cfr 2012 title21 vol7 chapi subchapf

7/25/2019 CFR 2012 Title21 Vol7 ChapI SubchapF

1/135

5

SUBCHAPTER FBIOLOGICS

PART 600BIOLOGICALPRODUCTS: GENERAL

Subpart AGeneral Provisions

Sec.600.2 Mailing addresses.600.3 Definitions.

Subpart BEstablishment Standards

600.10 Personnel.

600.11 Physical establishment, equipment,animals, and care.

600.12 Records.600.13 Retention samples.600.14 Reporting of biological product devi-

ations by licenses manufacturers.600.15 Temperatures during shipment.

Subpart CEstablishment Inspection

600.20 Inspectors.600.21 Time of inspection.600.22 Duties of inspector.

Subpart DReporting of AdverseExperiences

600.80 Postmarketing reporting of adverseexperiences.

600.81 Distribution reports.600.90 Waivers.

AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355,360, 360i, 371, 374; 42 U.S.C. 216, 262, 263, 263a,264, 300aa25.

CROSS REFERENCES: For U.S. CustomsService regulations relating to viruses, se-rums, and toxins, see 19 CFR 12.2112.23. ForU.S. Postal Service regulations relating tothe admissibility to the United States mailssee parts 124 and 125 of the Domestic MailManual, that is incorporated by reference in39 CFR part 111.


600.2 Mailing addresses.

(a) Licensed biological products regu-

lated by the Center for Biologics Evalua-tion and Research (CBER). Unless other-wise stated in paragraphs (c) or (d) ofthis section, or as otherwise prescribedby FDA regulation, all submissions toCBER referenced in parts 600 through680 of this chapter, as applicable, mustbe sent to: Document Control Center(HFM99), Center for Biologics Evalua-tion and Research, Food and Drug Ad-ministration, 1401 Rockville Pike, suite

200N, Rockville, MD 208521448. Exam-ples of such submissions include: Bio-logics license applications (BLAs) andtheir amendments and supplements,adverse experience reports, biologicalproduct deviation reports, fatality re-ports, and other correspondence. Bio-logical products samples must not besent to this address but must be sent tothe address in paragraph (c) of this sec-tion.

(b) Licensed biological products regu-lated by the Center for Drug Evaluation

and Research (CDER). Unless otherwisestated in paragraphs (b)(1), (b)(2), (b)(3),or (c) of this section, or as otherwiseprescribed by FDA regulation, all sub-missions to CDER referenced in parts600, 601, and 610 of this chapter, as ap-plicable, must be sent to: CDER Thera-peutic Biological Products DocumentRoom, Center for Drug Evaluation andResearch, Food and Drug Administra-tion, 12229 Wilkins Ave., Rockville, MD20852. Examples of such submissions in-clude: BLAs and their amendments andsupplements, and other correspond-ence.

(1) Biological Product Deviation Report-ing (CDER). All biological product devi-ation reports required under 600.14must be sent to: Division of Compli-ance Risk Management and Surveil-lance, Office of Compliance, Center forDrug Evaluation and Research, Foodand Drug Administration, 10903 NewHampshire Ave., Silver Spring, MD209930002.

(2) Postmarketing Adverse ExperienceReporting (CDER). All postmarketingreports required under 600.80 must besent to: Central Document Room, Cen-ter for Drug Evaluation and Research,Food and Drug Administration, 5901BAmmendale Rd., Beltsville, MD 20705

1266.(3) Advertising and Promotional Label-

ing (CDER). All advertising and pro-motional labeling supplements re-quired under 601.12(f) of this chaptermust be sent to: Division of Drug Mar-keting, Advertising and Communica-tion, Center for Drug Evaluation andResearch, Food and Drug Administra-tion, 5901B Ammendale Rd., Beltsville,MD 207051266.

VerDate Mar2010 11:47 Apr 26, 2012 Jkt 226073 PO 00000 Frm 00015 Fmt 8010 Sfmt 8010 Q:\21\21V7 ofr150 PsN: PC150


2/135

6

21 CFR Ch. I (4112 Edition) 600.3

(c) Samples and Protocols for licensedbiological products regulated by CBER or

CDER. (1) Biological product samplesand/or protocols, other than radio-active biological product samples andprotocols, required under 600.13,600.22, 601.15, 610.2, 660.6, 660.36, or 660.46of this chapter must be sent by courierservice to: Sample Custodian (ATTN:HFM672), Food and Drug Administra-tion, Center for Biologics Evaluationand Research, Bldg: NLRCB, rm. 113,5516 Nicholson Lane, Kensington, MD20895. The protocol(s) may be placed in

the box used to ship the samples toCBER. A cover letter should not be in-cluded when submitting the protocolwith the sample unless it contains per-tinent information affecting the re-lease of the lot.

(2) Radioactive biological productsrequired under 610.2 of this chaptermust be sent by courier service to:Sample Custodian (ATTN: HFM672),Food and Drug Administration, Centerfor Biologics Evaluation and Research,Nicholson Lane Research Center, c/oRadiation Safety Office, National In-stitutes of Health, 21 Wilson Dr., rm.107, Bethesda, MD 208926780.

(d) Vaccine Adverse Event Reporting

System (VAERS). All VAERS reports asspecified in 600.80(c) must be sent to:Vaccine Adverse Event Reporting Sys-tem (VAERS), P.O. Box 1100, Rockville,MD 208491100.

(e) Address information for submis-sions to CBER and CDER other thanthose listed in parts 600 through 680 ofthis chapter are included directly inthe applicable regulations.

(f) Obtain updated mailing addressinformation for biological productsregulated by CBER at http://www.fda.gov/cber/pubinquire.htm , or forbiological products regulated by CDERat http://www.fda.gov/cder/biologics/de-

fault.htm.

[70 FR 14981, Mar. 24, 2005, as amended at 74FR 13114, Mar. 26, 2009]

600.3 Definitions.

As used in this subchapter:(a) Act means the Public Health Serv-

ice Act (58 Stat. 682), approved July 1,1944.

(b) Secretary means the Secretary ofHealth and Human Services and anyother officer or employee of the De-

partment of Health and Human Serv-ices to whom the authority involvedhas been delegated.

(c) Commissioner of Food and Drugsmeans the Commissioner of the Foodand Drug Administration.

(d) Center for Biologics Evaluation andResearch means Center for BiologicsEvaluation and Research of the Foodand Drug Administration.

(e) State means a State or the Dis-trict of Columbia, Puerto Rico, or theVirgin Islands.

(f) Possession includes among otherpossessions, Puerto Rico and the Vir-gin Islands.

(g) Products includes biological prod-ucts and trivalent organic arsenicals.

(h) Biological product means anyvirus, therapeutic serum, toxin, anti-toxin, or analogous product applicableto the prevention, treatment or cure ofdiseases or injuries of man:

(1) A virus is interpreted to be a prod-uct containing the minute living causeof an infectious disease and includesbut is not limited to filterable viruses,bacteria, rickettsia, fungi, and pro-tozoa.

(2) A therapeutic serum is a productobtained from blood by removing theclot or clot components and the bloodcells.

(3) A toxin is a product containing asoluble substance poisonous to labora-tory animals or to man in doses of 1milliliter or less (or equivalent inweight) of the product, and having theproperty, following the injection ofnon-fatal doses into an animal, of caus-ing to be produced therein anothersoluble substance which specificallyneutralizes the poisonous substanceand which is demonstrable in theserum of the animal thus immunized.

(4) An antitoxin is a product con-

taining the soluble substance in serumor other body fluid of an immunizedanimal which specifically neutralizesthe toxin against which the animal isimmune.

(5) A product is analogous:

(i) To a virus if prepared from or witha virus or agent actually or potentiallyinfectious, without regard to the de-gree of virulence or toxicogenicity ofthe specific strain used.



3/135

7

Food and Drug Administration, HHS 600.3

(ii) To a therapeutic serum, if com-posed of whole blood or plasma or con-taining some organic constituent orproduct other than a hormone or anamino acid, derived from whole blood,plasma, or serum.

(iii) To a toxin or antitoxin, if in-tended, irrespective of its source of ori-gin, to be applicable to the prevention,treatment, or cure of disease or inju-ries of man through a specific immuneprocess.

(i) Trivalent organic arsenicals meansarsphenamine and its derivatives (or

any other trivalent organic arseniccompound) applicable to the preven-tion, treatment, or cure of diseases orinjuries of man.

(j) A product is deemed applicable tothe prevention, treatment, or cure of dis-

eases or injuries of man irrespective ofthe mode of administration or applica-tion recommended, including use whenintended through administration or ap-plication to a person as an aid in diag-nosis, or in evaluating the degree ofsusceptibility or immunity possessedby a person, and including also anyother use for purposes of diagnosis ifthe diagnostic substance so used is pre-pared from or with the aid of a biologi-

cal product.(k) Proper name, as applied to a prod-

uct, means the name designated in thelicense for use upon each package ofthe product.

(l) Dating period means the period be-yond which the product cannot be ex-pected beyond reasonable doubt toyield its specific results.

(m) Expiration date means the cal-endar month and year, and where ap-plicable, the day and hour, that thedating period ends.

