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CHAPTER I--FOOD = AND DRUG=20 ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES=20
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(a) The regulations in this part contain the = minimum=20 current good manufacturing practice for preparation of = drug=20 products for administration to humans or animals.
(b) The current good manufacturing practice = regulations in=20 this chapter as they pertain to drug products; in = parts 600=20 through 680 of this chapter, as they pertain to drugs = that are=20 also biological products for human use; and in part = 1271 of=20 this chapter, as they are applicable to drugs that are = also=20 human cells, tissues, and cellular and tissue-based = products=20 (HCT/Ps) and that are drugs (subject to review under = an=20 application submitted under section 505 of the act or = under a=20 biological product license application under section = 351 of=20 the Public Health Service Act); supplement and do not=20 supersede the regulations in this part unless the = regulations=20 explicitly provide otherwise. In the event of a = conflict=20 between applicable regulations in this part and in = other parts=20 of this chapter, or in parts 600 through 680 of this = chapter,=20 or in part 1271 of this chapter, the regulation = specifically=20 applicable to the drug product in question shall = supersede the=20 more general.
(c) Pending consideration of a proposed exemption,=20 published in the Federal Register of September 29, = 1978, the=20 requirements in this part shall not be enforced for = OTC drug=20 products if the products and all their ingredients are = ordinarily marketed and consumed as human foods, and = which=20 products may also fall within the legal definition of = drugs by=20 virtue of their intended use. Therefore, until further = notice,=20 regulations under part 110 of this chapter, and where=20 applicable, parts 113 to 129 of this chapter, shall be = applied=20 in determining whether these OTC drug products that = are also=20 foods are manufactured, processed, packed, or held = under=20 current good manufacturing practice.
[43 FR 45077, Sept. 29, 1978, as amended at 62 FR = 66522,=20 Dec. 19, 1997; 69 FR 29828, May 25, 2004]=20
The definitions set forth in 210.3 of this chapter = apply in=20 this part.
(a) There shall be a quality control unit that = shall have=20 the responsibility and authority to approve or reject = all=20 components, drug product containers, closures, = in-process=20 materials, packaging material, labeling, and drug = products,=20 and the authority to review production records to = assure that=20 no errors have occurred or, if errors have occurred, = that they=20 have been fully investigated. The quality control unit = shall=20 be responsible for approving or rejecting drug = products=20 manufactured, processed, packed, or held under = contract by=20 another company.
(b) Adequate laboratory facilities for the testing = and=20 approval (or rejection) of components, drug product=20 containers, closures, packaging materials, in-process=20 materials, and drug products shall be available to the = quality=20 control unit.
(c) The quality control unit shall have the = responsibility=20 for approving or rejecting all procedures or = specifications=20 impacting on the identity, strength, quality, and = purity of=20 the drug product.
(d) The responsibilities and procedures applicable = to the=20 quality control unit shall be in writing; such written = procedures shall be = followed.
(a) Each person engaged in the manufacture, = processing,=20 packing, or holding of a drug product shall have = education,=20 training, and experience, or any combination thereof, = to=20 enable that person to perform the assigned functions. = Training=20 shall be in the particular operations that the = employee=20 performs and in current good manufacturing practice = (including=20 the current good manufacturing practice regulations in = this=20 chapter and written procedures required by these = regulations)=20 as they relate to the employee's functions. Training = in=20 current good manufacturing practice shall be conducted = by=20 qualified individuals on a continuing basis and with=20 sufficient frequency to assure that employees remain = familiar=20 with CGMP requirements applicable to them.
(b) Each person responsible for supervising the=20 manufacture, processing, packing, or holding of a drug = product=20 shall have the education, training, and experience, or = any=20 combination thereof, to perform assigned functions in = such a=20 manner as to provide assurance that the drug product = has the=20 safety, identity, strength, quality, and purity that = it=20 purports or is represented to possess.
(c) There shall be an adequate number of qualified=20 personnel to perform and supervise the manufacture,=20 processing, packing, or holding of each drug=20 product.
(a) Personnel engaged in the manufacture, = processing,=20 packing, or holding of a drug product shall wear clean = clothing appropriate for the duties they perform. = Protective=20 apparel, such as head, face, hand, and arm coverings, = shall be=20 worn as necessary to protect drug products from=20 contamination.
(b) Personnel shall practice good sanitation and = health=20 habits.
(c) Only personnel authorized by supervisory = personnel=20 shall enter those areas of the buildings and = facilities=20 designated as limited-access areas.
(d) Any person shown at any time (either by medical = examination or supervisory observation) to have an = apparent=20 illness or open lesions that may adversely affect the = safety=20 or quality of drug products shall be excluded from = direct=20 contact with components, drug product containers, = closures,=20 in-process materials, and drug products until the = condition is=20 corrected or determined by competent medical personnel = not to=20 jeopardize the safety or quality of drug products. All = personnel shall be instructed to report to supervisory = personnel any health conditions that may have an = adverse=20 effect on drug = products.
Consultants advising on the manufacture, = processing,=20 packing, or holding of drug products shall have = sufficient=20 education, training, and experience, or any = combination=20 thereof, to advise on the subject for which they are = retained.=20 Records shall be maintained stating the name, address, = and=20 qualifications of any consultants and the type of = service they=20 provide.
(a) Any building or buildings used in the = manufacture,=20 processing, packing, or holding of a drug product = shall be of=20 suitable size, construction and location to facilitate = cleaning, maintenance, and proper operations.
(b) Any such building shall have adequate space for = the=20 orderly placement of equipment and materials to = prevent mixups=20 between different components, drug product containers, = closures, labeling, in-process materials, or drug = products,=20 and to prevent contamination. The flow of components, = drug=20 product containers, closures, labeling, in-process = materials,=20 and drug products through the building or buildings = shall be=20 designed to prevent contamination.
(c) Operations shall be performed within = specifically=20 defined areas of adequate size. There shall be = separate or=20 defined areas or such other control systems for the = firm's=20 operations as are necessary to prevent contamination = or mixups=20 during the course of the following procedures:
(1) Receipt, identification, storage, and = withholding from=20 use of components, drug product containers, closures, = and=20 labeling, pending the appropriate sampling, testing, = or=20 examination by the quality control unit before release = for=20 manufacturing or packaging;
(2) Holding rejected components, drug product = containers,=20 closures, and labeling before disposition;
(3) Storage of released components, drug product=20 containers, closures, and labeling;
(4) Storage of in-process materials;
(5) Manufacturing and processing operations;
(6) Packaging and labeling operations;
(7) Quarantine storage before release of drug = products;
(8) Storage of drug products after release;
(9) Control and laboratory operations;
(10) Aseptic processing, which includes as = appropriate:
(i) Floors, walls, and ceilings of smooth, hard = surfaces=20 that are easily cleanable;
(ii) Temperature and humidity controls;
(iii) An air supply filtered through = high-efficiency=20 particulate air filters under positive pressure, = regardless of=20 whether flow is laminar or nonlaminar;
(iv) A system for monitoring environmental = conditions;
(v) A system for cleaning and disinfecting the room = and=20 equipment to produce aseptic conditions;
(vi) A system for maintaining any equipment used to = control=20 the aseptic conditions.
(d) Operations relating to the manufacture, = processing, and=20 packing of penicillin shall be performed in facilities = separate from those used for other drug products for = human=20 use.
[43 FR 45077, Sept. 29, 1978, as amended at 60 FR = 4091,=20 Jan. 20, 1995] =
Adequate lighting shall be provided in all=20 areas.
(a) Adequate ventilation shall be provided.
(b) Equipment for adequate control over air = pressure,=20 micro-organisms, dust, humidity, and temperature shall = be=20 provided when appropriate for the manufacture, = processing,=20 packing, or holding of a drug product.
(c) Air filtration systems, including prefilters = and=20 particulate matter air filters, shall be used when = appropriate=20 on air supplies to production areas. If air is = recirculated to=20 production areas, measures shall be taken to control=20 recirculation of dust from production. In areas where = air=20 contamination occurs during production, there shall be = adequate exhaust systems or other systems adequate to = control=20 contaminants.
