmaceutical compounding services for University ofIowa Hospitals and Clinics and serves as a member of the ExpertCommittee on Radiopharmaceuticals Information Division USP Laura LPonto his wife serves as a member of the Expert Committee onRadiopharmaceuticals Information Division USP consultant to theMedical Imaging Drug Advisory Committee FDA and member-at-largeAPhAndashAPPM Section on Nuclear Pharmacy Practice Quinton served aschair APhAndashAPPM Section on Nuclear Pharmacy Practice 1998ndash1999Swanson serves on the Expert Committee on RadiopharmaceuticalsInformation Division USP and as a member of the Expert Committee onRadiopharmaceuticals and Medical Imaging Agents Noncomplex Activesand Excipients Division USP

Acknowledgments The authors thank Susan C Winckler Susan K Bishopand Anne L Burns American Pharmaceutical Association for their kindassistance in securing the approval of the Guidelines from APhArsquos Board ofTrustees We also express our sincere thanks to Vicki S Krage Mayo Clinicfor her assistance in the proofing and submission of the manuscript

Parts of this paper were presented by Hung at the Nuclear PharmacistsrsquoBreakfast and Business Meeting on March 7 1999 during the AnnualMeeting of the American Pharmaceutical Association

References

1 Application of federal law to practice of pharmacy compounding Foodand Drug Administration Modernization Act of 1997 Pub L No 105-115sect127 11 Stat 2296

2 Kotz D Congress passes FDA reform act nuclear medicine communi-ty stands to gain [news] J Nucl Med 19983915Nndash8N

3 Nuclear Pharmacy Guidelines for the Compounding ofRadiopharmaceuticals for Positron Emission TomographyWashington DC American Pharmaceutical Association 1993

4 Radiopharmaceuticals for positron emission tomographymdashcompound-ing In USP25ndashNF20 United States Pharmacopeia and NationalFormulary Rockville Md United States Pharmacopeial ConventionInc 20022068ndash71

5 Positron emission tomography Food and Drug AdministrationModernization Act of 1997 Pub L No 105-115 sect121 11 Stat 2296

6 Pharmacy compounding In USP25ndashNF20 United StatesPharmacopeia and National Formulary Rockville Md United StatesPharmacopeial Convention Inc 20022053ndash7

7 Stability considerations in dispensing practice In USP25ndashNF20 UnitedStates Pharmacopeia and National Formulary Rockville Md UnitedStates Pharmacopeial Convention Inc 20022231ndash4

8 Sterile drug products for home use In USP25ndashNF20 United StatesPharmacopeia and National Formulary Rockville Md United StatesPharmacopeial Convention Inc 20022234ndash47

9 ASHP guidelines on quality assurance for pharmacy-prepared sterileproducts American Society of Health-System Pharmacy Am J HealthSyst Pharm 2000571150ndash69

10 Adulterated drugs and devices Federal Food Drug and Cosmetic Actsect501(a)(2)(B) 21 USC sect301 (1998)

11 Misbranded drugs and devices Federal Food Drug and Cosmetic Actsect502(f)(1) 21 USC sect301 (1998)

12 New drugs Federal Food Drug and Cosmetic Act sect505 21 USC sect301(1998)

13 Current good manufacturing practice for finished pharmaceuticals 63Federal Register 14355ndash6 (1998) (codified at 21 CFR sect211)

14 Western States Medical Center v Shalala 238 F3d 1090 (9th Cir 2001)Available at wwwca9uscourtsgovca9newopinionsnsfF48E2BCB53CC88FD882569EB0062542F$file9917424pdfopenele-ment Accessed July 31 2002

15 Thompson Secretary of Health and Human Services et al v WesternStates Medical Center et al 535 US (2002) Available athttpa257gakamaitechnet7257242229apr20021100wwwsupre-mecourtusgovopinions01pdf01-344pdf Accessed August 3 2002

16 Manufacture distribution and promotion of adulterated misbrandedor unapproved new drugs for human use by state-licensed pharmaciesIn Compliance Policy Guides Manual Bethesda Md US Food andDrug Administration 1992sect460200 [formerly sect713216]

