Handbook of Pharmaceutical Manufacturing Formulations Uncompressed Solid Products

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Part I

Regulatory and Manufacturing Guidelines

2004 by CRC Press LLC


Global Good Manufacturing Practices Compliance


Good Manufacturing Practices (GMPs) is a universal con-cept with a dual purpose: to make pharmaceutical productsboth safe and consistent in their effectiveness. Remarkablechanges are taking place in the basic approach to achievethese goals. The key regulations and guidelines for themanufacturing of finished pharmaceuticals (as opposed toraw material or active ingredient manufacturing) in thisrespect are:

1. 21 Code of Federal Regulations, Parts 210 and211 (Part 210 Current Good ManufacturingPractice in Manufacturing, Processing, Packing,or Holding of Drugs; General Part 211 CurrentGood Manufacturing Practice for FinishedPharmaceuticals) (http://www.fda.gov/cder/dmpq/cgmpregs.htm)

2. The World Health Organization (WHO): Qual-ity Assurance of Pharmaceuticals: A compen-dium of guidelines and related materials,Volume 2, Good Manufacturing Practices andInspection (http://www.who.int/medicines/organization/qsm/activities/qualityassurance/gmp/gmpcover.html)

3. The Rules Governing Medicinal Products in theEuropean Union: Volume 4, Good Manufactur-

ing Practices (http://pharmacos.eudra.org/F2/eudralex/vol-4/home.htm)

4. The European Agency for the Evaluation ofMedicinal Products International Confer-ence on Harmonisation (ICH) Guidelines(http://www.emea.eu.int/index/indexh1.htm)

5. Health Products and Food Branch Inspectorateof Canada. Good Manufacturing PracticesGuidelines (http://www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/gmp_guidelines_2002_tc_e.html)

6. Therapeutic Goods Administration, Govern-ment of Australia Australian Code for GoodManufacturing Practices (http://www.health.gov.au/tga/docs/html/gmpcodau.htm)

The U.S. Food and Drug Administration (FDA) over-sees the quality of drug products using a two-prongedapproach including a review of information submitted in

applications as well as an inspection of manufacturingfacilities for conformance to requirements for currentGood Manufacturing Practices (CGMPs). These two pro-grams have served the United States well by helping toensure the quality of drug products available. Now, as weapproach the 25th anniversary of the last major revisionto the drug CGMP regulations, the U.S. FDA has under-taken a program to overhaul the entire process of CGMPcompliance so that:

The most up-to-date concepts of risk manage-ment and quality systems approaches are incor-porated while continuing to ensure productquality

The latest scientific advances in pharmaceuticalmanufacturing and technology are encouraged

The submission review program and the inspec-tion program operate in a coordinated and syn-ergistic manner

Regulation and manufacturing standards areapplied consistently

Management of the program encourages inno-vation in the pharmaceutical manufacturingsector

FDA resources are used most effectively andefficiently to address the most significant healthrisks

Over the last two decades, significant changes in theenvironment of pharmaceutical regulation have occurredand have resulted in incremental adjustments in the FDAsregulatory approach to product quality. These changesinclude:

Increased number of pharmaceutical productsand a greater role of medicines in health care

Decreased frequency of FDA manufacturinginspections as a result of fewer resources avail-able for pharmaceutical manufacturing inspec-tions

The FDAs accumulation of experience with,and lessons learned from, various approachesto the regulation of product quality

Advances in the pharmaceutical sciences andmanufacturing technologies

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Handbook of Pharmaceutical Manufacturing Formulations: Uncompressed Solid Products

Application of biotechnology in drug discoveryand manufacturing

Advances in the science and management ofquality

Globalization of the pharmaceutical industry

The cumulative impact of these changes has beengreater than the sum of the parts and warrants a systematicreappraisal of the FDAs approaches to product qualityregulation. The following principles will guide implemen-tation of the reappraisal:

Risk-based orientation

In order to provide themost effective public health protection, the FDAmust match its level of effort against the magni-tude of risk. Resource limitations prevent uni-formly intensive coverage of all pharmaceuticalproducts and production. Although the agencyhas been implementing risk-based programs, amore systematic and rigorous risk-basedapproach will be developed.

Science-based policies and standards

Signifi-cant advances in the pharmaceutical sciences andin manufacturing technologies have occurredover the last two decades. Although this knowl-edge has been incorporated in an ongoing mannerinto the FDAs approach to product quality reg-ulation, the fundamental nature of the changesdictates a thorough evaluation of the science baseto ensure that product quality regulation not onlyincorporates up-to-date science, but also encour-ages further advances in technology. Recent sci-ence can also contribute significantly to assess-ment of risk.

Integrated quality systems orientation

Principlesfrom various innovative approaches to manufac-turing quality that have been developed in thepast decade will be evaluated for applicability,and CGMP requirements and related preapprovalrequirements will be evaluated according toapplicable principles. In addition, interaction ofthe premarket chemistry, manufacturing and con-trol (CMC) review process and the applicationof CGMP requirements will be evaluated as anintegrated system.

International cooperation

The globalization ofpharmaceutical manufacturing requires a globalapproach to regulation. The FDA will collaboratewith other regulatory authorities via ICH andother venues.

Strong public health protection

The initiativewill strengthen the public health protectionachieved by the FDAs regulation of drug prod-uct manufacturing and will not interfere withstrong enforcement of the existing regulatory

requirements, even as we are examining andrevising our approach to these programs.

To accomplish the reappraisal, the FDA will carry outthe following broad actions:

Perform an external review of the existingCGMP program and product review practices,including evaluation of potential inconsisten-cies in implementation

Reassess and reevaluate our current scientificapproach to both the product review processand the CGMP program to achieve a consistent,integrated systems approach to product qualityregulation

Enhance the scientific approach of CGMPs toemphasize risk-based control point analysis andto facilitate the latest innovations in pharma-ceutical engineering

The following immediate steps are planned:

Holding scientific workshops with key stake-holders

Enhancing expertise in pharmaceutical technol-ogies (e.g., pharmaceutical engineering andindustrial pharmacy) by additional training andhiring, and by leveraging external expertise

Encouraging innovation within the existingframework of statutory provisions and regula-tions by allowing certain changes in the manu-facturing process without prior review/approval(e.g., comparability protocols)

Evaluating the optimal mechanisms to effec-tively and efficiently communicate deficienciesto industry, including content, consistency, dis-closure, and education

Shifting the agency lead on the implementationof Part 11 to Center for Drug Evaluation andResearch (CDER), with continued involvementfrom the other Centers of the FDA and theOffice of Regulatory Affairs (ORA)

Including product specialists, as needed, as apart of inspection teams

Having Centers provide a scientific and techni-cal review of all drug CGMP warning letters

Developing a technical dispute resolution pro-cess that integrates technical experts from theCenters and addresses perceived inconsisten-cies between Centers

Emphasizing a risk-based approach in the workplanning process

Improving the operations of Team Biologics ofthe Center for Biological Evaluation andResearch

2004 by CRC Press LLC

Global Good Manufacturing Practices Compliance


Intermediate steps are:

Use emerging science and data analysis toenhance compliance programs to target thehighest risk areas

Evaluate the feasibility of establishing dedi-cated cadres of pharmaceutical inspectors

Long-term steps are:

Enhanced training of agency staff on new sci-entific approaches and innovative pharmaceuti-cal manufacturing technology

Develop and publish policies and proceduresreflecting a science-based, risk managementapproach

Educate industry on new regulatory approachesthat encourage innovation

In conclusion, the industry must keep a close watch onthese developments as new CGMP guidelines are drafted.This is particularly important for the new start-ups whereinmuch of what the FDA would like to see in the future canbe readily provided. Whereas it is anticipated that the FDAwill loosen its noose on some of the less risky aspects ofCGMP, greater emphasis will be placed on protectingpatients when high-risk drugs are involved. The basicguidelines, however, are here to stay and an overview ofthese fundamental concepts is presented next.

