Good laboratory practice for nonclinical laboratory studies (21 CFR 58.1-58.219)

366 21 CFR Ch. I (4–1–16 Edition) Pt. 58 PART 58—GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES Subpart A—General Provisions Sec. 58.1 Scope. 58.3 Definitions. 58.10 Applicability to studies performed under grants and contracts. 58.15 Inspection of a testing facility. Subpart B—Organization and Personnel 58.29 Personnel. 58.31 Testing facility management. 58.33 Study director. 58.35 Quality assurance unit. Subpart C—Facilities 58.41 General. 58.43 Animal care facilities. 58.45 Animal supply facilities. 58.47 Facilities for handling test and con trol articles. 58.49 Laboratory operation areas. 58.51 Specimen and data storage facilities. Subpart D—Equipment 58.61 Equipment design. 58.63 Maintenance and calibration of equip ment. Subpart E—Testing Facilities Operation 58.81 Standard operating procedures. 58.83 Reagents and solutions. 58.90 Animal care. Subpart F—Test and Control Articles 58.105 Test and control article characteriza tion. 58.107 Test and control article handling. 58.113 Mixture of articles with carriers. Subpart G—Protocol for and Conduct of a Nonclinical Laboratory Study 58.120 Protocol. 58.130 Conduct of a nonclinical laboratory study. Subparts H–I [Reserved] Subpart J—Records and Reports 58.185 Reporting of nonclinical laboratory study results. 58.190 Storage and retrieval of records and data. 58.195 Retention of records. Subpart K—Disqualification of Testing Facilities 58.200 Purpose. 58.202 Grounds for disqualification. 58.204 Notice of and opportunity for hearing on proposed disqualification. 58.206 Final order on disqualification. 58.210 Actions upon disqualification. 58.213 Public disclosure of information re garding disqualification. 58.215 Alternative or additional actions to disqualification. 58.217 Suspension or termination of a test ing facility by a sponsor. 58.219 Reinstatement of a disqualified test ing facility. AUTHORITY: 21 U.S.C. 342, 346, 346a, 348, 351, 352, 353, 355, 360, 360b–360f, 360h–360j, 371, 379e, 381; 42 U.S.C. 216, 262, 263b–263n. SOURCE: 43 FR 60013, Dec. 22, 1978, unless otherwise noted. Subpart A—General Provisions § 58.1 Scope. (a) This part prescribes good labora tory practices for conducting nonclin ical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the Food and Drug Administration, including food and color additives, animal food addi tives, human and animal drugs, med ical devices for human use, biological products, and electronic products. Compliance with this part is intended to assure the quality and integrity of the safety data filed pursuant to sec tions 406, 408, 409, 502, 503, 505, 506, 510, 512–516, 518–520, 721, and 801 of the Fed eral Food, Drug, and Cosmetic Act and sections 351 and 354–360F of the Public Health Service Act. (b) References in this part to regu latory sections of the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33779, Sept. 4, 1987; 64 FR 399, Jan. 5, 1999] § 58.3 Definitions. As used in this part, the following terms shall have the meanings speci fied: (a) Act means the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201–902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 321–392)). VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00376 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 367 Food and Drug Administration, HHS § 58.3 (b) Test article means any food addi tive, color additive, drug, biological product, electronic product, medical device for human use, or any other ar ticle subject to regulation under the act or under sections 351 and 354–360F of the Public Health Service Act. (c) Control article means any food ad ditive, color additive, drug, biological product, electronic product, medical device for human use, or any article other than a test article, feed, or water that is administered to the test system in the course of a nonclinical labora tory study for the purpose of estab lishing a basis for comparison with the test article. (d) Nonclinical laboratory study means in vivo or in vitro experiments in which test articles are studied prospec tively in test systems under laboratory conditions to determine their safety. The term does not include studies uti lizing human subjects or clinical stud ies or field trials in animals. The term does not include basic exploratory studies carried out to determine whether a test article has any poten tial utility or to determine physical or chemical characteristics of a test arti cle. (e) Application for research or mar keting permit includes: (1) A color additive petition, de scribed in part 71. (2) A food additive petition, described in parts 171 and 571. (3) Data and information regarding a substance submitted as part of the pro cedures for establishing that a sub stance is generally recognized as safe for use, which use results or may rea sonably be expected to result, directly or indirectly, in its becoming a compo nent or otherwise affecting the charac teristics of any food, described in §§ 170.35 and 570.35. (4) Data and information regarding a food additive submitted as part of the procedures regarding food additives permitted to be used on an interim basis pending additional study, de scribed in § 180.1. (5) An investigational new drug appli cation, described in part 312 of this chapter. (6) A new drug application, described in part 314. (7) Data and information regarding an over-the-counter drug for human use, submitted as part of the proce dures for classifying such drugs as gen erally recognized as safe and effective and not misbranded, described in part 330. (8) Data and information about a sub stance submitted as part of the proce dures for establishing a tolerance for unavoidable contaminants in food and food-packaging materials, described in parts 109 and 509. (9) [Reserved] (10) A Notice of Claimed Investigational Exemption for a New Animal Drug, de scribed in part 511. (11) A new animal drug application, de scribed in part 514. (12) [Reserved] (13) An application for a biologics li cense, described in part 601 of this chap ter. (14) An application for an investiga tional device exemption, described in part 812. (15) An Application for Premarket Ap proval of a Medical Device, described in section 515 of the act. (16) A Product Development Protocol for a Medical Device, described in section 515 of the act. (17) Data and information regarding a medical device submitted as part of the procedures for classifying such devices, described in part 860. (18) Data and information regarding a medical device submitted as part of the procedures for establishing, amending, or repealing a performance standard for such devices, described in part 861. (19) Data and information regarding an electronic product submitted as part of the procedures for obtaining an exemption from notification of a radi ation safety defect or failure of compli ance with a radiation safety perform ance