17 Nuclear Pharmacy Guideline Criteria for Determining When to Registeras a Drug Establishment Washington DC Food and DrugAdministration 1984

18 Sec 460200 pharmacy compounding In Guidance for FDA Staff andIndustry Compliance Policy Guides Manual Rockville Md US Foodand Drug Administration May 2002 Available at wwwfdagovoracompliance_refcpgcpgdrgcpg460200html Accessed August 52002

19 Registration of producers of drugs and devices Federal Food Drug andCosmetic Act sect510(g)(1) 21 USC sect301 (1998)

20 Requirements for radiopharmaceuticalsmdashdefinition Food and DrugAdministration Modernization Act of 1997 Pub L No 105-115 sect122 11Stat 2296

21 Hung JC Regulation of the compounding of positron emission tomog-raphy drugs Am J Health Syst Pharm 200158134ndash9

22 Fast facts about nuclear medicine Society of Nuclear Medicine Website Available at wwwsnmorgnuclearnew_whats_nm_1htmlAccessed February 10 2002

23 CIS-SULFUR COLLOID [package insert] Bedford Mass CIS-US Inc1999

24 Ceretec [package insert] Arlington Heights Ill Amersham Healthcare1996

25 TechneScan MAG3 [package insert] St Louis Mo Mallinckrodt Inc2000

26 Choletec [package insert] Princeton NJ Bracco Diagnostics Inc 200027 Macrotec [package insert] Princeton NJ Bracco Diagnostics Inc 200028 Cardiolite [package insert] N Billerica Mass Bristol-Myers Squibb

Medical Imaging Inc 200129 Myoview [package insert] Arlington Heights Ill Amersham Health

200130 OncoScint CROV [package insert] Princeton NJ CYTOGEN

Corporation 199631 General notices and requirements In USP25ndashNF20 United States

Pharmacopeia and National Formulary Rockville Md United StatesPharmacopeial Convention Inc 20021ndash11

32 Hung JC Ponto JA Hammes RJ Radiopharmaceutical-related pitfallsand artifacts Semin Nuc Med 199626208ndash55

33 Hnatowich DJ Coupal JJ [moderators] Cost-containment and the prac-tice of pharmacy J Nucl Med 199536285N

34 ALARA program 10 CFR sect3520 (2001)35 Alternative Radiochemical Purity Testing Procedures for the

Compounded Radiopharmaceuticals Approved from 1988ndash1997Washington DC American Pharmaceutical Association 1998

36 Bacterial endotoxins test In USP25ndashNF20 United States Pharmacopeiaand National Formulary Rockville Md United States PharmacopeialConvention Inc 20021889ndash93



essential to the provision of high-quality cost-effective patientcare However neither federal drug laws nor the United StatesPharmacopeia (USP) includes specific requirements or standardsfor compounding radiopharmaceuticals or for the strength qualityand purity of most compounded radiopharmaceuticals used in rou-tine clinical practice today

To proactively develop a set of professional compoundingguidelines for nuclear pharmacy the APhA Academy ofPharmacy Practice and Management (APhAndashAPPM) Section onNuclear Pharmacy Practice formed the Nuclear PharmacyCompounding Practice Committee in early 1998 The group con-sisted of nuclear pharmacists from academic institutions commer-cial nuclear pharmacies and independent nuclear pharmacies Theapproved guidelines represent the end product of a nearly 4-yeareffort by the committee

This was not the first time that the Section had developed suchguidelines In 1993 APhA distributed a document on the com-pounding of radiopharmaceuticals for positron emission tomogra-phy (PET)3 That earlier endeavor served as the basis for com-pounding guidance as stated in the USP4 as well as the current reg-ulation of these PET agents under FDAMA5

The purpose of developing the Nuclear PharmacyCompounding Guidelines was not to rewrite the various nuclearpharmacy practice acts or model state board regulations Ratherthe intent was to propose principles and standards for nuclear phar-macy practice based on the related regulations (ie section 503Aof the FDampC Act)1 as well as the recommended guidelines pub-lished in the USP and by the American Society of Health-SystemPharmacists (ASHP)6ndash9 The intent of the Guidelines is to providenuclear pharmacists with information on minimum good com-pounding practices for radiopharmaceuticals and to assist stateboards of pharmacy the US Food and Drug Administration(FDA) and the United States Pharmacopeial Convention in devel-oping new regulatory guidance pertaining to the compounding ofradiopharmaceuticals