(n) The word standards means speci-fications and procedures applicable toan establishment or to the manufac-ture or release of products, which are

prescribed in this subchapter or estab-lished in the biologics license applica-tion designed to insure the continuedsafety, purity, and potency of suchproducts.

(o) The word continued as applied tothe safety, purity and potency of prod-ucts is interpreted to apply to the dat-ing period.

(p) The word safety means the rel-ative freedom from harmful effect to

persons affected, directly or indirectly,by a product when prudently adminis-tered, taking into consideration thecharacter of the product in relation tothe condition of the recipient at thetime.

(q) The word sterility is interpreted tomean freedom from viable contami-nating microorganisms, as determinedby the tests prescribed in 610.12 of thischapter.

(r) Purity means relative freedomfrom extraneous matter in the finishedproduct, whether or not harmful to the

recipient or deleterious to the product.Purity includes but is not limited torelative freedom from residual mois-ture or other volatile substances andpyrogenic substances.

(s) The wordpotency is interpreted tomean the specific ability or capacity ofthe product, as indicated by appro-priate laboratory tests or by ade-quately controlled clinical data ob-tained through the administration ofthe product in the manner intended, toeffect a given result.

(t) Manufacturer means any legal per-son or entity engaged in the manufac-ture of a product subject to licenseunder the act; Manufacturer also in-

cludes any legal person or entity whois an applicant for a license where theapplicant assumes responsibility forcompliance with the applicable productand establishment standards.

(u) Manufacture means all steps inpropagation or manufacture and prepa-ration of products and includes but isnot limited to filling, testing, labeling,packaging, and storage by the manu-facturer.

(v) Location includes all buildings,appurtenances, equipment and animalsused, and personnel engaged by a man-ufacturer within a particular area des-ignated by an address adequate foridentification.

(w) Establishment has the same mean-ing as facility in section 351 of thePublic Health Service Act and includesall locations.

(x) Lot means that quantity of uni-form material identified by the manu-facturer as having been thoroughlymixed in a single vessel.

(y) Afilling refers to a group of finalcontainers identical in all respects,which have been filled with the same



4/135

8

21 CFR Ch. I (4112 Edition) 600.10

product from the same bulk lot with-out any change that will affect the in-tegrity of the filling assembly.

(z) Process refers to a manufacturingstep that is performed on the productitself which may affect its safety, pu-rity or potency, in contrast to suchmanufacturing steps which do not af-fect intrinsically the safety, purity orpotency of the product.

(aa) Selling agent or distributor meansany person engaged in the unrestricteddistribution, other than by sale at re-tail, of products subject to license.

(bb) Container (referred to also asfinal container) is the immediateunit, bottle, vial, ampule, tube, orother receptacle containing the prod-uct as distributed for sale, barter, orexchange.

(cc) Package means the immediatecarton, receptacle, or wrapper, includ-ing all labeling matter therein andthereon, and the contents of the one ormore enclosed containers. If no pack-age, as defined in the preceding sen-tence, is used, the container shall bedeemed to be the package.

(dd) Label means any written, print-ed, or graphic matter on the containeror package or any such matter clearly

visible through the immediate carton,receptacle, or wrapper.

(ee) Radioactive biological productmeans a biological product which is la-beled with a radionuclide or intendedsolely to be labeled with a radio-nuclide.

(ff) Amendment is the submission ofinformation to a pending license appli-cation or supplement, to revise or mod-ify the application as originally sub-mitted.

(gg) Supplement is a request to ap-prove a change in an approved licenseapplication.

(hh) Distributed means the biologicalproduct has left the control of the li-

censed manufacturer.(ii) Control means having responsi-

bility for maintaining the continuedsafety, purity, and potency of the prod-uct and for compliance with applicableproduct and establishment standards,and for compliance with current goodmanufacturing practices.

(jj) Assess the effects of the change, asused in 601.12 of this chapter, meansto evaluate the effects of a manufac-

turing change on the identity,strength, quality, purity, and potencyof a product as these factors may re-late to the safety or effectiveness ofthe product.

(kk) Specification, as used in 601.12 ofthis chapter, means the quality stand-ard (i.e., tests, analytical procedures,and acceptance criteria) provided in anapproved application to confirm thequality of products, intermediates, rawmaterials, reagents, components, in-process materials, container closuresystems, and other materials used in

the production of a product. For thepurpose of this definition, acceptancecriteria means numerical limits, ranges,or other criteria for the tests de-scribed.

(ll) Complete response letter means awritten communication to an applicantfrom FDA usually describing all of thedeficiencies that the agency has identi-fied in a biologics license applicationor supplement that must be satisfac-torily addressed before it can be ap-proved.

(mm) Resubmission means a submis-sion by the biologics license applicantor supplement applicant of all mate-rials needed to fully address all defi-

ciencies identified in the complete re-sponse letter. A biologics license appli-cation or supplement for which FDAissued a complete response letter, butwhich was withdrawn before approvaland later submitted again, is not a re-submission.

[38 FR 32048, Nov. 20, 1973, as amended at 40FR 31313, July 25, 1975; 55 FR 11014, Mar. 26,1990; 61 FR 24232, May 14, 1996; 62 FR 39901,July 24, 1997; 64 FR 56449, Oct. 20, 1999; 65 FR66634, Nov. 7, 2000; 69 FR 18766, Apr. 8, 2004; 70FR 14982, Mar. 24, 2005; 73 FR 39610, July 10,2008]

Subpart BEstablishmentStandards

600.10 Personnel.

(a) [Reserved](b) Personnel. Personnel shall have

capabilities commensurate with theirassigned functions, a thorough under-standing of the manufacturing oper-ations which they perform, the nec-essary training and experience relatingto individual products, and adequateinformation concerning the application



5/135

9


of the pertinent provisions of this sub-chapter to their respective functions.

Personnel shall include such profes-

sionally trained persons as are nec-essary to insure the competent per-

formance of all manufacturing proc-esses.

(c) Restrictions on personnel(1) Spe-cific duties. Persons whose presence canaffect adversely the safety and purity

of a product shall be excluded from theroom where the manufacture of a prod-

uct is in progress.

(2) Sterile operations. Personnel per-forming sterile operations shall wearclean or sterilized protective clothing

and devices to the extent necessary toprotect the product from contamina-

tion.

(3) Pathogenic viruses and spore-form-

ing organisms. Persons working with vi-ruses pathogenic for man or with

spore-forming microorganisms, andpersons engaged in the care of animals

or animal quarters, shall be excludedfrom areas where other products are

manufactured, or such persons shallchange outer clothing, including shoes,

or wear protective covering prior to en-tering such areas.

(4) Live vaccine work areas. Personsmay not enter a live vaccine processing

area after having worked with other in-fectious agents in any other laboratoryduring the same working day. Onlypersons actually concerned with propa-gation of the culture, production of thevaccine, and unit maintenance, shall beallowed in live vaccine processingareas when active work is in progress.Casual visitors shall be excluded fromsuch units at all times and all othershaving business in such areas shall beadmitted only under supervision.Street clothing, including shoes, shallbe replaced or covered by suitable lab-

oratory clothing before entering a livevaccine processing unit. Persons caringfor animals used in the manufacture oflive vaccines shall be excluded fromother animal quarters and from con-tact with other animals during thesame working day.

[38 FR 32048, Nov. 20, 1973, as amended at 49

FR 23833, June 8, 1984; 55 FR 11014, Mar. 26,

1990; 62 FR 53538, Oct. 15, 1997; 68 FR 75119,

Dec. 30, 2003]

600.11 Physical establishment, equip-ment, animals, and care.

(a) Work areas. All rooms and workareas where products are manufacturedor stored shall be kept orderly, clean,and free of dirt, dust, vermin and ob-jects not required for manufacturing.Precautions shall be taken to avoidclogging and back-siphonage of drain-age systems. Precautions shall betaken to exclude extraneous infectiousagents from manufacturing areas.Work rooms shall be well lighted andventilated. The ventilation systemshall be arranged so as to prevent thedissemination of microorganisms fromone manufacturing area to another andto avoid other conditions unfavorableto the safety of the product. Fillingrooms, and other rooms where open,sterile operations are conducted, shallbe adequate to meet manufacturingneeds and such rooms shall be con-structed and equipped to permit thor-ough cleaning and to keep air-bornecontaminants at a minimum. If suchrooms are used for other purposes, theyshall be cleaned and prepared prior touse for sterile operations. Refrig-erators, incubators and warm roomsshall be maintained at temperatures

within applicable ranges and shall befree of extraneous material whichmight affect the safety of the product.

(b) Equipment. Apparatus for steri-lizing equipment and the method of op-eration shall be such as to insure thedestruction of contaminating micro-organisms. The effectiveness of thesterilization procedure shall be no lessthan that achieved by an attained tem-perature of 121.5 C maintained for 20minutes by saturated steam or by anattained temperature of 170 C main-tained for 2 hours with dry heat. Proc-essing and storage containers, filters,filling apparatus, and other pieces ofapparatus and accessory equipment, in-

cluding pipes and tubing, shall be de-signed and constructed to permit thor-ough cleaning and, where possible, in-spection for cleanliness. All surfacesthat come in contact with productsshall be clean and free of surface solids,leachable contaminants, and other ma-terials that will hasten the deteriora-tion of the product or otherwise renderit less suitable for the intended use.For products for which sterility is a



6/135

10

21 CFR Ch. I (4112 Edition) 600.11

factor, equipment shall be sterile, un-less sterility of the product is assuredby subsequent procedures.

