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2 Summit Place Suite 425, Independence, OH 44131
                 1-800-374-3818
                www.saiglobal.com
        [Code of Federal Regulations]
        [Title 21, Volume 4]
NOTES   [Revised as of April 1, 2006]
        [CITE: 21CFR210.1]


        Title 21 Food and Drugs
        Parts 210 and 211

        PART 210 -- CURRENT GOOD MANUFACTURING
        PRACTICE IN MANUFACTURING,
        PROCESSING, PACKING, OR HOLDING
        OF DRUGS; GENERAL

        Part 211 -- CURRENT GOOD MANUFACTURING
        PRACTICE FOR FINISHED PHARMACEUTICALS



        PART 210 -- CURRENT GOOD MANUFACTURING
        PRACTICE IN MANUFACTURING, PROCESSING,
        PACKING, OR HOLDING OF DRUGS; GENERAL

        Sec.
        210.1 - Status of current good manufacturing
                practice regulations.
        210.2 - Applicability of current good
                manufacturing practice regulations.
        210.3 - Definitions.
        AUTHORITY: Secs. 201, 501, 502, 505, 506, 507, 512, 701, 704
        of the Federal Food, Drug, and Cosmetics Act (21 U.S.C. 321, 351,
        352, 355, 356, 357, 360b, 371, 374).
        SOURCE: 43 FR 45076, Sept. 29, 1978, unless otherwise noted.
§ 210.1 Status of current good manufacturing practice
regulations.                                               NOTES
(a) The regulations set forth in this part and in parts
    211 through 226 of this chapter contain the min-
    imum current good manufacturing practice for
    methods to be used in, and the facilities or con-
    trols to be used for, the manufacture, process-
    ing, packing, or holding of a drug to assure that
    such drug meets the requirements of the act as
    to safety, and has the identity and strength and
    meets the quality and purity characteristics that it
    purports or is represented to possess.
(b) The failure to comply with any regulation set forth
    in this part and in parts 211 through 226 of this
    chapter in the manufacture, processing, pack-
    ing, or holding of a drug shall render such drug
    to be adulterated under section 501(a)(2)(B) of
    the act and such drug, as well as the person who
    is responsible for the failure to comply, shall be
    subject to regulatory action.
(c) Owners and operators of establishments engaged
    in the recovery, donor screening, testing (includ-
    ing donor testing), processing, storage, label-
    ing, packaging, or distribution of human cells,
    tissues, and cellular and tissue-based products
    (HCT/Ps), as defined in 1271.3(d) of this chap-
    ter, that are drugs (subject to review under an ap-
    plication submitted under section 505 of the act
    or under a biological product license application
    under section 351 of the Public Health Service
    Act), are subject to the donor-eligibility and ap-
    plicable current good tissue practice procedures
    set forth in part 1271 subparts C and D of this
    chapter, in addition to the regulations in this part
    and in parts 211 through 226 of this chapter.
           Failure to comply with any applicable regulation
NOTES      set forth in this part, in parts 211 through 226 of
           this chapter, in part 1271 subpart C of this chap-
           ter, or in part 1271 subpart D of this chapter with
           respect to the manufacture, processing, packing
           or holding of a drug, renders an HCT/P adulter-
           ated under section 501(a)(2)(B) of the act. Such
           HCT/P, as well as the person who is responsible
           for the failure to comply, is subject to regulatory
           action.

         [43 FR 45076, Sept, 29, 1978, as amended at 69 FR 29828,
         May 25, 2004]


        § 210.2 Applicability of current good manufacturing
        practice regulations.
        (a) The regulations in this part and in parts 211
            through 226 of this chapter as they may pertain
            to a drug; in parts 600 through 680 of this chap-
            ter as they may pertain to a biological product
            for human use; and in part 1271 of this chapter
            as they are applicable to a human cell, tissue, or
            cellular or tissue-based product (HCT/P) that is a
            drug (subject to review under an application sub-
            mitted under section 505 of the act or under a
            biological product license application under sec-
            tion 351 of the Public Health Service Act); shall
            be considered to supplement, not supersede,
            each other, unless the regulations explicitly pro-
            vide otherwise. In the event of a conflict between
            applicable regulations in this part and in other
            parts of this chapter, the regulation specifically
            applicable to the drug product in question shall
            supersede the more general.
        (b) If a person engages in only some operations sub-
    ject to the regulations in this part, in parts 211
    through 226 of this chapter, in parts 600 through         NOTES
    680 of this chapter, and in part 1271 of this
    chapter, and not in others, that person need only
    comply with those regulations applicable to the
    operations in which he or she is engaged.
(c) An investigational drug for use in a Phase 1
    study, as defined in 312.21(a) of this chapter, is
    subject to the statutory requirements set forth at
    21 U.S.C. 351(a)(2)(B). The production of such
    drug is exempt from compliance with the regula-
    tions in part 211 of this chapter. However, this
    exemption does not apply to an investigational
    drug for use in a Phase 1 study once the investi-
    gational drug has been made available for use by
    or for the sponsor in a Phase 2 or Phase 3 study,
    as defined in 312.21(b) and (c) of this chapter,
    or the drug has been lawfully marketed. If the
    investigational drug has been made available in a
    Phase 2 or 3 study or the drug has been lawfully
    marketed, the drug for use in the Phase 1 study
    must comply with part 211.

 [69 FR 29828, May 25, 2004, as amended at 71 FR 2462, Jan.
 17, 2006]



§ Sec. 210.3 Definitions.
(a) The definitions and interpretations contained in
    section 201 of the act shall be applicable to such
    terms when used in this part and in parts 211
    through 226 of this chapter.
(b) The following definitions of terms apply to this
    part and to parts 211 through 226 of this chap-
    ter.
        (1) Act means the Federal Food, Drug, and Cosmetic
NOTES       Act, as amended (21 U.S.C. 301 et seq.).
        (2) Batch means a specific quantity of a drug or
            other material that is intended to have uniform
            character and quality, within specified limits, and
            is produced according to a single manufacturing
            order during the same cycle of manufacture.
        (3) Component means any ingredient intended for
            use in the manufacture of a drug product, in-
            cluding those that may not appear in such drug
            product.
        (4) Drug product means a finished dosage form, for
            example, tablet, capsule, solution, etc., that con-
            tains an active drug ingredient generally, but not
            necessarily, in association with inactive ingredi-
            ents. The term also includes a finished dosage
            form that does not contain an active ingredient
            but is intended to be used as a placebo.
        (5) Fiber means any particulate contaminant with a
            length at least three times greater than its width.
        (6) Non-fiber-releasing filter means any filter, which
            after any appropriate pretreatment such as wash-
            ing or flushing, will not release fibers into the
            component or drug product that is being filtered.
            All filters composed of asbestos are deemed to
            be fiber-releasing filters.
        (7) Active ingredient means any component that is
            intended to furnish pharmacological activity or
            other direct effect in the diagnosis, cure, mitiga-
            tion, treatment, or prevention of disease, or to af-
            fect the structure or any function of the body of
            man or other animals. The term includes those
            components that may undergo chemical change
            in the manufacture of the drug product and be
            present in the drug product in a modified form
    intended to furnish the specified activity or ef-      or equipment failures shall not be salvaged and
    fect.                                                 returned to the marketplace. Whenever there is a
(8) Inactive ingredient means any component other         question whether drug products have been subject-
    than an active ingredient.                            ed to such conditions, salvaging operations may be
(9) In-process material means any material fabricat-      conducted only if there is (a) evidence from labora-
    ed, compounded, blended, or derived by chemi-         tory tests and assays (including animal feeding stud-
    cal reaction that is produced for, and used in, the   ies where applicable) that the drug products meet
    preparation of the drug product.                      all applicable standards of identity, strength, quality,
(10) Lot means a batch, or a specific identified por-       and purity and (b) evidence from inspection of the
    tion of a batch, having uniform character and         premises that the drug products and their associated
    quality within specified limits; or, in the case of    packaging were not subjected to improper storage
    a drug product produced by continuous process,        conditions as a result of the disaster or accident. Or-
    it is a specific identified amount produced in a        ganoleptic examinations shall be acceptable only as
    unit of time or quantity in a manner that assures     supplemental evidence that the drug products meet
    its having uniform character and quality within       appropriate standards of identity, strength, quality,
    specified limits.                                      and purity. Records including name, lot number,
(11) Lot number, control number, or batch num-            and disposition shall be maintained for drug prod-
    ber means any distinctive combination of let-         ucts subject to this section.
    ters, numbers, or symbols, or any combination
    of them, from which the complete history of the
    manufacture, processing, packing, holding, and
    distribution of a batch or lot of drug product or
    other material can be determined.
(12) Manufacture, processing, packing, or hold-
    ing of a drug product includes packaging and
    labeling operations, testing, and quality control
    of drug products.
(13) The term medicated feed means any Type B
    or Type C medicated feed as defined in 558.3
    of this chapter. The feed contains one or more
    drugs as defined in section 201(g) of the act. The
    manufacture of medicated feeds is subject to the
    requirements of part 225 of this chapter.