Drafts of the Guidelines were posted on The Nuclear PharmacyWeb site (httpnuclearpharmacyuamsedu) and distributed to vari-ous organizations (eg FDA USP National Association of Boardsof Pharmacy state boards of pharmacy Council on Radionuclidesand Radiopharmaceuticals Inc [CORAR]) with requests for com-ments and suggestions Comments received were considered by theNuclear Pharmacy Compounding Practice Committee and incorpo-rated into the final guidelines as appropriate

Objectives

The purpose of the present article is to provide backgroundinformation relating to the development of the Nuclear PharmacyCompounding Guidelines to discuss issues related to the currentstate of radiopharmaceutical compounding and to summarize anygaps that exist in the current compounding regulations with regardto radiopharmaceuticals Certain sections of the Guidelines appear

as footnotes in this article to place into context the issues dis-cussed Headings throughout the text address specific regulatoryissues related to radiopharmaceutical compounding

FDA Enforcement Policy Guidance

From June 2000 through August 2001 the Nuclear PharmacyCompounding Practice Committee received several pieces of cor-respondence from FDArsquos Pharmacy Compounding SteeringCommittee (PCSC) concerning the draft guidelines principallywith regard to FDArsquos ldquoenforcement discretionrdquo on the practice ofradiopharmaceutical compounding While PCSC indicated that thedraft guidelines closely followed the provisions of section 503A ofthe FDampC Act1 current law does not exempt compounded radio-pharmaceuticals from three provisions of the FDampC Act section501(a)(2)(B)mdashadulteration (concerning the current good manu-facturing practice [CGMP] requirements)10 section 502(f)(1)mdashmisbranding (concerning the labeling of drugs with adequatedirections for use)11 and section 505mdashnew drug provisions (con-cerning the approval of drugs and requirements for New DrugApplications [NDA] and Abbreviated New Drug Applications[ANDA])12 On that basis PCSC suggested that all references toany exemption from the above three statutory requirements withregard to radiopharmaceuticals be removed from item 6a of theGeneral Provisions section of the Nuclear PharmacyCompounding Guidelines

To help readers better understand this confusing issue the fol-lowing discussion is divided into subsections

Section 503A of the FDampC ActSection 503A of the FDampC Act stipulates that drug products

that are compounded by a pharmacist or physician for an identifiedindividual patient pursuant to a valid prescription order and thatconform to other requirements listed in section 503A are exempt-ed from the FDampC Actrsquos adulteration misbranding and new drugprovisions110ndash12



aWhen a radiopharmaceutical is compounded by a nuclear pharmacistbased on a valid prescription while engaging in compounding activitieswhich are in conformance with the normal practice of pharmacy as gov-erned by the board of pharmacy which licenses the practice site and asstated in Section 510(g)(1) of the FFDCA (FDA 1998f) that compound-ed radiopharmaceutical has historically been exempted by FDA enforce-ment policy guidelines (FDA 1984 1992) from enforcement of at leastthree provisions of the FFDCA ie adulteration [eg CGMP require-ments as stated in Section 501(a)(2)(B)] (FDA 1998b) misbranding [eglabeling of drugs with adequate directions for use as stipulated in Section502(f)(1)](FDA 1998c) and the new drug provisions [ie NDA orANDA regulation as described in Section 505] (FDA 1998e) Theenforcement policy guidance for compounded radiopharmaceuticals iscurrently being reviewed by the FDA In that guidance the FDA mayaddress and clarify situations where FDA could exercise its enforcementdiscretion for the aforementioned three statutory requirements (LanaOgram FDA written communication August 2001)















































































































Conclusion














References




















































































































































Conclusion














References









































References






































Explanations and Unresolved Issues Pertaining to the Development of the Nuclear Pharmacy Compounding...

Documents

Transcript of Explanations and Unresolved Issues Pertaining to the Development of the Nuclear Pharmacy Compounding...