(c) Laboratory and bleeding rooms.Rooms used for the processing of prod-ucts, including bleeding rooms, shall beeffectively fly-proofed and kept free offlies and vermin. Such rooms shall beso constructed as to insure freedomfrom dust, smoke and other deleterioussubstances and to permit thoroughcleaning and disinfection. Rooms foranimal injection and bleeding, androoms for smallpox vaccine animals,

shall be disinfected and be providedwith the necessary water, electricaland other services.

(d) Animal quarters and stables. Ani-mal quarters, stables and food storageareas shall be of appropriate construc-tion, fly-proofed, adequately lightedand ventilated, and maintained in aclean, vermin-free and sanitary condi-tion. No manure or refuse shall bestored as to permit the breeding of flieson the premises, nor shall the estab-lishment be located in close proximityto off-property manure or refuse stor-age capable of engendering fly breed-ing.

(e) Restrictions on building and equip-

ment use(1) Work of a diagnostic na-ture. Laboratory procedures of a clin-ical diagnostic nature involving mate-rials that may be contaminated, shallnot be performed in space used for themanufacture of products except thatmanufacturing space which is usedonly occasionally may be used for diag-nostic work provided spore-formingpathogenic microorganisms are not in-volved and provided the space is thor-oughly cleaned and disinfected beforethe manufacture of products is re-sumed.

(2) Spore-forming organisms for supple-mental sterilization procedure control test.

Spore-forming organisms used as an

additional control in sterilization pro-cedures may be introduced into areasused for the manufacture of products,only for the purposes of the test andonly immediately before use for suchpurposes: Provided, That (i) the orga-nism is not pathogenic for man or ani-mals and does not produce pyrogens ortoxins, (ii) the culture is demonstratedto be pure, (iii) transfer of test culturesto culture media shall be limited to the

sterility test area or areas designatedfor work with spore-forming orga-nisms, (iv) each culture be labeled withthe name of the microorganism and thestatement Caution: microbial spores.See directions for storage, use and dis-position., and (v) the container ofeach culture is designed to withstandhandling without breaking.

(3) Work with spore-forming microorga-nisms. (i) Manufacturing processesusing spore-forming microorganismsconducted in a multiproduct manufac-turing site must be performed under

appropriate controls to prevent con-tamination of other products and areaswithin the site. Prevention of sporecontamination can be achieved byusing a separate dedicated building orby using process containment if manu-facturing is conducted in a multi-product manufacturing building. Allproduct and personnel movement be-tween the area where the spore-form-ing microorganisms are manufacturedand other manufacturing areas must beconducted under conditions that willprevent the introduction of spores intoother areas of the facility.

(ii) If process containment is em-ployed in a multiproduct manufac-

turing area, procedures must be inplace to demonstrate adequate removalof the spore-forming microorganism(s)from the manufacturing area for subse-quent manufacture of other products.These procedures must provide for ade-quate removal or decontamination ofthe spore-forming microorganisms onand within manufacturing equipment,facilities, and ancillary room items aswell as the removal of disposable orproduct dedicated items from the man-ufacturing area. Environmental moni-toring specific for the spore-formingmicroorganism(s) must be conducted inadjacent areas during manufacturingoperations and in the manufacturing

area after completion of cleaning anddecontamination.

(4) Live vaccine processing. Live vac-cine processing must be performedunder appropriate controls to preventcross contamination of other productsand other manufacturing areas withinthe building. Appropriate controlsmust include, at a minimum:

(i)(A) Using a dedicated manufac-turing area that is either in a separate



7/135

11


building, in a separate wing of a build-ing, or in quarters at the blind end of acorridor and includes adequate spaceand equipment for all processing stepsup to, but not including, filling intofinal containers; and

(B) Not conducting test proceduresthat potentially involve the presence ofmicroorganisms other than the vaccinestrains or the use of tissue culture celllines other than primary cultures inspace used for processing live vaccine;or

(ii) If manufacturing is conducted in

a multiproduct manufacturing buildingor area, using procedural controls, andwhere necessary, process containment.Process containment is deemed to benecessary unless procedural controlsare sufficient to prevent cross contami-nation of other products and othermanufacturing areas within the build-ing. Process containment is a systemdesigned to mechanically isolate equip-ment or an area that involves manufac-turing using live vaccine organisms.All product, equipment, and personnelmovement between distinct live vac-cine processing areas and between livevaccine processing areas and othermanufacturing areas, up to, but not in-

cluding, filling in final containers,must be conducted under conditionsthat will prevent cross contaminationof other products and manufacturingareas within the building, includingthe introduction of live vaccine orga-nisms into other areas. In addition,written procedures and effective proc-esses must be in place to adequately re-move or decontaminate live vaccine or-ganisms from the manufacturing areaand equipment for subsequent manu-facture of other products. Written pro-cedures must be in place forverification that processes to removeor decontaminate live vaccine orga-nisms have been followed.

(5) Equipment and suppliescontami-nation. Equipment and supplies used inwork on or otherwise exposed to anypathogenic or potentially pathogenicagent shall be kept separated fromequipment and supplies used in themanufacture of products to the extentnecessary to prevent cross-contamina-tion.

(f) Animals used in manufacture(1)Care of animals used in manufacturing.

Caretakers and attendants for animals

used for the manufacture of products

shall be sufficient in number and have

adequate experience to insure adequate

care. Animal quarters and cages shall

be kept in sanitary condition. Animals

on production shall be inspected daily

to observe response to production pro-

cedures. Animals that become ill for

reasons not related to production shall

be isolated from other animals and

shall not be used for production until

recovery is complete. Competent vet-

erinary care shall be provided as need-ed.

(2) Quarantine of animals(i) General.

No animal shall be used in processing

unless kept under competent daily in-

spection and preliminary quarantine

for a period of at least 7 days before

use, or as otherwise provided in this

subchapter. Only healthy animals free

from detectable communicable diseases

shall be used. Animals must remain in

overt good health throughout the quar-

antine periods and particular care shall

be taken during the quarantine periods

to reject animals of the equine genus

which may be infected with glanders

and animals which may be infected

with tuberculosis.

(ii) Quarantine of monkeys. In addi-

tion to observing the pertinent general

quarantine requirements, monkeys

used as a source of tissue in the manu-

facture of vaccine shall be maintained

in quarantine for at least 6 weeks prior

to use, except when otherwise provided

in this part. Only monkeys that have

reacted negatively to tuberculin at the

start of the quarantine period and

again within 2 weeks prior to use shall

be used in the manufacture of vaccine.

Due precaution shall be taken to pre-

vent cross-infection from any infected

or potentially infected monkeys on the

premises. Monkeys to be used in the

manufacture of a live vaccine shall be

maintained throughout the quarantine

period in cages closed on all sides with

solid materials except the front which

shall be screened, with no more than

two monkeys housed in one cage. Cage

mates shall not be interchanged.

(3) Immunization against tetanus.

Horses and other animals susceptible



8/135

12

21 CFR Ch. I (4112 Edition) 600.11

to tetanus, that are used in the proc-essing steps of the manufacture of bio-logical products, shall be treated ade-quately to maintain immunity to tet-anus.

(4) Immunization and bleeding of ani-mals used as a source of products. Toxinsor other nonviable antigens adminis-tered in the immunization of animalsused in the manufacture of productsshall be sterile. Viable antigens, whenso used, shall be free of contaminants,as determined by appropriate testsprior to use. Injections shall not be

made into horses within 6 inches ofbleeding site. Horses shall not be bledfor manufacturing purposes whileshowing persistent general reaction orlocal reaction near the site of bleeding.Blood shall not be used if it was drawnwithin 5 days of injecting the animalswith viable microorganisms. Animalsshall not be bled for manufacturingpurposes when they have an intercur-rent disease. Blood intended for use asa source of a biological product shallbe collected in clean, sterile vessels.When the product is intended for useby injection, such vessels shall also bepyrogen-free.

(5) [Reserved]

(6) Reporting of certain diseases. Incases of actual or suspected infectionwith foot and mouth disease, glanders,tetanus, anthrax, gas gangrene, equineinfectious anemia; equineencephalomyelitis, or any of the pockdiseases among animals intended foruse or used in the manufacture of prod-ucts, the manufacturer shall imme-diately notify the Director, Center forBiologics Evaluation and Research orthe Director, Center for Drug Evalua-tion and Research (see mailing address-es in 600.2).

(7) Monkeys used previously for experi-mental or test purposes. Monkeys thathave been used previously for experi-

mental or test purposes with livemicrobiological agents shall not beused as a source of kidney tissue forthe manufacture of vaccine. Except asprovided otherwise in this subchapter,monkeys that have been used pre-viously for other experimental or testpurposes may be used as a source ofkidney tissue upon their return to anormal condition, provided all quar-antine requirements have been met.