(14) The term medicated premix means a Type A
    medicated article as defined in 558.3 of this
Subpart K--Returned and Salvaged Drug Products                chapter. The article contains one or more drugs
                                                              as defined in section 201(g) of the act. The man-
§ 211.204 Returned drug products.                             ufacture of medicated premixes is subject to the
Returned drug products shall be identified as such             requirements of part 226 of this chapter.
and held. If the conditions under which returned           (15) Quality control unit means any person or or-
drug products have been held, stored, or shipped              ganizational element designated by the firm to
before or during their return, or if the condition of         be responsible for the duties relating to quality
the drug product, its container, carton, or labeling,         control.
as a result of storage or shipping, casts doubt on         (16) Strength means:
the safety, identity, strength, quality or purity of the      (i) The concentration of the drug substance (for
drug product, the returned drug product shall be                   example, weight/weight, weight/volume, or
destroyed unless examination, testing, or other in-                unit dose/volume basis), and/or
vestigations prove the drug product meets appropri-           (ii) The potency, that is, the therapeutic activity of
ate standards of safety, identity, strength, quality, or           the drug product as indicated by appropriate
purity. A drug product may be reprocessed provided                 laboratory tests or by adequately developed
the subsequent drug product meets appropriate                      and controlled clinical data (expressed, for
standards, specifications, and characteristics. Re-                 example, in terms of units by reference to a
cords of returned drug products shall be maintained                standard).
and shall include the name and label potency of the        (17) Theoretical yield means the quantity that would
drug product dosage form, lot number (or control              be produced at any appropriate phase of manu-
number or batch number), reason for the return,               facture, processing, or packing of a particular
quantity returned, date of disposition, and ultimate          drug product, based upon the quantity of com-
disposition of the returned drug product. If the rea-         ponents to be used, in the absence of any loss or
son for a drug product being returned implicates as-          error in actual production.
sociated batches, an appropriate investigation shall       (18) Actual yield means the quantity that is actually
be conducted in accordance with the requirements              produced at any appropriate phase of manufac-
of 211.192. Procedures for the holding, testing, and          ture, processing, or packing of a particular drug
reprocessing of returned drug products shall be in            product.
writing and shall be followed.                             (19) Percentage of theoretical yield means the ratio
                                                              of the actual yield (at any appropriate phase of
§ 211.208 Drug product salvaging.                             manufacture, processing, or packing of a partic-
Drug products that have been subjected to improper            ular drug product) to the theoretical yield (at the
storage conditions including extremes in tempera-             same phase), stated as a percentage.
ture, humidity, smoke, fumes, pressure, age, or            (20) Acceptance criteria means the product speci-
radiation due to natural disasters, fires, accidents,          fications and acceptance/rejection criteria, such
   as acceptable quality level and unacceptable                   ufactured, processed, or packed, or such file
   quality level, with an associated sampling plan,               may be maintained at another facility if the writ-
   that are necessary for making a decision to ac-                ten records in such files are readily available for
   cept or reject a lot or batch (or any other conve-             inspection at that other facility. Written records
   nient subgroups of manufactured units).                        involving a drug product shall be maintained un-
(21) Representative sample means a sample that                    til at least 1 year after the expiration date of the
   consists of a number of units that are drawn                   drug product, or 1 year after the date that the
   based on rational criteria such as random sam-                 complaint was received, whichever is longer. In
   pling and intended to assure that the sample ac-               the case of certain OTC drug products lacking
   curately portrays the material being sampled.                  expiration dating because they meet the criteria
(22) Gang-printed labeling means labeling derived                 for exemption under 211.137, such written re-
   from a sheet of material on which more than one                cords shall be maintained for 3 years after distri-
   item of labeling is printed.                                   bution of the drug product.
                                                                  (1) The written record shall include the follow-
 [43 FR 45076, Sept. 29, 1978, as amended at 51 FR 7389, Mar.          ing information, where known: the name and
 3, 1986; 58 FR 41353, Aug. 3, 1993]
                                                                       strength of the drug product, lot number,
                                                                       name of complainant, nature of complaint,
                                                                       and reply to complainant.
                                                                  (2) Where an investigation under 211.192 is
Part 211 -CURRENT GOOD MANUFACTURING
                                                                       conducted, the written record shall include
PRACTICE FOR FINISHED PHARMACEUTICALS
                                                                       the findings of the investigation and followup.
(21 CFR Part 211 As of April, 1996)
Authority: Secs. 201, 501, 502, 505, 506, 507, 512, 701,               The record or copy of the record of the in-
704 of the Federal Food, Drug, and Cosmetic Act (21                    vestigation shall be maintained at the estab-
U.S.C. 321, 351, 352, 355, 356, 357, 360b, 371, 374).                  lishment where the investigation occurred in
Source: 43 FR 45077, Sept. 29, 1978, unless otherwise                  accordance with 211.180(c).
noted.                                                            (3) Where an investigation under 211.192 is not
                                                                       conducted, the written record shall include
PART 211 - CURRENT GOOD MANUFACTURING                                  the reason that an investigation was found not
PRACTICE FOR FINISHED PHARMACEUTICALS                                  to be necessary and the name of the respon-
                                                                       sible person making such a determination.
Subpart A - General Provisions
                                                                [43 FR 45077, Sept. 29, 1978, as amended at 51 FR 24479, July
                                                                3, 1986; 68 FR 15364, Mar. 31, 2003]
Sec.
 211.1 Scope
 211.3 Definitions
and quantity shipped, and lot or control number of       Subpart B - Organization and Personnel
the drug product. For compressed medical gas prod-        211.22 Responsibilities of quality control unit.
ucts, distribution records are not required to contain    211.25 Personnel Qualifications.
lot or control numbers.                                   211.28 Personnel responsibilities.
Distribution records shall contain the name and           211.34 Consultants.
strength of the product and description of the dos-
age form, name and address of the consignee, date        Subpart C - Buildings and Facilities
and quantity shipped, and lot or control number of        211.42 Design and construction features.
the drug product. For compressed medical gas prod-        211.44 Lighting.
ucts, distribution records are not required to contain    211.46 Ventilation, air filtration, air heating and
lot or control numbers.                                   cooling.
                                                          211.48 Plumbing.
 [49 FR 9865, Mar. 16, 1984]                              211.50 Sewage and refuse.
                                                          211.52 Washing and toilet facilities.
§ 211.198 Complaint files.                                211.56 Sanitation.
(a) Written procedures describing the handling of         211.58 Maintenance
    all written and oral complaints regarding a drug
    product shall be established and followed. Such      Subpart D - Equipment
    procedures shall include provisions for review        211.63 Equipment design, size, and location.
    by the quality control unit, of any complaint in-     211.65 Equipment construction.
    volving the possible failure of a drug product to     211.67 Equipment cleaning and maintenance.
    meet any of its specifications and, for such drug      211.68 Automatic, mechanical, and electronic
    products, a determination as to the need for an       equipment.
    investigation in accordance with 211.192. Such        211.72 Filters.
    procedures shall include provisions for review to
    determine whether the complaint represents a         Subpart E - Control of Components and Drug Product
    serious and unexpected adverse drug experience       Containers and Closures
    which is required to be reported to the Food and      211.80 General requirements.
    Drug Administration in accordance with 310.305        211.82 Receipt and storage of untested compo-
    and 514.80 of this chapter.                           nents, drug product containers, and closures.
(b) A written record of each complaint shall be           211.84 Testing and approval or rejection of compo-
    maintained in a file designated for drug product       nents, drug product containers, and closures.
    complaints. The file regarding such drug product       211.86 Use of approved components, drug prod-
    complaints shall be maintained at the establish-      uct containers, and closures.
    ment where the drug product involved was man-         211.87 Retesting of approved components, drug
 product containers and closures.                             for the component, drug product container,
 211.89 Rejected components, drug product con-                closure, in-process material, or drug product
 tainers, and closures.                                       tested.
 211.94 Drug product containers and closures.             (7) The initials or signature of the person who
                                                              performs each test and the date(s) the tests
Subpart F - Production and Process Controls                   were performed.
 211.100 Written procedures; deviations.                  (8) The initials or signature of a second person
 211.101 Charge-in of components.                             showing that the original records have been
 211.103 Calculation of yield.                                reviewed for accuracy, completeness, and
 211.105 Equipment identification.                             compliance with established standards.
 211.110 Sampling and testing of in-process materi-   (b) Complete records shall be maintained of any
 als and drug products.                                   modification of an established method employed
 211.111 Time limitations on production.                  in testing. Such records shall include the reason
 211.113 Control of microbiological contamination.        for the modification and data to verify that the
 211.115 Reprocessing.                                    modification produced results that are at least
                                                          as accurate and reliable for the material being
Subpart G - Packaging and Labeling Control                tested as the established method.
 211.122 Materials examination and usage criteria.    (c) Complete records shall be maintained of any test-
 211.125 Labeling issuance.                               ing and standardization of laboratory reference
 211.130 Packaging and labeling operations.               standards, reagents, and standard solutions.
 211.132 Tamper-resistant packaging requirements      (d) Complete records shall be maintained of the pe-
 for over-the-counter (OTC) human drug products.          riodic calibration of laboratory instruments, ap-
 211.134 Drug product inspection.                         paratus, gauges, and recording devices required
 211.137 Expiration dating.                               by 211.160(b)(4).
                                                      (e) Complete records shall be maintained of all
Subpart H - Holding and Distribution                      stability testing performed in accordance with
 211.142 Warehousing procedures.                          211.166.
 211.150 Distribution procedures.
                                                       [43 FR 45077, Sept. 29, 1978, as amended at 55 FR 11577, Mar.
                                                       29, 1990; 65 FR 18889, Apr. 10, 2000; 70 FR 40880, July 15,
Subpart I - Laboratory Controls                        2005; 70 FR 67651, Nov. 8, 2005]
 211.160 General requirements.
 211.165 Testing and release for distribution.        § 211.196 Distribution records.
 211.166 Stability testing.                           Distribution records shall contain the name and
 211.167 Special testing requirements.                strength of the product and description of the dos-
 211.170 Reserve samples.                             age form, name and address of the consignee, date
(2) A statement of each method used in the test-         211.173 Laboratory animals.
    ing of the sample. The statement shall indi-         211.176 Penicillin contamination.
    cate the location of data that establish that
    the methods used in the testing of the sample       Subpart J - Records and Reports
    meet proper standards of accuracy and reli-          211.180 General requirements.
    ability as applied to the product tested. (If the    211.182 Equipment cleaning and use log.
    method employed is in the current revision           211.184 Component, drug product container, clo-
    of the United States Pharmacopeia, National          sure, and labeling records.
    Formulary, AOAC INTERNATIONAL, Book of               211.186 Master production and control records.