(d) Air-handling systems for the manufacture, = processing,=20 and packing of penicillin shall be completely separate = from=20 those for other drug products for human=20 use.
(a) Potable water shall be supplied under = continuous=20 positive pressure in a plumbing system free of defects = that=20 could contribute contamination to any drug product. = Potable=20 water shall meet the standards prescribed in the = Environmental=20 Protection Agency's Primary Drinking Water Regulations = set=20 forth in 40 CFR part 141. Water not meeting such = standards=20 shall not be permitted in the potable water = system.
(b) Drains shall be of adequate size and, where = connected=20 directly to a sewer, shall be provided with an air = break or=20 other mechanical device to prevent back-siphonage.
[43 FR 45077, Sept. 29, 1978, as amended at 48 FR = 11426,=20 Mar. 18, 1983] =
Sewage, trash, and other refuse in and from the = building=20 and immediate premises shall be disposed of in a safe = and=20 sanitary = manner.
Adequate washing facilities shall be provided, = including=20 hot and cold water, soap or detergent, air driers or=20 single-service towels, and clean toilet facilities = easily=20 accesible to working = areas.
(a) Any building used in the manufacture, = processing,=20 packing, or holding of a drug product shall be = maintained in a=20 clean and sanitary condition, Any such building shall = be free=20 of infestation by rodents, birds, insects, and other = vermin=20 (other than laboratory animals). Trash and organic = waste=20 matter shall be held and disposed of in a timely and = sanitary=20 manner.
(b) There shall be written procedures assigning=20 responsibility for sanitation and describing in = sufficient=20 detail the cleaning schedules, methods, equipment, and = materials to be used in cleaning the buildings and = facilities;=20 such written procedures shall be followed.
(c) There shall be written procedures for use of = suitable=20 rodenticides, insecticides, fungicides, fumigating = agents, and=20 cleaning and sanitizing agents. Such written = procedures shall=20 be designed to prevent the contamination of equipment, = components, drug product containers, closures, = packaging,=20 labeling materials, or drug products and shall be = followed.=20 Rodenticides, insecticides, and fungicides shall not = be used=20 unless registered and used in accordance with the = Federal=20 Insecticide, Fungicide, and Rodenticide Act (7 U.S.C.=20 135).
(d) Sanitation procedures shall apply to work = performed by=20 contractors or temporary employees as well as work = performed=20 by full-time employees during the ordinary course of=20 operations.
Any building used in the manufacture, processing, = packing,=20 or holding of a drug product shall be maintained in a = good=20 state of = repair.
Equipment used in the manufacture, processing, = packing, or=20 holding of a drug product shall be of appropriate = design,=20 adequate size, and suitably located to facilitate = operations=20 for its intended use and for its cleaning and=20 maintenance.
(a) Equipment shall be constructed so that surfaces = that=20 contact components, in-process materials, or drug = products=20 shall not be reactive, additive, or absorptive so as = to alter=20 the safety, identity, strength, quality, or purity of = the drug=20 product beyond the official or other established=20 requirements.
(b) Any substances required for operation, such as=20 lubricants or coolants, shall not come into contact = with=20 components, drug product containers, closures, = in-process=20 materials, or drug products so as to alter the safety, = identity, strength, quality, or purity of the drug = product=20 beyond the official or other established=20 requirements.
(a) Equipment and utensils shall be cleaned, = maintained,=20 and sanitized at appropriate intervals to prevent = malfunctions=20 or contamination that would alter the safety, = identity,=20 strength, quality, or purity of the drug product = beyond the=20 official or other established requirements.
(b) Written procedures shall be established and = followed=20 for cleaning and maintenance of equipment, including = utensils,=20 used in the manufacture, processing, packing, or = holding of a=20 drug product. These procedures shall include, but are = not=20 necessarily limited to, the following:
(1) Assignment of responsibility for cleaning and=20 maintaining equipment;
(2) Maintenance and cleaning schedules, including, = where=20 appropriate, sanitizing schedules;
(3) A description in sufficient detail of the = methods,=20 equipment, and materials used in cleaning and = maintenance=20 operations, and the methods of disassembling and = reassembling=20 equipment as necessary to assure proper cleaning and=20 maintenance;
(4) Removal or obliteration of previous batch=20 identification;
(5) Protection of clean equipment from = contamination prior=20 to use;
(6) Inspection of equipment for cleanliness = immediately=20 before use.
(c) Records shall be kept of maintenance, cleaning, = sanitizing, and inspection as specified in 211.180 and = 211.182.
(a) Automatic, mechanical, or electronic equipment = or other=20 types of equipment, including computers, or related = systems=20 that will perform a function satisfactorily, may be = used in=20 the manufacture, processing, packing, and holding of a = drug=20 product. If such equipment is so used, it shall be = routinely=20 calibrated, inspected, or checked according to a = written=20 program designed to assure proper performance. Written = records=20 of those calibration checks and inspections shall be=20 maintained.
(b) Appropriate controls shall be exercised over = computer=20 or related systems to assure that changes in master = production=20 and control records or other records are instituted = only by=20 authorized personnel. Input to and output from the = computer or=20 related system of formulas or other records or data = shall be=20 checked for accuracy. The degree and frequency of = input/output=20 verification shall be based on the complexity and = reliability=20 of the computer or related system. A backup file of = data=20 entered into the computer or related system shall be=20 maintained except where certain data, such as = calculations=20 performed in connection with laboratory analysis, are=20 eliminated by computerization or other automated = processes. In=20 such instances a written record of the program shall = be=20 maintained along with appropriate validation data. = Hard copy=20 or alternative systems, such as duplicates, tapes, or=20 microfilm, designed to assure that backup data are = exact and=20 complete and that it is secure from alteration, = inadvertent=20 erasures, or loss shall be maintained.
[43 FR 45077, Sept. 29, 1978, as amended at 60 FR = 4091,=20 Jan. 20, 1995] =
Filters for liquid filtration used in the = manufacture,=20 processing, or packing of injectable drug products = intended=20 for human use shall not release fibers into such = products.=20 Fiber-releasing filters may not be used in the = manufacture,=20 processing, or packing of these injectable drug = products=20 unless it is not possible to manufacture such drug = products=20 without the use of such filters. If use of a = fiber-releasing=20 filter is necessary, an additional non-fiber-releasing = filter=20 of 0.22 micron maximum mean porosity (0.45 micron if = the=20 manufacturing conditions so dictate) shall = subsequently be=20 used to reduce the content of particles in the = injectable drug=20 product. Use of an asbestos-containing filter, with or = without=20 subsequent use of a specific non-fiber-releasing = filter, is=20 permissible only upon submission of proof to the = appropriate=20 bureau of the Food and Drug Administration that use of = a=20 non-fiber-releasing filter will, or is likely to, = compromise=20 the safety or effectiveness of the injectable drug=20 product.
(a) There shall be written procedures describing in = sufficient detail the receipt, identification, = storage,=20 handling, sampling, testing, and approval or rejection = of=20 components and drug product containers and closures; = such=20 written procedures shall be followed.
(b) Components and drug product containers and = closures=20 shall at all times be handled and stored in a manner = to=20 prevent contamination.
(c) Bagged or boxed components of drug product = containers,=20 or closures shall be stored off the floor and suitably = spaced=20 to permit cleaning and inspection.
(d) Each container or grouping of containers for = components=20 or drug product containers, or closures shall be = identified=20 with a distinctive code for each lot in each shipment=20 received. This code shall be used in recording the = disposition=20 of each lot. Each lot shall be appropriately = identified as to=20 its status (i.e., quarantined, approved, or=20 rejected).
(a) Upon receipt and before acceptance, each = container or=20 grouping of containers of components, drug product = containers,=20 and closures shall be examined visually for = appropriate=20 labeling as to contents, container damage or broken = seals, and=20 contamination.