(8) Necropsy examination of monkeys.Each monkey used in the manufactureof vaccine shall be examined at ne-cropsy under the direction of a quali-fied pathologist, physician, or veteri-narian having experience with diseasesof monkeys, for evidence of ill health,particularly for (i) evidence of tuber-culosis, (ii) presence of herpes-like le-sions, including eruptions or plaqueson or around the lips, in the buccalcavity or on the gums, and (iii) signs ofconjunctivitis. If there are any suchsigns or other significant gross patho-

logical lesions, the tissue shall not beused in the manufacture of vaccine.

(g) Filling procedures. Filling proce-dures shall be such as will not affectadversely the safety, purity or potencyof the product.

(h) Containers and closures. All finalcontainers and closures shall be madeof material that will not hasten the de-terioration of the product or otherwiserender it less suitable for the intendeduse. All final containers and closuresshall be clean and free of surface solids,leachable contaminants and other ma-terials that will hasten the deteriora-tion of the product or otherwise renderit less suitable for the intended use.

After filling, sealing shall be performedin a manner that will maintain the in-tegrity of the product during the dat-ing period. In addition, final containersand closures for products intended foruse by injection shall be sterile andfree from pyrogens. Except as other-wise provided in the regulations of thissubchapter, final containers for prod-ucts intended for use by injection shallbe colorless and sufficiently trans-parent to permit visual examination ofthe contents under normal light. Assoon as possible after filling final con-tainers shall be labeled as prescribed in 610.60 et seq. of this chapter, exceptthat final containers may be stored

without such prescribed labeling pro-vided they are stored in a sealed recep-tacle labeled both inside and outsidewith at least the name of the product,the lot number, and the filling identi-fication.

[38 FR 32048, Nov. 20, 1973, as amended at 41FR 10428, Mar. 11, 1976; 49 FR 23833, June 8,1984; 55 FR 11013, Mar. 26, 1990; 68 FR 75119,Dec. 30, 2003; 70 FR 14982, Mar. 24, 2005; 72 FR59003, Oct. 18, 2007]



9/135

13


600.12 Records.

(a) Maintenance of records. Recordsshall be made, concurrently with theperformance, of each step in the manu-facture and distribution of products, insuch a manner that at any time succes-sive steps in the manufacture and dis-tribution of any lot may be traced byan inspector. Such records shall be leg-ible and indelible, shall identify theperson immediately responsible, shallinclude dates of the various steps, andbe as detailed as necessary for clear un-derstanding of each step by one experi-enced in the manufacture of products.

(b) Records retention(1) General.Records shall be retained for such in-terval beyond the expiration date as isnecessary for the individual product, topermit the return of any clinical reportof unfavorable reactions. The retentionperiod shall be no less than five yearsafter the records of manufacture havebeen completed or six months after thelatest expiration date for the indi-vidual product, whichever represents alater date.

(2) Records of recall. Complete recordsshall be maintained pertaining to therecall from distribution of any productupon notification by the Director, Cen-

ter for Biologics Evaluation and Re-search or the Director, Center for DrugEvaluation and Research, to recall forfailure to conform with the standardsprescribed in the regulations of thissubchapter, because of deterioration ofthe product or for any other factor byreason of which the distribution of theproduct would constitute a danger tohealth.

(3) Suspension of requirement for reten-tion. The Director, Center for BiologicsEvaluation and Research or the Direc-tor, Center for Drug Evaluation andResearch, may authorize the suspen-sion of the requirement to retainrecords of a specific manufacturing

step upon a showing that such recordsno longer have significance for the pur-poses for which they were made: Pro-vided, That a summary of such recordsshall be retained.

(c) Records of sterilization of equipmentand supplies. Records relating to themode of sterilization, date, duration,temperature and other conditions re-lating to each sterilization of equip-ment and supplies used in the proc-

essing of products shall be made bymeans of automatic recording devicesor by means of a system of recordingwhich gives equivalent assurance of theaccuracy and reliability of the record.Such records shall be maintained in amanner that permits an identificationof the product with the particular man-ufacturing process to which the steri-lization relates.

(d) Animal necropsy records. A ne-cropsy record shall be kept on eachanimal from which a biological producthas been obtained and which dies or is

sacrificed while being so used.(e) Records in case of divided manufac-

turing responsibility. If two or more es-tablishments participate in the manu-facture of a product, the records ofeach such establishment must showplainly the degree of its responsibility.In addition, each participating manu-facturer shall furnish to the manufac-turer who prepares the product in finalform for sale, barter or exchange, acopy of all records relating to the man-ufacturing operations performed bysuch participating manufacturer inso-far as they concern the safety, purityand potency of the lots of the productinvolved, and the manufacturer who

prepares the product in final form shallretain a complete record of all themanufacturing operations relating tothe product.

[38 FR 32048, Nov. 20, 1973, as amended at 49FR 23833, June 8, 1984; 55 FR 11013, Mar. 26,1990; 70 FR 14982, Mar. 24, 2005]

600.13 Retention samples.

Manufacturers shall retain for a pe-riod of at least 6 months after the expi-ration date, unless a different time pe-riod is specified in additional stand-ards, a quantity of representative ma-terial of each lot of each product, suffi-cient for examination and testing forsafety and potency, except Whole

Blood, Cryoprecipitated AHF, Plate-lets, Red Blood Cells, Plasma, andSource Plasma and Allergenic Productsprepared to a physicians prescription.Samples so retained shall be selectedat random from either final containermaterial, or from bulk and final con-tainers, provided they include at leastone final container as a final package,or package-equivalent of such filling ofeach lot of the product as intended for



10/135

14

21 CFR Ch. I (4112 Edition) 600.14

distribution. Such sample materialshall be stored at temperatures andunder conditions which will maintainthe identity and integrity of the prod-uct. Samples retained as required inthis section shall be in addition tosamples of specific products required tobe submitted to the Center for Bio-logics Evaluation and Research or theCenter for Drug Evaluation and Re-search (see mailing addresses in 600.2).Exceptions may be authorized by theDirector, Center for Biologics Evalua-tion and Research or the Director, Cen-

ter for Drug Evaluation and Research,when the lot yields relatively few finalcontainers and when such lots are pre-pared by the same method in largenumber and in close succession.

[41 FR 10428, Mar. 11, 1976, as amended at 49FR 23833, June 8, 1984; 50 FR 4133, Jan. 29,1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14982,Mar. 24, 2005]

600.14 Reporting of biological prod-uct deviations by licensed manufac-turers.

(a) Who must report under this section?(1) You, the manufacturer who holdsthe biological product license and whohad control over the product when the

deviation occurred, must report underthis section. If you arrange for anotherperson to perform a manufacturing,holding, or distribution step, while theproduct is in your control, that step isperformed under your control. Youmust establish, maintain, and follow aprocedure for receiving informationfrom that person on all deviations,complaints, and adverse events con-cerning the affected product.

(2) Exceptions:(i) Persons who manufacture only in

vitro diagnostic products that are notsubject to licensing under section 351 ofthe Public Health Service Act do notreport biological product deviations for

those products under this section butmust report in accordance with part803 of this chapter;

(ii) Persons who manufacture bloodand blood components, including li-censed manufacturers, unlicensed reg-istered blood establishments, andtransfusion services, do not report bio-logical product deviations for thoseproducts under this section but mustreport under 606.171 of this chapter;

(iii) Persons who manufacture SourcePlasma or any other blood componentand use that Source Plasma or anyother blood component in the furthermanufacture of another licensed bio-logical product must report:

(A) Under 606.171 of this chapter, if abiological product deviation occursduring the manufacture of that SourcePlasma or any other blood component;or

(B) Under this section, if a biologicalproduct deviation occurs after themanufacture of that Source Plasma or

any other blood component, and duringmanufacture of the licensed biologicalproduct.

(b) What do I report under this section?You must report any event, and infor-mation relevant to the event, associ-ated with the manufacturing, to in-clude testing, processing, packing, la-beling, or storage, or with the holdingor distribution, of a licensed biologicalproduct, if that event meets all the fol-lowing criteria:

(1) Either:(i) Represents a deviation from cur-

rent good manufacturing practice, ap-plicable regulations, applicable stand-ards, or established specifications that

may affect the safety, purity, or po-tency of that product; or

(ii) Represents an unexpected or un-foreseeable event that may affect thesafety, purity, or potency of that prod-uct; and

(2) Occurs in your facility or anotherfacility under contract with you; and

(3) Involves a distributed biologicalproduct.

(c) When do I report under this section?You should report a biological productdeviation as soon as possible but youmust report at a date not to exceed 45-calendar days from the date you, youragent, or another person who performsa manufacturing, holding, or distribu-

tion step under your control, acquireinformation reasonably suggestingthat a reportable event has occurred.

(d) How do I report under this sectionYou must report on Form FDA3486.

(e) Where do I report under this section?(1) For biological products regulated bythe Center for Biologics Evaluationand Research (CBER), send the com-pleted Form FDA3486 to the Director,Office of Compliance and Biologics



11/135

15


Quality (HFM600) (see mailing ad-dresses in 600.2), or an electronic fil-ing through CBERs Web site at http://www.fda.gov/cber/biodev/biodev.htm .