standard, described in subpart D of part 1003. (20) Data and information regarding an electronic product submitted as part of the procedures for establishing, amending, or repealing a standard for such product, described in section 358 of the Public Health Service Act. (21) Data and information regarding an electronic product submitted as part of the procedures for obtaining a variance from any electronic product VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00377 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 368 21 CFR Ch. I (4–1–16 Edition) § 58.10 performance standard as described in § 1010.4. (22) Data and information regarding an electronic product submitted as part of the procedures for granting, amending, or extending an exemption from any electronic product perform ance standard, as described in § 1010.5. (23) A premarket notification for a food contact substance, described in part 170, subpart D, of this chapter. (f) Sponsor means: (1) A person who initiates and sup ports, by provision of financial or other resources, a nonclinical laboratory study; (2) A person who submits a nonclin ical study to the Food and Drug Ad ministration in support of an applica tion for a research or marketing per mit; or (3) A testing facility, if it both initi ates and actually conducts the study. (g) Testing facility means a person who actually conducts a nonclinical laboratory study, i.e., actually uses the test article in a test system. Testing fa cility includes any establishment re quired to register under section 510 of the act that conducts nonclinical lab oratory studies and any consulting lab oratory described in section 704 of the act that conducts such studies. Testing facility encompasses only those oper ational units that are being or have been used to conduct nonclinical lab oratory studies. (h) Person includes an individual, partnership, corporation, association, scientific or academic establishment, government agency, or organizational unit thereof, and any other legal enti ty. (i) Test system means any animal, plant, microorganism, or subparts thereof to which the test or control ar ticle is administered or added for study. Test system also includes appro priate groups or components of the sys tem not treated with the test or con trol articles. (j) Specimen means any material de rived from a test system for examina tion or analysis. (k) Raw data means any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the result of original observations and activities of a nonclinical laboratory study and are necessary for the recon struction and evaluation of the report of that study. In the event that exact transcripts of raw data have been pre pared (e.g., tapes which have been tran scribed verbatim, dated, and verified accurate by signature), the exact copy or exact transcript may be substituted for the original source as raw data. Raw data may include photographs, microfilm or microfiche copies, com puter printouts, magnetic media, in cluding dictated observations, and re corded data from automated instru ments. (l) Quality assurance unit means any person or organizational element, ex cept the study director, designated by testing facility management to per form the duties relating to quality as surance of nonclinical laboratory stud ies. (m) Study director means the indi vidual responsible for the overall con duct of a nonclinical laboratory study. (n) Batch means a specific quantity or lot of a test or control article that has been characterized according to § 58.105(a). (o) Study initiation date means the date the protocol is signed by the study director. (p) Study completion date means the date the final report is signed by the study director. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33779, Sept. 4, 1987; 54 FR 9039, Mar. 3, 1989; 64 FR 56448, Oct. 20, 1999; 67 FR 35729, May 21, 2002] § 58.10 Applicability to studies per formed under grants and contracts. When a sponsor conducting a non clinical laboratory study intended to be submitted to or reviewed by the Food and Drug Administration utilizes the services of a consulting laboratory, contractor, or grantee to perform an analysis or other service, it shall no tify the consulting laboratory, con tractor, or grantee that the service is part of a nonclinical laboratory study that must be conducted in compliance with the provisions of this part. § 58.15 Inspection of a testing facility. (a) A testing facility shall permit an authorized employee of the Food and Drug Administration, at reasonable VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00378 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 369 Food and Drug Administration, HHS § 58.33 times and in a reasonable manner, to inspect the facility and to inspect (and in the case of records also to copy) all records and specimens required to be maintained regarding studies within the scope of this part. The records in spection and copying requirements shall not apply to quality assurance unit records of findings and problems, or to actions recommended and taken. (b) The Food and Drug Administra tion will not consider a nonclinical lab oratory study in support of an applica tion for a research or marketing per mit if the testing facility refuses to permit inspection. The determination that a nonclinical laboratory study will not be considered in support of an application for a research or marketing permit does not, however, relieve the applicant for such a permit of any obli gation under any applicable statute or regulation to submit the results of the study to the Food and Drug Adminis tration. Subpart B—Organization and Personnel § 58.29 Personnel. (a) Each individual engaged in the conduct of or responsible for the super vision of a nonclinical laboratory study shall have education, training, and ex perience, or combination thereof, to enable that individual to perform the assigned functions. (b) Each testing facility shall main tain a current summary of training and experience and job description for each individual engaged in or supervising the conduct of a nonclinical laboratory study. (c) There shall be a sufficient number of personnel for the timely and proper conduct of the study according to the protocol. (d) Personnel shall take necessary personal sanitation and health pre cautions designed to avoid contamina tion of test and control articles and test systems. (e) Personnel engaged in a nonclin ical laboratory study shall wear cloth ing appropriate for the duties they per form. Such clothing shall be changed as often as necessary to prevent micro biological, radiological, or chemical contamination of test systems and test and control articles. (f) Any individual found at any time to have an illness that may adversely affect the quality and integrity of the nonclinical laboratory study shall be excluded from direct contact with test systems, test and control articles and any other