A. G




Section 211.1, Scope, states that: The regulations inthis part contain the minimum current good manufacturingpractice for preparation of drug products for administra-tion to humans or animals.

Pending consideration of a proposed exemption, pub-lished in the Federal Register of September 29, 1978, therequirements in this part shall not be enforced for over-the-counter (OTC) drug products if the products and alltheir ingredients are ordinarily marketed and consumed ashuman foods, and which products may also fall within thelegal definition of drugs by virtue of their intended use.

B. O





Section 211.22, Responsibilities of Quality ControlUnit, states that: (a) There shall be a quality control unitthat shall have the responsibility and authority to approveor reject all components, drug product containers, clo-sures, in-process materials, packaging material, labeling,and drug products, and the authority to review productionrecords to assure that no errors have occurred or, if errorshave occurred, that they have been fully investigated. Thequality control unit shall be responsible for approving or

rejecting drug products manufactured, processed, packed,or held under contract by another company. (b) Adequatelaboratory facilities for the testing and approval (or rejec-tion) of components, drug product containers, closures,packaging materials, in-process materials, and drug prod-ucts shall be available to the quality control unit. (c) Thequality control unit shall have the responsibility forapproving or rejecting all procedures or specificationsimpacting on the identity, strength, quality, and purity ofthe drug product. (d) The responsibilities and proceduresapplicable to the quality control unit shall be in writing;such written procedures shall be followed.

Section 211.25, Personnel Qualifications, statesthat: (a) Each person engaged in the manufacture, pro-cessing, packing, or holding of a drug product shall haveeducation, training, and experience, or any combinationthereof, to enable that person to perform the assignedfunctions. Training shall be in the particular operationsthat the employee performs and in current good manufac-turing practice (including the current good manufacturingpractice regulations in this chapter and written proceduresrequired by these regulations) as they relate to theemployees functions. Training in current good manufac-turing practice shall be conducted by qualified individualson a continuing basis and with sufficient frequency toassure that employees remain familiar with CGMPrequirements applicable to them. (b) Each person respon-sible for supervising the manufacture, processing, pack-ing, or holding of a drug product shall have the education,training, and experience, or any combination thereof, toperform assigned functions in such a manner as to provideassurance that the drug product has the safety, identity,strength, quality, and purity that it purports or is repre-sented to possess. (c) There shall be an adequate numberof qualified personnel to perform and supervise the man-ufacture, processing, packing, or holding of each drugproduct.

Section 211.28, Personnel Responsibilities, statesthat: (a) Personnel engaged in the manufacture, process-ing, packing, or holding of a drug product shall wear cleanclothing appropriate for the duties they perform. Protec-tive apparel, such as head, face, hand, and arm coverings,shall be worn as necessary to protect drug products fromcontamination. (b) Personnel shall practice good sanita-tion and health habits. (c) Only personnel authorized bysupervisory personnel shall enter those areas of the build-ings and facilities designated as limited-access areas. (d)Any person shown at any time (either by medical exami-nation or supervisory observation) to have an apparentillness or open lesions that may adversely affect the safetyor quality of drug products shall be excluded from directcontact with components, drug product containers, clo-sures, in-process materials, and drug products until thecondition is corrected or determined by competentmedical personnel not to jeopardize the safety or quality

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Handbook of Pharmaceutical Manufacturing Formulations: Uncompressed Solid Products

of drug products. All personnel shall be instructed to reportto supervisory personnel any health conditions that mayhave an adverse effect on drug products.

Section 211.34, Consultants, states that: Consult-ants advising on the manufacture, processing, packing, orholding of drug products shall have sufficient education,training, and experience, or any combination thereof, toadvise on the subject for which they are retained. Recordsshall be maintained stating the name, address, and quali-fications of any consultants and the type of service theyprovide.

C. B





Section 211.42, Design and Construction Features,states that: (a) Any building or buildings used in themanufacture, processing, packing, or holding of a drugproduct shall be of suitable size, construction, and locationto facilitate cleaning, maintenance, and proper operations.(b) Any such building shall have adequate space for theorderly placement of equipment and materials to preventmixups between different components, drug product con-tainers, closures, labeling, in-process materials, or drugproducts, and to prevent contamination. The flow of com-ponents, drug product containers, closures, labeling, in-process materials, and drug products through the buildingor buildings shall be designed to prevent contamination.(c) Operations shall be performed within specificallydefined areas of adequate size. There shall be separate ordefined areas for the firms operations to prevent contam-ination or mixups as follows:

1. Receipt, identification, storage, and withhold-ing from use of components, drug product con-tainers, closures, and labeling, pending theappropriate sampling, testing, or examinationby the quality control unit before release formanufacturing or packaging;

2. Holding rejected components, drug productcontainers, closures, and labeling before dispo-sition;

3. Storage of released components, drug productcontainers, 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 prod-

ucts;8. Storage of drug products after release;9. Control and laboratory operations;

10. Aseptic processing, which includes as appro-priate:i. Floors, walls, and ceilings of smooth, hard

surfaces that are easily cleanable;ii. Temperature and humidity controls;

iii. An air supply filtered through high-effi-ciency particulate air filters under positivepressure, regardless of whether flow is lam-inar or nonlaminar;

iv. A system for monitoring environmentalconditions;

v. A system for cleaning and disinfecting theroom and equipment to produce asepticconditions;

vi. A system for maintaining any equipmentused to control the aseptic conditions.

(d) Operations relating to the manufacture, processing,and packing of penicillin shall be performed in facilitiesseparate from those used for other drug products forhuman use. (43 FR 45077, Sept. 29, 1978, as amendedat 60 FR 4091, Jan. 20, 1995.)

Section 211.44, Lighting, states that: Adequatelighting shall be provided in all areas.

Section 211.46, Ventilation, Air Filtration, Air Heat-ing, and Cooling, states that: (a) Adequate ventilationshall be provided. (b) Equipment for adequate control overair pressure, micro-organisms, dust, humidity, and tem-perature shall be provided when appropriate for the man-ufacture, processing, packing, or holding of a drug prod-uct. (c) Air filtration systems, including prefilters andparticulate matter air filters, shall be used when appropri-ate on air supplies to production areas. If air is recirculatedto production areas, measures shall be taken to controlrecirculation of dust from production. In areas where aircontamination occurs during production, there shall beadequate exhaust systems or other systems adequate tocontrol contaminants. (d) Air-handling systems for themanufacture, processing, and packing of penicillin shallbe completely separate from those for other drug productsfor human use.

Section 211.48, Plumbing, states that: (a) Potablewater shall be supplied under continuous positive pressurein a plumbing system free of defects that could contributecontamination to any drug product. Potable water shallmeet the standards prescribed in the Environmental Pro-tection Agencys (EPA) Primary Drinking Water Regula-tions set forth in 40 CFR Part 141. Water not meeting suchstandards shall not be permitted in the potable water sys-tem. (b) Drains shall be of adequate size and, where con-nected directly to a sewer, shall be provided with an airbreak or other mechanical device to prevent back-sipho-nage. (43 FR 45077, Sept. 29, 1978, as amended at 48FR 11426, Mar. 18, 1983.)

Section 211.50, Sewage and Refuse, states that:Sewage, trash, and other refuse in and from the buildingand immediate premises shall be disposed of in a safe andsanitary manner.

Section 211.52, Washing and Toilet Facilities, statesthat: Adequate washing facilities shall be provided,

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Global Good Manufacturing Practices Compliance


including hot and cold water, soap or detergent, air driersor single-service towels, and clean toilet facilities easilyaccessible to working areas.