(2) For biological products regulatedby the Center for Drug Evaluation andResearch (CDER), send the completedForm FDA3486 to the Division of Com-pliance Risk Management and Surveil-lance (HFD330) (see mailing addressesin 600.2). CDER does not currently ac-cept electronic filings.

(3) If you make a paper filing, youshould identify on the envelope that a

biological product deviation report(BPDR) is enclosed.

(f) How does this regulation affect otherFDA regulations? This part supplements

and does not supersede other provisionsof the regulations in this chapter. Allbiological product deviations, whetheror not they are required to be reportedunder this section, should be inves-tigated in accordance with the applica-ble provisions of parts 211 and 820 ofthis chapter.


FR 14982, Mar. 24, 2005]

600.15 Temperatures during ship-ment.

The following products shall be main-tained during shipment at the specifiedtemperatures:

(a) Products.

Product Temperature

Cryoprecipitated AHF ....................................................... 18 C or colder.Measles and Rubella Virus Vaccine Live ......................... 10 C or colder.Measles Live and Smallpox Vaccine ................................ Do.Measles, Mumps, and Rubella Virus Vaccine Live .......... Do.Measles and Mumps Virus Vaccine Live ......................... Do.Measles Virus Vaccine Live ............................................. Do.Mumps Virus Vaccine Live ............................................... Do.Fresh Frozen Plasma ................... .................... ................ 18 C or colder.Liquid Plasma ................................................................... 1 to 10 C.Plasma .............................................................................. 18 C or colder.Platelet Rich Plasma ........................................................ Between 1 and 10 C if the label indicates storage between 1 and 6

C, or all reasonable methods to maintain the temperature as closeas possible to a range between 20 and 24 C, if the label indicatesstorage between 20 and 24 C.

Platelets ............................................................................ Between 1 and 10 C if the label indicates storage between 1 and 6C, or all reasonable methods to maintain the temperature as closeas possible to a range between 20 to 24 C, if the label indicatesstorage between 20 and 24 C.

Poliovirus Vaccine Live Oral Trivalent .............................. 0 C or colder.Poliovirus Vaccine Live Oral Type I ................................. Do.Poliovirus Vaccine Live Oral Type II ................................ Do.Poliovirus Vaccine Live Oral Type III ............................... Do.Red Blood Cells (liquid product) ....................................... Between 1 and 10 C.Red Blood Cells Frozen ................................................... 65 C or colder.Rubella and Mumps Virus Vaccine Live .......................... 10 C or colder.Rubella Virus Vaccine Live ............................................... Do.Smallpox Vaccine (Liquid Product) .................................. 0 C or colder.Source Plasma ................................................................. 5 C or colder.Source Plasma Liquid ....................................................... 10 C or colder.Whole Blood ..................................................................... Blood that is transported from the collecting facility to the processing

facility shall be transported in an environment capable of continu-ously cooling the blood toward a temperature range of 1 to 10 C,or at a temperature as close as possible to 20 to 24 C for a periodnot to exceed 6 hours. Blood transported from the storage facilityshall be placed in an appropriate environment to maintain a tem-perature range between 1 to 10 C during shipment.

Yellow Fever Vaccine ....................................................... 0 C or colder.

(b) Exemptions. Exemptions or modi-

fications shall be made only upon writ-

ten approval, in the form of a supple-

ment to the biologics license applica-

tion, approved by the Director, Center

for Biologics Evaluation and Research.


FR 23833, June 8, 1984; 50 FR 4133, Jan. 29,

1985; 50 FR 9000, Mar. 6, 1985; 55 FR 11013,

Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 64 FR

56449, Oct. 20, 1999]



12/135

16

21 CFR Ch. I (4112 Edition) 600.20

Subpart CEstablishmentInspection

600.20 Inspectors.

Inspections shall be made by an offi-cer of the Food and Drug Administra-tion having special knowledge of themethods used in the manufacture andcontrol of products and designated forsuch purposes by the Commissioner ofFood and Drugs, or by any officer,agent, or employee of the Departmentof Health and Human Services specifi-

cally designated for such purpose bythe Secretary.

[38 FR 32048, Nov. 20, 1973]

600.21 Time of inspection.

The inspection of an establishmentfor which a biologics license applica-tion is pending need not be made untilthe establishment is in operation andis manufacturing the complete productfor which a biologics license is desired.In case the license is denied followinginspection for the original license, noreinspection need be made until assur-ance has been received that the faultyconditions which were the basis of thedenial have been corrected. An inspec-tion of each licensed establishment andits additional location(s) shall be madeat least once every 2 years. Inspectionsmay be made with or without notice,and shall be made during regular busi-ness hours unless otherwise directed.

[38 FR 32048, Nov. 20, 1973, as amended at 48FR 26314, June 7, 1983; 64 FR 56449, Oct. 20,1999]

600.22 Duties of inspector.

The inspector shall:

(a) Call upon the active head of theestablishment, stating the object of hisvisit,

(b) Interrogate the proprietor or

other personnel of the establishment ashe may deem necessary,

(c) Examine the details of location,construction, equipment and mainte-nance, including stables, barns, ware-houses, manufacturing laboratories,bleeding clinics maintained for the col-lection of human blood, shippingrooms, record rooms, and any otherstructure or appliance used in any partof the manufacture of a product,

(d) Investigate as fully as he deemsnecessary the methods of propagation,processing, testing, storing, dispensing,recording, or other details of manufac-ture and distribution of each licensedproduct, or product for which a licensehas been requested, including observa-tion of these procedures in actual oper-ation,

(e) Obtain and cause to be sent to theDirector, Center for Biologics Evalua-tion and Research or the Director, Cen-ter for Drug Evaluation and Research(see mailing addresses in 600.2), ade-

quate samples for the examination ofany product or ingredient used in itsmanufacture,

(f) Bring to the attention of the man-ufacturer any fault observed in thecourse of inspection in location, con-struction, manufacturing methods, oradministration of a licensed establish-ment which might lead to impairmentof a product,

(g) Inspect and copy, as cir-cumstances may require, any recordsrequired to be kept pursuant to 600.12,

(h) Certify as to the condition of theestablishment and of the manufac-turing methods followed and make rec-ommendations as to action deemed ap-

propriate with respect to any applica-tion for license or any license pre-viously issued.

[38 FR 32048, Nov. 20, 1973, as amended at 49FR 23833, June 8, 1984; 55 FR 11013, Mar. 26,1990; 70 FR 14982, Mar. 24, 2005]

Subpart DReporting of AdverseExperiences

SOURCE: 59 FR 54042, Oct. 27, 1994, unlessotherwise noted.

600.80 Postmarketing reporting ofadverse experiences.

(a) Definitions. The following defini-tions of terms apply to this section:

Adverse experience. Any adverse eventassociated with the use of a biologicalproduct in humans, whether or notconsidered product related, includingthe following: An adverse event occur-ring in the course of the use of a bio-logical product in professional prac-tice; an adverse event occurring fromoverdose of the product whether acci-dental or intentional; an adverse eventoccurring from abuse of the product; an



13/135

17


adverse event occurring from with-drawal of the product; and any failureof expected pharmacological action.

Blood Component. As defined in 606.3(c) of this chapter.

Disability. A substantial disruption ofa persons ability to conduct normallife functions.

Life-threatening adverse experience.

Any adverse experience that places thepatient, in the view of the initial re-porter, at immediate risk of deathfrom the adverse experience as it oc-curred, i.e., it does not include an ad-

verse experience that, had it occurredin a more severe form, might havecaused death.

Serious adverse experience. Any ad-verse experience occurring at any dosethat results in any of the followingoutcomes: Death, a life-threatening ad-verse experience, inpatient hospitaliza-tion or prolongation of existing hos-pitalization, a persistent or significantdisability/incapacity, or a congenitalanomaly/birth defect. Important med-ical events that may not result indeath, be life-threatening, or requirehospitalization may be considered a se-rious adverse experience when, basedupon appropriate medical judgment,

they may jeopardize the patient or sub-ject and may require medical or sur-gical intervention to prevent one of theoutcomes listed in this definition. Ex-amples of such medical events includeallergic bronchospasm requiring inten-sive treatment in an emergency roomor at home, blood dyscrasias or convul-sions that do not result in inpatienthospitalization, or the development ofdrug dependency or drug abuse.

Unexpected adverse experience: Any ad-verse experience that is not listed inthe current labeling for the biologicalproduct. This includes events that maybe symptomatically andpathophysiologically related to an

event listed in the labeling, but differfrom the event because of greater se-verity or specificity. For example,under this definition, hepatic necrosiswould be unexpected (by virtue ofgreater severity) if the labeling onlyreferred to elevated hepatic enzymes orhepatitis. Similarly, cerebral thrombo-embolism and cerebral vasculitis wouldbe unexpected (by virtue of greaterspecificity) if the labeling only listed

cerebral vascular accidents. Unex-pected, as used in this definition, re-fers to an adverse experience that hasnot been previously observed (i.e., in-cluded in the labeling) rather thanfrom the perspective of such experiencenot being anticipated from the pharma-cological properties of the pharma-ceutical product.