    Methods, 1 or in other recognized standard           211.188 Batch production and control records.
    references, or is detailed in an approved new        211.192 Production record review.
    drug application and the referenced method           211.194 Laboratory records.
    is not modified, a statement indicating the           211.196 Distribution records.
    method and reference will suffice). The suit-         211.198 Complaint files.
    ability of all testing methods used shall be
    verified under actual conditions of use.             Subpart K - Returned and Salvaged Drug Products
     {1}Copies may be obtained from: AOAC INTER-         211.204 Returned drug products.
     NATIONAL, 481 North Frederick Ave., suite 500,      211.208 Drug product salvaging.
     Gaithersburg, MD 20877.
(3) A statement of the weight or measure of sam-
    ple used for each test, where appropriate.          Subpart A--General Provisions
(4) A complete record of all data secured in the
    course of each test, including all graphs,          § 211.1 Scope
    charts, and spectra from laboratory instru-         (a) The regulations in this part contain the minimum
    mentation, properly identified to show the               current good manufacturing practice for prepa-
    specific component, drug product container,              ration of drug products for administration to hu-
    closure, in-process material, or drug product,          mans or animals.
    and lot tested.                                     (b) The current good manufacturing practice regula-
(5) A record of all calculations performed in con-          tions in this chapter as they pertain to drug prod-
    nection with the test, including units of mea-          ucts; in parts 600 through 680 of this chapter,
    sure, conversion factors, and equivalency               as they pertain to drugs that are also biological
    factors.                                                products for human use; and in part 1271 of this
(6) A statement of the results of tests and how             chapter, as they are applicable to drugs that are
    the results compare with established stan-              also human cells, tissues, and cellular and tis-
    dards of identity, strength, quality, and purity        sue-based products (HCT/Ps) and that are drugs
    (subject to review under an application submitted               (13) Results of examinations made in accor-
    under section 505 of the act or under a biological                 dance with 211.134.
    product license application under section 351 of
    the Public Health Service Act); supplement and               § 211.192 Production record review.
    do not supersede the regulations in this part un-            All drug product production and control records, in-
    less the regulations explicitly provide otherwise.           cluding those for packaging and labeling, shall be
    In the event of a conflict between applicable                 reviewed and approved by the quality control unit
    regulations in this part and in other parts of this          to determine compliance with all established, ap-
    chapter, or in parts 600 through 680 of this chap-           proved written procedures before a batch is released
    ter, or in part 1271 of this chapter, the regula-            or distributed. Any unexplained discrepancy (includ-
    tion specifically applicable to the drug product in           ing a percentage of theoretical yield exceeding the
    question shall supersede the more general.                   maximum or minimum percentages established in
(c) Pending consideration of a proposed exemp-                   master production and control records) or the fail-
    tion, published in the Federal Register of Sep-              ure of a batch or any of its components to meet any
    tember 29, 1978, the requirements in this part               of its specifications shall be thoroughly investigated,
    shall not be enforced for OTC drug products if               whether or not the batch has already been distribut-
    the products and all their ingredients are ordi-             ed. The investigation shall extend to other batches of
    narily marketed and consumed as human foods,                 the same drug product and other drug products that
    and which products may also fall within the legal            may have been associated with the specific failure
    definition of drugs by virtue of their intended use.          or discrepancy. A written record of the investigation
    Therefore, until further notice, regulations under           shall be made and shall include the conclusions and
    part 110 of this chapter, and where applicable,              followup.
    parts 113 to 129 of this chapter, shall be applied
    in determining whether these OTC drug products               § 211.194 Laboratory records.
    that are also foods are manufactured, processed,             (a) Laboratory records shall include complete data
    packed, or held under current good manufactur-                   derived from all tests necessary to assure com-
    ing practice.                                                    pliance with established specifications and stan-
                                                                     dards, including examinations and assays, as
 [43 FR 45077, Sept. 29, 1978, as amended at 62 FR 66522, Dec.       follows:
 19, 1997; 69 FR 29828, May 25, 2004]
                                                                     (1) A description of the sample received for test-
                                                                          ing with identification of source (that is, lo-
                                                                          cation from where sample was obtained),
§ 211.3 Definitions.
                                                                          quantity, lot number or other distinctive code,
The definitions set forth in § 210.3 of this chapter
                                                                          date sample was taken, and date sample was
apply in this part.
                                                                          received for testing.
§ 211.188 Batch production and control records.          Subpart B-Organization and Personnel
Batch production and control records shall be pre-
pared for each batch of drug product produced and        § 211.22 Responsibilities of quality control unit.
shall include complete information relating to the       (a) There shall be a quality control unit that shall
production and control of each batch. These records          have the responsibility and authority to approve
shall include:                                               or reject all components, drug product contain-
(a) An accurate reproduction of the appropriate              ers, closures, in-process materials, packaging
    master production or control record, checked for         material, labeling, and drug products, and the
    accuracy, dated, and signed;                             authority to review production records to assure
(b) Documentation that each significant step in the           that no errors have occurred or, if errors have
    manufacture, processing, packing, or holding of          occurred, that they have been fully investigated.
    the batch was accomplished, including:                   The quality control unit shall be responsible for
    (1) Dates;                                               approving or rejecting drug products manufac-
    (2) Identity of individual major equipment and           tured, processed, packed, or held under contract
        lines used;                                          by another company.
    (3) Specific identification of each batch of com-      (b) Adequate laboratory facilities for the testing and
        ponent or in-process material used;                  approval (or rejection) of components, drug prod-
    (4) Weights and measures of components used              uct containers, closures, packaging materials,
        in the course of processing;                         in-process materials, and drug products shall be
    (5) In-process and laboratory control results;           available to the quality control unit.
    (6) Inspection of the packaging and labeling area    (c) The quality control unit shall have the responsi-
        before and after use;                                bility for approving or rejecting all procedures or
    (7) A statement of the actual yield and a state-         specifications impacting on the identity, strength,
        ment of the percentage of theoretical yield at       quality, and purity of the drug product.
        appropriate phases of processing;                (d) The responsibilities and procedures applicable to
    (8) Complete labeling control records, including         the quality control unit shall be in writing; such
        specimens or copies of all labeling used;            written procedures shall be followed.
    (9) Description of drug product containers and
        closures;                                        § 211.25 Personnel qualifications.
    (10) Any sampling performed;                         (a) Each person engaged in the manufacture, pro-
    (11) Identification of the persons performing and         cessing, packing, or holding of a drug product
        directly supervising or checking each signifi-        shall have education, training, and experience,
        cant step in the operation;                          or any combination thereof, to enable that person
    (12) Any investigation made according to                 to perform the assigned functions. Training shall
        211.192.                                             be in the particular operations that the employee
    performs and in current good manufacturing            (2) The name and weight or measure of each ac-
    practice (including the current good manufactur-          tive ingredient per dosage unit or per unit of
    ing practice regulations in this chapter and writ-        weight or measure of the drug product, and
    ten procedures required by these regulations) as          a statement of the total weight or measure of
    they relate to the employee’s functions. Training         any dosage unit;
    in current good manufacturing practice shall be       (3) A complete list of components designated by
    conducted by qualified individuals on a continu-           names or codes sufficiently specific to indi-
    ing basis and with sufficient frequency to assure          cate any special quality characteristic;
    that employees remain familiar with CGMP re-          (4) An accurate statement of the weight or
    quirements applicable to them.                            measure of each component, using the
(b) Each person responsible for supervising the               same weight system (metric, avoirdupois, or
    manufacture, processing, packing, or holding of           apothecary) for each component. Reason-
    a drug product shall have the education, training,        able variations may be permitted, however,
    and experience, or any combination thereof, to            in the amount of components necessary for
    perform assigned functions in such a manner as            the preparation in the dosage form, provided
    to provide assurance that the drug product has            they are justified in the master production
    the safety, identity, strength, quality, and purity       and control records;
    that it purports or is represented to possess.        (5) A statement concerning any calculated ex-
(c) There shall be an adequate number of qualified             cess of component;
    personnel to perform and supervise the manu-          (6) A statement of theoretical weight or measure
    facture, processing, packing, or holding of each          at appropriate phases of processing;
    drug product.                                         (7) A statement of theoretical yield, including
                                                              the maximum and minimum percentages of
§ 211.28 Personnel responsibilities.                          theoretical yield beyond which investigation
(a) Personnel engaged in the manufacture, process-            according to 211.192 is required;
    ing, packing, or holding of a drug product shall      (8) A description of the drug product containers,
    wear clean clothing appropriate for the duties            closures, and packaging materials, including
    they perform. Protective apparel, such as head,           a specimen or copy of each label and all oth-
    face, hand, and arm coverings, shall be worn as           er labeling signed and dated by the person
    necessary to protect drug products from con-              or persons responsible for approval of such
    tamination.                                               labeling;
(b) Personnel shall practice good sanitation and          (9) Complete manufacturing and control in-
    health habits.                                            structions, sampling and testing procedures,
(c) Only personnel authorized by supervisory person-          specifications, special notations, and precau-
    nel shall enter those areas of the buildings and          tions to be followed.
    manufacturer, if different from the supplier, shall       facilities designated as limited-access areas.
    be listed if known.                                   (d) Any person shown at any time (either by medical
(b) The results of any test or examination performed          examination or supervisory observation) to have
    (including those performed as required by                 an apparent illness or open lesions that may ad-
    211.82(a), 211.84(d), or 211.122(a)) and the              versely affect the safety or quality of drug prod-
    conclusions derived therefrom.                            ucts shall be excluded from direct contact with
(c) An individual inventory record of each compo-             components, drug product containers, closures,
    nent, drug product container, and closure and,            in-process materials, and drug products until the
    for each component, a reconciliation of the use           condition is corrected or determined by com-
    of each lot of such component. The inventory re-          petent medical personnel not to jeopardize the
    cord shall contain sufficient information to allow         safety or quality of drug products. All personnel
    determination of any batch or lot of drug product         shall be instructed to report to supervisory per-
    associated with the use of each component, drug           sonnel any health conditions that may have an
    product container, and closure.                           adverse effect on drug products.