Section 211.56, Sanitation, states that: (a) Anybuilding used in the manufacture, processing, packing, orholding of a drug product shall be maintained in a cleanand sanitary condition, Any such building shall be free ofinfestation by rodents, birds, insects, and other vermin(other than laboratory animals). Trash and organic wastematter shall be held and disposed of in a timely andsanitary manner. (b) There shall be written proceduresassigning responsibility for sanitation and describing insufficient detail the cleaning schedules, methods, equip-ment, and materials to be used in cleaning the buildingsand facilities; such written procedures shall be followed.(c) There shall be written procedures for use of suitablerodenticides, insecticides, fungicides, fumigating agents,and cleaning and sanitizing agents. Such written proce-dures shall be designed to prevent the contamination ofequipment, components, drug product containers, clo-sures, packaging, labeling materials, or drug products andshall be followed. Rodenticides, insecticides, and fungi-cides shall not be used unless registered and used in accor-dance with the Federal Insecticide, Fungicide, and Roden-ticide Act (7 U.S.C. 135). (d) Sanitation procedures shallapply to work performed by contractors or temporaryemployees as well as work performed by full-timeemployees during the ordinary course of operations.

Section 211.58, Maintenance, states that: Anybuilding used in the manufacture, processing, packing, orholding of a drug product shall be maintained in a goodstate of repair.

D. E


Section 211.63, Equipment Design, Size, and Location,states that: Equipment used in the manufacture, process-ing, packing, or holding of a drug product shall be ofappropriate design, adequate size, and suitably located tofacilitate operations for its intended use and for its clean-ing and maintenance.

Section 211.65, Equipment Construction, statesthat: (a) Equipment shall be constructed so that surfacesthat contact components, in-process materials, or drugproducts shall not be reactive, additive, or absorptive soas to alter the safety, identity, strength, quality, or purityof the drug product beyond the official or other establishedrequirements. (b) Any substances required for operation,such as lubricants or coolants, shall not come into contactwith components, drug product containers, closures, in-process materials, or drug products so as to alter the safety,identity, strength, quality, or purity of the drug productbeyond the official or other established requirements.

Section 211.67, Equipment Cleaning and Mainte-nance, states that: (a) Equipment and utensils shall be

cleaned, maintained, and sanitized at appropriate intervalsto prevent malfunctions or contamination that would alterthe safety, identity, strength, quality, or purity of the drugproduct beyond the official or other established require-ments. (b) Written procedures shall be established andfollowed for cleaning and maintenance of equipment,including utensils, used in the manufacture, processing,packing, or holding of a drug product. These proceduresshall include, but are not necessarily limited to, thefollowing:

1. Assignment of responsibility for cleaning andmaintaining equipment;

2. Maintenance and cleaning schedules, includ-ing, where appropriate, sanitizing schedules;

3. A description in sufficient detail of the methods,equipment, and materials used in cleaning andmaintenance operations, and the methods ofdisassembling and reassembling equipment asnecessary to assure proper cleaning and main-tenance;

4. Removal or obliteration of previous batch iden-tification;

5. Protection of clean equipment from contamina-tion prior to use;

6. Inspection of equipment for cleanliness imme-diately before use.

(c) Records shall be kept of maintenance, cleaning, sani-tizing, and inspection as specified in Sections 211.180 and211.182.

Section 211.68, Automatic, Mechanical, and Elec-tronic Equipment, states that: (a) Automatic, mechani-cal, or electronic equipment or other types of equipment,including computers, or related systems that will performa function satisfactorily, may be used in the manufacture,processing, packing, and holding of a drug product. If suchequipment is so used, it shall be routinely calibrated,inspected, or checked according to a written programdesigned to assure proper performance. Written recordsof those calibration checks and inspections shall be main-tained. (b) Appropriate controls shall be exercised overcomputer or related systems to assure that changes in mas-ter production and control records or other records areinstituted only by authorized personnel. Input to and outputfrom the computer or related system of formulas or otherrecords or data shall be checked for accuracy. The degreeand frequency of input/output verification shall be basedon the complexity and reliability of the computer or relatedsystem. A backup file of data entered into the computer orrelated system shall be maintained except where certaindata, such as calculations performed in connection withlaboratory analysis, are eliminated by computerization orother automated processes. In such instances a writtenrecord of the program shall be maintained along with

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Handbook of Pharmaceutical Manufacturing Formulations: Uncompressed Solid Products

appropriate validation data. Hard copy or alternative sys-tems, such as duplicates, tapes, or microfilm, designed toassure that backup data are exact and complete and thatit is secure from alteration, inadvertent erasures, or lossshall be maintained. (43 FR 45077, Sept. 29, 1978, asamended at 60 FR 4091, Jan. 20, 1995.)

Section 211.72, Filters, states that: Filters for liquidfiltration used in the manufacture, processing, or packingof injectable drug products intended for human use shallnot release fibers into such products. Fiber-releasing filtersmay not be used in the manufacture, processing, or pack-ing of these injectable drug products unless it is not pos-sible to manufacture such drug products without the useof such filters. If use of a fiber-releasing filter is necessary,an additional non-fiber-releasing filter of 0.22


m maxi-mum mean porosity (0.45 micron if the manufacturingconditions so dictate) shall subsequently be used to reducethe content of particles in the injectable drug product. Useof an asbestos-containing filter, with or without subse-quent use of a specific non-fiber-releasing filter, is permis-sible only upon submission of proof to the appropriatebureau of the Food and Drug Administration that use ofa non-fiber-releasing filter will, or is likely to, compromisethe safety or effectiveness of the injectable drug product.

E. C















Section 211.80, General Requirements, states that: (a)There shall be written procedures describing in sufficientdetail the receipt, identification, storage, handling, sam-pling, testing, and approval or rejection of componentsand drug product containers and closures; such writtenprocedures shall be followed. (b) Components and drugproduct containers and closures shall at all times be han-dled and stored in a manner to prevent contamination. (c)Bagged or boxed components of drug product containers,or closures shall be stored off the floor and suitably spacedto permit cleaning and inspection. (d) Each container orgrouping of containers for components or drug productcontainers, or closures shall be identified with a distinctivecode for each lot in each shipment received. This codeshall be used in recording the disposition of each lot. Eachlot shall be appropriately identified as to its status (i.e.,quarantined, approved, or rejected).

Section 211.82, Receipt and Storage of UntestedComponents, Drug Product Containers, and Closures,states that: (a) Upon receipt and before acceptance, eachcontainer or grouping of containers of components, drugproduct containers, and closures shall be examined visu-ally for appropriate labeling as to contents, container dam-age or broken seals, and contamination. (b) Components,drug product containers, and closures shall be stored underquarantine until they have been tested or examined, as

appropriate, and released. Storage within the area shallconform to the requirements of Section 211.80.

Section 211.84, Testing and Approval or Rejectionof Components, Drug Product Containers, and Closures,states that: (a) Each lot of components, drug productcontainers, and closures shall be withheld from use untilthe lot has been sampled, tested, or examined, as appro-priate, and released for use by the quality control unit. (b)Representative samples of each shipment of each lot shallbe collected for testing or examination. The number ofcontainers to be sampled, and the amount of material tobe taken from each container, shall be based upon appro-priate criteria such as statistical criteria for componentvariability, confidence levels, and degree of precisiondesired, the past quality history of the supplier, and thequantity needed for analysis and reserve where requiredby Section 211.170. (c) Samples shall be collected inaccordance with the following procedures:

1. The containers of components selected shall becleaned where necessary, by appropriate means.

2. The containers shall be opened, sampled, andresealed in a manner designed to prevent con-tamination of their contents and contaminationof other components, drug product containers,or closures.

3. Sterile equipment and aseptic sampling tech-niques shall be used when necessary.

4. If it is necessary to sample a component fromthe top, middle, and bottom of its container,such sample subdivisions shall not be compos-ited for testing.

5. Sample containers shall be identified so that thefollowing information can be determined: nameof the material sampled, the lot number, thecontainer from which the sample was taken, thedate on which the sample was taken, and thename of the person who collected the sample.

6. Containers from which samples have beentaken shall be marked to show that sampleshave been removed from them.

(d) Samples shall be examined and tested as follows:

1. At least one test shall be conducted to verifythe identity of each component of a drug prod-uct. Specific identity tests, if they exist, shallbe used.