(b) Components, drug product containers, and = closures shall=20 be stored under quarantine until they have been tested = or=20 examined, as appropriate, and released. Storage within = the=20 area shall conform to the requirements of=20 211.80.
(a) Each lot of components, drug product = containers, and=20 closures shall be withheld from use until the lot has = been=20 sampled, tested, or examined, as appropriate, and = released for=20 use by the quality control unit.
(b) Representative samples of each shipment of each = lot=20 shall be collected for testing or examination. The = number of=20 containers to be sampled, and the amount of material = to be=20 taken from each container, shall be based upon = appropriate=20 criteria such as statistical criteria for component=20 variability, confidence levels, and degree of = precision=20 desired, the past quality history of the supplier, and = the=20 quantity needed for analysis and reserve where = required by=20 211.170.
(c) Samples shall be collected in accordance with = the=20 following procedures:
(1) The containers of components selected shall be = cleaned=20 where necessary, by appropriate means.
(2) The containers shall be opened, sampled, and = resealed=20 in a manner designed to prevent contamination of their = contents and contamination of other components, drug = product=20 containers, or closures.
(3) Sterile equipment and aseptic sampling = techniques shall=20 be used when necessary.
(4) If it is necessary to sample a component from = the top,=20 middle, and bottom of its container, such sample = subdivisions=20 shall not be composited for testing.
(5) Sample containers shall be identified so that = the=20 following information can be determined: name of the = material=20 sampled, the lot number, the container from which the = sample=20 was taken, the date on which the sample was taken, and = the=20 name of the person who collected the sample.
(6) Containers from which samples have been taken = shall be=20 marked to show that samples have been removed from = them.
(d) Samples shall be examined and tested as = follows:
(1) At least one test shall be conducted to verify = the=20 identity of each component of a drug product. Specific = identity tests, if they exist, shall be used.
(2) Each component shall be tested for conformity = with all=20 appropriate written specifications for purity, = strength, and=20 quality. In lieu of such testing by the manufacturer, = a report=20 of analysis may be accepted from the supplier of a = component,=20 provided that at least one specific identity test is = conducted=20 on such component by the manufacturer, and provided = that the=20 manufacturer establishes the reliability of the = supplier's=20 analyses through appropriate validation of the = supplier's test=20 results at appropriate intervals.
(3) Containers and closures shall be tested for = conformance=20 with all appropriate written procedures. In lieu of = such=20 testing by the manufacturer, a certificate of testing = may be=20 accepted from the supplier, provided that at least a = visual=20 identification is conducted on such = containers/closures by the=20 manufacturer and provided that the manufacturer = establishes=20 the reliability of the supplier's test results through = appropriate validation of the supplier's test results = at=20 appropriate intervals.
(4) When appropriate, components shall be = microscopically=20 examined.
(5) Each lot of a component, drug product = container, or=20 closure that is liable to contamination with filth, = insect=20 infestation, or other extraneous adulterant shall be = examined=20 against established specifications for such = contamination.
(6) Each lot of a component, drug product = container, or=20 closure that is liable to microbiological = contamination that=20 is objectionable in view of its intended use shall be=20 subjected to microbiological tests before use.
(e) Any lot of components, drug product containers, = or=20 closures that meets the appropriate written = specifications of=20 identity, strength, quality, and purity and related = tests=20 under paragraph (d) of this section may be approved = and=20 released for use. Any lot of such material that does = not meet=20 such specifications shall be rejected.
[43 FR 45077, Sept. 29, 1978, as amended at 63 FR = 14356,=20 Mar. 25, 1998] =
Components, drug product containers, and closures = approved=20 for use shall be rotated so that the oldest approved = stock is=20 used first. Deviation from this requirement is = permitted if=20 such deviation is temporary and=20 appropriate.
Components, drug product containers, and closures = shall be=20 retested or reexamined, as appropriate, for identity,=20 strength, quality, and purity and approved or rejected = by the=20 quality control unit in accordance with 211.84 as = necessary,=20 e.g., after storage for long periods or after exposure = to air,=20 heat or other conditions that might adversely affect = the=20 component, drug product container, or=20 closure.
Rejected components, drug product containers, and = closures=20 shall be identified and controlled under a quarantine = system=20 designed to prevent their use in manufacturing or = processing=20 operations for which they are=20 unsuitable.
(a) Drug product containers and closures shall not = be=20 reactive, additive, or absorptive so as to alter the = safety,=20 identity, strength, quality, or purity of the drug = beyond the=20 official or established requirements.
(b) Container closure systems shall provide = adequate=20 protection against foreseeable external factors in = storage and=20 use that can cause deterioration or contamination of = the drug=20 product.
(c) Drug product containers and closures shall be = clean=20 and, where indicated by the nature of the drug, = sterilized and=20 processed to remove pyrogenic properties to assure = that they=20 are suitable for their intended use.
(d) Standards or specifications, methods of = testing, and,=20 where indicated, methods of cleaning, sterilizing, and = processing to remove pyrogenic properties shall be = written and=20 followed for drug product containers and=20 closures.
(a) There shall be written procedures for = production and=20 process control designed to assure that the drug = products have=20 the identity, strength, quality, and purity they = purport or=20 are represented to possess. Such procedures shall = include all=20 requirements in this subpart. These written = procedures,=20 including any changes, shall be drafted, reviewed, and = approved by the appropriate organizational units and = reviewed=20 and approved by the quality control unit.
(b) Written production and process control = procedures shall=20 be followed in the execution of the various production = and=20 process control functions and shall be documented at = the time=20 of performance. Any deviation from the written = procedures=20 shall be recorded and = justified.
Written production and control procedures shall = include the=20 following, which are designed to assure that the drug = products=20 produced have the identity, strength, quality, and = purity they=20 purport or are represented to possess:
(a) The batch shall be formulated with the intent = to=20 provide not less than 100 percent of the labeled or=20 established amount of active ingredient.
(b) Components for drug product manufacturing shall = be=20 weighed, measured, or subdivided as appropriate. If a=20 component is removed from the original container to = another,=20 the new container shall be identified with the = following=20 information:
(1) Component name or item code;
(2) Receiving or control number;
(3) Weight or measure in new container;
(4) Batch for which component was dispensed, = including its=20 product name, strength, and lot number.
(c) Weighing, measuring, or subdividing operations = for=20 components shall be adequately supervised. Each = container of=20 component dispensed to manufacturing shall be examined = by a=20 second person to assure that:
(1) The component was released by the quality = control=20 unit;
(2) The weight or measure is correct as stated in = the batch=20 production records;
(3) The containers are properly identified.
(d) Each component shall be added to the batch by = one=20 person and verified by a second=20 person.
Actual yields and percentages of theoretical yield = shall be=20 determined at the conclusion of each appropriate phase = of=20 manufacturing, processing, packaging, or holding of = the drug=20 product. Such calculations shall be performed by one = person=20 and independently verified by a second=20 person.
(a) All compounding and storage containers, = processing=20 lines, and major equipment used during the production = of a=20 batch of a drug product shall be properly identified = at all=20 times to indicate their contents and, when necessary, = the=20 phase of processing of the batch.
(b) Major equipment shall be identified by a = distinctive=20 identification number or code that shall be recorded = in the=20 batch production record to show the specific equipment = used in=20 the manufacture of each batch of a drug product. In = cases=20 where only one of a particular type of equipment = exists in a=20 manufacturing facility, the name of the equipment may = be used=20 in lieu of a distinctive identification number or=20 code.
(a) To assure batch uniformity and integrity of = drug=20 products, written procedures shall be established and = followed=20 that describe the in-process controls, and tests, or=20 examinations to be conducted on appropriate samples of = in-process materials of each batch. Such control = procedures=20 shall be established to monitor the output and to = validate the=20 performance of those manufacturing processes that may = be=20 responsible for causing variability in the = characteristics of=20 in-process material and the drug product. Such control = procedures shall include, but are not limited to, the=20 following, where appropriate:
(1) Tablet or capsule weight variation;
(2) Disintegration time;
(3) Adequacy of mixing to assure uniformity and=20 homogeneity;
(4) Dissolution time and rate;
(5) Clarity, completeness, or pH of solutions.