(d) Documentation of the examination and review
    of labels and labeling for conformity with estab-     § 211.34 Consultants.
    lished specifications in accord with 211.122(c)        Consultants advising on the manufacture, process-
    and 211.130(c).                                       ing, packing, or holding of drug products shall have
(e) The disposition of rejected components, drug          sufficient education, training, and experience, or any
    product containers, closure, and labeling.            combination thereof, to advise on the subject for
                                                          which they are retained. Records shall be maintained
§ 211.186 Master production and control records.          stating the name, address, and qualifications of any
(a) To assure uniformity from batch to batch, mas-        consultants and the type of service they provide.
    ter production and control records for each drug
    product, including each batch size thereof, shall     Subpart C--Buildings and Facilities
    be prepared, dated, and signed (full signature,
    handwritten) by one person and independently          § 211.42 Design and construction features.
    checked, dated, and signed by a second person.        (a) Any building or buildings used in the manufac-
    The preparation of master production and control          ture, processing, packing, or holding of a drug
    records shall be described in a written procedure         product shall be of suitable size, construction
    and such written procedure shall be followed.             and location to facilitate cleaning, maintenance,
(b) Master production and control records shall in-           and proper operations.
    clude:                                                (b) Any such building shall have adequate space
    (1) The name and strength of the product and a            for the orderly placement of equipment and
        description of the dosage form;                       materials to prevent mixups between different
    components, drug product containers, closures,           of inspectional observations issued by the Food
    labeling, in-process materials, or drug products,        and Drug Administration, or any regulatory ac-
    and to prevent contamination. The flow of com-            tions relating to good manufacturing practices
    ponents, drug product containers, closures, la-          brought by the Food and Drug Administration.
    beling, in-process materials, and drug products
    through the building or buildings shall be de-         [43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan.
                                                           20, 1995]
    signed to prevent contamination.
(c) Operations shall be performed within specifically
                                                          § 211.182 Equipment cleaning and use log.
    defined areas of adequate size. There shall be
                                                          A written record of major equipment cleaning, main-
    separate or defined areas or such other control
                                                          tenance (except routine maintenance such as lubri-
    systems for the firm’s operations as are neces-
                                                          cation and adjustments), and use shall be included
    sary to prevent contamination or mixups during
                                                          in individual equipment logs that show the date, time,
    the course of the following procedures:
                                                          product, and lot number of each batch processed. If
    (1) Receipt, identification, storage, and withhold-
                                                          equipment is dedicated to manufacture of one prod-
        ing from use of components, drug product
                                                          uct, then individual equipment logs are not required,
        containers, closures, and labeling, pending
                                                          provided that lots or batches of such product follow
        the appropriate sampling, testing, or exami-
                                                          in numerical order and are manufactured in numeri-
        nation by the quality control unit before re-
                                                          cal sequence. In cases where dedicated equipment
        lease for manufacturing or packaging;
                                                          is employed, the records of cleaning, maintenance,
    (2) Holding rejected components, drug product
                                                          and use shall be part of the batch record. The per-
        containers, closures, and labeling before dis-
                                                          sons performing and double-checking the cleaning
        position;
                                                          and maintenance shall date and sign or initial the log
    (3) Storage of released components, drug prod-
                                                          indicating that the work was performed. Entries in
        uct containers, closures, and labeling;
                                                          the log shall be in chronological order.
    (4) Storage of in-process materials;
    (5) Manufacturing and processing operations;
                                                          § 211.184 Component, drug product
    (6) Packaging and labeling operations;
                                                          container, closure, and labeling records.
    (7) Quarantine storage before release of drug
                                                          These records shall include the following:
        products;
                                                          (a) The identity and quantity of each shipment of
    (8) Storage of drug products after release;
                                                              each lot of components, drug product containers,
    (9) Control and laboratory operations;
                                                              closures, and labeling; the name of the supplier;
    (10) Aseptic processing, which includes as ap-
                                                              the supplier’s lot number(s) if known; the receiv-
        propriate:
                                                              ing code as specified in 211.80; and the date
        (i) Floors, walls, and ceilings of smooth, hard
                                                              of receipt. The name and location of the prime
             surfaces that are easily cleanable;
     thereof shall be subject to photocopying or other
     means of reproduction as part of such inspec-                  (ii) Temperature and humidity controls;
     tion. Records that can be immediately retrieved                (iii) An air supply filtered through high-effi-
     from another location by computer or other elec-                    ciency particulate air filters under positive
     tronic means shall be considered as meeting the                     pressure, regardless of whether flow is
     requirements of this paragraph.                                     laminar or nonlaminar;
(d) Records required under this part may be retained                (iv) A system for monitoring environmental
     either as original records or as true copies such                   conditions;
     as photocopies, microfilm, microfiche, or other                  (v) A system for cleaning and disinfecting the
     accurate reproductions of the original records.                     room and equipment to produce aseptic
     Where reduction techniques, such as microfilm-                       conditions;
     ing, are used, suitable reader and photocopying                (vi) A system for maintaining any equipment
     equipment shall be readily available.                               used to control the aseptic conditions.
(e) Written records required by this part shall be          (d) Operations relating to the manufacture, process-
     maintained so that data therein can be used for            ing, and packing of penicillin shall be performed
     evaluating, at least annually, the quality standards       in facilities separate from those used for other
     of each drug product to determine the need for             drug products for human use.
     changes in drug product specifications or manu-
                                                             [43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan.
     facturing or control procedures. Written proce-         20, 1995]
     dures shall be established and followed for such
     evaluations and shall include provisions for:          § 211.44 Lighting.
     (1) A review of a representative number of             Adequate lighting shall be provided in all areas.
         batches, whether approved or rejected, and,
         where applicable, records associated with the      § 211.46 Ventilation, air filtration, air heating and
         batch.                                             cooling.
     (2) A review of complaints, recalls, returned or       (a) Adequate ventilation shall be provided.
         salvaged drug products, and investigations         (b) Equipment for adequate control over air pres-
         conducted under 211.192 for each drug                  sure, micro-organisms, dust, humidity, and tem-
         product.                                               perature shall be provided when appropriate for
(f) Procedures shall be established to assure that the          the manufacture, processing, packing, or hold-
     responsible officials of the firm, if they are not           ing of a drug product.
     personally involved in or immediately aware of         (c) Air filtration systems, including prefilters and par-
     such actions, are notified in writing of any inves-         ticulate matter air filters, shall be used when ap-
     tigations conducted under 211.198, 211.204, or             propriate on air supplies to production areas. If
     211.208 of these regulations, any recalls, reports         air is recirculated to production areas, measures
    shall be taken to control recirculation of dust from    at the National Archives and Records Administra-
    production. In areas where air contamination oc-        tion (NARA). For information on the availability of
    curs during production, there shall be adequate         this material at NARA, call 202-741-6030, or go to:
    exhaust systems or other systems adequate to            http://www.archives.gov/federal_register/code_of_
    control contaminants.                                   federal_regulations/ibr_locations.html.
(d) Air-handling systems for the manufacture, pro-
                                                             [43 FR 45077, Sept. 29, 1978, as amended at 47 FR 9396, Mar.
    cessing, and packing of penicillin shall be com-         5, 1982; 50 FR 8996, Mar. 6, 1985; 55 FR 11577, Mar. 29, 1990;
    pletely separate from those for other drug prod-         66 FR 56035, Nov. 6, 2001; 69 FR 18803, Apr. 9, 2004]
    ucts for human use.
                                                            Subpart J--Records and Reports
§ 211.48 Plumbing.
(a) Potable water shall be supplied under continu-          § 211.180 General requirements.
    ous positive pressure in a plumbing system free         (a) Any production, control, or distribution record
    of defects that could contribute contamination to           that is required to be maintained in compliance
    any drug product. Potable water shall meet the              with this part and is specifically associated with
    standards prescribed in the Environmental Pro-              a batch of a drug product shall be retained for at
    tection Agency’s Primary Drinking Water Regu-               least 1 year after the expiration date of the batch
    lations set forth in 40 CFR part 141. Water not             or, in the case of certain OTC drug products lack-
    meeting such standards shall not be permitted in            ing expiration dating because they meet the cri-
    the potable water system.                                   teria for exemption under 211.137, 3 years after
(b) Drains shall be of adequate size and, where con-            distribution of the batch.
    nected directly to a sewer, shall be provided with      (b) Records shall be maintained for all components,
    an air break or other mechanical device to pre-             drug product containers, closures, and labeling
    vent back-siphonage.                                        for at least 1 year after the expiration date or, in
                                                                the case of certain OTC drug products lacking
 [43 FR 45077, Sept. 29, 1978, as amended at 48 FR 11426,
                                                                expiration dating because they meet the crite-
 Mar. 18, 1983]
                                                                ria for exemption under 211.137, 3 years after
                                                                distribution of the last lot of drug product incor-
§ 211.50 Sewage and refuse.
                                                                porating the component or using the container,
Sewage, trash, and other refuse in and from the
                                                                closure, or labeling.
building and immediate premises shall be disposed
                                                            (c) All records required under this part, or copies of
of in a safe and sanitary manner.
                                                                such records, shall be readily available for autho-
                                                                rized inspection during the retention period at the
§ 211.52 Washing and toilet facilities.
                                                                establishment where the activities described in
Adequate washing facilities shall be provided, in-
                                                                such records occurred. These records or copies
          drug product if the expiration dating period         cluding hot and cold water, soap or detergent, air
          of the drug product is more than 30 days.            driers or single-service towels, and clean toilet facili-
   (3) For an OTC drug product that is exempt for              ties easily accesible to working areas.
       bearing an expiration date under 211.137,
       the reserve sample must be retained for 3               § 211.56 Sanitation.
       years after the lot or batch of drug product            (a) Any building used in the manufacture, process-
       is distributed.                                             ing, packing, or holding of a drug product shall
                                                                   be maintained in a clean and sanitary condition,
 [48 FR 13025, Mar. 29, 1983, as amended at 60 FR 4091, Jan.       Any such building shall be free of infestation by
 20, 1995]
                                                                   rodents, birds, insects, and other vermin (other
                                                                   than laboratory animals). Trash and organic
                                                                   waste matter shall be held and disposed of in a
§ 211.173 Laboratory animals.