2. Each component shall be tested for conformitywith all appropriate written specifications forpurity, strength, and quality. In lieu of suchtesting by the manufacturer, a report of analysismay be accepted from the supplier of a compo-nent, provided that at least one specific identitytest is conducted on such component by the

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Global Good Manufacturing Practices Compliance


manufacturer, and provided that the manufac-turer establishes the reliability of the suppliersanalyses through appropriate validation of thesuppliers test results at appropriate intervals.

3. Containers and closures shall be tested for con-formance with all appropriate written proce-dures. In lieu of such testing by the manufacturer,a certificate of testing may be accepted fromthe supplier, provided that at least a visual iden-tification is conducted on such containers/clo-sures by the manufacturer and provided that themanufacturer establishes the reliability of thesuppliers test results through appropriate vali-dation of the suppliers test results at appropri-ate intervals.

4. When appropriate, components shall be micro-scopically examined.

5. Each lot of a component, drug product con-tainer, or closure that is liable to contaminationwith filth, insect infestation, or other extraneousadulterant shall be examined against estab-lished specifications for such contamination.

6. Each lot of a component, drug product con-tainer, or closure that is liable to microbiolog-ical contamination that is objectionable in viewof its intended use shall be subjected to micro-biological tests before use.

(e) Any lot of components, drug product containers, orclosures that meets the appropriate written specificationsof identity, strength, quality, and purity and related testsunder paragraph (d) of this section may be approved andreleased for use. Any lot of such material that does notmeet such specifications shall be rejected.

Section 211.86, Use of Approved Components, DrugProduct Containers, and Closures, states that: Compo-nents, drug product containers, and closures approved foruse shall be rotated so that the oldest approved stock isused first. Deviation from this requirement is permitted ifsuch deviation is temporary and appropriate.

Section 211.87, Retesting of Approved Components,Drug Product Containers, and Closures, states that:Components, drug product containers, and closures shallbe retested or reexamined, as appropriate, for identity,strength, quality, and purity and approved or rejected bythe quality control unit in accordance with Section 211.84as necessary (e.g., after storage for long periods or afterexposure to air, heat or other conditions that mightadversely affect the component, drug product container,or closure).

Section 211.89, Rejected Components, Drug ProductContainers, and Closures, states that: Rejected compo-nents, drug product containers, and closures shall be iden-tified and controlled under a quarantine system designed

to prevent their use in manufacturing or processing oper-ations for which they are unsuitable.

Section 211.94, Drug Product Containers and Clo-sures, states that: (a) Drug product containers and clo-sures shall not be reactive, additive, or absorptive so as toalter the safety, identity, strength, quality, or purity of thedrug beyond the official or established requirements. (b)Container closure systems shall provide adequate protec-tion against foreseeable external factors in storage and usethat can cause deterioration or contamination of the drugproduct. (c) Drug product containers and closures shall beclean and, where indicated by the nature of the drug,sterilized and processed to remove pyrogenic propertiesto assure that they are suitable for their intended use. (d)Standards or specifications, methods of testing, and, whereindicated, methods of cleaning, sterilizing, and processingto remove pyrogenic properties shall be written and fol-lowed for drug product containers and closures.

F. P







Section 211.100, Written Procedures; Deviations, statesthat: (a) There shall be written procedures for productionand process control designed to assure that the drug prod-ucts have the identity, strength, quality, and purity theypurport or are represented to possess. Such proceduresshall include all requirements in this subpart. These writ-ten procedures, including any changes, shall be drafted,reviewed, and approved by the appropriate organizationalunits and reviewed and approved by the quality controlunit. (b) Written production and process control proce-dures shall be followed in the execution of the variousproduction and process control functions and shall bedocumented at the time of performance. Any deviationfrom the written procedures shall be recorded and justi-fied.

Section 211.101, Charge-In of Components, statesthat: Written production and control procedures shallinclude the following, which are designed to assure thatthe drug products produced have the identity, strength,quality, and purity they purport or are represented to pos-sess: (a) The batch shall be formulated with the intent toprovide not less than 100 percent of the labeled or estab-lished amount of active ingredient. (b) Components fordrug product manufacturing shall be weighed, measured,or subdivided as appropriate. If a component is removedfrom the original container to another, the new containershall be identified with the following 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 product name, strength, and lotnumber.

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Handbook of Pharmaceutical Manufacturing Formulations: Uncompressed Solid Products

(c) Weighing, measuring, or subdividing operations forcomponents shall be adequately supervised. Each con-tainer of component dispensed to manufacturing shall beexamined by a second person to assure that:

1. The component was released by the qualitycontrol unit;

2. The weight or measure is correct as stated inthe batch production records;

3. The containers are properly identified.

(d) Each component shall be added to the batch by oneperson and verified by a second person.

Section 211.103, Calculation of Yield, states that:Actual yields and percentages of theoretical yields shallbe determined at the conclusion of each appropriate phaseof manufacturing, processing, packaging, or holding ofthe drug product. Such calculations shall be performed byone person and independently verified by a secondperson.

Section 211.105, Equipment Identification, statesthat: (a) All compounding and storage containers, pro-cessing lines, and major equipment used during the pro-duction of a batch of a drug product shall be properlyidentified at all times to indicate their contents and, whennecessary, the phase of processing of the batch. (b) Majorequipment shall be identified by a distinctive identificationnumber or code that shall be recorded in the batch pro-duction record to show the specific equipment used in themanufacture of each batch of a drug product. In caseswhere only one of a particular type of equipment existsin a manufacturing facility, the name of the equipmentmay be used in lieu of a distinctive identification numberor code.

Section 211.110, Sampling and Testing of In-ProcessMaterials and Drug Products, states that: (a) To assurebatch uniformity and integrity of drug products, writtenprocedures shall be established and followed that describethe in-process controls, and tests, or examinations to beconducted on appropriate samples of in-process materialsof each batch. Such control procedures shall be establishedto monitor the output and to validate the performance ofthose manufacturing processes that may be responsible forcausing variability in the characteristics of in-processmaterial and the drug product. Such control proceduresshall include, but are not limited to, the following, whereappropriate:

1. Tablet or capsule weight variation;2. Disintegration time;3. Adequacy of mixing to assure uniformity and

homogeneity;4. Dissolution time and rate;5. Clarity, completeness, or pH of solutions.

(b) Valid in-process specifications for such characteristicsshall be consistent with drug product final specificationsand shall be derived from previous acceptable processaverage and process variability estimates where possibleand determined by the application of suitable statisticalprocedures where appropriate. Examination and testing ofsamples shall assure that the drug product and in-processmaterial conform to specifications. (c) In-process materi-als shall be tested for identity, strength, quality, and purityas appropriate, and approved or rejected by the qualitycontrol unit, during the production process (e.g., at com-mencement or completion of significant phases or afterstorage for long periods). (d) Rejected in-process materi-als shall be identified and controlled under a quarantinesystem designed to prevent their use in manufacturing orprocessing operations for which they are unsuitable.

Section 211.111, Time Limitations on Production,states that: When appropriate, time limits for the com-pletion of each phase of production shall be establishedto assure the quality of the drug product. Deviation fromestablished time limits may be acceptable if such deviationdoes not compromise the quality of the drug product. Suchdeviation shall be justified and documented.

Section 211.113, Control of Microbiological Con-tamination, states that: (a) Appropriate written proce-dures, designed to prevent objectionable microorganismsin drug products not required to be sterile, shall be estab-lished and followed. (b) Appropriate written procedures,designed to prevent microbiological contamination ofdrug products purporting to be sterile, shall be establishedand followed. Such procedures shall include validation ofany sterilization process.

Section 211.115, Reprocessing, states that: (a)Written procedures shall be established and followed pre-scribing a system for reprocessing batches that do notconform to standards or specifications and the steps to betaken to insure that the reprocessed batches will conformwith all established standards, specifications, and charac-teristics. (b) Reprocessing shall not be performed withoutthe review and approval of the quality control unit.