(b) Valid in-process specifications for such=20 characteristics shall be consistent with drug product = final=20 specifications and shall be derived from previous = acceptable=20 process average and process variability estimates = where=20 possible and determined by the application of suitable = statistical procedures where appropriate. Examination = and=20 testing of samples shall assure that the drug product = and=20 in-process material conform to specifications.
(c) In-process materials shall be tested for = identity,=20 strength, quality, and purity as appropriate, and = approved or=20 rejected by the quality control unit, during the = production=20 process, e.g., at commencement or completion of = significant=20 phases or after storage for long periods.
(d) Rejected in-process materials shall be = identified and=20 controlled under a quarantine system designed to = prevent their=20 use in manufacturing or processing operations for = which they=20 are = unsuitable.
When appropriate, time limits for the completion of = each=20 phase of production shall be established to assure the = quality=20 of the drug product. Deviation from established time = limits=20 may be acceptable if such deviation does not = compromise the=20 quality of the drug product. Such deviation shall be = justified=20 and = documented.
(a) Appropriate written procedures, designed to = prevent=20 objectionable microorganisms in drug products not = required to=20 be sterile, shall be established and followed.
(b) Appropriate written procedures, designed to = prevent=20 microbiological contamination of drug products = purporting to=20 be sterile, shall be established and followed. Such = procedures=20 shall include validation of any sterilization=20 process.
(a) Written procedures shall be established and = followed=20 prescribing a system for reprocessing batches that do = not=20 conform to standards or specifications and the steps = to be=20 taken to insure that the reprocessed batches will = conform with=20 all established standards, specifications, and=20 characteristics.
(b) Reprocessing shall not be performed without the = review=20 and approval of the quality control=20 unit.
(a) There shall be written procedures describing in = sufficient detail the receipt, identification, = storage,=20 handling, sampling, examination, and/or testing of = labeling=20 and packaging materials; such written procedures shall = be=20 followed. Labeling and packaging materials shall be=20 representatively sampled, and examined or tested upon = receipt=20 and before use in packaging or labeling of a drug = product.
(b) Any labeling or packaging materials meeting = appropriate=20 written specifications may be approved and released = for use.=20 Any labeling or packaging materials that do not meet = such=20 specifications shall be rejected to prevent their use = in=20 operations for which they are unsuitable.
(c) Records shall be maintained for each shipment = received=20 of each different labeling and packaging material = indicating=20 receipt, examination or testing, and whether accepted = or=20 rejected.
(d) Labels and other labeling materials for each = different=20 drug product, strength, dosage form, or quantity of = contents=20 shall be stored separately with suitable = identification.=20 Access to the storage area shall be limited to = authorized=20 personnel.
(e) Obsolete and outdated labels, labeling, and = other=20 packaging materials shall be destroyed.
(f) Use of gang-printed labeling for different drug = products, or different strengths or net contents of = the same=20 drug product, is prohibited unless the labeling from=20 gang-printed sheets is adequately differentiated by = size,=20 shape, or color.
(g) If cut labeling is used, packaging and labeling = operations shall include one of the following special = control=20 procedures:
(1) Dedication of labeling and packaging lines to = each=20 different strength of each different drug product;
(2) Use of appropriate electronic or = electromechanical=20 equipment to conduct a 100-percent examination for = correct=20 labeling during or after completion of finishing = operations;=20 or
(3) Use of visual inspection to conduct a = 100-percent=20 examination for correct labeling during or after = completion of=20 finishing operations for hand-applied labeling. Such=20 examination shall be performed by one person and = independently=20 verified by a second person.
(h) Printing devices on, or associated with, = manufacturing=20 lines used to imprint labeling upon the drug product = unit=20 label or case shall be monitored to assure that all = imprinting=20 conforms to the print specified in the batch = production=20 record.
[43 FR 45077, Sept. 29, 1978, as amended at 58 FR = 41353,=20 Aug. 3, 1993]
(a) Strict control shall be exercised over labeling = issued=20 for use in drug product labeling operations.
(b) Labeling materials issued for a batch shall be=20 carefully examined for identity and conformity to the = labeling=20 specified in the master or batch production = records.
(c) Procedures shall be used to reconcile the = quantities of=20 labeling issued, used, and returned, and shall require = evaluation of discrepancies found between the quantity = of drug=20 product finished and the quantity of labeling issued = when such=20 discrepancies are outside narrow preset limits based = on=20 historical operating data. Such discrepancies shall be = investigated in accordance with 211.192. Labeling=20 reconciliation is waived for cut or roll labeling if a = 100-percent examination for correct labeling is = performed in=20 accordance with 211.122(g)(2).
(d) All excess labeling bearing lot or control = numbers=20 shall be destroyed.
(e) Returned labeling shall be maintained and = stored in a=20 manner to prevent mixups and provide proper=20 identification.
(f) Procedures shall be written describing in = sufficient=20 detail the control procedures employed for the = issuance of=20 labeling; such written procedures shall be = followed.
[43 FR 45077, Sept. 29, 1978, as amended at 58 FR = 41354,=20 Aug. 3, 1993]
There shall be written procedures designed to = assure that=20 correct labels, labeling, and packaging materials are = used for=20 drug products; such written procedures shall be = followed.=20 These procedures shall incorporate the following = features:
(a) Prevention of mixups and cross-contamination by = physical or spatial separation from operations on = other drug=20 products.
(b) Identification and handling of filled drug = product=20 containers that are set aside and held in unlabeled = condition=20 for future labeling operations to preclude mislabeling = of=20 individual containers, lots, or portions of lots.=20 Identification need not be applied to each individual=20 container but shall be sufficient to determine name, = strength,=20 quantity of contents, and lot or control number of = each=20 container.
(c) Identification of the drug product with a lot = or=20 control number that permits determination of the = history of=20 the manufacture and control of the batch.
(d) Examination of packaging and labeling materials = for=20 suitability and correctness before packaging = operations, and=20 documentation of such examination in the batch = production=20 record.
(e) Inspection of the packaging and labeling = facilities=20 immediately before use to assure that all drug = products have=20 been removed from previous operations. Inspection = shall also=20 be made to assure that packaging and labeling = materials not=20 suitable for subsequent operations have been removed. = Results=20 of inspection shall be documented in the batch = production=20 records.
[43 FR 45077, Sept. 29, 1978, as amended at 58 FR = 41354,=20 Aug. 3, 1993]
(a) General. The Food and Drug = Administration has=20 the authority under the Federal Food, Drug, and = Cosmetic Act=20 (the act) to establish a uniform national requirement = for=20 tamper-evident packaging of OTC drug products that = will=20 improve the security of OTC drug packaging and help = assure the=20 safety and effectiveness of OTC drug products. An OTC = drug=20 product (except a dermatological, dentifrice, insulin, = or=20 lozenge product) for retail sale that is not packaged = in a=20 tamper-resistant package or that is not properly = labeled under=20 this section is adulterated under section 501 of the = act or=20 misbranded under section 502 of the act, or both.
(b) Requirements for tamper-evident package. = (1)=20 Each manufacturer and packer who packages an OTC drug = product=20 (except a dermatological, dentifrice, insulin, or = lozenge=20 product) for retail sale shall package the product in = a=20 tamper-evident package, if this product is accessible = to the=20 public while held for sale. A tamper-evident package = is one=20 having one or more indicators or barriers to entry = which, if=20 breached or missing, can reasonably be expected to = provide=20 visible evidence to consumers that tampering has = occurred. To=20 reduce the likelihood of successful tampering and to = increase=20 the likelihood that consumers will discover if a = product has=20 been tampered with, the package is required to be = distinctive=20 by design or by the use of one or more indicators or = barriers=20 to entry that employ an identifying characteristic = (e.g., a=20 pattern, name, registered trademark, logo, or = picture). For=20 purposes of this section, the term "distinctive by = design"=20 means the packaging cannot be duplicated with commonly = available materials or through commonly available = processes. A=20 tamper-evident package may involve an = immediate-container and=20 closure system or secondary-container or carton system = or any=20 combination of systems intended to provide a visual = indication=20 of package integrity. The tamper-evident feature shall = be=20 designed to and shall remain intact when handled in a=20 reasonable manner during manufacture, distribution, = and retail=20 display.