                                                                   timely and sanitary manner.
Animals used in testing components, in-process
                                                               (b) There shall be written procedures assigning re-
materials, or drug products for compliance with
                                                                   sponsibility for sanitation and describing in suf-
established specifications shall be maintained and
                                                                   ficient detail the cleaning schedules, methods,
controlled in a manner that assures their suitability
                                                                   equipment, and materials to be used in cleaning
for their intended use. They shall be identified, and
                                                                   the buildings and facilities; such written proce-
adequate records shall be maintained showing the
                                                                   dures shall be followed.
history of their use.
                                                               (c) There shall be written procedures for use of
                                                                   suitable rodenticides, insecticides, fungicides,
§ 211.176 Penicillin contamination.
                                                                   fumigating agents, and cleaning and sanitizing
If a reasonable possibility exists that a non-penicillin
                                                                   agents. Such written procedures shall be de-
drug product has been exposed to cross-contamina-
                                                                   signed to prevent the contamination of equip-
tion with penicillin, the non-penicillin drug product
                                                                   ment, components, drug product containers,
shall be tested for the presence of penicillin. Such
                                                                   closures, packaging, labeling materials, or drug
drug product shall not be marketed if detectable lev-
                                                                   products and shall be followed. Rodenticides, in-
els are found when tested according to procedures
                                                                   secticides, and fungicides shall not be used un-
specified in `Procedures for Detecting and Measur-
                                                                   less registered and used in accordance with the
ing Penicillin Contamination in Drugs,’ which is in-
                                                                   Federal Insecticide, Fungicide, and Rodenticide
corporated by reference. Copies are available from
                                                                   Act (7 U.S.C. 135).
the Division of Research and Testing (HFD-470),
                                                               (d) Sanitation procedures shall apply to work per-
Center for Drug Evaluation and Research, Food and
                                                                   formed by contractors or temporary employees
Drug Administration, 5100 Paint Branch Pkwy., Col-
                                                                   as well as work performed by full-time employees
lege Park, MD 20740, or available for inspection
                                                                   during the ordinary course of operations.
§ 211.58 Maintenance.                                         consistent with product labeling. The reserve
Any building used in the manufacture, processing,             sample shall be stored in the same immediate
packing, or holding of a drug product shall be main-          container-closure system in which the drug prod-
tained in a good state of repair.                             uct is marketed or in one that has essentially the
                                                              same characteristics. The reserve sample con-
Subpart D--Equipment                                          sists of at least twice the quantity necessary to
                                                              perform all the required tests, except those for
§ 211.63 Equipment design, size, and location.                sterility and pyrogens. Except for those for drug
Equipment used in the manufacture, processing,                products described in paragraph (b)(2) of this
packing, or holding of a drug product shall be of ap-         section, reserve samples from representative
propriate design, adequate size, and suitably located         sample lots or batches selected by acceptable
to facilitate operations for its intended use and for its     statistical procedures shall be examined visually
cleaning and maintenance.                                     at least once a year for evidence of deteriora-
                                                              tion unless visual examination would affect the
§. 211.65 Equipment construction.                             integrity of the reserve sample. Any evidence of
(a) Equipment shall be constructed so that surfaces           reserve sample deterioration shall be investigated
    that contact components, in-process materials,            in accordance with 211.192. The results of the
    or drug products shall not be reactive, additive,         examination shall be recorded and maintained
    or absorptive so as to alter the safety, identity,        with other stability data on the drug product.
    strength, quality, or purity of the drug product          Reserve samples of compressed medical gases
    beyond the official or other established require-          need not be retained. The retention time is as
    ments.                                                    follows:
(b) Any substances required for operation, such as            (1) For a drug product other than those de-
    lubricants or coolants, shall not come into con-               scribed in paragraphs (b) (2) and (3) of this
    tact with components, drug product containers,                 section, the reserve sample shall be retained
    closures, in-process materials, or drug products               for 1 year after the expiration date of the drug
    so as to alter the safety, identity, strength, quality,        product.
    or purity of the drug product beyond the official          (2) For a radioactive drug product, except for
    or other established requirements.                             nonradioactive reagent kits, the reserve sam-
                                                                   ple shall be retained for:
§ 211.67 Equipment cleaning and maintenance.                     (i) Three months after the expiration date of
(a) Equipment and utensils shall be cleaned, main-                    the drug product if the expiration dating
    tained, and sanitized at appropriate intervals                    period of the drug product is 30 days or
    to prevent malfunctions or contamination that                     less; or
    would alter the safety, identity, strength, quality,         (ii) Six months after the expiration date of the
    is representative of each lot in each shipment               or purity of the drug product beyond the official
    of each active ingredient shall be retained. The             or other established requirements.
    reserve sample consists of at least twice the            (b) Written procedures shall be established and fol-
    quantity necessary for all tests required to de-             lowed for cleaning and maintenance of equip-
    termine whether the active ingredient meets its              ment, including utensils, used in the manufac-
    established specifications, except for sterility and          ture, processing, packing, or holding of a drug
    pyrogen testing. The retention time is as follows:           product. These procedures shall include, but are
    (1) For an active ingredient in a drug product               not necessarily limited to, the following:
         other than those described in paragraphs (a)            (1) Assignment of responsibility for cleaning and
         (2) and (3) of this section, the reserve sample             maintaining equipment;
         shall be retained for 1 year after the expira-          (2) Maintenance and cleaning schedules, includ-
         tion date of the last lot of the drug product               ing, where appropriate, sanitizing schedules;
         containing the active ingredient.                       (3) A description in sufficient detail of the meth-
    (2) For an active ingredient in a radioactive drug               ods, equipment, and materials used in clean-
         product, except for nonradioactive reagent                  ing and maintenance operations, and the
         kits, the reserve sample shall be retained for:             methods of disassembling and reassembling
       (i) Three months after the expiration date of                 equipment as necessary to assure proper
            the last lot of the drug product containing              cleaning and maintenance;
            the active ingredient if the expiration dat-         (4) Removal or obliteration of previous batch
            ing period of the drug product is 30 days                identification;
            or less; or                                          (5) Protection of clean equipment from contami-
       (ii) Six months after the expiration date of the              nation prior to use;
            last lot of the drug product containing the          (6) Inspection of equipment for cleanliness im-
            active ingredient if the expiration dating pe-           mediately before use.
            riod of the drug product is more than 30         (c) Records shall be kept of maintenance, cleaning,
            days.                                                sanitizing, and inspection as specified in 211.180
    (3) For an active ingredient in an OTC drug prod-            and 211.182.
         uct that is exempt from bearing an expiration
         date under 211.137, the reserve sample shall        § 211.68 Automatic, mechanical, and electronic
         be retained for 3 years after distribution of the   equipment.
         last lot of the drug product containing the ac-     (a) Automatic, mechanical, or electronic equipment
         tive ingredient.                                        or other types of equipment, including comput-
(b) An appropriately identified reserve sample that is            ers, or related systems that will perform a func-
    representative of each lot or batch of drug prod-            tion satisfactorily, may be used in the manufac-
    uct shall be retained and stored under conditions            ture, processing, packing, and holding of a drug
    product. If such equipment is so used, it shall                     ingredients, and based on marketing experi-
    be routinely calibrated, inspected, or checked                      ence with the drug product to indicate that
    according to a written program designed to as-                      there is no degradation of the product for the
    sure proper performance. Written records of                         normal or expected period of use.
    those calibration checks and inspections shall be               (2) Evaluation of stability shall be based on the
    maintained.                                                         same container-closure system in which the
(b) Appropriate controls shall be exercised over com-                   drug product is being marketed.
    puter or related systems to assure that changes             (d) Allergenic extracts that are labeled “No U.S.
    in master production and control records or other               Standard of Potency” are exempt from the re-
    records are instituted only by authorized person-               quirements of this section.
    nel. Input to and output from the computer or
    related system of formulas or other records or               [43 FR 45077, Sept. 29, 1978, as amended at 46 FR 56412,
                                                                 Nov. 17, 1981]
    data shall be checked for accuracy. The degree
    and frequency of input/output verification shall
                                                                § 211.167 Special testing requirements.
    be based on the complexity and reliability of the
                                                                (a) For each batch of drug product purporting to be
    computer or related system. A backup file of data
                                                                    sterile and/or pyrogen-free, there shall be ap-
    entered into the computer or related system shall
                                                                    propriate laboratory testing to determine con-
    be maintained except where certain data, such
                                                                    formance to such requirements. The test proce-
    as calculations performed in connection with
                                                                    dures shall be in writing and shall be followed.
    laboratory analysis, are eliminated by comput-
                                                                (b) For each batch of ophthalmic ointment, there
    erization or other automated processes. In such
                                                                    shall be appropriate testing to determine confor-
    instances a written record of the program shall
                                                                    mance to specifications regarding the presence
    be maintained along with appropriate validation
                                                                    of foreign particles and harsh or abrasive sub-
    data. Hard copy or alternative systems, such as
                                                                    stances. The test procedures shall be in writing
    duplicates, tapes, or microfilm, designed to as-
                                                                    and shall be followed.
    sure that backup data are exact and complete
                                                                (c) For each batch of controlled-release dosage form,
    and that it is secure from alteration, inadvertent
                                                                    there shall be appropriate laboratory testing to
    erasures, or loss shall be maintained.
                                                                    determine conformance to the specifications for
 [43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan.       the rate of release of each active ingredient. The
 20, 1995]                                                          test procedures shall be in writing and shall be
                                                                    followed.
§ 211.72 Filters.
