CFR 2013 Title21 Vol7

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Title 21

Food and Drugs

Parts 600 to 799

Revised as of April 1, 2013

Containing a codification of documents

of general applicability and future effect

As of April 1, 2013

Published by the Office of the Federal Register

National Archives and Records Administration

as a Special Edition of the Federal Register

VerDate Mar2010 15:53 Apr 23, 2013 Jkt 229074 PO 00000 Frm 00001 Fmt 8091 Sfmt 8091 Q:\21\21V7.TXT ofr150 PsN: PC150

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U.S. GOVERNMENT OFFICIAL EDITION NOTICE

Legal Status and Use of Seals and Logos

The seal of the National Archives and Records Administration

(NARA) authenticates the Code of Federal Regulations (CFR) as

the official codification of Federal regulations established under

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contents of the CFR, a special edition of the Federal Register, shall

be judicially noticed. The CFR is prima facie evidence of the origi-

nal documents published in the Federal Register (44 U.S.C. 1510).

It is prohibited to use NARAs official seal and the stylized Code

of Federal Regulations logo on any republication of this material

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NARAs official seals and logos in a manner inconsistent with the

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Use of ISBN Prefix

This is the Official U.S. Government edition of this publication

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Phone: toll-free (866) 512-1800; DC area (202) 512-1800


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iii

Table of ContentsPage

Explanation ................................................................................................ v

Title 21:

Chapter IFood and Drug Administration, Department of Health

and Human Services (Continued) ................................................. 3

Finding Aids:

Table of CFR Titles and Chapters ....................................................... 165

Alphabetical List of Agencies Appearing in the CFR ......................... 185

List of CFR Sections Affected ............................................................. 195


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Cite this Code: CFR

To cite the regulations in

this volume use title,part and section num-

ber. Thus, 21 CFR 600.2refers to title 21, part600, section 2.


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v

Explanation

The Code of Federal Regulations is a codification of the general and permanent

rules published in the Federal Register by the Executive departments and agen-

cies of the Federal Government. The Code is divided into 50 titles which represent

broad areas subject to Federal regulation. Each title is divided into chapters

which usually bear the name of the issuing agency. Each chapter is further sub-divided into parts covering specific regulatory areas.

Each volume of the Code is revised at least once each calendar year and issued

on a quarterly basis approximately as follows:

Title 1 through Title 16..............................................................as of January 1

Title 17 through Title 27 .................................................................as of April 1

Title 28 through Title 41 ..................................................................as of July 1

Title 42 through Title 50 .............................................................as of October 1

The appropriate revision date is printed on the cover of each volume.

LEGAL STATUS

The contents of the Federal Register are required to be judicially noticed (44

U.S.C. 1507). The Code of Federal Regulations is prima facie evidence of the text

of the original documents (44 U.S.C. 1510).

HOW TO USE THE CODE OF FEDERAL REGULATIONS

The Code of Federal Regulations is kept up to date by the individual issues

of the Federal Register. These two publications must be used together to deter-

mine the latest version of any given rule.

To determine whether a Code volume has been amended since its revision date

(in this case, April 1, 2013), consult the List of CFR Sections Affected (LSA),

which is issued monthly, and the Cumulative List of Parts Affected, which

appears in the Reader Aids section of the daily Federal Register. These two lists

will identify the Federal Register page number of the latest amendment of any

given rule.

EFFECTIVE AND EXPIRATION DATES

Each volume of the Code contains amendments published in the Federal Reg-

ister since the last revision of that volume of the Code. Source citations for

the regulations are referred to by volume number and page number of the Federal

Register and date of publication. Publication dates and effective dates are usu-

ally not the same and care must be exercised by the user in determining the

actual effective date. In instances where the effective date is beyond the cut-

off date for the Code a note has been inserted to reflect the future effective

date. In those instances where a regulation published in the Federal Register

states a date certain for expiration, an appropriate note will be inserted following

the text.

OMB CONTROL NUMBERS

The Paperwork Reduction Act of 1980 (Pub. L. 96511) requires Federal agencies

to display an OMB control number with their information collection request.


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vi

Many agencies have begun publishing numerous OMB control numbers as amend-

ments to existing regulations in the CFR. These OMB numbers are placed as

close as possible to the applicable recordkeeping or reporting requirements.

PAST PROVISIONS OF THE CODE

Provisions of the Code that are no longer in force and effect as of the revision

date stated on the cover of each volume are not carried. Code users may find

the text of provisions in effect on any given date in the past by using the appro-

priate List of CFR Sections Affected (LSA). For the convenience of the reader,

a List of CFR Sections Affected is published at the end of each CFR volume.

For changes to the Code prior to the LSA listings at the end of the volume,

consult previous annual editions of the LSA. For changes to the Code prior to

2001, consult the List of CFR Sections Affected compilations, published for 1949-

1963, 1964-1972, 1973-1985, and 1986-2000.