(2) In addition to the tamper-evident packaging = feature=20 described in paragraph (b)(1) of this section, any = two-piece,=20 hard gelatin capsule covered by this section must be = sealed=20 using an acceptable tamper-evident technology.
(c) Labeling. (1) In order to alert = consumers to the=20 specific tamper-evident feature(s) used, each retail = package=20 of an OTC drug product covered by this section (except = ammonia=20 inhalant in crushable glass ampules, containers of = compressed=20 medical oxygen, or aerosol products that depend upon = the power=20 of a liquefied or compressed gas to expel the contents = from=20 the container) is required to bear a statement = that:
(i) Identifies all tamper-evident feature(s) and = any=20 capsule sealing technologies used to comply with = paragraph (b)=20 of this section;
(ii) Is prominently placed on the package; and
(iii) Is so placed that it will be unaffected if = the=20 tamper-evident feature of the package is breached or=20 missing.
(2) If the tamper-evident feature chosen to meet = the=20 requirements in paragraph (b) of this section uses an=20 identifying characteristic, that characteristic is = required to=20 be referred to in the labeling statement. For example, = the=20 labeling statement on a bottle with a shrink band = could say=20 "For your protection, this bottle has an imprinted = seal around=20 the neck."
(d) Request for exemptions from packaging and = labeling=20 requirements. A manufacturer or packer may request = an=20 exemption from the packaging and labeling requirements = of this=20 section. A request for an exemption is required to be=20 submitted in the form of a citizen petition under = 10.30 of=20 this chapter and should be clearly identified on the = envelope=20 as a "Request for Exemption from the Tamper-Evident = Packaging=20 Rule." The petition is required to contain the = following:
(1) The name of the drug product or, if the = petition seeks=20 an exemption for a drug class, the name of the drug = class, and=20 a list of products within that class.
(2) The reasons that the drug product's compliance = with the=20 tamper-evident packaging or labeling requirements of = this=20 section is unnecessary or cannot be achieved.
(3) A description of alternative steps that are = available,=20 or that the petitioner has already taken, to reduce = the=20 likelihood that the product or drug class will be the = subject=20 of malicious adulteration.
(4) Other information justifying an exemption.
(e) OTC drug products subject to approved new = drug=20 applications. Holders of approved new drug = applications=20 for OTC drug products are required under 314.70 of = this=20 chapter to provide the agency with notification of = changes in=20 packaging and labeling to comply with the requirements = of this=20 section. Changes in packaging and labeling required by = this=20 regulation may be made before FDA approval, as = provided under=20 314.70(c) of this chapter. Manufacturing changes by = which=20 capsules are to be sealed require prior FDA approval = under=20 314.70(b) of this chapter.
(f) Poison Prevention Packaging Act of 1970. = This=20 section does not affect any requirements for "special=20 packaging" as defined under 310.3(l) of this chapter = and=20 required under the Poison Prevention Packaging Act of=20 1970.
[54 FR 5228, Feb. 2, 1989, as amended at 63 FR = 59470, Nov.=20 4, 1998]
(a) Packaged and labeled products shall be examined = during=20 finishing operations to provide assurance that = containers and=20 packages in the lot have the correct label.
(b) A representative sample of units shall be = collected at=20 the completion of finishing operations and shall be = visually=20 examined for correct labeling.
(c) Results of these examinations shall be recorded = in the=20 batch production or control=20 records.
(a) To assure that a drug product meets applicable=20 standards of identity, strength, quality, and purity = at the=20 time of use, it shall bear an expiration date = determined by=20 appropriate stability testing described in = 211.166.
(b) Expiration dates shall be related to any = storage=20 conditions stated on the labeling, as determined by = stability=20 studies described in 211.166.
(c) If the drug product is to be reconstituted at = the time=20 of dispensing, its labeling shall bear expiration = information=20 for both the reconstituted and unreconstituted drug=20 products.
(d) Expiration dates shall appear on labeling in = accordance=20 with the requirements of 201.17 of this chapter.
(e) Homeopathic drug products shall be exempt from = the=20 requirements of this section.
(f) Allergenic extracts that are labeled "No U.S. = Standard=20 of Potency" are exempt from the requirements of this=20 section.
(g) New drug products for investigational use are = exempt=20 from the requirements of this section, provided that = they meet=20 appropriate standards or specifications as = demonstrated by=20 stability studies during their use in clinical = investigations.=20 Where new drug products for investigational use are to = be=20 reconstituted at the time of dispensing, their = labeling shall=20 bear expiration information for the reconstituted drug = product.
(h) Pending consideration of a proposed exemption,=20 published in the Federal Register of September 29, = 1978, the=20 requirements in this section shall not be enforced for = human=20 OTC drug products if their labeling does not bear = dosage=20 limitations and they are stable for at least 3 years = as=20 supported by appropriate stability data.
[43 FR 45077, Sept. 29, 1978, as amended at 46 FR = 56412,=20 Nov. 17, 1981; 60 FR 4091, Jan. 20, 1995]=20
Written procedures describing the warehousing of = drug=20 products shall be established and followed. They shall = include:
(a) Quarantine of drug products before release by = the=20 quality control unit.
(b) Storage of drug products under appropriate = conditions=20 of temperature, humidity, and light so that the = identity,=20 strength, quality, and purity of the drug products are = not=20 affected.
Written procedures shall be established, and = followed,=20 describing the distribution of drug products. They = shall=20 include:
(a) A procedure whereby the oldest approved stock = of a drug=20 product is distributed first. Deviation from this = requirement=20 is permitted if such deviation is temporary and=20 appropriate.
(b) A system by which the distribution of each lot = of drug=20 product can be readily determined to facilitate its = recall if=20 necessary.
(a) The establishment of any specifications, = standards,=20 sampling plans, test procedures, or other laboratory = control=20 mechanisms required by this subpart, including any = change in=20 such specifications, standards, sampling plans, test=20 procedures, or other laboratory control mechanisms, = shall be=20 drafted by the appropriate organizational unit and = reviewed=20 and approved by the quality control unit. The = requirements in=20 this subpart shall be followed and shall be documented = at the=20 time of performance. Any deviation from the written=20 specifications, standards, sampling plans, test = procedures, or=20 other laboratory control mechanisms shall be recorded = and=20 justified.
(b) Laboratory controls shall include the = establishment of=20 scientifically sound and appropriate specifications,=20 standards, sampling plans, and test procedures = designed to=20 assure that components, drug product containers, = closures,=20 in-process materials, labeling, and drug products = conform to=20 appropriate standards of identity, strength, quality, = and=20 purity. Laboratory controls shall include:
(1) Determination of conformance to appropriate = written=20 specifications for the acceptance of each lot within = each=20 shipment of components, drug product containers, = closures, and=20 labeling used in the manufacture, processing, packing, = or=20 holding of drug products. The specifications shall = include a=20 description of the sampling and testing procedures = used.=20 Samples shall be representative and adequately = identified.=20 Such procedures shall also require appropriate = retesting of=20 any component, drug product container, or closure that = is=20 subject to deterioration.
(2) Determination of conformance to written = specifications=20 and a description of sampling and testing procedures = for=20 in-process materials. Such samples shall be = representative and=20 properly identified.
(3) Determination of conformance to written = descriptions of=20 sampling procedures and appropriate specifications for = drug=20 products. Such samples shall be representative and = properly=20 identified.
(4) The calibration of instruments, apparatus, = gauges, and=20 recording devices at suitable intervals in accordance = with an=20 established written program containing specific = directions,=20 schedules, limits for accuracy and precision, and = provisions=20 for remedial action in the event accuracy and/or = precision=20 limits are not met. Instruments, apparatus, gauges, = and=20 recording devices not meeting established = specifications shall=20 not be used.