operation or function that may adversely affect the study until the condition is corrected. All per sonnel shall be instructed to report to their immediate supervisors any health or medical conditions that may reason ably be considered to have an adverse effect on a nonclinical laboratory study. § 58.31 Testing facility management. For each nonclinical laboratory study, testing facility management shall: (a) Designate a study director as de scribed in § 58.33, before the study is initiated. (b) Replace the study director promptly if it becomes necessary to do so during the conduct of a study. (c) Assure that there is a quality as surance unit as described in § 58.35. (d) Assure that test and control arti cles or mixtures have been appro priately tested for identity, strength, purity, stability, and uniformity, as applicable. (e) Assure that personnel, resources, facilities, equipment, materials, and methodologies are available as sched uled. (f) Assure that personnel clearly un derstand the functions they are to per form. (g) Assure that any deviations from these regulations reported by the qual ity assurance unit are communicated to the study director and corrective ac tions are taken and documented. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4, 1987] § 58.33 Study director. For each nonclinical laboratory study, a scientist or other professional of appropriate education, training, and experience, or combination thereof, shall be identified as the study direc tor. The study director has overall re sponsibility for the technical conduct VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00379 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 370 21 CFR Ch. I (4–1–16 Edition) § 58.35 of the study, as well as for the inter pretation, analysis, documentation and reporting of results, and represents the single point of study control. The study director shall assure that: (a) The protocol, including any change, is approved as provided by § 58.120 and is followed. (b) All experimental data, including observations of unanticipated re sponses of the test system are accu rately recorded and verified. (c) Unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented. (d) Test systems are as specified in the protocol. (e) All applicable good laboratory practice regulations are followed. (f) All raw data, documentation, pro tocols, specimens, and final reports are transferred to the archives during or at the close of the study. [43 FR 60013, Dec. 22, 1978; 44 FR 17657, Mar. 23, 1979] § 58.35 Quality assurance unit. (a) A testing facility shall have a quality assurance unit which shall be responsible for monitoring each study to assure management that the facili ties, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in this part. For any given study, the quality assurance unit shall be entirely separate from and independent of the personnel engaged in the direction and conduct of that study. (b) The quality assurance unit shall: (1) Maintain a copy of a master schedule sheet of all nonclinical lab oratory studies conducted at the test ing facility indexed by test article and containing the test system, nature of study, date study was initiated, cur rent status of each study, identity of the sponsor, and name of the study di rector. (2) Maintain copies of all protocols pertaining to all nonclinical laboratory studies for which the unit is respon sible. (3) Inspect each nonclinical labora tory study at intervals adequate to as sure the integrity of the study and maintain written and properly signed records of each periodic inspection showing the date of the inspection, the study inspected, the phase or segment of the study inspected, the person per forming the inspection, findings and problems, action recommended and taken to resolve existing problems, and any scheduled date for reinspection. Any problems found during the course of an inspection which are likely to af fect study integrity shall be brought to the attention of the study director and management immediately. (4) Periodically submit to manage ment and the study director written status reports on each study, noting any problems and the corrective ac tions taken. (5) Determine that no deviations from approved protocols or standard operating procedures were made with out proper authorization and docu mentation. (6) Review the final study report to assure that such report accurately de scribes the methods and standard oper ating procedures, and that the reported results accurately reflect the raw data of the nonclinical laboratory study. (7) Prepare and sign a statement to be included with the final study report which shall specify the dates inspec tions were made and findings reported to management and to the study direc tor. (c) The responsibilities and proce dures applicable to the quality assur ance unit, the records maintained by the quality assurance unit, and the method of indexing such records shall be in writing and shall be maintained. These items including inspection dates, the study inspected, the phase or seg ment of the study inspected, and the name of the individual performing the inspection shall be made available for inspection to authorized employees of the Food and Drug Administration. (d) A designated representative of the Food and Drug Administration shall have access to the written procedures established for the inspection and may request testing facility management to certify that inspections are being im plemented, performed, documented, VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00380 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 371 Food and Drug Administration, HHS § 58.61 and followed-up in accordance with this paragraph. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4, 1987; 67 FR 9585, Mar. 4, 2002] Subpart C—Facilities § 58.41 General. Each testing facility shall be of suit able size and construction to facilitate the proper conduct of nonclinical lab oratory studies. It shall be designed so that there is a degree of separation that will prevent any function or activ ity from having an adverse effect on the study. [52 FR 33780, Sept. 4, 1987] § 58.43 Animal care facilities. (a) A testing facility shall have a suf ficient number of animal rooms or areas, as needed, to assure proper: (1) Separation of species or test systems, (2) isolation of individual projects, (3) quarantine of animals, and (4) routine or specialized housing of animals. (b) A testing facility shall have a number of animal rooms or areas sepa rate from those described in paragraph (a) of this section to ensure isolation of studies being done with test systems or test and control articles known to be biohazardous, including volatile sub stances, aerosols, radioactive mate rials, and infectious agents. (c) Separate areas shall be provided, as appropriate, for the diagnosis, treat ment, and control of laboratory animal diseases. These areas shall provide ef fective isolation for the housing of ani mals either known or suspected of being diseased, or of being carriers of disease, from other animals. (d) When animals are housed, facili ties shall exist for the collection and disposal of all animal waste and refuse or for safe sanitary storage of waste be fore removal from the testing facility. Disposal facilities shall be so provided and operated as to minimize vermin in festation, odors, disease hazards, and environmental contamination. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4, 1987] § 58.45 Animal supply facilities. There shall be storage areas, as need ed, for feed, bedding, supplies, and equipment. Storage areas for feed and bedding shall be separated from areas housing the test systems and shall be protected against infestation or con tamination. Perishable supplies shall be preserved by appropriate means. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4, 1987] § 58.47 Facilities for handling test and control articles. (a) As necessary to prevent contami nation or mixups, there shall be sepa rate areas for: (1) Receipt and storage of the test and control articles. (2) Mixing of the test and control ar ticles with a carrier, e.g., feed. (3) Storage of the test and control ar ticle mixtures. (b) Storage areas for the test and/or control article and test and control mixtures shall be separate from areas housing the test systems and shall be adequate to preserve the identity, strength, purity, and stability of the articles and mixtures. § 58.49 Laboratory operation areas. Separate laboratory space shall be provided, as needed, for the perform ance of the routine and specialized pro cedures required by nonclinical labora tory studies. [52 FR 33780, Sept. 4, 1987] § 58.51 Specimen and data storage fa cilities. Space shall be provided for archives, limited to access by authorized per sonnel only, for the storage and re trieval of all raw data and specimens from completed studies. Subpart D—Equipment § 58.61 Equipment design. Equipment used in the generation, measurement, or assessment of data and equipment used for facility envi ronmental control shall be of appro priate design and adequate capacity to function according to the protocol and VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00381 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 372 21 CFR Ch. I (4–1–16 Edition) § 58.63 shall be suitably located for operation, inspection, cleaning, and maintenance. [52 FR 33780, Sept. 4, 1987] § 58.63 Maintenance and calibration of equipment. (a) Equipment shall be adequately in spected, cleaned, and maintained. Equipment used for the generation, measurement, or assessment of data shall be adequately tested, calibrated and/or standardized. (b) The written standard operating procedures required under § 58.81(b)(11) shall set forth in sufficient detail the methods, materials, and schedules to be used in the routine inspection, cleaning, maintenance, testing, cali bration, and/or standardization of equipment, and shall specify, when ap propriate, remedial action to be taken in the event of failure or malfunction of equipment. The written standard op erating procedures shall designate the person responsible for the performance of each operation. (c) Written records shall be main tained of all inspection, maintenance, testing, calibrating and/or standard izing operations. These records, con taining the date of the operation, shall describe whether the maintenance op erations were routine and followed the written standard operating procedures. Written records shall be kept of non routine repairs performed on equip ment as a result of failure and mal function. Such records shall document the nature of the defect, how and when the defect was discovered, and any re medial action taken in response to the defect. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4, 1987; 67 FR 9585, Mar. 4, 2002] Subpart E—Testing Facilities Operation § 58.81 Standard operating procedures. (a) A testing facility shall have standard operating procedures in writ ing setting forth nonclinical laboratory study methods that management is satisfied are adequate to insure the quality and integrity of the data gen erated in the course of a study. All de viations in a study from standard oper ating procedures shall be authorized by the study director and shall be docu mented in the raw data. Significant changes in established standard oper ating procedures shall be properly au thorized in writing by management. (b) Standard operating procedures shall be established for, but not limited to, the following: (1) Animal room preparation. (2) Animal care. (3) Receipt, identification, storage, handling, mixing, and method of sam pling of the test and control articles. (4) Test system observations. (5) Laboratory tests. (6) Handling of animals found mori bund or dead during study. (7) Necropsy of animals or post mortem examination of animals. (8) Collection and identification of specimens. (9) Histopathology. (10) Data handling, storage, and re trieval. (11) Maintenance and calibration of equipment. (12) Transfer, proper placement, and identification of animals. (c) Each laboratory area shall have immediately available laboratory manuals and standard operating proce dures relative to the laboratory proce dures being performed. Published lit erature may be used as a supplement to standard operating procedures. (d) A historical file of standard oper ating procedures, and all revisions thereof, including the dates of such re visions, shall be maintained. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4, 1987] § 58.83 Reagents and solutions. All reagents and solutions in the lab oratory areas shall be labeled to indi cate identity, titer or concentration, storage requirements, and expiration date. Deteriorated or outdated re agents and solutions shall not be used. § 58.90 Animal care. (a) There shall be standard operating procedures for the housing, feeding, handling, and care of animals. (b) All newly received animals from outside sources shall be isolated and their health status shall be evaluated VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00382 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 373 Food and Drug Administration, HHS § 58.105 in accordance with acceptable veteri nary medical practice. (c) At the initiation of a nonclinical laboratory study, animals shall be free of any disease or condition that might interfere with the purpose or conduct of the study. If, during the course of the study, the animals contract such a disease or condition, the diseased ani mals shall be isolated, if necessary. These animals may be treated for dis ease or signs of disease provided that such treatment does not interfere with the study. The diagnosis, authoriza tions of treatment, description of treatment, and each date of treatment shall be documented and shall be re