G. P







Section 211.122, Materials Examination and Usage Cri-teria, states that: (a) There shall be written proceduresdescribing in sufficient detail the receipt, identification,storage, handling, sampling, examination, and/or testingof labeling and packaging materials; such written proce-dures shall be followed. Labeling and packaging materialsshall be representatively sampled, and examined or testedupon receipt and before use in packaging or labeling of adrug product. (b) Any labeling or packaging materialsmeeting appropriate written specifications may beapproved and released for use. Any labeling or packagingmaterials that do not meet such specifications shall be

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rejected to prevent their use in operations for which theyare unsuitable. (c) Records shall be maintained for eachshipment received of each different labeling and packag-ing material indicating receipt, examination or testing, andwhether accepted or rejected. (d) Labels and other labelingmaterials for each different drug product, strength, dosageform, or quantity of contents shall be stored separatelywith suitable identification. Access to the storage areashall be limited to authorized personnel. (e) Obsolete andoutdated labels, labeling, and other packaging materialsshall be destroyed. (f) Use of gang printing of labeling fordifferent drug products or different strengths, or net con-tents of the same drug product, is prohibited unless thelabeling from gang-printed sheets is adequately differen-tiated by size, shape, or color. (g) If cut labeling is used,packaging and labeling operations shall include one of thefollowing special control procedures:

1. Dedication of labeling and packaging lines toeach different strength of each different drugproduct;

2. Use of appropriate electronic or electromechan-ical equipment to conduct a 100-percent exam-ination for correct labeling during or aftercompletion of finishing operations; or

3. Use of visual inspection to conduct a 100-per-cent examination for correct labeling during orafter completion of finishing operations forhand-applied labeling. Such examination shallbe performed by one person and independentlyverified by a second person.

(h) Printing devices on, or associated with, manufacturinglines used to imprint labeling upon the drug product unitlabel or case shall be monitored to assure that all imprint-ing conforms to the print specified in the batch productionrecord. (43 FR 45077, Sept. 29, 1978, as amended at 58FR 41353, Aug. 3, 1993.)

Section 211.125, Labeling Issuance, states that: (a)Strict control shall be exercised over labeling issued foruse in drug product labeling operations. (b) Labelingmaterials issued for a batch shall be carefully examinedfor identity and conformity to the labeling specified in themaster or batch production records. (c) Procedures shallbe utilized to reconcile the quantities of labeling issued,used, and returned, and shall require evaluation of discrep-ancies found between the quantity of drug product finishedand the quantity of labeling issued when such discrepan-cies are outside narrow preset limits based on historicaloperating data. Such discrepancies shall be investigatedin accordance with Section 211.192. Labeling reconcilia-tion is waived for cut or roll labeling if a 100-percentexamination for correct labeling is performed in accor-dance with Section 211.122(g)(2). (d) All excess labelingbearing lot or control numbers shall be destroyed.

(e) Returned labeling shall be maintained and stored in amanner to prevent mixups and provide proper identifica-tion. (f) Procedures shall be written describing in sufficientdetail the control procedures employed for the issuanceof labeling; such written procedures shall be followed.(43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41345,Aug. 3, 1993.)

Section 211.130, Packaging and Labeling Opera-tions, states that: There shall be written proceduresdesigned to assure that correct labels, labeling, and pack-aging materials are used for drug products; such writtenprocedures shall be followed. These procedures shallincorporate the following features: (a) Prevention of mix-ups and cross-contamination by physical or spatial sepa-ration from operations on other drug products. (b) Identi-fication and handling of filled drug product containers thatare set aside and held in unlabeled condition for futurelabeling operations to preclude mislabeling of individualcontainers, lots, or portions of lots. Identification need notbe applied to each individual container but shall be suffi-cient to determine name, strength, quantity of contents,and lot or control number of each container. (c) Identifi-cation of the drug product with a lot or control numberthat permits determination of the history of the manufac-ture and control of the batch. (d) Examination of packag-ing and labeling materials for suitability and correctnessbefore packaging operations, and documentation of suchexamination in the batch production record. (e) Inspectionof the packaging and labeling facilities immediatelybefore use to assure that all drug products have beenremoved from previous operations. Inspection shall alsobe made to assure that packaging and labeling materialsnot suitable for subsequent operations have been removed.Results of inspection shall be documented in the batchproduction records. (43 FR 45077, Sept. 29, 1978, asamended at 58 FR 41354, Aug. 3, 1993.)

Section 211.132, Tamper-Resistant PackagingRequirements for Over-the-Counter (OTC) Human DrugProducts, states that: (a)


The Food and DrugAdministration has the authority under the Federal Food,Drug, and Cosmetic Act (the Act) to establish a uniformnational requirement for tamper-resistant packaging ofOTC drug products that will improve the security of OTCdrug packaging and help assure the safety and effective-ness of OTC drug products. An OTC drug product (excepta dermatological, dentifrice, insulin, or throat lozengeproduct) for retail sale that is not packaged in a tamper-resistant package or that is not properly labeled under thissection is adulterated under section 501 of the Act ormisbranded under Section 502 of the Act, or both.(b)

Requirement for tamper-resistant package.

Each man-ufacturer and packer who packages an OTC drug product(except a dermatological, dentifrice, insulin, or throat loz-enge product) for retail sale shall package the product ina tamper-resistant package, if this product is accessible to

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the public while held for sale. A tamper-resistant packageis one having one or more indicators or barriers to entrywhich, if breached or missing, can reasonably be expectedto provide visible evidence to consumers that tamperinghas occurred. To reduce the likelihood of successful tam-pering and to increase the likelihood that consumers willdiscover if a product has been tampered with, the packageis required to be distinctive by design (e.g., an aerosolproduct container) or by the use of one or more indicatorsor barriers to entry that employ an identifying character-istic (e.g., a pattern, name, registered trademark, logo, orpicture). For purposes of this section, the term distinctiveby design means the packaging cannot be duplicated withcommonly available materials or through commonly avail-able processes. For purposes of this section, the termaerosol product means a product which depends uponthe power of a liquified or compressed gas to expel thecontents from the container. A tamper-resistant packagemay involve an immediate-container and closure systemor secondary-container or carton system or any combina-tion of systems intended to provide a visual indication ofpackage integrity. The tamper-resistant feature shall bedesigned to and shall remain intact when handled in areasonable manner during manufacture, distribution, andretail display.

1. For two-piece, hard gelatin capsule productssubject to this requirement, a minimum of twotamper-resistant packaging features is required,unless the capsules are sealed by a tamper-resis-tant technology.

2. For all other products subject to this require-ment, including two-piece, hard gelatin cap-sules that are sealed by a tamper-resistanttechnology, a minimum of one tamper-resistantfeature is required.



Each retail package of an OTC drug productcovered by this section, except ammonia inhalant in crush-able glass ampules, aerosol products as defined in para-graph (b) of this section, or containers of compressedmedical oxygen, is required to bear a statement that isprominently placed so that consumers are alerted to thespecific tamper-resistant feature of the package. The label-ing statement is also required to be so placed that it willbe unaffected if the tamper-resistant feature of the packageis breached or missing. If the tamper-resistant feature cho-sen to meet the requirement in paragraph (b) of this sectionis one that uses an identifying characteristic, that charac-teristic is required to be referred to in the labeling state-ment. For example, the labeling statement on a bottle witha shrink band could say, For your protection, this bottlehas an imprinted seal around the neck. (d)

Request forexemptions from packaging and labeling requirements.


manufacturer or packer may request an exemption fromthe packaging and labeling requirements of this section.A request for an exemption is required to be submitted inthe form of a citizen petition under Section 10.30 of thischapter and should be clearly identified on the envelopeas a Request for Exemption from Tamper-ResistantRule. The petition is required to contain the following:

1. The name of the drug product or, if the petitionseeks an exemption for a drug class, the nameof the drug class, and a list of products withinthat class.

2. The reasons that the drug products compliancewith the tamper-resistant packaging or labelingrequirements of this section is unnecessary orcannot be achieved.

3. A description of alternative steps that are avail-able, or that the petitioner has already taken, toreduce the likelihood that the product or drugclass will be the subject of malicious adultera-tion.

4. Other information justifying an exemption.


OTC drug products subject to approved new drugapplications.