(a) For each batch of drug product, there shall be=20 appropriate laboratory determination of satisfactory=20 conformance to final specifications for the drug = product,=20 including the identity and strength of each active = ingredient,=20 prior to release. Where sterility and/or pyrogen = testing are=20 conducted on specific batches of shortlived=20 radiopharmaceuticals, such batches may be released = prior to=20 completion of sterility and/or pyrogen testing, = provided such=20 testing is completed as soon as possible.
(b) There shall be appropriate laboratory testing, = as=20 necessary, of each batch of drug product required to = be free=20 of objectionable microorganisms.
(c) Any sampling and testing plans shall be = described in=20 written procedures that shall include the method of = sampling=20 and the number of units per batch to be tested; such = written=20 procedure shall be followed.
(d) Acceptance criteria for the sampling and = testing=20 conducted by the quality control unit shall be = adequate to=20 assure that batches of drug products meet each = appropriate=20 specification and appropriate statistical quality = control=20 criteria as a condition for their approval and = release. The=20 statistical quality control criteria shall include = appropriate=20 acceptance levels and/or appropriate rejection = levels.
(e) The accuracy, sensitivity, specificity, and=20 reproducibility of test methods employed by the firm = shall be=20 established and documented. Such validation and = documentation=20 may be accomplished in accordance with = 211.194(a)(2).
(f) Drug products failing to meet established = standards or=20 specifications and any other relevant quality control = criteria=20 shall be rejected. Reprocessing may be performed. = Prior to=20 acceptance and use, reprocessed material must meet = appropriate=20 standards, specifications, and any other relevant=20 critieria.
(a) There shall be a written testing program = designed to=20 assess the stability characteristics of drug products. = The=20 results of such stability testing shall be used in = determining=20 appropriate storage conditions and expiration dates. = The=20 written program shall be followed and shall = include:
(1) Sample size and test intervals based on = statistical=20 criteria for each attribute examined to assure valid = estimates=20 of stability;
(2) Storage conditions for samples retained for=20 testing;
(3) Reliable, meaningful, and specific test = methods;
(4) Testing of the drug product in the same=20 container-closure system as that in which the drug = product is=20 marketed;
(5) Testing of drug products for reconstitution at = the time=20 of dispensing (as directed in the labeling) as well as = after=20 they are reconstituted.
(b) An adequate number of batches of each drug = product=20 shall be tested to determine an appropriate expiration = date=20 and a record of such data shall be maintained. = Accelerated=20 studies, combined with basic stability information on = the=20 components, drug products, and container-closure = system, may=20 be used to support tentative expiration dates provided = full=20 shelf life studies are not available and are being = conducted.=20 Where data from accelerated studies are used to = project a=20 tentative expiration date that is beyond a date = supported by=20 actual shelf life studies, there must be stability = studies=20 conducted, including drug product testing at = appropriate=20 intervals, until the tentative expiration date is = verified or=20 the appropriate expiration date determined.
(c) For homeopathic drug products, the requirements = of this=20 section are as follows:
(1) There shall be a written assessment of = stability based=20 at least on testing or examination of the drug product = for=20 compatibility of the ingredients, and based on = marketing=20 experience with the drug product to indicate that = there is no=20 degradation of the product for the normal or expected = period=20 of use.
(2) Evaluation of stability shall be based on the = same=20 container-closure system in which the drug product is = being=20 marketed.
(d) Allergenic extracts that are labeled "No U.S. = Standard=20 of Potency" are exempt from the requirements of this=20 section.
[43 FR 45077, Sept. 29, 1978, as amended at 46 FR = 56412,=20 Nov. 17, 1981] =
(a) For each batch of drug product purporting to be = sterile=20 and/or pyrogen-free, there shall be appropriate = laboratory=20 testing to determine conformance to such requirements. = The=20 test procedures shall be in writing and shall be = followed.
(b) For each batch of ophthalmic ointment, there = shall be=20 appropriate testing to determine conformance to = specifications=20 regarding the presence of foreign particles and harsh = or=20 abrasive substances. The test procedures shall be in = writing=20 and shall be followed.
(c) For each batch of controlled-release dosage = form, there=20 shall be appropriate laboratory testing to determine=20 conformance to the specifications for the rate of = release of=20 each active ingredient. The test procedures shall be = in=20 writing and shall be = followed.
(a) An appropriately identified reserve sample that = is=20 representative of each lot in each shipment of each = active=20 ingredient shall be retained. The reserve sample = consists of=20 at least twice the quantity necessary for all tests = required=20 to determine whether the active ingredient meets its=20 established specifications, except for sterility and = pyrogen=20 testing. The retention time is as follows:
(1) For an active ingredient in a drug product = other than=20 those described in paragraphs (a) (2) and (3) of this = section,=20 the reserve sample shall be retained for 1 year after = the=20 expiration date of the last lot of the drug product = containing=20 the active ingredient.
(2) For an active ingredient in a radioactive drug = product,=20 except for nonradioactive reagent kits, the reserve = sample=20 shall be retained for:
(i) Three months after the expiration date of the = last lot=20 of the drug product containing the active ingredient = if the=20 expiration dating period of the drug product is 30 = days or=20 less; or
(ii) Six months after the expiration date of the = last lot=20 of the drug product containing the active ingredient = if the=20 expiration dating period of the drug product is more = than 30=20 days.
(3) For an active ingredient in an OTC drug product = that is=20 exempt from bearing an expiration date under 211.137, = the=20 reserve sample shall be retained for 3 years after=20 distribution of the last lot of the drug product = containing=20 the active ingredient.
(b) An appropriately identified reserve sample that = is=20 representative of each lot or batch of drug product = shall be=20 retained and stored under conditions consistent with = product=20 labeling. The reserve sample shall be stored in the = same=20 immediate container-closure system in which the drug = product=20 is marketed or in one that has essentially the same=20 characteristics. The reserve sample consists of at = least twice=20 the quantity necessary to perform all the required = tests,=20 except those for sterility and pyrogens. Except for = those for=20 drug products described in paragraph (b)(2) of this = section,=20 reserve samples from representative sample lots or = batches=20 selected by acceptable statistical procedures shall be = examined visually at least once a year for evidence of = deterioration unless visual examination would affect = the=20 integrity of the reserve sample. Any evidence of = reserve=20 sample deterioration shall be investigated in = accordance with=20 211.192. The results of the examination shall be = recorded and=20 maintained with other stability data on the drug = product.=20 Reserve samples of compressed medical gases need not = be=20 retained. The retention time is as follows:
(1) For a drug product other than those described = in=20 paragraphs (b) (2) and (3) of this section, the = reserve sample=20 shall be retained for 1 year after the expiration date = of the=20 drug product.
(2) For a radioactive drug product, except for=20 nonradioactive reagent kits, the reserve sample shall = be=20 retained for:
(i) Three months after the expiration date of the = drug=20 product if the expiration dating period of the drug = product is=20 30 days or less; or
(ii) Six months after the expiration date of the = drug=20 product if the expiration dating period of the drug = product is=20 more than 30 days.
(3) For an OTC drug product that is exempt for = bearing an=20 expiration date under 211.137, the reserve sample must = be=20 retained for 3 years after the lot or batch of drug = product is=20 distributed.
[48 FR 13025, Mar. 29, 1983, as amended at 60 FR = 4091, Jan.=20 20, 1995]
Animals used in testing components, in-process = materials,=20 or drug products for compliance with established=20 specifications shall be maintained and controlled in a = manner=20 that assures their suitability for their intended use. = They=20 shall be identified, and adequate records shall be = maintained=20 showing the history of their=20 use.