tained. (d) Warm-blooded animals, excluding suckling rodents, used in laboratory procedures that require manipulations and observations over an extended pe riod of time or in studies that require the animals to be removed from and re turned to their home cages for any rea son (e.g., cage cleaning, treatment, etc.), shall receive appropriate identi fication. All information needed to spe cifically identify each animal within an animal-housing unit shall appear on the outside of that unit. (e) Animals of different species shall be housed in separate rooms when nec essary. Animals of the same species, but used in different studies, should not ordinarily be housed in the same room when inadvertent exposure to control or test articles or animal mixup could affect the outcome of ei ther study. If such mixed housing is necessary, adequate differentiation by space and identification shall be made. (f) Animal cages, racks and accessory equipment shall be cleaned and sani tized at appropriate intervals. (g) Feed and water used for the ani mals shall be analyzed periodically to ensure that contaminants known to be capable of interfering with the study and reasonably expected to be present in such feed or water are not present at levels above those specified in the pro tocol. Documentation of such analyses shall be maintained as raw data. (h) Bedding used in animal cages or pens shall not interfere with the pur pose or conduct of the study and shall be changed as often as necessary to keep the animals dry and clean. (i) If any pest control materials are used, the use shall be documented. Cleaning and pest control materials that interfere with the study shall not be used. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4, 1987; 54 FR 15924, Apr. 20, 1989; 56 FR 32088, July 15, 1991; 67 FR 9585, Mar. 4, 2002] Subpart F—Test and Control Articles § 58.105 Test and control article char acterization. (a) The identity, strength, purity, and composition or other characteris tics which will appropriately define the test or control article shall be deter mined for each batch and shall be docu mented. Methods of synthesis, fabrica tion, or derivation of the test and con trol articles shall be documented by the sponsor or the testing facility. In those cases where marketed products are used as control articles, such prod ucts will be characterized by their la beling. (b) The stability of each test or con trol article shall be determined by the testing facility or by the sponsor ei ther: (1) Before study initiation, or (2) concomitantly according to written standard operating procedures, which provide for periodic analysis of each batch. (c) Each storage container for a test or control article shall be labeled by name, chemical abstract number or code number, batch number, expiration date, if any, and, where appropriate, storage conditions necessary to main tain the identity, strength, purity, and composition of the test or control arti cle. Storage containers shall be as signed to a particular test article for the duration of the study. (d) For studies of more than 4 weeks’ duration, reserve samples from each batch of test and control articles shall be retained for the period of time pro vided by § 58.195. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept. 4, 1987; 67 FR 9585, Mar. 4, 2002] VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00383 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 374 21 CFR Ch. I (4–1–16 Edition) § 58.107 § 58.107 Test and control article han dling. Procedures shall be established for a system for the handling of the test and control articles to ensure that: (a) There is proper storage. (b) Distribution is made in a manner designed to preclude the possibility of contamination, deterioration, or dam age. (c) Proper identification is main tained throughout the distribution process. (d) The receipt and distribution of each batch is documented. Such docu mentation shall include the date and quantity of each batch distributed or returned. § 58.113 Mixtures of articles with car riers. (a) For each test or control article that is mixed with a carrier, tests by appropriate analytical methods shall be conducted: (1) To determine the uniformity of the mixture and to determine, periodi cally, the concentration of the test or control article in the mixture. (2) To determine the stability of the test and control articles in the mixture as required by the conditions of the study either: (i) Before study initiation, or (ii) Concomitantly according to writ ten standard operating procedures which provide for periodic analysis of the test and control articles in the mixture. (b) [Reserved] (c) Where any of the components of the test or control article carrier mix ture has an expiration date, that date shall be clearly shown on the con tainer. If more than one component has an expiration date, the earliest date shall be shown. [43 FR 60013, Dec. 22, 1978, as amended at 45 FR 24865, Apr. 11, 1980; 52 FR 33781, Sept. 4, 1987] Subpart G—Protocol for and Con duct of a Nonclinical Labora tory Study § 58.120 Protocol. (a) Each study shall have an ap proved written protocol that clearly in dicates the objectives and all methods for the conduct of the study. The pro tocol shall contain, as applicable, the following information: (1) A descriptive title and statement of the purpose of the study. (2) Identification of the test and con trol articles by name, chemical ab stract number, or code number. (3) The name of the sponsor and the name and address of the testing facil ity at which the study is being con ducted. (4) The number, body weight range, sex, source of supply, species, strain, substrain, and age of the test system. (5) The procedure for identification of the test system. (6) A description of the experimental design, including the methods for the control of bias. (7) A description and/or identification of the diet used in the study as well as solvents, emulsifiers, and/or other ma terials used to solubilize or suspend the test or control articles before mixing with the carrier. The description shall include specifications for acceptable levels of contaminants that are reason ably expected to be present in the die tary materials and are known to be ca pable of interfering with the purpose or conduct of the study if present at lev els greater than established by the specifications. (8) Each dosage level, expressed in milligrams per kilogram of body weight or other appropriate units, of the test or control article to be admin istered and the method and frequency of administration. (9) The type and frequency of tests, analyses, and measurements to be made. (10) The records to be maintained. (11) The date of approval of the pro tocol by the sponsor and the dated sig nature of the study director. (12) A statement of the proposed sta tistical methods to be used. (b) All changes in or revisions of an approved protocol and the reasons therefore shall be documented, signed by the study director, dated, and main tained with the protocol. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept. 4, 1987; 67 FR 9585, Mar. 4, 2002] VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00384 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 375 Food and Drug Administration, HHS § 58.185 § 58.130 Conduct of a nonclinical lab oratory study. (a) The nonclinical laboratory study shall be conducted in accordance with the protocol. (b) The test systems shall be mon itored in conformity with the protocol. (c) Specimens shall be identified by test system, study, nature, and date of collection. This information shall be located on the specimen container or shall accompany the specimen in a manner that precludes error in the re cording and storage of data. (d) Records of gross findings for a specimen from postmortem observa tions should be available to a patholo gist when examining that specimen histopathologically. (e) All data generated during the con duct of a nonclinical laboratory study, except those that are generated by automated data collection systems, shall be recorded directly, promptly, and legibly in ink. All data entries shall be dated on the date of entry and signed or initialed by the person enter ing the data. Any change in entries shall be made so as not to obscure the original entry, shall indicate the rea son for such change, and shall be dated and signed or identified at the time of the change. In automated data collec tion systems, the individual respon sible for direct data input shall be iden tified at the time of data input. Any change in automated data entries shall be made so as not to obscure the origi nal entry, shall indicate the reason for change, shall be dated, and the respon sible individual shall be identified. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept. 4, 1987; 67 FR 9585, Mar. 4, 2002] Subparts H–I [Reserved] Subpart J—Records and Reports § 58.185 Reporting of nonclinical lab oratory study results. (a) A final report shall be prepared for each nonclinical laboratory study and shall include, but not necessarily be limited to, the following: (1) Name and address of the facility performing the study and the dates on which the study was initiated and com pleted. (2) Objectives and procedures stated in the approved protocol, including any changes in the original protocol. (3) Statistical methods employed for analyzing the data. (4) The test and control articles iden tified by name, chemical abstracts number or code number, strength, pu rity, and composition or other appro priate characteristics. (5) Stability of the test and control articles under the conditions of admin istration. (6) A description of the methods used. (7) A description of the test system used. Where applicable, the final report shall include the number of animals used, sex, body weight range, source of supply, species, strain and substrain, age, and procedure used for identifica tion. (8) A description of the dosage, dos age regimen, route of administration, and duration. (9) A description of all circumstances that may have affected the quality or integrity of the data. (10) The name of the study director, the names of other scientists or profes sionals, and the names of all super visory personnel, involved in the study. (11) A description of the trans formations, calculations, or operations performed on the data, a summary and analysis of the data, and a statement of the conclusions drawn from the analysis. (12) The signed and dated reports of each of the individual scientists or other professionals involved in the study. (13) The locations where all speci mens, raw data, and the final report are to be stored. (14) The statement prepared and signed by the quality assurance unit as described in § 58.35(b)(7). (b) The final report shall be signed and dated by the study director. (c) Corrections or additions to a final report shall be in the form of an amendment by the study director. The amendment shall clearly identify that part of the final report that is being added to or corrected and the reasons for the correction or addition, and VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00385 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 376 21 CFR Ch. I (4–1–16 Edition) § 58.190 shall be signed and dated by the person responsible. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept. 4, 1987] § 58.190 Storage and retrieval of records and data. (a) All raw data, documentation, pro tocols, final reports, and specimens (except those specimens obtained from mutagenicity tests and wet specimens of blood, urine, feces, and biological fluids) generated as a result of a non clinical laboratory study shall be re tained. (b) There shall be archives for orderly storage and expedient retrieval of all raw data, documentation, protocols, specimens, and interim and final re ports. Conditions of storage shall mini mize deterioration of the documents or specimens in accordance with the re quirements for the time period of their retention and the nature of the docu ments or specimens. A testing facility may contract with commercial ar chives to provide a repository for all material to be retained. Raw data and specimens may be retained elsewhere provided that the archives have spe cific reference to those other locations. (c) An individual shall be identified as responsible for the archives. (d) Only authorized personnel shall enter the archives. (e) Material retained or referred to in the archives shall be indexed to permit expedient retrieval. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept. 4, 1987; 67 FR 9585, Mar. 4, 2002] § 58.195 Retention of records. (a) Record retention requirements set forth in this section do not supersede the record retention requirements of any other regulations in this chapter. (b) Except as provided in paragraph (c) of this section, documentation records, raw data and specimens per taining to a nonclinical laboratory study and required to be made by this part shall be retained in the archive(s) for whichever of the following periods is shortest: (1) A period of at least 2 years fol lowing the date on which an applica tion for a research or marketing per mit, in support of which the results of the nonclinical laboratory study were submitted, is approved by the Food and Drug Administration. This require ment does not apply to studies sup porting investigational new drug appli cations (IND’s) or applications for in vestigational device exemptions (IDE’s), records of which shall be gov erned by the provisions of paragraph (b)(2) of this section. (2) A period of at least 5 years fol lowing the date on which the results of the nonclinical laboratory study are submitted to the Food and Drug Ad ministration in support of an applica tion for a research or marketing per mit. (3) In other situations (e.g., where the nonclinical