Holders of approved new drug applicationsfor OTC drug products are required under Section 314.70of this chapter to provide the agency with notification ofchanges in packaging and labeling to comply with therequirements of this section. Changes in packaging andlabeling required by this regulation may be made beforeFDA approval, as provided under Section 314.70(c) of thischapter. Manufacturing changes by which capsules are tobe sealed require prior FDA approval under Section314.70(b) of this chapter. (f)

Poison Prevention PackagingAct of 1970

. This section does not affect any requirementsfor special packaging as defined under Section 310.3(l)of this chapter and required under the Poison PreventionPackaging Act of 1970. (Approved by the Office of Man-agement and Budget [OMB] under OMB control number0910-0149) (54 FR 5228, Feb. 2, 1989.)

Section 211.134, Drug Product Inspection, statesthat: (a) Packaged and labeled products shall be exam-ined during finishing operations to provide assurance thatcontainers and packages in the lot have the correct label.(b) A representative sample of units shall be collected atthe completion of finishing operations and shall be visu-ally examined for correct labeling. (c) Results of theseexaminations shall be recorded in the batch production orcontrol records.

Section 211.137, Expiration Dating, states that: (a)To assure that a drug product meets applicable standardsof identity, strength, quality, and purity at the time of use,it shall bear an expiration date determined by appropriatestability testing described in Section 211.166.

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(b) Expiration dates shall be related to any storage con-ditions stated on the labeling, as determined by stabilitystudies described in Section 211.166. (c) If the drug prod-uct is to be reconstituted at the time of dispensing, itslabeling shall bear expiration information for both thereconstituted and unreconstituted drug products. (d) Expi-ration dates shall appear on labeling in accordance withthe requirements of Section 201.17 of this chapter. (e)Homeopathic drug products shall be exempt from therequirements of this section. (f) Allergenic extracts thatare labeled No U.S. Standard of Potency are exemptfrom the requirements of this section. (g) New drug prod-ucts for investigational use are exempt from the require-ments of this section, provided that they meet appropriatestandards or specifications as demonstrated by stabilitystudies during their use in clinical investigations. Wherenew drug products for investigational use are to be recon-stituted at the time of dispensing, their labeling shall bearexpiration information for the reconstituted drug product.(h) Pending consideration of a proposed exemption, pub-lished in the Federal Register of September 29, 1978, therequirements in this section shall not be enforced forhuman OTC drug products if their labeling does not beardosage limitations and they are stable for at least 3 yearsas supported by appropriate stability data. (43 FR 45077,Sept. 29, 1978, as amended at 46 FR 56412, Nov. 17,1981; 60 FR 4091, Jan. 20, 1995.)

H. H





Section 211.142, Warehousing Procedures, states that:Written procedures describing the warehousing of drugproducts shall be established and followed. They shallinclude: (a) Quarantine of drug products before release bythe quality control unit. (b) Storage of drug products underappropriate conditions of temperature, humidity, and lightso that the identity, strength, quality, and purity of the drugproducts are not affected.

Section 211.150, Distribution Procedures, statesthat: Written procedures shall be established, and fol-lowed, describing the distribution of drug products. Theyshall include: (a) A procedure whereby the oldestapproved stock of a drug product is distributed first. Devi-ation from this requirement is permitted if such deviationis temporary and appropriate. (b) A system by which thedistribution of each lot of drug product can be readilydetermined to facilitate its recall if necessary. Writtenprocedures shall be established, and followed, describingthe distribution of drug products. They shall include: (a)A procedure whereby the oldest approved stock of a drugproduct is distributed first. Deviation from this require-ment is permitted if such deviation is temporary andappropriate. (b) A system by which the distribution of eachlot of drug product can be readily determined to facilitateits recall if necessary.

I. L




Section 211.160, General Requirements, states that: (a)The establishment of any specifications, standards, sam-pling plans, test procedures, or other laboratory controlmechanisms required by this subpart, including anychange in such specifications, standards, sampling plans,test procedures, or other laboratory control mechanisms,shall be drafted by the appropriate organizational unit andreviewed and approved by the quality control unit. Therequirements in this subpart shall be followed and shallbe documented at the time of performance. Any deviationfrom the written specifications, standards, sampling plans,test procedures, or other laboratory control mechanismsshall be recorded and justified. (b) Laboratory controlsshall include the establishment of scientifically sound andappropriate specifications, standards, sampling plans, andtest procedures designed to assure that components, drugproduct containers, closures, in-process materials, label-ing, and drug products conform to appropriate standardsof identity, strength, quality, and purity. Laboratory con-trols shall include:

1. Determination of conformance to appropriatewritten specifications for the acceptance of eachlot within each shipment of components, drugproduct containers, closures, and labeling usedin the manufacture, processing, packing, orholding of drug products. The specificationsshall include a description of the sampling andtesting procedures used. Samples shall be rep-resentative and adequately identified. Such pro-cedures shall also require appropriate retestingof any component, drug product container, orclosure that is subject to deterioration.

2. Determination of conformance to written spec-ifications and a description of sampling andtesting procedures for in-process materials.Such samples shall be representative and prop-erly identified.

3. Determination of conformance to writtendescriptions of sampling procedures and appro-priate specifications for drug products. Suchsamples shall be representative and properlyidentified.

4. The calibration of instruments, apparatus,gauges, and recording devices at suitable inter-vals in accordance with an established writtenprogram containing specific directions, sched-ules, limits for accuracy and precision, and pro-visions for remedial action in the eventaccuracy and/or precision limits are not met.Instruments, apparatus, gauges, and recordingdevices not meeting established specificationsshall not be used.

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Section 211.165, Testing and Release for Distribu-tion, states that: (a) For each batch of drug product, thereshall be appropriate laboratory determination of satisfac-tory conformance to final specifications for the drug prod-uct, including the identity and strength of each activeingredient, prior to release. Where sterility and/or pyrogentesting are conducted on specific batches of short-livedradiopharmaceuticals, such batches may be released priorto completion of sterility and/or pyrogen testing, providedsuch testing is completed as soon as possible. (b) Thereshall be appropriate laboratory testing, as necessary, ofeach batch of drug product required to be free of objec-tionable microorganisms. (c) Any sampling and testingplans shall be described in written procedures that shallinclude the method of sampling and the number of unitsper batch to be tested; such written procedure shall befollowed. (d) Acceptance criteria for the sampling andtesting conducted by the quality control unit shall be ade-quate to assure that batches of drug products meet eachappropriate specification and appropriate statistical qualitycontrol criteria as a condition for their approval andrelease. The statistical quality control criteria shall includeappropriate acceptance levels and/or appropriate rejectionlevels. (e) The accuracy, sensitivity, specificity, and repro-ducibility of test methods employed by the firm shall beestablished and documented. Such validation and docu-mentation may be accomplished in accordance with Sec-tion 211.194(a)(2). (f) Drug products failing to meet estab-lished standards or specifications and any other relevantquality control criteria shall be rejected. Reprocessingmay be performed. Prior to acceptance and use, repro-cessed material must meet appropriate standards, specifi-cations, and any other relevant criteria.

Section 211.166, Stability Testing, states that: (a)There shall be a written testing program designed toassess the stability characteristics of drug products. Theresults of such stability testing shall be used in determin-ing appropriate storage conditions and expiration dates.The written program shall be followed and shall include:

1. Sample size and test intervals based on statis-tical criteria for each attribute examined toassure valid estimates of stability;

2. Storage conditions for samples retained for test-ing;

3. Reliable, meaningful, and specific test methods;4. Testing of the drug product in the same con-

tainer-closure system as that in which the drugproduct is marketed;

5. Testing of drug products for reconstitution atthe time of dispensing (as directed in the label-ing) as well as after they are reconstituted.