[RESERVED] TERMINOLOGY

The term [Reserved] is used as a place holder within the Code of Federal

Regulations. An agency may add regulatory information at a [Reserved] loca-

tion at any time. Occasionally [Reserved] is used editorially to indicate that

a portion of the CFR was left vacant and not accidentally dropped due to a print-

ing or computer error.

INCORPORATION BY REFERENCE

What is incorporation by reference? Incorporation by reference was established

by statute and allows Federal agencies to meet the requirement to publish regu-

lations in the Federal Register by referring to materials already published else-

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must approve it. The legal effect of incorporation by reference is that the mate-

rial is treated as if it were published in full in the Federal Register (5 U.S.C.

552(a)). This material, like any other properly issued regulation, has the force

of law.

What is a proper incorporation by reference? The Director of the Federal Register

will approve an incorporation by reference only when the requirements of 1 CFR

part 51 are met. Some of the elements on which approval is based are:

(a) The incorporation will substantially reduce the volume of material pub-

lished in the Federal Register.

(b) The matter incorporated is in fact available to the extent necessary to

afford fairness and uniformity in the administrative process.

(c) The incorporating document is drafted and submitted for publication in

accordance with 1 CFR part 51.

What if the material incorporated by reference cannot be found? If you have any

problem locating or obtaining a copy of material listed as an approved incorpora-

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call 202-741-6010.

CFR INDEXES AND TABULAR GUIDES

A subject index to the Code of Federal Regulations is contained in a separate

volume, revised annually as of January 1, entitled CFR I NDEX AND FINDING AIDS.

This volume contains the Parallel Table of Authorities and Rules. A list of CFR

titles, chapters, subchapters, and parts and an alphabetical list of agencies pub-

lishing in the CFR are also included in this volume.


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An index to the text of Title 3The President is carried within that volume.

The Federal Register Index is issued monthly in cumulative form. This index

is based on a consolidation of the Contents entries in the daily Federal Reg-

ister.

A List of CFR Sections Affected (LSA) is published monthly, keyed to the

revision dates of the 50 CFR titles.

REPUBLICATION OF MATERIAL

There are no restrictions on the republication of material appearing in the

Code of Federal Regulations.

INQUIRIES

For a legal interpretation or explanation of any regulation in this volume,

contact the issuing agency. The issuing agencys name appears at the top of

odd-numbered pages.

For inquiries concerning CFR reference assistance, call 2027416000 or write

to the Director, Office of the Federal Register, National Archives and Records

Administration, 8601 Adelphi Road, College Park, MD 20740-6001 or e-mail

[email protected].

SALES

The Government Printing Office (GPO) processes all sales and distribution of

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ELECTRONIC SERVICES

The full text of the Code of Federal Regulations, the LSA (List of CFR SectionsAffected), The United States Government Manual, the Federal Register, Public

Laws, Public Papers of the Presidents of the United States, Compilation of Presi-

dential Documents and the Privacy Act Compilation are available in electronic

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tact Center, U.S. Government Printing Office. Phone 202-512-1800, or 866-512-1800

(toll-free). E-mail, [email protected].

The Office of the Federal Register also offers a free service on the National

Archives and Records Administrations (NARA) World Wide Web site for public

law numbers, Federal Register finding aids, and related information. Connect

to NARAs web site at www.archives.gov/federal-register .

The e-CFR is a regularly updated, unofficial editorial compilation of CFR ma-

terial and Federal Register amendments, produced by the Office of the Federal

Register and the Government Printing Office. It is available at www.ecfr.gov.

CHARLES A. BARTH,

Director,

Office of the Federal Register.

April 1, 2013.


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ix

THIS TITLE

Title 21FOOD AND DRUGS is composed of nine volumes. The parts in these

volumes are arranged in the following order: Parts 199, 100169, 170199, 200299,

300499, 500599, 600799, 8001299 and 1300end. The first eight volumes, containing

parts 11299, comprise Chapter IFood and Drug Administration, Department of

Health and Human Services. The ninth volume, containing part 1300 to end, in-cludes Chapter IIDrug Enforcement Administration, Department of Justice, and

Chapter IIIOffice of National Drug Control Policy. The contents of these vol-

umes represent all current regulations codified under this title of the CFR as

of April 1, 2013.

For this volume, Bonnie Fritts was Chief Editor. The Code of Federal Regula-

tions publication program is under the direction of Michael L. White, assisted

by Ann Worley.


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Title 21Food and

Drugs(This book contains parts 600 to 799)

Part

CHAPTER IFood and Drug Administration, Department ofHealth and Human Services (Continued) ........................... 600


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CHAPTER IFOOD AND DRUG

ADMINISTRATION, DEPARTMENT OF HEALTH

AND HUMAN SERVICES (CONTINUED)

EDITORIAL NOTE: Nomenclature changes to chapter I appear at 59 FR 14366, Mar. 28, 1994,

and 66 FR 56035, Nov. 6, 2001.