laboratory study does not result in the submission of the study in support of an application for a research or marketing permit), a pe riod of at least 2 years following the date on which the study is completed, terminated, or discontinued. (c) Wet specimens (except those specimens obtained from mutagenicity tests and wet specimens of blood, urine, feces, and biological fluids), samples of test or control articles, and specially prepared material, which are relatively fragile and differ markedly in stability and quality during storage, shall be retained only as long as the quality of the preparation affords eval uation. In no case shall retention be re quired for longer periods than those set forth in paragraphs (a) and (b) of this section. (d) The master schedule sheet, copies of protocols, and records of quality as surance inspections, as required by § 58.35(c) shall be maintained by the quality assurance unit as an easily ac cessible system of records for the pe riod of time specified in paragraphs (a) and (b) of this section. (e) Summaries of training and experi ence and job descriptions required to be maintained by § 58.29(b) may be re tained along with all other testing fa cility employment records for the length of time specified in paragraphs (a) and (b) of this section. (f) Records and reports of the mainte nance and calibration and inspection of equipment, as required by § 58.63(b) and (c), shall be retained for the length of VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00386 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 377 Food and Drug Administration, HHS § 58.206 time specified in paragraph (b) of this section. (g) Records required by this part may be retained either as original records or as true copies such as photocopies, microfilm, microfiche, or other accu rate reproductions of the original records. (h) If a facility conducting nonclin ical testing goes out of business, all raw data, documentation, and other material specified in this section shall be transferred to the archives of the sponsor of the study. The Food and Drug Administration shall be notified in writing of such a transfer. [43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept. 4, 1987; 54 FR 9039, Mar. 3, 1989] Subpart K—Disqualification of Testing Facilities § 58.200 Purpose. (a) The purposes of disqualification are: (1) To permit the exclusion from con sideration of completed studies that were conducted by a testing facility which has failed to comply with the re quirements of the good laboratory practice regulations until it can be adequately demonstrated that such noncompliance did not occur during, or did not affect the validity or accept ability of data generated by, a par ticular study; and (2) To exclude from consideration all studies completed after the date of dis qualification until the facility can sat isfy the Commissioner that it will con duct studies in compliance with such regulations. (b) The determination that a nonclin ical laboratory study may not be con sidered in support of an application for a research or marketing permit does not, however, relieve the applicant for such a permit of any obligation under any other applicable regulation to sub mit the results of the study to the Food and Drug Administration. § 58.202 Grounds for disqualification. The Commissioner may disqualify a testing facility upon finding all of the following: (a) The testing facility failed to com ply with one or more of the regulations set forth in this part (or any other reg ulations regarding such facilities in this chapter); (b) The noncompliance adversely af fected the validity of the nonclinical laboratory studies; and (c) Other lesser regulatory actions (e.g., warnings or rejection of indi vidual studies) have not been or will probably not be adequate to achieve compliance with the good laboratory practice regulations. § 58.204 Notice of and opportunity for hearing on proposed disqualifica tion. (a) Whenever the Commissioner has information indicating that grounds exist under § 58.202 which in his opinion justify disqualification of a testing fa cility, he may issue to the testing fa cility a written notice proposing that the facility be disqualified. (b) A hearing on the disqualification shall be conducted in accordance with the requirements for a regulatory hear ing set forth in part 16 of this chapter. § 58.206 Final order on disqualifica tion. (a) If the Commissioner, after the regulatory hearing, or after the time for requesting a hearing expires with out a request being made, upon an evaulation of the administrative record of the disqualification proceeding, makes the findings required in § 58.202, he shall issue a final order disquali fying the facility. Such order shall in clude a statement of the basis for that determination. Upon issuing a final order, the Commissioner shall notify (with a copy of the order) the testing facility of the action. (b) If the Commissioner, after a regu latory hearing or after the time for re questing a hearing expires without a request being made, upon an evalua tion of the administrative record of the disqualification proceeding, does not make the findings required in § 58.202, he shall issue a final order terminating the disqualification proceeding. Such order shall include a statement of the basis for that determination. Upon issuing a final order the Commissioner VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00387 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 378 21 CFR Ch. I (4–1–16 Edition) § 58.210 shall notify the testing facility and provide a copy of the order. § 58.210 Actions upon disqualification. (a) Once a testing facility has been disqualified, each application for a re search or marketing permit, whether approved or not, containing or relying upon any nonclinical laboratory study conducted by the disqualified testing facility may be examined to determine whether such study was or would be es sential to a decision. If it is determined that a study was or would be essential, the Food and Drug Administration shall also determine whether the study is acceptable, notwithstanding the dis qualification of the facility. Any study done by a testing facility before or after disqualification may be presumed to be unacceptable, and the person re lying on the study may be required to establish that the study was not af fected by the circumstances that led to the disqualification, e.g., by submit ting validating information. If the study is then determined to be unac ceptable, such data will be eliminated from consideration in support of the application; and such elimination may serve as new information justifying the termination or withdrawal of approval of the application. (b) No nonclinical laboratory study begun by a testing facility after the date of the facility’s disqualification shall be considered in support of any application for a research or marketing