If a reasonable possibility exists that a = non-penicillin=20 drug product has been exposed to cross-contamination = with=20 penicillin, the non-penicillin drug product shall be = tested=20 for the presence of penicillin. Such drug product = shall not be=20 marketed if detectable levels are found when tested = according=20 to procedures specified in `Procedures for Detecting = and=20 Measuring Penicillin Contamination in Drugs,' which is = incorporated by reference. Copies are available from = the=20 Division of Research and Testing (HFD-470), Center for = Drug=20 Evaluation and Research, Food and Drug Administration, = 5100=20 Paint Branch Pkwy., College Park, MD 20740, or = available for=20 inspection at the National Archives and Records = Administration=20 (NARA). For information on the availability of this = material=20 at NARA, call 202-741-6030, or go to:=20 = http://www.archives.gov/federal_register/code_of_federal_regulations/i= br_locations.html.=20
[43 FR 45077, Sept. 29, 1978, as amended at 47 FR = 9396,=20 Mar. 5, 1982; 50 FR 8996, Mar. 6, 1985; 55 FR 11577, = Mar. 29,=20 1990; 66 FR 56035, Nov. 6, 2001; 69 FR 18803, Apr. 9, = 2004]=20
(a) Any production, control, or distribution record = that is=20 required to be maintained in compliance with this part = and is=20 specifically associated with a batch of a drug product = shall=20 be retained for at least 1 year after the expiration = date of=20 the batch or, in the case of certain OTC drug products = lacking=20 expiration dating because they meet the criteria for = exemption=20 under 211.137, 3 years after distribution of the = batch.
(b) Records shall be maintained for all components, = drug=20 product containers, closures, and labeling for at = least 1 year=20 after the expiration date or, in the case of certain = OTC drug=20 products lacking expiration dating because they meet = the=20 criteria for exemption under 211.137, 3 years after=20 distribution of the last lot of drug product = incorporating the=20 component or using the container, closure, or = labeling.
(c) All records required under this part, or copies = of such=20 records, shall be readily available for authorized = inspection=20 during the retention period at the establishment where = the=20 activities described in such records occurred. These = records=20 or copies thereof shall be subject to photocopying or = other=20 means of reproduction as part of such inspection. = Records that=20 can be immediately retrieved from another location by = computer=20 or other electronic means shall be considered as = meeting the=20 requirements of this paragraph.
(d) Records required under this part may be = retained either=20 as original records or as true copies such as = photocopies,=20 microfilm, microfiche, or other accurate reproductions = of the=20 original records. Where reduction techniques, such as=20 microfilming, are used, suitable reader and = photocopying=20 equipment shall be readily available.
(e) Written records required by this part shall be=20 maintained so that data therein can be used for = evaluating, at=20 least annually, the quality standards of each drug = product to=20 determine the need for changes in drug product = specifications=20 or manufacturing or control procedures. Written = procedures=20 shall be established and followed for such evaluations = and=20 shall include provisions for:
(1) A review of a representative number of batches, = whether=20 approved or rejected, and, where applicable, records=20 associated with the batch.
(2) A review of complaints, recalls, returned or = salvaged=20 drug products, and investigations conducted under = 211.192 for=20 each drug product.
(f) Procedures shall be established to assure that = the=20 responsible officials of the firm, if they are not = personally=20 involved in or immediately aware of such actions, are = notified=20 in writing of any investigations conducted under = 211.198,=20 211.204, or 211.208 of these regulations, any recalls, = reports=20 of inspectional observations issued by the Food and = Drug=20 Administration, or any regulatory actions relating to = good=20 manufacturing practices brought by the Food and Drug=20 Administration.
[43 FR 45077, Sept. 29, 1978, as amended at 60 FR = 4091,=20 Jan. 20, 1995] =
A written record of major equipment cleaning, = maintenance=20 (except routine maintenance such as lubrication and=20 adjustments), and use shall be included in individual=20 equipment logs that show the date, time, product, and = lot=20 number of each batch processed. If equipment is = dedicated to=20 manufacture of one product, then individual equipment = logs are=20 not required, provided that lots or batches of such = product=20 follow in numerical order and are manufactured in = numerical=20 sequence. In cases where dedicated equipment is = employed, the=20 records of cleaning, maintenance, and use shall be = part of the=20 batch record. The persons performing and = double-checking the=20 cleaning and maintenance shall date and sign or = initial the=20 log indicating that the work was performed. Entries in = the log=20 shall be in chronological = order.
These records shall include the following:
(a) The identity and quantity of each shipment of = each lot=20 of components, drug product containers, closures, and=20 labeling; the name of the supplier; the supplier's lot = number(s) if known; the receiving code as specified in = 211.80;=20 and the date of receipt. The name and location of the = prime=20 manufacturer, if different from the supplier, shall be = listed=20 if known.
(b) The results of any test or examination = performed=20 (including those performed as required by 211.82(a),=20 211.84(d), or 211.122(a)) and the conclusions derived=20 therefrom.
(c) An individual inventory record of each = component, drug=20 product container, and closure and, for each = component, a=20 reconciliation of the use of each lot of such = component. The=20 inventory record shall contain sufficient information = to allow=20 determination of any batch or lot of drug product = associated=20 with the use of each component, drug product = container, and=20 closure.
(d) Documentation of the examination and review of = labels=20 and labeling for conformity with established = specifications in=20 accord with 211.122(c) and 211.130(c).
(e) The disposition of rejected components, drug = product=20 containers, closure, and=20 labeling.
(a) To assure uniformity from batch to batch, = master=20 production and control records for each drug product,=20 including each batch size thereof, shall be prepared, = dated,=20 and signed (full signature, handwritten) by one person = and=20 independently checked, dated, and signed by a second = person.=20 The preparation of master production and control = records shall=20 be described in a written procedure and such written = procedure=20 shall be followed.
(b) Master production and control records shall=20 include:
(1) The name and strength of the product and a = description=20 of the dosage form;
(2) The name and weight or measure of each active=20 ingredient per dosage unit or per unit of weight or = measure of=20 the drug product, and a statement of the total weight = or=20 measure of any dosage unit;
(3) A complete list of components designated by = names or=20 codes sufficiently specific to indicate any special = quality=20 characteristic;
(4) An accurate statement of the weight or measure = of each=20 component, using the same weight system (metric, = avoirdupois,=20 or apothecary) for each component. Reasonable = variations may=20 be permitted, however, in the amount of components = necessary=20 for the preparation in the dosage form, provided they = are=20 justified in the master production and control = records;
(5) A statement concerning any calculated excess of = component;
(6) A statement of theoretical weight or measure at = appropriate phases of processing;
(7) A statement of theoretical yield, including the = maximum=20 and minimum percentages of theoretical yield beyond = which=20 investigation according to 211.192 is required;
(8) A description of the drug product containers, = closures,=20 and packaging materials, including a specimen or copy = of each=20 label and all other labeling signed and dated by the = person or=20 persons responsible for approval of such labeling;
(9) Complete manufacturing and control = instructions,=20 sampling and testing procedures, specifications, = special=20 notations, and precautions to be=20 followed.
Batch production and control records shall be = prepared for=20 each batch of drug product produced and shall include = complete=20 information relating to the production and control of = each=20 batch. These records shall include:
(a) An accurate reproduction of the appropriate = master=20 production or control record, checked for accuracy, = dated, and=20 signed;
(b) Documentation that each significant step in the = manufacture, processing, packing, or holding of the = batch was=20 accomplished, including:
(1) Dates;
(2) Identity of individual major equipment and = lines=20 used;
(3) Specific identification of each batch of = component or=20 in-process material used;
(4) Weights and measures of components used in the = course=20 of processing;
(5) In-process and laboratory control results;
(6) Inspection of the packaging and labeling area = before=20 and after use;
(7) A statement of the actual yield and a statement = of the=20 percentage of theoretical yield at appropriate phases = of=20 processing;
(8) Complete labeling control records, including = specimens=20 or copies of all labeling used;
(9) Description of drug product containers and=20 closures;
(10) Any sampling performed;
(11) Identification of the persons performing and = directly=20 supervising or checking each significant step in the=20 operation;
(12) Any investigation made according to = 211.192.
(13) Results of examinations made in accordance = with=20 211.134.