(b) Review of adverse experiences. Anyperson having a biologics license under 601.20 of this chapter shall promptlyreview all adverse experience informa-tion pertaining to its product obtainedor otherwise received by the licensedmanufacturer from any source, foreignor domestic, including information de-rived from commercial marketing ex-perience, postmarketing clinical inves-tigations, postmarketing epidemiolog-ical/surveillance studies, reports in thescientific literature, and unpublishedscientific papers. Licensed manufactur-ers are not required to resubmit toFDA adverse product experience re-ports forwarded to the licensed manu-facturer by FDA; licensed manufactur-ers, however, must submit all followupinformation on such reports to FDA.Any person subject to the reporting re-

quirements under paragraph (c) of thissection shall also develop written pro-cedures for the surveillance, receipt,evaluation, and reporting of post-marketing adverse experiences to FDA.

(c) Reporting requirements. The li-censed manufacturer shall report toFDA adverse experience information,as described in this section. The li-censed manufacturer shall submit twocopies of each report described in thissection for nonvaccine biological prod-ucts to the Center for Biologics Eval-uation and Research (HFM210), or tothe Center for Drug Evaluation and Re-search (see mailing addresses in 600.2).Submit all vaccine adverse experience

reports to: Vaccine Adverse Event Re-porting System (VAERS) (see mailingaddresses in 600.2). FDA may waivethe requirement for the second copy inappropriate instances.

(1)(i) Postmarketing 15-day Alert re-ports. The licensed manufacturer shallreport each adverse experience that isboth serious and unexpected, whetherforeign or domestic, as soon as possiblebut in no case later than 15 calendar



14/135

18

21 CFR Ch. I (4112 Edition) 600.80

days of initial receipt of the informa-tion by the licensed manufacturer.

(ii) Postmarketing 15-day Alert re-portsfollowup. The licensed manufac-turer shall promptly investigate all ad-verse experiences that are the subjectof these postmarketing 15-day Alert re-ports and shall submit followup reportswithin 15 calendar days of receipt ofnew information or as requested byFDA. If additional information is notobtainable, records should be main-tained of the unsuccessful steps takento seek additional information. Post-marketing 15-day Alert reports andfollowups to them shall be submittedunder separate cover.

(iii) Submission of reports. The re-quirements of paragraphs (c)(1)(i) and(c)(1)(ii) of this section, concerning thesubmission of postmarketing 15-dayAlert reports, shall also apply to anyperson whose name appears on thelabel of a licensed biological product asa manufacturer, packer, distributor,shared manufacturer, joint manufac-turer, or any other participant in-volved in divided manufacturing. Toavoid unnecessary duplication in thesubmission to FDA of reports required

by paragraphs (c)(1)(i) and (c)(1)(ii) ofthis section, obligations of personsother than the licensed manufacturerof the final biological product may bemet by submission of all reports of se-rious adverse experiences to the li-censed manufacturer of the final prod-uct. If a person elects to submit ad-verse experience reports to the licensedmanufacturer of the final product rath-er than to FDA, the person shall sub-mit each report to the licensed manu-facturer of the final product within 5calendar days of receipt of the reportby the person, and the licensed manu-facturer of the final product shall thencomply with the requirements of this

section. Under this circumstance, aperson who elects to submit reports tothe licensed manufacturer of the finalproduct shall maintain a record of thisaction which shall include:

(A) A copy of all adverse biologicalproduct experience reports submittedto the licensed manufacturer of thefinal product;

(B) The date the report was receivedby the person;

(C) The date the report was sub-

mitted to the licensed manufacturer of

the final product; and

(D) The name and address of the li-

censed manufacturer of the final prod-

uct.

(iv) Report identification. Each report

submitted under this paragraph shall

bear prominent identification as to its

contents, i.e., 15-day Alert report, or

15-day Alert report-followup.

(2) Periodic adverse experience reports.

(i) The licensed manufacturer shall re-

port each adverse experience not re-ported under paragraph (c)(1)(i) of this

section at quarterly intervals, for 3

years from the date of issuance of the

biologics license, and then at annual

intervals. The licensed manufacturer

shall submit each quarterly report

within 30 days of the close of the quar-

ter (the first quarter beginning on the

date of issuance of the biologics li-

cense) and each annual report within 60

days of the anniversary date of the

issuance of the biologics license. Upon

written notice, FDA may extend or re-

establish the requirement that a li-

censed manufacturer submit quarterly

reports, or require that the licensedmanufacturer submit reports under

this section at different times than

those stated. Followup information to

adverse experiences submitted in a

periodic report may be submitted in

the next periodic report.

(ii) Each periodic report shall con-

tain:

(A) A narrative summary and anal-

ysis of the information in the report

and an analysis of the 15-day Alert re-

ports submitted during the reporting

interval (all 15-day Alert reports being

appropriately referenced by the li-

censed manufacturers patient identi-

fication number, adverse reaction

term(s), and date of submission to

FDA);

(B) A form designated for Adverse

Experience Reporting by FDA for each

adverse experience not reported under

paragraph (c)(1)(i) of this section (with

an index consisting of a line listing of

the licensed manufacturers patient

identification number and adverse re-

action term(s)); and



15/135

19


(C) A history of actions taken sincethe last report because of adverse expe-riences (for example, labeling changesor studies initiated).

(iii) Periodic reporting, except for in-formation regarding 15-day Alert re-ports, does not apply to adverse experi-ence information obtained from post-marketing studies (whether or not con-ducted under an investigational newdrug application), from reports in thescientific literature, and from foreignmarketing experience.

(d) Scientific literature. (1) A 15-dayAlert report based on information fromthe scientific literature shall be ac-companied by a copy of the publishedarticle. The 15-day Alert reporting re-quirements in paragraph (c)(1)(i) of thissection (i.e., serious, unexpected ad-verse experiences) apply only to re-ports found in scientific and medicaljournals either as case reports or as theresult of a formal clinical trial.

(2) As with all reports submittedunder paragraph (c)(1)(i) of this sec-tion, reports based on the scientific lit-erature shall be submitted on the re-porting form designated by FDA orcomparable format as prescribed by

paragraph (f) of this section. In caseswhere the licensed manufacturer be-lieves that preparing the form des-ignated by FDA constitutes an unduehardship, the licensed manufacturermay arrange with the Division of Bio-statistics and Epidemiology (HFM210)for an acceptable alternative reportingformat.

(e) Postmarketing studies. (1) Licensedmanufacturers are not required to sub-mit a 15-day Alert report under para-graph (c) of this section for an adverseexperience obtained from a post-marketing clinical study (whether ornot conducted under a biological inves-tigational new drug application) unless

the licensed manufacturer concludesthat there is a reasonable possibilitythat the product caused the adverse ex-perience.

(2) The licensed manufacturer shallseparate and clearly mark reports ofadverse experiences that occur during apostmarketing study as being distinctfrom those experiences that are beingreported spontaneously to the licensedmanufacturer.

(f) Reporting forms. (1) Except as pro-vided in paragraph (f)(3) of this section,the licensed manufacturer shall com-plete the reporting form designated byFDA for each report of an adverse expe-rience (FDA Form 3500A, or, for vac-cines, a VAERS form; foreign eventsincluding those associated with the useof vaccines, may be submitted eitheron an FDA Form 3500A or, if preferred,on a CIOMS I form).

(2) Each completed form should referonly to an individual patient or singleattached publication.

(3) Instead of using a designated re-porting form, a licensed manufacturermay use a computer-generated form orother alternative format (e.g., a com-puter-generated tape or tabular listing)provided that:

(i) The content of the alternative for-mat is equivalent in all elements of in-formation to those specified in theform designated by FDA; and

(ii) the format is approved in advanceby MEDWATCH: The FDA MedicalProducts Reporting Program; or, foralternatives to the VAERS Form, bythe Division of Biostatistics and Epide-miology.

(4) Copies of the reporting form des-ignated by FDA (FDA3500A) for non-vaccine biological products may be ob-tained from http://www.fda.gov/medwatch/getforms.htm. Additional sup-plies of the form may be obtained fromthe Consolidated Forms and Publica-tions Distribution Center, 3222 HubbardRd., Landover, MD 20785. Supplies ofthe VAERS form may be obtained fromVAERS by calling 18008227967.

(g) Multiple reports. A licensed manu-facturer should not include in reportsunder this section any adverse experi-ence that occurred in clinical trials ifthey were previously submitted as partof the biologics license application. If a

report refers to more than one biologi-cal product marketed by a licensedmanufacturer, the licensed manufac-turer should submit the report to thebiologics license application for theproduct listed first in the report.

(h) Patient privacy. For nonvaccine bi-ological products, a licensed manufac-turer should not include in reportsunder this section the names and ad-dresses of individual patients; instead,



16/135

20

21 CFR Ch. I (4112 Edition) 600.81

the licensed manufacturer should as-sign a unique code number to each re-port, preferably not more than eightcharacters in length. The licensed man-ufacturer should include the name ofthe reporter from whom the informa-tion was received. The names of pa-tients, health care professionals, hos-pitals, and geographical identifiers inadverse experience reports are not re-leasable to the public under FDAs pub-lic information regulations in part 20this of chapter. For vaccine adverse ex-perience reports, these data will be-

come part of the CDC Privacy Act Sys-tem 09200136, Epidemiologic Studiesand Surveillance of Disease Problems.Information identifying the person whoreceived the vaccine or that personslegal representative will not be madeavailable to the public, but may beavailable to the vaccinee or legal rep-resentative.