(b) An adequate number of batches of each drug productshall be tested to determine an appropriate expiration date

and a record of such data shall be maintained. Acceleratedstudies, combined with basic stability information on thecomponents, drug products, and container-closure system,may be used to support tentative expiration dates providedfull shelf life studies are not available and are being con-ducted. Where data from accelerated studies are used toproject a tentative expiration date that is beyond a datesupported by actual shelf life studies, there must be sta-bility studies conducted, including drug product testing atappropriate intervals, until the tentative expiration date isverified or the appropriate expiration date determined. (c)For homeopathic drug products, the requirements of thissection are as follows:

1. There shall be a written assessment of stabilitybased at least on testing or examination of thedrug product for compatibility of the ingredi-ents, and based on marketing experience withthe drug product to indicate that there is nodegradation of the product for the normal orexpected period of use.

2. Evaluation of stability shall be based on thesame container-closure system in which thedrug product is being marketed.

(d) Allergenic extracts that are labeled No U.S. Standardof Potency are exempt from the requirements of thissection. (43 FR 45077, Sept. 29, 1978, as amended at 46FR 56412, Nov. 17, 1981.)

Section 211.167, Special Testing Requirements,states that: (a) For each batch of drug product purportingto be sterile and/or pyrogen-free, there shall be appropriatelaboratory testing to determine conformance to suchrequirements. The test procedures shall be in writing andshall be followed. (b) For each batch of ophthalmic oint-ment, there shall be appropriate testing to determine con-formance to specifications regarding the presence of for-eign particles and harsh or abrasive substances. The testprocedures shall be in writing and shall be followed. (c)For each batch of controlled-release dosage form, thereshall be appropriate laboratory testing to determine con-formance to the specifications for the rate of release ofeach active ingredient. The test procedures shall be inwriting and shall be followed.

Section 211.170, Reserve Samples, states that: (a)An appropriately identified reserve sample that is repre-sentative of each lot in each shipment of each active ingre-dient shall be retained. The reserve sample consists of atleast twice the quantity necessary for all tests required todetermine whether the active ingredient meets its estab-lished specifications, except for sterility and pyrogen test-ing. The retention time is as follows:

1. For an active ingredient in a drug product otherthan those described in paragraphs (a) (2) and

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(3) of this section, the reserve sample shall beretained for 1 year after the expiration date ofthe last lot of the drug product containing theactive ingredient.

2. For an active ingredient in a radioactive drugproduct, except for nonradioactive reagent kits,the reserve sample shall be retained for:i. Three months after the expiration date of

the last lot of the drug product containingthe active ingredient if the expiration dat-ing period of the drug product is 30 daysor less; or

ii. Six months after the expiration date of thelast lot of the drug product containing theactive ingredient if the expiration datingperiod of the drug product is more than 30days.

3. For an active ingredient in an OTC drug productthat is exempt from bearing an expiration dateunder Section 211.137, the reserve sample shallbe retained for 3 years after distribution of thelast lot of the drug product containing the activeingredient.

(b) An appropriately identified reserve sample that is rep-resentative of each lot or batch of drug product shall beretained and stored under conditions consistent with prod-uct labeling. The reserve sample shall be stored in thesame immediate container-closure system in which thedrug product is marketed or in one that has essentially thesame characteristics. The reserve sample consists of atleast twice the quantity necessary to perform all therequired tests, except those for sterility and pyrogens.Except for those drug products described in paragraph(b) (2) of this section, reserve samples from representativesample lots or batches selected by acceptable statisticalprocedures shall be examined visually at least once a yearfor evidence of deterioration unless visual examinationwould affect the integrity of the reserve sample. Any evi-dence of reserve sample deterioration shall be investigatedin accordance with Section 211.192. The results of exam-ination shall be recorded and maintained with other sta-bility data on the drug product. Reserve samples of com-pressed medical gases need not be retained. The retentiontime is as follows:

1. For a drug product other than those describedin paragraphs (b) (2) and (3) of this section, thereserve sample shall be retained for 1 year afterthe expiration date of the drug product.

2. For a radioactive drug product, except for non-radioactive reagent kits, the reserve sampleshall be retained for:

i. Three months after the expiration date ofthe drug product if the expiration datingperiod of the drug product is 30 days orless; or

ii. Six months after the expiration date of thedrug product if the expiration dating periodof the drug product is more than 30 days.

3. For an OTC drug product that is exempt forbearing an expiration date under Section211.137, the reserve sample must be retainedfor 3 years after the lot or batch of drug productis distributed. (48 FR 13025, Mar. 29, 1983,as amended at 60 FR 4091, Jan. 20, 1995.)

Section 211.173, Laboratory Animals, states that:Animals used in testing components, in-process materi-als, or drug products for compliance with established spec-ifications shall be maintained and controlled in a mannerthat assures their suitability for their intended use. Theyshall be identified, and adequate records shall be main-tained showing the history of their use.

Section 211.176, Penicillin Contamination, statesthat: If a reasonable possibility exists that a non-penicillindrug product has been exposed to cross-contaminationwith penicillin, the non-penicillin drug product shall betested for the presence of penicillin. Such drug productshall not be marketed if detectable levels are found whentested according to procedures specified in Proceduresfor Detecting and Measuring Penicillin Contamination inDrugs, which is incorporated by reference. Copies areavailable from the Division of Research and Testing(HFD-470), Center for Drug Evaluation and Research,Food and Drug Administration, 200 C Street S.W., Wash-ington, D.C. 20204, or available for inspection at theOffice of the Federal Register, 800 North Capitol StreetN.W., Suite 700, Washington, D.C. 20408. (43 FR 45077,Sept. 29, 1978, as amended at 47 FR 9396, Mar. 5, 1982;50 FR 8996, Mar. 6, 1985; 55 FR 11577, Mar. 29, 1990.)

J. R





Section 211.180, General Requirements, states that: (a)Any production, control, or distribution record that isrequired to be maintained in compliance with this part andis specifically associated with a batch of a drug productshall be retained for at least 1 year after the expirationdate of the batch or, in the case of certain OTC drugproducts lacking expiration dating because they meet thecriteria for exemption under Section 211.137, 3 years afterdistribution of the batch. (b) Records shall be maintainedfor all components, drug product containers, closures, andlabeling for at least 1 year after the expiration date or, inthe case of certain OTC drug products lacking expirationdating because they meet the criteria for exemption underSection 211.137, 3 years after distribution of the last lot

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of drug product incorporating the component or using thecontainer, closure, or labeling. (c) All records requiredunder this part, or copies of such records, shall be readilyavailable for authorized inspection during the retentionperiod at the establishment where the activities describedin such records occurred. These records or copies thereofshall be subject to photocopying or other means of repro-duction as part of such inspection. Records that can beimmediately retrieved from another location by computeror other electronic means shall be considered as meetingthe requirements of this paragraph. (d) Records requiredunder this part may be retained either as original recordsor as true copies such as photocopies, microfilm, micro-fiche, or other accurate reproductions of the originalrecords. Where reduction techniques, such as microfilm-ing, are used, suitable reader and photocopying equipmentshall be readily available. (e) Written records required bythis part shall be maintained so that data therein can beused for evaluating, at least annually, the quality standardsof each drug product to determine the need for changesin drug product specifications or manufacturing or controlprocedures. Written procedures shall be established andfollowed for such evaluations and shall include provisionsfor:

1. A review of a representative number of batches,whether approved or rejected, and, where appli-cable, records associated with the batch.

2. A review of complaints, recalls, returned or sal-vaged drug products, and investigations con-ducted under Section 211.192 for each drugproduct.

(f) Procedures shall be established to assure that theresponsible officials of the firm, if they are not personallyinvolved in or immediately aware of such actions, arenotified in writing of any investigations conducted underSections 211.198, 211.204, or 211.208 of these regula-tions, any recalls, reports of inspectional observationsissued by the Food and Drug Administration, or any reg-ulatory actions relating to good manufacturing practicesbrought by the Food and Drug Administration. (43 FR45077, Sept. 29, 1978, as amended at 60 FR 4901, Jan.20, 1995.)