Filters for liquid filtration used in the manufacture,           § 211.170 Reserve samples.
processing, or packing of injectable drug products              (a) An appropriately identified reserve sample that
    (1) Sample size and test intervals based on sta-       intended for human use shall not release fibers into
        tistical criteria for each attribute examined to   such products. Fiber-releasing filters may not be
        assure valid estimates of stability;               used in the manufacture, processing, or packing of
    (2) Storage conditions for samples retained for        these injectable drug products unless it is not pos-
        testing;                                           sible to manufacture such drug products without the
    (3) Reliable, meaningful, and specific test meth-       use of such filters. If use of a fiber-releasing filter is
        ods;                                               necessary, an additional non-fiber-releasing filter of
    (4) Testing of the drug product in the same con-       0.22 micron maximum mean porosity (0.45 micron
        tainer-closure system as that in which the         if the manufacturing conditions so dictate) shall sub-
        drug product is marketed;                          sequently be used to reduce the content of particles
    (5) Testing of drug products for reconstitution        in the injectable drug product. Use of an asbestos-
        at the time of dispensing (as directed in the      containing filter, with or without subsequent use of a
        labeling) as well as after they are reconsti-      specific non-fiber-releasing filter, is permissible only
        tuted.                                             upon submission of proof to the appropriate bureau
(b) An adequate number of batches of each drug             of the Food and Drug Administration that use of a
    product shall be tested to determine an appro-         non-fiber-releasing filter will, or is likely to, compro-
    priate expiration date and a record of such data       mise the safety or effectiveness of the injectable drug
    shall be maintained. Accelerated studies, com-         product.
    bined with basic stability information on the com-
    ponents, drug products, and container-closure          Subpart E--Control of Components and Drug Product
    system, may be used to support tentative expira-       Containers and Closures
    tion dates provided full shelf life studies are not
    available and are being conducted. Where data          § 211.80 General requirements.
    from accelerated studies are used to project a         (a) There shall be written procedures describing in
    tentative expiration date that is beyond a date            sufficient detail the receipt, identification, stor-
    supported by actual shelf life studies, there must         age, handling, sampling, testing, and approval or
    be stability studies conducted, including drug             rejection of components and drug product con-
    product testing at appropriate intervals, until the        tainers and closures; such written procedures
    tentative expiration date is verified or the appro-         shall be followed.
    priate expiration date determined.                     (b) Components and drug product containers and
(c) For homeopathic drug products, the require-                closures shall at all times be handled and stored
    ments of this section are as follows:                      in a manner to prevent contamination.
    (1) There shall be a written assessment of stabil-     (c) Bagged or boxed components of drug product
        ity based at least on testing or examination           containers, or closures shall be stored off the
        of the drug product for compatibility of the           floor and suitably spaced to permit cleaning and
    inspection.                                               to be free of objectionable microorganisms.
(d) Each container or grouping of containers for com-     (c) Any sampling and testing plans shall be de-
    ponents or drug product containers, or closures           scribed in written procedures that shall include
    shall be identified with a distinctive code for each       the method of sampling and the number of units
    lot in each shipment received. This code shall            per batch to be tested; such written procedure
    be used in recording the disposition of each lot.         shall be followed.
    Each lot shall be appropriately identified as to its   (d) Acceptance criteria for the sampling and testing
    status (i.e., quarantined, approved, or rejected).        conducted by the quality control unit shall be ad-
                                                              equate to assure that batches of drug products
§ 211.82 Receipt and storage of untested                      meet each appropriate specification and appro-
components, drug product containers, and closures.            priate statistical quality control criteria as a condi-
(a) Upon receipt and before acceptance, each con-             tion for their approval and release. The statistical
    tainer or grouping of containers of components,           quality control criteria shall include appropriate
    drug product containers, and closures shall be            acceptance levels and/or appropriate rejection
    examined visually for appropriate labeling as to          levels.
    contents, container damage or broken seals, and       (e) The accuracy, sensitivity, specificity, and repro-
    contamination.                                            ducibility of test methods employed by the firm
(b) Components, drug product containers, and clo-             shall be established and documented. Such vali-
    sures shall be stored under quarantine until they         dation and documentation may be accomplished
    have been tested or examined, as appropriate,             in accordance with 211.194(a)(2).
    and released. Storage within the area shall con-      (f) Drug products failing to meet established stan-
    form to the requirements of 211.80.                       dards or specifications and any other relevant
                                                              quality control criteria shall be rejected. Repro-
§ 211.84 Testing and approval or rejection of                 cessing may be performed. Prior to acceptance
components, drug product containers, and closures.            and use, reprocessed material must meet appro-
(a) Each lot of components, drug product contain-             priate standards, specifications, and any other
    ers, and closures shall be withheld from use until        relevant critieria.
    the lot has been sampled, tested, or examined,
    as appropriate, and released for use by the qual-     § 211.166 Stability testing.
    ity control unit.                                     (a) There shall be a written testing program designed
(b) Representative samples of each shipment of                to assess the stability characteristics of drug prod-
    each lot shall be collected for testing or examina-       ucts. The results of such stability testing shall be
    tion. The number of containers to be sampled,             used in determining appropriate storage condi-
    and the amount of material to be taken from               tions and expiration dates. The written program
    each container, shall be based upon appropriate           shall be followed and shall include:
   (2) Determination of conformance to written               criteria such as statistical criteria for component
       specifications and a description of sampling           variability, confidence levels, and degree of preci-
       and testing procedures for in-process mate-           sion desired, the past quality history of the sup-
       rials. Such samples shall be representative           plier, and the quantity needed for analysis and
       and properly identified.                               reserve where required by 211.170.
   (3) Determination of conformance to written de-       (c) Samples shall be collected in accordance with
       scriptions of sampling procedures and appro-          the following procedures:
       priate specifications for drug products. Such          (1) The containers of components selected shall
       samples shall be representative and properly              be cleaned where necessary, by appropriate
       identified.                                                means.
   (4) The calibration of instruments, apparatus,            (2) The containers shall be opened, sampled,
       gauges, and recording devices at suitable                 and resealed in a manner designed to pre-
       intervals in accordance with an established               vent contamination of their contents and con-
       written program containing specific direc-                 tamination of other components, drug prod-
       tions, schedules, limits for accuracy and                 uct containers, or closures.
       precision, and provisions for remedial action         (3) Sterile equipment and aseptic sampling tech-
       in the event accuracy and/or precision limits             niques shall be used when necessary.
       are not met. Instruments, apparatus, gauges,          (4) If it is necessary to sample a component from
       and recording devices not meeting estab-                  the top, middle, and bottom of its container,
       lished specifications shall not be used.                   such sample subdivisions shall not be com-
                                                                 posited for testing.
§ 211.165 Testing and release for distribution.              (5) Sample containers shall be identified so that
(a) For each batch of drug product, there shall be               the following information can be determined:
    appropriate laboratory determination of satisfac-            name of the material sampled, the lot num-
    tory conformance to final specifications for the               ber, the container from which the sample
    drug product, including the identity and strength            was taken, the date on which the sample was
    of each active ingredient, prior to release. Where           taken, and the name of the person who col-
    sterility and/or pyrogen testing are conducted               lected the sample.
    on specific batches of shortlived radiopharma-            (6) Containers from which samples have been
    ceuticals, such batches may be released prior                taken shall be marked to show that samples
    to completion of sterility and/or pyrogen testing,           have been removed from them.
    provided such testing is completed as soon as        (d) Samples shall be examined and tested as fol-
    possible.                                                lows:
(b) There shall be appropriate laboratory testing, as
    necessary, of each batch of drug product required       (1) At least one test shall be conducted to verify
    the identity of each component of a drug                 dards, sampling plans, test procedures, or other
    product. Specific identity tests, if they exist,          laboratory control mechanisms required by this
    shall be used.                                           subpart, including any change in such specifi-
(2) Each component shall be tested for confor-               cations, standards, sampling plans, test proce-
    mity with all appropriate written specifications          dures, or other laboratory control mechanisms,
    for purity, strength, and quality. In lieu of such       shall be drafted by the appropriate organizational
    testing by the manufacturer, a report of analy-          unit and reviewed and approved by the quality
    sis may be accepted from the supplier of a               control unit. The requirements in this subpart
    component, provided that at least one specif-            shall be followed and shall be documented at
    ic identity test is conducted on such compo-             the time of performance. Any deviation from
    nent by the manufacturer, and provided that              the written specifications, standards, sampling
    the manufacturer establishes the reliability of          plans, test procedures, or other laboratory con-
    the supplier’s analyses through appropriate              trol mechanisms shall be recorded and justified.
    validation of the supplier’s test results at ap-     (b) Laboratory controls shall include the establish-
    propriate intervals.                                     ment of scientifically sound and appropriate
(3) Containers and closures shall be tested for              specifications, standards, sampling plans, and
    conformance with all appropriate written                 test procedures designed to assure that com-
    procedures. In lieu of such testing by the               ponents, drug product containers, closures, in-
    manufacturer, a certificate of testing may be             process materials, labeling, and drug products
    accepted from the supplier, provided that at             conform to appropriate standards of identity,
    least a visual identification is conducted on             strength, quality, and purity. Laboratory controls
    such containers/closures by the manufac-                 shall include:
    turer and provided that the manufacturer es-             (1) Determination of conformance to appropri-
    tablishes the reliability of the supplier’s test              ate written specifications for the acceptance
    results through appropriate validation of the                 of each lot within each shipment of compo-
    supplier’s test results at appropriate inter-                 nents, drug product containers, closures, and
    vals.                                                         labeling used in the manufacture, process-
(4) When appropriate, components shall be mi-                     ing, packing, or holding of drug products.
    croscopically examined.                                       The specifications shall include a descrip-
(5) Each lot of a component, drug product con-                    tion of the sampling and testing procedures
    tainer, or closure that is liable to contami-                 used. Samples shall be representative and
    nation with filth, insect infestation, or other                adequately identified. Such procedures shall
    extraneous adulterant shall be examined                       also require appropriate retesting of any com-
    against established specifications for such                    ponent, drug product container, or closure
    contamination.                                                that is subject to deterioration.
   and they are stable for at least 3 years as sup-                  (6) Each lot of a component, drug product con-
   ported by appropriate stability data.                                 tainer, or closure that is liable to microbio-
                                                                         logical contamination that is objectionable in
 [43 FR 45077, Sept. 29, 1978, as amended at 46 FR 56412, Nov.           view of its intended use shall be subjected to
 17, 1981; 60 FR 4091, Jan. 20, 1995]
                                                                         microbiological tests before use.