(i) Recordkeeping. The licensed manu-facturer shall maintain for a period of10 years records of all adverse experi-ences known to the licensed manufac-turer, including raw data and any cor-respondence relating to the adverse ex-periences.

(j) Revocation of biologics license. If a

licensed manufacturer fails to estab-lish and maintain records and make re-ports required under this section withrespect to a licensed biological prod-uct, FDA may revoke the biologics li-cense for such a product in accordancewith the procedures of 601.5 of thischapter.

(k) Exemptions. Manufacturers of thefollowing listed products are not re-quired to submit adverse experience re-ports under this section:

(1) Whole blood or components ofwhole blood.

(2) In vitro diagnostic products, in-cluding assay systems for the detectionof antibodies or antigens to

retroviruses. These products are sub-ject to the reporting requirements fordevices.

(l) Disclaimer. A report or informationsubmitted by a licensed manufacturerunder this section (and any release byFDA of that report or information)does not necessarily reflect a conclu-sion by the licensed manufacturer orFDA that the report or informationconstitutes an admission that the bio-

logical product caused or contributedto an adverse effect. A licensed manu-facturer need not admit, and may deny,that the report or information sub-mitted under this section constitutesan admission that the biological prod-uct caused or contributed to an adverseeffect. For purposes of this provision,this paragraph also includes any personreporting under paragraph (c)(1)(iii) ofthis section.

[59 FR 54042, Oct. 27, 1994, as amended at 62FR 34168, June 25, 1997; 62 FR 52252, Oct. 7,1997; 63 FR 14612, Mar. 26, 1998; 64 FR 56449,

Oct. 20, 1999; 70 FR 14982, Mar. 24, 2005]

600.81 Distribution reports.

The licensed manufacturer shall sub-mit to the Center for Biologics Evalua-tion and Research or the Center forDrug Evaluation and Research (seemailing addresses in 600.2), informa-tion about the quantity of the productdistributed under the biologics license,including the quantity distributed todistributors. The interval between dis-tribution reports shall be 6 months.Upon written notice, FDA may requirethat the licensed manufacturer submitdistribution reports under this sectionat times other than every 6 months.

The distribution report shall consist ofthe bulk lot number (from which thefinal container was filled), the fill lotnumbers for the total number of dosageunits of each strength or potency dis-tributed (e.g., fifty thousand per 10-milliliter vials), the label lot number(if different from fill lot number), la-beled date of expiration, number ofdoses in fill lot/label lot, date of releaseof fill lot/label lot for distribution atthat time. If any significant amount ofa fill lot/label lot is returned, includethis information. Disclosure of finan-cial or pricing data is not required. Asneeded, FDA may require submission ofmore detailed product distribution in-

formation. Upon written notice, FDAmay require that the licensed manufac-turer submit reports under this sectionat times other than those stated. Re-quests by a licensed manufacturer tosubmit reports at times other thanthose stated should be made as a re-quest for a waiver under 600.90.

[59 FR 54042, Oct. 27, 1994, as amended at 64FR 56449, Oct. 20, 1999; 70 FR 14983, Mar. 24,2005]



17/135

21

Food and Drug Administration, HHS Pt. 601

600.90 Waivers.

(a) A licensed manufacturer may askthe Food and Drug Administration towaive under this section any require-ment that applies to the licensed man-ufacturer under 600.80 and 600.81. Awaiver request under this section is re-quired to be submitted with supportingdocumentation. The waiver request isrequired to contain one of the fol-lowing:

(1) An explanation why the licensedmanufacturers compliance with the re-

quirement is unnecessary or cannot beachieved,(2) A description of an alternative

submission that satisfies the purpose ofthe requirement, or

(3) Other information justifying awaiver.

(b) FDA may grant a waiver if itfinds one of the following:

(1) The licensed manufacturers com-pliance with the requirement is unnec-essary or cannot be achieved,

(2) The licensed manufacturers alter-native submission satisfies the require-ment, or

(3) The licensed manufacturers sub-mission otherwise justifies a waiver.

PART 601LICENSING


Sec.601.2 Applications for biologics licenses;

procedures for filing.601.3 Complete response letter to the appli-

cant.601.4 Issuance and denial of license.601.5 Revocation of license.601.6 Suspension of license.601.7 Procedure for hearings.601.8 Publication of revocation.601.9 Licenses; reissuance.

Subpart B [Reserved]

Subpart CBiologics Licensing601.12 Changes to an approved application.601.14 Regulatory submissions in electronic

format.601.15 Foreign establishments and products:

Samples for each importation.601.20 Biologics licenses; issuance and con-

ditions.601.21 Products under development.601.22 Products in short supply; initial man-

ufacturing at other than licensed loca-tion.

601.25 Review procedures to determine thatlicensed biological products are safe, ef-fective, and not misbranded under pre-scribed, recommended, or suggested con-ditions of use.

601.26 Reclassification procedures to deter-mine that licensed biological productsare safe, effective, and not misbrandedunder prescribed, recommended, or sug-gested conditions of use.

601.27 Pediatric studies.601.28 Annual reports of postmarketing pe-

diatric studies.601.29 Guidance documents.

Subpart DDiagnosticRadiopharmaceuticals

601.30 Scope.601.31 Definition.601.32 General factors relevant to safety and

effectiveness.601.33 Indications.601.34 Evaluation of effectiveness.601.35 Evaluation of safety.

Subpart EAccelerated Approval of Bio-logical Products for Serious or Life-Threatening Illnesses

601.40 Scope.601.41 Approval based on a surrogate end-

point or on an effect on a clinical end-point other than survival or irreversiblemorbidity.

601.42 Approval with restrictions to assuresafe use.

601.43 Withdrawal procedures.601.44 Postmarketing safety reporting.601.45 Promotional materials.601.46 Termination of requirements.

Subpart FConfidentiality of Information

601.50 Confidentiality of data and informa-tion in an investigational new drug no-tice for a biological product.

601.51 Confidentiality of data and informa-tion in applications for biologics li-censes.

Subpart GPostmarketing Studies

601.70 Annual progress reports of post-marketing studies.

Subpart HApproval of Biological Prod-ucts When Human Efficacy Studies AreNot Ethical or Feasible

601.90 Scope.601.91 Approval based on evidence of effec-

tiveness from studies in animals.601.92 Withdrawal procedures.601.93 Postmarketing safety reporting.601.94 Promotional materials.601.95 Termination of requirements.



18/135

22

21 CFR Ch. I (4112 Edition) 601.2

AUTHORITY: 15 U.S.C. 14511561; 21 U.S.C.321, 351, 352, 353, 355, 356b, 360, 360c360f, 360h360j, 371, 374, 379e, 381; 42 U.S.C. 216, 241, 262,263, 264; sec 122, Pub. L. 105115, 111 Stat. 2322(21 U.S.C. 355 note).

SOURCE: 38 FR 32052, Nov. 20, 1973, unlessotherwise noted.

CROSS REFERENCES: For U.S. CustomsService regulations relating to viruses, se-rums, and toxins, see 19 CFR 12.2112.23. ForU.S. Postal Service regulations relating tothe admissibility to the United States mailssee parts 124 and 125 of the Domestic MailManual, that is incorporated by reference in39 CFR part 111.


601.2 Applications for biologics li-censes; procedures for filing.

(a) General. To obtain a biologics li-cense under section 351 of the PublicHealth Service Act for any biologicalproduct, the manufacturer shall submitan application to the Director, Centerfor Biologics Evaluation and Researchor the Director, Center for Drug Eval-uation and Research (see mailing ad-dresses in 600.2 of this chapter), onforms prescribed for such purposes, andshall submit data derived from non-clinical laboratory and clinical studies

which demonstrate that the manufac-tured product meets prescribed re-quirements of safety, purity, and po-tency; with respect to each nonclinicallaboratory study, either a statementthat the study was conducted in com-pliance with the requirements set forthin part 58 of this chapter, or, if thestudy was not conducted in compliancewith such regulations, a brief state-ment of the reason for the noncompli-ance; statements regarding each clin-ical investigation involving humansubjects contained in the application,that it either was conducted in compli-ance with the requirements for institu-tional review set forth in part 56 of this

chapter; or was not subject to such re-quirements in accordance with 56.104or 56.105, and was conducted in com-pliance with requirements for informedconsent set forth in part 50 of thischapter. A full description of manufac-turing methods; data establishing sta-bility of the product through the dat-ing period; sample(s) representative ofthe product for introduction or deliv-ery for introduction into interstate

commerce; summaries of results oftests performed on the lot(s) rep-resented by the submitted sample(s);specimens of the labels, enclosures, andcontainers, and if applicable, any Medi-cation Guide required under part 208 ofthis chapter proposed to be used for theproduct; and the address of each loca-tion involved in the manufacture of thebiological product shall be listed in thebiologics license application. The ap-plicant shall also include a financialcertification or disclosure statement(s)or both for clinical investigators as re-

quired by part 54 of this chapter. Anapplication for a biologics license shallnot be considered as filed until all per-tinent information and data have beenreceived by the Food and Drug Admin-istration. The applicant shall also in-clude either a claim for categorical ex-clusion under 25.30 or 25.31 of thischapter or an environmental assess-ment under 25.40 of this chapter. Theapplicant, or the applicants attorney,agent, or other authorized official shallsign the application. An application forany of the following specified cat-egories of biological products subjectto licensure shall be handled as setforth in paragraph (c) of this section:

(1) Therapeutic DNA plasmid prod-ucts;

(2) Therapeutic synthetic peptideproducts of 40 or fewer amino acids;

(3) Monoclonal antibody products forin vivo use; and

(4) Therapeutic recombinant DNA-de-rived products.