All drug product production and control records, = including=20 those for packaging and labeling, shall be reviewed = and=20 approved by the quality control unit to determine = compliance=20 with all established, approved written procedures = before a=20 batch is released or distributed. Any unexplained = discrepancy=20 (including a percentage of theoretical yield exceeding = the=20 maximum or minimum percentages established in master=20 production and control records) or the failure of a = batch or=20 any of its components to meet any of its = specifications shall=20 be thoroughly investigated, whether or not the batch = has=20 already been distributed. The investigation shall = extend to=20 other batches of the same drug product and other drug = products=20 that may have been associated with the specific = failure or=20 discrepancy. A written record of the investigation = shall be=20 made and shall include the conclusions and=20 followup.
(a) Laboratory records shall include complete data = derived=20 from all tests necessary to assure compliance with = established=20 specifications and standards, including examinations = and=20 assays, as follows:
(1) A description of the sample received for = testing with=20 identification of source (that is, location from where = sample=20 was obtained), quantity, lot number or other = distinctive code,=20 date sample was taken, and date sample was received = for=20 testing.
(2) A statement of each method used in the testing = of the=20 sample. The statement shall indicate the location of = data that=20 establish that the methods used in the testing of the = sample=20 meet proper standards of accuracy and reliability as = applied=20 to the product tested. (If the method employed is in = the=20 current revision of the United States Pharmacopeia, = National=20 Formulary, AOAC INTERNATIONAL, Book of = Methods,1or=20 in other recognized standard references, or is = detailed in an=20 approved new drug application and the referenced = method is not=20 modified, a statement indicating the method and = reference will=20 suffice). The suitability of all testing methods used = shall be=20 verified under actual conditions of use.
(3) A statement of the weight or measure of sample = used for=20 each test, where appropriate.
(4) A complete record of all data secured in the = course of=20 each test, including all graphs, charts, and spectra = from=20 laboratory instrumentation, properly identified to = show the=20 specific component, drug product container, closure,=20 in-process material, or drug product, and lot = tested.
(5) A record of all calculations performed in = connection=20 with the test, including units of measure, conversion = factors,=20 and equivalency factors.
(6) A statement of the results of tests and how the = results=20 compare with established standards of identity, = strength,=20 quality, and purity for the component, drug product = container,=20 closure, in-process material, or drug product = tested.
(7) The initials or signature of the person who = performs=20 each test and the date(s) the tests were = performed.
(8) The initials or signature of a second person = showing=20 that the original records have been reviewed for = accuracy,=20 completeness, and compliance with established = standards.
(b) Complete records shall be maintained of any=20 modification of an established method employed in = testing.=20 Such records shall include the reason for the = modification and=20 data to verify that the modification produced results = that are=20 at least as accurate and reliable for the material = being=20 tested as the established method.
(c) Complete records shall be maintained of any = testing and=20 standardization of laboratory reference standards, = reagents,=20 and standard solutions.
(d) Complete records shall be maintained of the = periodic=20 calibration of laboratory instruments, apparatus, = gauges, and=20 recording devices required by 211.160(b)(4).
(e) Complete records shall be maintained of all = stability=20 testing performed in accordance with 211.166.
1Copies may be obtained from: AOAC=20 INTERNATIONAL, 481 North Frederick Ave., suite 500,=20 Gaithersburg, MD 20877.
[43 FR 45077, Sept. 29, 1978, as amended at 55 FR = 11577,=20 Mar. 29, 1990; 65 FR 18889, Apr. 10, 2000; 70 FR = 40880, July=20 15, 2005; 70 FR 67651, Nov. 8, 2005]=20
Distribution records shall contain the name and = strength of=20 the product and description of the dosage form, name = and=20 address of the consignee, date and quantity shipped, = and lot=20 or control number of the drug product. For compressed = medical=20 gas products, distribution records are not required to = contain=20 lot or control numbers.
[49 FR 9865, Mar. 16, 1984] =
(a) Written procedures describing the handling of = all=20 written and oral complaints regarding a drug product = shall be=20 established and followed. Such procedures shall = include=20 provisions for review by the quality control unit, of = any=20 complaint involving the possible failure of a drug = product to=20 meet any of its specifications and, for such drug = products, a=20 determination as to the need for an investigation in=20 accordance with 211.192. Such procedures shall include = provisions for review to determine whether the = complaint=20 represents a serious and unexpected adverse drug = experience=20 which is required to be reported to the Food and Drug=20 Administration in accordance with 310.305 and 514.80 = of this=20 chapter.
(b) A written record of each complaint shall be = maintained=20 in a file designated for drug product complaints. The = file=20 regarding such drug product complaints shall be = maintained at=20 the establishment where the drug product involved was=20 manufactured, processed, or packed, or such file may = be=20 maintained at another facility if the written records = in such=20 files are readily available for inspection at that = other=20 facility. Written records involving a drug product = shall be=20 maintained until at least 1 year after the expiration = date of=20 the drug product, or 1 year after the date that the = complaint=20 was received, whichever is longer. In the case of = certain OTC=20 drug products lacking expiration dating because they = meet the=20 criteria for exemption under 211.137, such written = records=20 shall be maintained for 3 years after distribution of = the drug=20 product.
(1) The written record shall include the following=20 information, where known: the name and strength of the = drug=20 product, lot number, name of complainant, nature of = complaint,=20 and reply to complainant.
(2) Where an investigation under 211.192 is = conducted, the=20 written record shall include the findings of the = investigation=20 and followup. The record or copy of the record of the=20 investigation shall be maintained at the establishment = where=20 the investigation occurred in accordance with = 211.180(c).
(3) Where an investigation under 211.192 is not = conducted,=20 the written record shall include the reason that an=20 investigation was found not to be necessary and the = name of=20 the responsible person making such a = determination.
[43 FR 45077, Sept. 29, 1978, as amended at 51 FR = 24479,=20 July 3, 1986; 68 FR 15364, Mar. 31, 2003]=20
Returned drug products shall be identified as such = and=20 held. If the conditions under which returned drug = products=20 have been held, stored, or shipped before or during = their=20 return, or if the condition of the drug product, its=20 container, carton, or labeling, as a result of storage = or=20 shipping, casts doubt on the safety, identity, = strength,=20 quality or purity of the drug product, the returned = drug=20 product shall be destroyed unless examination, = testing, or=20 other investigations prove the drug product meets = appropriate=20 standards of safety, identity, strength, quality, or = purity. A=20 drug product may be reprocessed provided the = subsequent drug=20 product meets appropriate standards, specifications, = and=20 characteristics. Records of returned drug products = shall be=20 maintained and shall include the name and label = potency of the=20 drug product dosage form, lot number (or control = number or=20 batch number), reason for the return, quantity = returned, date=20 of disposition, and ultimate disposition of the = returned drug=20 product. If the reason for a drug product being = returned=20 implicates associated batches, an appropriate = investigation=20 shall be conducted in accordance with the requirements = of=20 211.192. Procedures for the holding, testing, and = reprocessing=20 of returned drug products shall be in writing and = shall be=20 followed.
Drug products that have been subjected to improper = storage=20 conditions including extremes in temperature, = humidity, smoke,=20 fumes, pressure, age, or radiation due to natural = disasters,=20 fires, accidents, or equipment failures shall not be = salvaged=20 and returned to the marketplace. Whenever there is a = question=20 whether drug products have been subjected to such = conditions,=20 salvaging operations may be conducted only if there is = (a)=20 evidence from laboratory tests and assays (including = animal=20 feeding studies where applicable) that the drug = products meet=20 all applicable standards of identity, strength, = quality, and=20 purity and (b) evidence from inspection of the = premises that=20 the drug products and their associated packaging were = not=20 subjected to improper storage conditions as a result = of the=20 disaster or accident. Organoleptic examinations shall = be=20 acceptable only as supplemental evidence that the drug = products meet appropriate standards of identity, = strength,=20 quality, and purity. Records including name, lot = number, and=20 disposition shall be maintained for drug products = subject to=20 this section.
Source: 43 FR 45077, Sept. = 29, 1978,=20 unless otherwise noted. =
Database Updated April 1, 2007