                                                                 (e) Any lot of components, drug product containers,
Subpart H--Holding and Distribution
                                                                     or closures that meets the appropriate written
                                                                     specifications of identity, strength, quality, and
§ 211.142 Warehousing procedures.
                                                                     purity and related tests under paragraph (d) of
Written procedures describing the warehousing of
                                                                     this section may be approved and released for
drug products shall be established and followed.
                                                                     use. Any lot of such material that does not meet
They shall include:
                                                                     such specifications shall be rejected.
(a) Quarantine of drug products before release by
    the quality control unit.                                     [43 FR 45077, Sept. 29, 1978, as amended at 63 FR 14356,
(b) Storage of drug products under appropriate con-               Mar. 25, 1998]
    ditions of temperature, humidity, and light so that
    the identity, strength, quality, and purity of the
    drug products are not affected.                              § 211.86 Use of approved components, drug product
                                                                 containers, and closures.
§ 211.150 Distribution procedures.                               Components, drug product containers, and closures
Written procedures shall be established, and fol-                approved for use shall be rotated so that the oldest
lowed, describing the distribution of drug products.             approved stock is used first. Deviation from this re-
They shall include:                                              quirement is permitted if such deviation is temporary
(a) A procedure whereby the oldest approved stock                and appropriate.
    of a drug product is distributed first. Deviation
    from this requirement is permitted if such devia-            § 211.87 Retesting of approved components,
    tion is temporary and appropriate.                           drug product containers, and closures.
(b) A system by which the distribution of each lot of            Components, drug product containers, and closures
    drug product can be readily determined to facili-            shall be retested or reexamined, as appropriate, for
    tate its recall if necessary.                                identity, strength, quality, and purity and approved
                                                                 or rejected by the quality control unit in accordance
Subpart I--Laboratory Controls                                   with 211.84 as necessary, e.g., after storage for long
                                                                 periods or after exposure to air, heat or other con-
§ 211.160 General requirements.                                  ditions that might adversely affect the component,
(a) The establishment of any specifications, stan-                drug product container, or closure.
§ 211.89 Rejected components, drug product con-             § 211.137 Expiration dating.
tainers, and closures.                                      (a) To assure that a drug product meets applicable
Rejected components, drug product containers, and                standards of identity, strength, quality, and pu-
closures shall be identified and controlled under a               rity at the time of use, it shall bear an expiration
quarantine system designed to prevent their use in               date determined by appropriate stability testing
manufacturing or processing operations for which                 described in 211.166.
they are unsuitable.                                        (b) Expiration dates shall be related to any storage
                                                                 conditions stated on the labeling, as determined
§ 211.94 Drug product containers and closures.                   by stability studies described in 211.166.
(a) Drug product containers and closures shall not          (c) If the drug product is to be reconstituted at the
    be reactive, additive, or absorptive so as to alter          time of dispensing, its labeling shall bear expi-
    the safety, identity, strength, quality, or purity of        ration information for both the reconstituted and
    the drug beyond the official or established re-               unreconstituted drug products.
    quirements.                                             (d) Expiration dates shall appear on labeling in ac-
(b) Container closure systems shall provide adequate             cordance with the requirements of 201.17 of this
    protection against foreseeable external factors in           chapter.
    storage and use that can cause deterioration or         (e) Homeopathic drug products shall be exempt
    contamination of the drug product.                           from the requirements of this section.
(c) Drug product containers and closures shall be           (f) Allergenic extracts that are labeled “No U.S. Stan-
    clean and, where indicated by the nature of the              dard of Potency” are exempt from the require-
    drug, sterilized and processed to remove pyro-               ments of this section.
    genic properties to assure that they are suitable       (g) New drug products for investigational use are
    for their intended use.                                      exempt from the requirements of this section,
(d) Standards or specifications, methods of test-                 provided that they meet appropriate standards
    ing, and, where indicated, methods of cleaning,              or specifications as demonstrated by stability
    sterilizing, and processing to remove pyrogenic              studies during their use in clinical investigations.
    properties shall be written and followed for drug            Where new drug products for investigational use
    product containers and closures.                             are to be reconstituted at the time of dispensing,
                                                                 their labeling shall bear expiration information for
Subpart F--Production and Process Controls                       the reconstituted drug product.
                                                            (h) Pending consideration of a proposed exemption,
§ 211.100 Written procedures; deviations.                        published in the Federal Register of September
(a) There shall be written procedures for production             29, 1978, the requirements in this section shall
    and process control designed to assure that the              not be enforced for human OTC drug products
    drug products have the identity, strength, qual-             if their labeling does not bear dosage limitations
(e) OTC drug products subject to approved new drug                ity, and purity they purport or are represented to
    applications. Holders of approved new drug ap-                possess. Such procedures shall include all re-
    plications for OTC drug products are required                 quirements in this subpart. These written proce-
    under 314.70 of this chapter to provide the                   dures, including any changes, shall be drafted,
    agency with notification of changes in packaging               reviewed, and approved by the appropriate or-
    and labeling to comply with the requirements of               ganizational units and reviewed and approved by
    this section. Changes in packaging and labeling               the quality control unit.
    required by this regulation may be made before            (b) Written production and process control proce-
    FDA approval, as provided under 314.70(c) of                  dures shall be followed in the execution of the
    this chapter. Manufacturing changes by which                  various production and process control functions
    capsules are to be sealed require prior FDA ap-               and shall be documented at the time of perfor-
    proval under 314.70(b) of this chapter.                       mance. Any deviation from the written proce-
(f) Poison Prevention Packaging Act of 1970. This                 dures shall be recorded and justified.
    section does not affect any requirements for
    “special packaging” as defined under 310.3(l) of           § 211.101 Charge-in of components.
    this chapter and required under the Poison Pre-           Written production and control procedures shall in-
    vention Packaging Act of 1970.                            clude the following, which are designed to assure
                                                              that the drug products produced have the identity,
 [54 FR 5228, Feb. 2, 1989, as amended at 63 FR 59470, Nov.   strength, quality, and purity they purport or are rep-
 4, 1998]
                                                              resented to possess:
                                                              (a) The batch shall be formulated with the intent to
§ 211.134 Drug product inspection.
                                                                  provide not less than 100 percent of the labeled
(a) Packaged and labeled products shall be exam-
                                                                  or established amount of active ingredient.
    ined during finishing operations to provide as-
                                                              (b) Components for drug product manufacturing
    surance that containers and packages in the lot
                                                                  shall be weighed, measured, or subdivided as
    have the correct label.
                                                                  appropriate. If a component is removed from the
(b) A representative sample of units shall be collect-
                                                                  original container to another, the new container
    ed at the completion of finishing operations and
                                                                  shall be identified with the following information:
    shall be visually examined for correct labeling.
                                                                  (1) Component name or item code;
(c) Results of these examinations shall be recorded
                                                                  (2) Receiving or control number;
    in the batch production or control records.
                                                                  (3) Weight or measure in new container;
                                                                  (4) Batch for which component was dispensed,
                                                                      including its product name, strength, and lot
                                                                      number.
(c) Weighing, measuring, or subdividing operations                    tamper-evident feature of the package is
    for components shall be adequately supervised.                    breached or missing.
    Each container of component dispensed to man-              (2) If the tamper-evident feature chosen to meet
    ufacturing shall be examined by a second person                the requirements in paragraph (b) of this sec-
    to assure that:                                                tion uses an identifying characteristic, that
    (1) The component was released by the quality                  characteristic is required to be referred to
        control unit;                                              in the labeling statement. For example, the
    (2) The weight or measure is correct as stated in              labeling statement on a bottle with a shrink
        the batch production records;                              band could say “For your protection, this bot-
    (3) The containers are properly identified.                     tle has an imprinted seal around the neck.”
(d) Each component shall be added to the batch by          (d) Request for exemptions from packaging and la-
    one person and verified by a second person.                 beling requirements. A manufacturer or packer
                                                               may request an exemption from the packaging
§ 211.103 Calculation of yield.                                and labeling requirements of this section. A re-
Actual yields and percentages of theoretical yield shall       quest for an exemption is required to be submit-
be determined at the conclusion of each appropriate            ted in the form of a citizen petition under 10.30
phase of manufacturing, processing, packaging, or              of this chapter and should be clearly identified on
holding of the drug product. Such calculations shall           the envelope as a “Request for Exemption from
be performed by one person and independently veri-             the Tamper-Evident Packaging Rule.” The peti-
fied by a second person.                                        tion is required to contain the following:
                                                               (1) The name of the drug product or, if the peti-
§ 211.105 Equipment identification.                                tion seeks an exemption for a drug class, the
(a) All compounding and storage containers, pro-                   name of the drug class, and a list of products
    cessing lines, and major equipment used during                 within that class.
    the production of a batch of a drug product shall          (2) The reasons that the drug product’s compli-
    be properly identified at all times to indicate their           ance with the tamper-evident packaging or
    contents and, when necessary, the phase of pro-                labeling requirements of this section is un-
    cessing of the batch.                                          necessary or cannot be achieved.