(b) [Reserved]

(c)(1) To obtain marketing approvalfor a biological product subject to li-censure which is a therapeutic DNAplasmid product, therapeutic syntheticpeptide product of 40 or fewer aminoacids, monoclonal antibody product forin vivo use, or therapeutic recombinant

DNA-derived product, an applicantshall submit a biologics license appli-cation in accordance with paragraph(a) of this section except that the fol-lowing sections in parts 600 through 680of this chapter shall not be applicableto such products: 600.10(b) and (c),600.11, 600.12, 600.13, 610.11, 610.53, and610.62 of this chapter.

(2) To the extent that the require-ments in this paragraph (c) conflict



19/135

23


with other requirements in this sub-chapter, this paragraph (c) shall super-sede other requirements.

(d) Approval of a biologics license ap-plication or issuance of a biologics li-cense shall constitute a determinationthat the establishment(s) and the prod-uct meet applicable requirements toensure the continued safety, purity,and potency of such products. Applica-ble requirements for the maintenanceof establishments for the manufactureof a product subject to this sectionshall include but not be limited to the

good manufacturing practice require-ments set forth in parts 210, 211, 600,606, and 820 of this chapter.

(e) Any establishment and product li-cense for a biological product issuedunder section 351 of the Public HealthService Act (42 U.S.C. 201 et seq.) thathas not been revoked or suspended asof December 20, 1999, shall constitutean approved biologics license applica-tion in effect under the same terms andconditions set forth in such product li-cense and such portions of the estab-lishment license relating to such prod-uct.

[64 FR 56450, Oct. 20, 1999, as amended at 70FR 14983, Mar. 24, 2005]

601.3 Complete response letter to theapplicant.

(a) Complete response letter. The Foodand Drug Administration will send thebiologics license applicant or supple-ment applicant a complete responseletter if the agency determines that itwill not approve the biologics licenseapplication or supplement in itspresent form.

(1) Description of specific deficiencies. Acomplete response letter will describeall of the deficiencies that the agencyhas identified in a biologics license ap-plication or supplement, except as stat-ed in paragraph (a)(2) of this section.

(2) Inadequate data. If FDA deter-mines, after a biologics license applica-tion or supplement is filed, that thedata submitted are inadequate to sup-port approval, the agency might issue acomplete response letter without firstconducting required inspections, test-ing submitted product lots, and/or re-viewing proposed product labeling.

(3) Recommendation of actions for ap-proval. When possible, a complete re-

sponse letter will recommend actionsthat the applicant might take to placeits biologics license application or sup-plement in condition for approval.

(b) Applicant actions. After receivinga complete response letter, the bio-logics license applicant or supplementapplicant must take either of the fol-lowing actions:

(1) Resubmission. Resubmit the appli-cation or supplement, addressing alldeficiencies identified in the completeresponse letter.

(2) Withdrawal. Withdraw the applica-

tion or supplement. A decision to with-draw the application or supplement iswithout prejudice to a subsequent sub-mission.

(c) Failure to take action. (1) FDA mayconsider a biologics license applicantor supplement applicants failure to ei-ther resubmit or withdraw the applica-tion or supplement within 1 year afterissuance of a complete response letterto be a request by the applicant towithdraw the application or supple-ment, unless the applicant has re-quested an extension of time in whichto resubmit the application or supple-ment. FDA will grant any reasonablerequest for such an extension. FDA

may consider an applicants failure toresubmit the application or supple-ment within the extended time periodor request an additional extension tobe a request by the applicant to with-draw the application.

(2) If FDA considers an applicantsfailure to take action in accordancewith paragraph (c)(1) of this section tobe a request to withdraw the applica-tion, the agency will notify the appli-cant in writing. The applicant willhave 30 days from the date of the noti-fication to explain why the applicationor supplement should not be withdrawnand to request an extension of time inwhich to resubmit the application or

supplement. FDA will grant any rea-sonable request for an extension. If theapplicant does not respond to the noti-fication within 30 days, the applicationor supplement will be deemed to bewithdrawn.

[73 FR 39611, July 10, 2008]

601.4 Issuance and denial of license.

(a) A biologics license shall be issuedupon a determination by the Director,



20/135

24

21 CFR Ch. I (4112 Edition) 601.5

Center for Biologics Evaluation andResearch or the Director, Center forDrug Evaluation and Research that theestablishment(s) and the product meetthe applicable requirements estab-lished in this chapter. A biologics li-cense shall be valid until suspended orrevoked.

(b) If the Commissioner determinesthat the establishment or product doesnot meet the requirements establishedin this chapter, the biologics licenseapplication shall be denied and the ap-plicant shall be informed of the

grounds for, and of an opportunity fora hearing on, the decision. If the appli-cant so requests, the Commissionershall issue a notice of opportunity forhearing on the matter pursuant to 12.21(b) of this chapter.

[42 FR 4718, Jan. 25, 1977, as amended at 42FR 15676, Mar. 22, 1977; 42 FR 19142, Apr. 12,1977; 64 FR 56450, Oct. 20, 1999; 70 FR 14983,Mar. 24, 2005]

601.5 Revocation of license.

(a) A biologics license shall be re-voked upon application of the manu-facturer giving notice of intention todiscontinue the manufacture of allproducts manufactured under such li-

cense or to discontinue the manufac-ture of a particular product for which alicense is held and waiving an oppor-tunity for a hearing on the matter.

(b)(1) The Commissioner shall notifythe licensed manufacturer of the inten-tion to revoke the biologics license,setting forth the grounds for, and offer-ing an opportunity for a hearing on theproposed revocation if the Commis-sioner finds any of the following:

(i) Authorized Food and Drug Admin-istration employees after reasonableefforts have been unable to gain accessto an establishment or a location forthe purpose of carrying out the inspec-tion required under 600.21 of this chap-

ter,(ii) Manufacturing of products or of a

product has been discontinued to an ex-tent that a meaningful inspection orevaluation cannot be made,

(iii) The manufacturer has failed toreport a change as required by 601.12of this chapter,

(iv) The establishment or any loca-tion thereof, or the product for whichthe license has been issued, fails to

conform to the applicable standards es-tablished in the license and in thischapter designed to ensure the contin-ued safety, purity, and potency of themanufactured product,

(v) The establishment or the manu-facturing methods have been sochanged as to require a new showingthat the establishment or productmeets the requirements established inthis chapter in order to protect thepublic health, or

(vi) The licensed product is not safeand effective for all of its intended uses

or is misbranded with respect to anysuch use.

(2) Except as provided in 601.6 of thischapter, or in cases involving willful-ness, the notification required in thisparagraph shall provide a reasonableperiod for the licensed manufacturer todemonstrate or achieve compliancewith the requirements of this chapter,before proceedings will be institutedfor the revocation of the license. Ifcompliance is not demonstrated orachieved and the licensed manufac-turer does not waive the opportunityfor a hearing, the Commissioner shallissue a notice of opportunity for hear-ing on the matter under 12.21(b) of

this chapter.

[64 FR 56451, Oct. 20, 1999]

601.6 Suspension of license.

(a) Whenever the Commissioner hasreasonable grounds to believe that anyof the grounds for revocation of a li-cense exist and that by reason thereofthere is a danger to health, the Com-missioner may notify the licensedmanufacturer that the biologics licenseis suspended and require that the li-censed manufacturer do the following:

(1) Notify the selling agents and dis-tributors to whom such product orproducts have been delivered of such

suspension, and(2) Furnish to the Center for Bio-

logics Evaluation and Research or theCenter for Drug Evaluation and Re-search, complete records of such deliv-eries and notice of suspension.

(b) Upon suspension of a license, theCommissioner shall either:

(1) Proceed under the provisions of 601.5(b) of this chapter to revoke thelicense, or



21/135

25


(2) If the licensed manufactureragrees, hold revocation in abeyancepending resolution of the matters in-volved.

[64 FR 56451, Oct. 20, 1999, as amended at 70FR 14983, Mar. 24, 2005]

601.7 Procedure for hearings.

(a) A notice of opportunity for hear-ing, notice of appearance and requestfor hearing, and grant or denial ofhearing for a biological drug pursuantto this part, for which the exemptionfrom the Federal Fo

cfr 2012 title21 vol7 chapi subchapf

Documents