SUBCHAPTER FBIOLOGICS

Part Page

600 Biological products: general .................................... 5

601 Licensing ................................................................. 21

606 Current good manufacturing practice for blood andblood components ................................................. 48

607 Establishment registration and product listing for

manufacturers of human blood and blood prod-ucts ...................................................................... 61

610 General biological products standards .................... 67

630 General requirements for blood, blood components,and blood derivatives ........................................... 92

640 Additional standards for human blood and bloodproducts ............................................................... 93

660 Additional standards for diagnostic substances forlaboratory tests .................................................... 116

680 Additional standards for miscellaneous products ... 129

SUBCHAPTER GCOSMETICS

700 General .................................................................... 133

701 Cosmetic labeling .................................................... 141710 Voluntary registration of cosmetic product estab-

lishments .............................................................. 154

720 Voluntary filing of cosmetic product ingredientcomposition statements ....................................... 155

740 Cosmetic product warning statements .................... 159

741799 [Reserved]


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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. Customs

Service 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 Mail

Manual, that is incorporated by reference in

39 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.


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21 CFR Ch. I (4113 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 74

FR 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 involved

has been delegated.

(c) Commissioner of Food and Drugs

means the Commissioner of the Food

and Drug Administration.

(d) Center for Biologics Evaluation and

Research means Center for Biologics

Evaluation and Research of the Foodand Drug Administration.

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

Virgin 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 any

virus, therapeutic serum, toxin, anti-

toxin, or analogous product applicable

to the prevention, treatment or cure ofdiseases or injuries of man:

(1) A virus is interpreted to be a prod-uct containing the minute living cause

of an infectious disease and includes

but is not limited to filterable viruses,

bacteria, rickettsia, fungi, and pro-

tozoa.

(2) A therapeutic serum is a product

obtained from blood by removing theclot or clot components and the blood

cells.

(3) A toxin is a product containing a

soluble substance poisonous to labora-

tory animals or to man in doses of 1

milliliter or less (or equivalent in

weight) of the product, and having theproperty, following the injection of

non-fatal doses into an animal, of caus-

ing to be produced therein another

soluble substance which specifically

neutralizes the poisonous substanceand which is demonstrable in the

serum of the animal thus immunized.

(4) An antitoxin is a product con-

taining the soluble substance in serumor other body fluid of an immunized

animal which specifically neutralizes

the 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.


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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 conducted under 610.12 ofthis chapter.

(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


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21 CFR Ch. I (4113 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 40

FR 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 FR

66634, Nov. 7, 2000; 69 FR 18766, Apr. 8, 2004; 70

FR 14982, Mar. 24, 2005; 73 FR 39610, July 10,

2008; 77 FR 26174, May 3, 2012]

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


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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 can

affect adversely the safety and purity

of a product shall be excluded from the

room where the manufacture of a prod-

uct is in progress.

(2) Sterile operations. Personnel per-forming sterile operations shall wear

clean or sterilized protective clothing

and devices to the extent necessary to

protect 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, and

persons engaged in the care of animals

or animal quarters, shall be excluded

from areas where other products are

manufactured, or such persons shall

change outer clothing, including shoes,

or wear protective covering prior to en-

tering such areas.

(4) Live vaccine work areas. Persons

may not enter a live vaccine processing

area after having worked with other in-

fectious agents in any other laboratory

during the same working day. Only

persons actually concerned with propa-gation of the culture, production of the

vaccine, and unit maintenance, shall be

allowed in live vaccine processing

areas when active work is in progress.

Casual visitors shall be excluded fromsuch units at all times and all others

having business in such areas shall be

admitted only under supervision.

Street clothing, including shoes, shallbe replaced or covered by suitable lab-

oratory clothing before entering a livevaccine processing unit. Persons caring

for animals used in the manufacture of

live vaccines shall be excluded fromother animal quarters and from con-

tact with other animals during the

same working day.


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


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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


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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


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21 CFR Ch. I (4113 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.


FR 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]


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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.


FR 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


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21 CFR Ch. I (4113 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 49

FR 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


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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 provisions

of the regulations in this chapter. All

biological 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 specified

temperatures:

(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]


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21 CFR Ch. I (4113 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.


FR 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.


FR 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


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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 has

not been previously observed (i.e., in-cluded in the labeling) rather than

from the perspective of such experience

not being anticipated from the pharma-

cological properties of the pharma-

ceutical product.

(b) Review of adverse experiences. Any

person having a biologics license under 601.20 of this chapter shall promptly

review 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 in

appropriate 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


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21 CFR Ch. I (4113 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 the

submission 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


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(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 from

the 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 or

comparable 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 adverse

experience 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 by

FDA 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, for

alternatives 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,


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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 that

licensed 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 products

are safe, effective, and not misbranded

under 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 irreversible

morbidity.

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 Withd