(b) Major equipment shall be identified by a distinc-           (3) A description of alternative steps that are
    tive identification number or code that shall be                available, or that the petitioner has already
    recorded in the batch production record to show                taken, to reduce the likelihood that the prod-
    the specific equipment used in the manufacture                  uct or drug class will be the subject of mali-
    of each batch of a drug product. In cases where                cious adulteration.
    only one of a particular type of equipment ex-             (4) Other information justifying an exemption.
    ists in a manufacturing facility, the name of the
        registered trademark, logo, or picture). For            equipment may be used in lieu of a distinctive
        purposes of this section, the term “distinctive         identification number or code.
        by design” means the packaging cannot be
        duplicated with commonly available materials         § 211.110 Sampling and testing of in-
        or through commonly available processes. A           process materials and drug products.
        tamper-evident package may involve an im-            (a) To assure batch uniformity and integrity of drug
        mediate-container and closure system or                  products, written procedures shall be established
        secondary-container or carton system or any              and followed that describe the in-process con-
        combination of systems intended to provide               trols, and tests, or examinations to be conducted
        a visual indication of package integrity. The            on appropriate samples of in-process materials
        tamper-evident feature shall be designed to              of each batch. Such control procedures shall be
        and shall remain intact when handled in a                established to monitor the output and to validate
        reasonable manner during manufacture, dis-               the performance of those manufacturing pro-
        tribution, and retail display.                           cesses that may be responsible for causing vari-
    (2) In addition to the tamper-evident packaging              ability in the characteristics of in-process material
        feature described in paragraph (b)(1) of this            and the drug product. Such control procedures
        section, any two-piece, hard gelatin capsule             shall include, but are not limited to, the following,
        covered by this section must be sealed using             where appropriate:
        an acceptable tamper-evident technology.                 (1) Tablet or capsule weight variation;
(c) Labeling.                                                    (2) Disintegration time;
    (1) In order to alert consumers to the specific               (3) Adequacy of mixing to assure uniformity and
        tamper-evident feature(s) used, each retail                   homogeneity;
        package of an OTC drug product covered                   (4) Dissolution time and rate;
        by this section (except ammonia inhalant in              (5) Clarity, completeness, or pH of solutions.
        crushable glass ampules, containers of com-          (b) Valid in-process specifications for such character-
        pressed medical oxygen, or aerosol products              istics shall be consistent with drug product final
        that depend upon the power of a liquefied or              specifications and shall be derived from previous
        compressed gas to expel the contents from                acceptable process average and process variabil-
        the container) is required to bear a statement           ity estimates where possible and determined by
        that:                                                    the application of suitable statistical procedures
      (i) Identifies all tamper-evident feature(s) and            where appropriate. Examination and testing of
            any capsule sealing technologies used to             samples shall assure that the drug product and
            comply with paragraph (b) of this section;           in-process material conform to specifications.
      (ii) Is prominently placed on the package; and         (c) In-process materials shall be tested for identity,
      (iii) Is so placed that it will be unaffected if the       strength, quality, and purity as appropriate, and
    approved or rejected by the quality control unit,     § 211.132 Tamper-evident packaging requirements
    during the production process, e.g., at com-          for over-the-counter (OTC) human drug products.
    mencement or completion of significant phases          (a) General. The Food and Drug Administration has
    or after storage for long periods.                        the authority under the Federal Food, Drug, and
(d) Rejected in-process materials shall be identi-            Cosmetic Act (the act) to establish a uniform na-
    fied and controlled under a quarantine system              tional requirement for tamper-evident packaging
    designed to prevent their use in manufacturing            of OTC drug products that will improve the secu-
    or processing operations for which they are un-           rity of OTC drug packaging and help assure the
    suitable.                                                 safety and effectiveness of OTC drug products.
                                                              An OTC drug product (except a dermatological,
§ 211.111 Time limitations on production.                     dentifrice, insulin, or lozenge product) for retail
When appropriate, time limits for the completion of           sale that is not packaged in a tamper-resistant
each phase of production shall be established to as-          package or that is not properly labeled under this
sure the quality of the drug product. Deviation from          section is adulterated under section 501 of the
established time limits may be acceptable if such             act or misbranded under section 502 of the act,
deviation does not compromise the quality of the              or both.
drug product. Such deviation shall be justified and        (b) Requirements for tamper-evident package.
documented.                                                   (1) Each manufacturer and packer who pack-
                                                                   ages an OTC drug product (except a derma-
§ 211.113 Control of microbiological contamination.                tological, dentifrice, insulin, or lozenge prod-
(a) Appropriate written procedures, designed to                    uct) for retail sale shall package the product
    prevent objectionable microorganisms in drug                   in a tamper-evident package, if this product
    products not required to be sterile, shall be es-              is accessible to the public while held for sale.
    tablished and followed.                                        A tamper-evident package is one having one
(b) Appropriate written procedures, designed to pre-               or more indicators or barriers to entry which,
    vent microbiological contamination of drug prod-               if breached or missing, can reasonably be
    ucts purporting to be sterile, shall be established            expected to provide visible evidence to con-
    and followed. Such procedures shall include vali-              sumers that tampering has occurred. To re-
    dation of any sterilization process.                           duce the likelihood of successful tampering
                                                                   and to increase the likelihood that consumers
§ 211.115 Reprocessing.                                            will discover if a product has been tampered
(a) Written procedures shall be established and                    with, the package is required to be distinctive
    followed prescribing a system for reprocessing                 by design or by the use of one or more indica-
    batches that do not conform to standards or                    tors or barriers to entry that employ an iden-
    specifications and the steps to be taken to insure              tifying characteristic (e.g., a pattern, name,
shall be followed. These procedures shall incorpo-              that the reprocessed batches will conform with
rate the following features:                                    all established standards, specifications, and
(a) Prevention of mixups and cross-contamination                characteristics.
    by physical or spatial separation from operations       (b) Reprocessing shall not be performed without the
    on other drug products.                                     review and approval of the quality control unit.
(b) Identification and handling of filled drug product
    containers that are set aside and held in unla-         Subpart G--Packaging and Labeling Control
    beled condition for future labeling operations to
    preclude mislabeling of individual containers,          § 211.122 Materials examination and usage criteria.
    lots, or portions of lots. Identification need not be
    applied to each individual container but shall be       (a) There shall be written procedures describing in
    sufficient to determine name, strength, quantity             sufficient detail the receipt, identification, stor-
    of contents, and lot or control number of each              age, handling, sampling, examination, and/or
    container.                                                  testing of labeling and packaging materials; such
(c) Identification of the drug product with a lot or             written procedures shall be followed. Labeling
    control number that permits determination of                and packaging materials shall be representatively
    the history of the manufacture and control of the           sampled, and examined or tested upon receipt
    batch.                                                      and before use in packaging or labeling of a drug
(d) Examination of packaging and labeling materials             product.
    for suitability and correctness before packaging        (b) Any labeling or packaging materials meeting ap-
    operations, and documentation of such examina-              propriate written specifications may be approved
    tion in the batch production record.                        and released for use. Any labeling or packaging
(e) Inspection of the packaging and labeling facilities         materials that do not meet such specifications
    immediately before use to assure that all drug              shall be rejected to prevent their use in opera-
    products have been removed from previous op-                tions for which they are unsuitable.
    erations. Inspection shall also be made to assure       (c) Records shall be maintained for each shipment
    that packaging and labeling materials not suitable          received of each different labeling and packaging
    for subsequent operations have been removed.                material indicating receipt, examination or test-
    Results of inspection shall be documented in the            ing, and whether accepted or rejected.
    batch production records.                               (d) Labels and other labeling materials for each dif-
                                                                ferent drug product, strength, dosage form, or
 [43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354,       quantity of contents shall be stored separately
 Aug. 3, 1993]
                                                                with suitable identification. Access to the storage
                                                                area shall be limited to authorized personnel.
(e) Obsolete and outdated labels, labeling, and other           tions.
    packaging materials shall be destroyed.                 (b) Labeling materials issued for a batch shall be
(f) Use of gang-printed labeling for different drug             carefully examined for identity and conformity to
    products, or different strengths or net contents of         the labeling specified in the master or batch pro-
    the same drug product, is prohibited unless the             duction records.
    labeling from gang-printed sheets is adequately         (c) Procedures shall be used to reconcile the quanti-
    differentiated by size, shape, or color.                    ties of labeling issued, used, and returned, and
(g) If cut labeling is used, packaging and labeling op-         shall require evaluation of discrepancies found
    erations shall include one of the following special         between the quantity of drug product finished
    control procedures:                                         and the quantity of labeling issued when such
    (1) Dedication of labeling and packaging lines to           discrepancies are outside narrow preset limits
         each different strength of each different drug         based on historical operating data. Such discrep-
         product;                                               ancies shall be investigated in accordance with
    (2) Use of appropriate electronic or electrome-             211.192. Labeling reconciliation is waived for cut
         chanical equipment to conduct a 100-per-               or roll labeling if a 100-percent examination for
         cent examination for correct labeling during           correct labeling is performed in accordance with
         or after completion of finishing operations; or         211.122(g)(2).
    (3) Use of visual inspection to conduct a 100-          (d) All excess labeling bearing lot or control numbers
         percent examination for correct labeling dur-          shall be destroyed.
         ing or after completion of finishing operations     (e) Returned labeling shall be maintained and stored
         for hand-applied labeling. Such examination            in a manner to prevent mixups and provide prop-
         shall be performed by one person and inde-             er identification.
         pendently verified by a second person.              (f) Procedures shall be written describing in suffi-
(h) Printing devices on, or associated with, manu-              cient detail the control procedures employed for
    facturing lines used to imprint labeling upon the           the issuance of labeling; such written procedures
    drug product unit label or case shall be moni-              shall be followed.
    tored to assure that all imprinting conforms to the
    print specified in the batch production record.           [43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354,
                                                             Aug. 3, 1993]
 [43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41353,
 Aug. 3, 1993]
                                                            § 211.130 Packaging and labeling operations.
§ 211.125 Labeling issuance.                                There shall be written procedures designed to assure
(a) Strict control shall be exercised over labeling         that correct labels, labeling, and packaging materials
    issued for use in drug product labeling opera-          are used for drug products; such written procedures

				
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