permit, unless the facility has been re instated under § 58.219. The determina tion that a study may not be consid ered in support of an application for a research or marketing permit does not, however, relieve the applicant for such a permit of any obligation under any other applicable regulation to submit the results of the study to the Food and Drug Administration. [43 FR 60013, Dec. 22, 1978, as amended at 59 FR 13200, Mar. 21, 1994] § 58.213 Public disclosure of informa tion regarding disqualification. (a) Upon issuance of a final order dis qualifying a testing facility under § 58.206(a), the Commissioner may no tify all or any interested persons. Such notice may be given at the discretion of the Commissioner whenever he be lieves that such disclosure would fur ther the public interest or would pro mote compliance with the good labora tory practice regulations set forth in this part. Such notice, if given, shall include a copy of the final order issued under § 58.206(a) and shall state that the disqualification constitutes a deter mination by the Food and Drug Admin istration that nonclinical laboratory studies performed by the facility will not be considered by the Food and Drug Administration in support of any application for a research or marketing permit. If such notice is sent to an other Federal Government agency, the Food and Drug Administration will recommend that the agency also con sider whether or not it should accept nonclinical laboratory studies per formed by the testing facility. If such notice is sent to any other person, it shall state that it is given because of the relationship between the testing fa cility and the person being notified and that the Food and Drug Administra tion is not advising or recommending that any action be taken by the person notified. (b) A determination that a testing fa cility has been disqualified and the ad ministrative record regarding such de termination are disclosable to the pub lic under part 20 of this chapter. § 58.215 Alternative or additional ac tions to disqualification. (a) Disqualification of a testing facil ity under this subpart is independent of, and neither in lieu of nor a pre condition to, other proceedings or ac tions authorized by the act. The Food and Drug Administration may, at any time, institute against a testing facil ity and/or against the sponsor of a non clinical laboratory study that has been submitted to the Food and Drug Ad ministration any appropriate judicial proceedings (civil or criminal) and any other appropriate regulatory action, in addition to or in lieu of, and prior to, simultaneously with, or subsequent to, disqualification. The Food and Drug Administration may also refer the matter to another Federal, State, or local government law enforcement or regulatory agency for such action as that agency deems appropriate. VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00388 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 379 Food and Drug Administration, HHS Pt. 60 (b) The Food and Drug Administra tion may refuse to consider any par ticular nonclinical laboratory study in support of an application for a research or marketing permit, if it finds that the study was not conducted in accord ance with the good laboratory practice regulations set forth in this part, with out disqualifying the testing facility that conducted the study or under taking other regulatory action. § 58.217 Suspension or termination of a testing facility by a sponsor. Termination of a testing facility by a sponsor is independent of, and neither in lieu of nor a precondition to, pro ceedings or actions authorized by this subpart. If a sponsor terminates or sus pends a testing facility from further participation in a nonclinical labora tory study that is being conducted as part of any application for a research or marketing permit that has been sub mitted to any Center of the Food and Drug Administration (whether ap proved or not), it shall notify that Cen ter in writing within 15 working days of the action; the notice shall include a statement of the reasons for such ac tion. Suspension or termination of a testing facility by a sponsor does not relieve it of any obligation under any other applicable regulation to submit the results of the study to the Food and Drug Administration. [43 FR 60013, Dec. 22, 1978, as amended at 50 FR 8995, Mar. 6, 1985] § 58.219 Reinstatement of a disquali fied testing facility. A testing facility that has been dis qualified may be reinstated as an ac ceptable source of nonclinical labora tory studies to be submitted to the Food and Drug Administration if the Commissioner determines, upon an evaluation of the submission of the testing facility, that the facility can adequately assure that it will conduct future nonclinical laboratory studies in compliance with the good laboratory practice regulations set forth in this part and, if any studies are currently being conducted, that the quality and integrity of such studies have not been seriously compromised. A disqualified testing facility that wishes to be so re instated shall present in writing to the Commissioner reasons why it believes it should be reinstated and a detailed description of the corrective actions it has taken or intends to take to assure that the acts or omissions which led to its disqualification will not recur. The Commissioner may condition rein statement upon the testing facility being found in compliance with the good laboratory practice regulations upon an inspection. If a testing facility is reinstated, the Commissioner shall so notify the testing facility and all or ganizations and persons who were noti fied, under § 58.213 of the disqualifica tion of the testing facility. A deter mination that a testing facility has been reinstated is disclosable to the public under part 20 of this chapter. PART 60—PATENT TERM RESTORATION Subpart A—General Provisions Sec. 60.1 Scope. 60.2 Purpose. 60.3 Definitions. Subpart B—Eligibility Assistance 60.10 FDA assistance on eligibility. Subpart C—Regulatory Review Period Determinations 60.20 FDA action on regulatory review pe riod determinations. 60.22 Regulatory review period determina tions. 60.24 Revision of regulatory review period determinations. 60.26 Final action on regulatory review pe riod determinations. 60.28 Time frame for determining regu latory review periods. Subpart D—Due Diligence Petitions 60.30 Filing, format, and content of peti tions. 60.32 Applicant response to petition. 60.34 FDA action on petitions. 60.36 Standard of due diligence. Subpart E—Due Diligence Hearings 60.40 Request for hearing. 60.42 Notice of hearing. 60.44 Hearing procedures. 60.46 Administrative decision. AUTHORITY: 21 U.S.C. 348, 355, 360e, 360j, 371, 379e; 35 U.S.C. 156; 42 U.S.C. 262. VerDate Sep<11>2014 14:18 Apr 18, 2016 Jkt 238070 PO 00000 Frm 00389 Fmt 8010 Sfmt 8010 Q:\21\21V1.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B