Section 211.182, Equipment Cleaning and Use Log,states that: A written record of major equipment cleaning,maintenance (except routine maintenance such as lubrica-tion and adjustments), and use shall be included in indi-vidual equipment logs that show the date, time, product,and lot number of each batch processed. If equipment isdedicated to manufacture of one product, then individualequipment logs are not required, provided that lots orbatches of such product follow in numerical order and aremanufactured in numerical sequence. In cases where ded-icated equipment is employed, the records of cleaning,

maintenance, and use shall be part of the batch record.The persons performing and double-checking the cleaningand maintenance shall date and sign or initial the logindicating that the work was performed. Entries in the logshall be in chronological order.

Section 211.184, Component, Drug Product Con-tainer, Closure, and Labeling Records, states that: Theserecords shall include the following: (a) The identity andquantity of each shipment of each lot of components, drugproduct containers, closures, and labeling; the name of thesupplier; the suppliers lot number(s) if known; the receiv-ing code as specified in Section 211.80; and the date ofreceipt. The name and location of the prime manufacturer,if different from the supplier, shall be listed if known. (b)The results of any test or examination performed (includ-ing those performed as required by Sections 211.82(a),211.84(d), or 211.122(a)) and the conclusions derivedtherefrom. (c) An individual inventory record of each com-ponent, drug product container, and closure and, for eachcomponent, a reconciliation of the use of each lot of suchcomponent. The inventory record shall contain sufficientinformation to allow determination of any batch or lot ofdrug product associated with the use of each component,drug product container, and closure. (d) Documentationof the examination and review of labels and labeling forconformity with established specifications in accord withSections 211.122(c) and 211.130(c). (e) The dispositionof rejected components, drug product containers, closure,and labeling.

Section 211.186, Master Production and ControlRecords, states that: (a) To assure uniformity from batchto batch, master production and control records for eachdrug product, including each batch size thereof, shall beprepared, dated, and signed (full signature, handwritten)by one person and independently checked, dated, andsigned by a second person. The preparation of masterproduction and control records shall be described in awritten procedure and such written procedure shall befollowed. (b) Master production and control records shallinclude:

1. The name and strength of the product and adescription of the dosage form;

2. The name and weight or measure of each activeingredient per dosage unit or per unit of weightor measure of the drug product, and a statementof the total weight or measure of any dosageunit;

3. A complete list of components designated bynames or codes sufficiently specific to indicateany special quality characteristic;

4. An accurate statement of the weight or measureof each component, using the same weight sys-tem (metric, avoirdupois, or apothecary) foreach component. Reasonable variations may be

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permitted, however, in the amount of compo-nents necessary for the preparation in the dos-age form, provided they are justified in themaster production and control records;

5. A statement concerning any calculated excessof component;

6. A statement of theoretical weight or measure atappropriate phases of processing;

7. A statement of theoretical yield, including themaximum and minimum percentages of theo-retical yield beyond which investigationaccording to Section 211.192 is required;

8. A description of the drug product containers,closures, and packaging materials, including aspecimen or copy of each label and all otherlabeling signed and dated by the person or per-sons responsible for approval of such labeling;

9. Complete manufacturing and control instruc-tions, sampling and testing procedures, specifi-cations, special notations, and precautions to befollowed.

Section 211.188, Batch Production and ControlRecords, states that: Batch production and controlrecords shall be prepared for each batch of drug productproduced and shall include complete information relatingto the production and control of each batch. These recordsshall include: (a) An accurate reproduction of the appro-priate master production or control record, checked foraccuracy, dated, and signed; (b) Documentation that eachsignificant step in the manufacture, processing, packing,or holding of the batch was accomplished, including:

1. Dates;2. Identity of individual major equipment and

lines used;3. Specific identification of each batch of compo-

nent or in-process material used;4. Weights and measures of components used in

the course of processing;5. In-process and laboratory control results;6. Inspection of the packaging and labeling area

before and after use;7. A statement of the actual yield and a statement

of the percentage of theoretical yield at appro-priate phases of processing;

8. Complete labeling control records, includingspecimens or copies of all labeling used;

9. Description of drug product containers andclosures;

10. Any sampling performed;11. Identification of the persons performing and

directly supervising or checking each signifi-cant step in the operation;

12. Any investigation made according to Section211.192.

13. Results of examinations made in accordancewith Section 211.134.

Section 211.192, Production Record Review, statesthat: All drug product production and control records,including those for packaging and labeling, shall bereviewed and approved by the quality control unit to deter-mine compliance with all established, approved writtenprocedures before a batch is released or distributed. Anyunexplained discrepancy (including a percentage of theo-retical yield exceeding the maximum or minimum per-centages established in master production and controlrecords) or the failure of a batch or any of its componentsto meet any of its specifications shall be thoroughly inves-tigated, whether or not the batch has already been distrib-uted. The investigation shall extend to other batches of thesame drug product and other drug products that may havebeen associated with the specific failure or discrepancy.A written record of the investigation shall be made andshall include the conclusions and followup.

Section 211.194, Laboratory Records, states that:(a) Laboratory records shall include complete dataderived from all tests necessary to assure compliance withestablished specifications and standards, including exam-inations and assays, as follows:

1. A description of the sample received for testingwith identification of source (that is, locationfrom where sample was obtained), quantity, lotnumber or other distinctive code, date samplewas taken, and date sample was received fortesting.

2. A statement of each method used in the testingof the sample. The statement shall indicate thelocation of data that establish that the methodsused in the testing of the sample meet properstandards of accuracy and reliability as appliedto the product tested. (If the method employedis in the current revision of the United StatesPharmacopeia, National Formulary, Associa-tion of Official Analytical Chemists, Book ofMethods, or in other recognized standard refer-ences, or is detailed in an approved new drugapplication and the referenced method is notmodified, a statement indicating the method andreference will suffice.) The suitability of all test-ing methods used shall be verified under actualconditions of use. Copies may be obtainedfrom: Association of Official Analytical Chem-ists, 2200 Wilson Blvd., Suite 400, Arlington,VA 22201-3301.

3. A statement of the weight or measure of sampleused for each test, where appropriate.

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Handbook of Pharmaceutical Manufacturing Formulations: Uncompressed Solid Products

4. A complete record of all data secured in thecourse of each test, including all graphs, charts,and spectra from laboratory instrumentation,properly identified to show the specific compo-nent, drug product container, closure, in-pro-cess material, or drug product, and lot tested.

5. A record of all calculations performed inconnection with the test, including units ofmeasure, conversion factors, and equivalencyfactors.

6. A statement of the results of tests and how theresults compare with established standards ofidentity, strength, quality, and purity for thecomponent, drug product container, closure, in-process material, or drug product tested.

7. The initials or signature of the person who per-forms each test and the date(s) the tests wereperformed.

8. The initials or signature of a second personshowing that the original records have beenreviewed for accuracy, completeness, and com-pliance with established standards.

(b) Complete records shall be maintained of any modifi-cation of an established method employed in testing. Suchrecords shall include the reason for the modification anddata to verify that the modification produced results thatare at least as accurate and reliable for the material beingtested as the established method. (c) Complete recordsshall be maintained of any testing and standardization oflaboratory reference standards, reagents, and standardsolutions. (d) Complete records shall be maintained of theperiodic calibration of laboratory instruments, apparatus,gauges, and recording devices required by Section211.160(b)(4). (e) Complete records shall be maintainedof all stability testing performed in accordance with Sec-tion 211.166. (43 FR 45077, Sept. 29, 1978, as amendedat 55 FR 11577, Mar. 29, 1990.)

Section 211.196, Distribution Records, Distribu-tion records shall contain the name and strength of theproduct and description of the dosage form, name andaddress of the consignee, date and quantity shipped, andlot or control number of the drug product. For compressedmedical gas products, distribution records are not requiredto contain lot or control numbers. (Approved by theOffice of Management and Budget [OMB] under controlnumber 0910-0139) (49 FR 9865, Mar. 16, 1984)

Section 211.198, Complaint Files, states that: (a)Written procedures describing the handling of all writtenand oral complaints regarding a drug product shall beestablished and followed. Such procedures shall includeprovisions for review by the quality control unit, of anycomplaint involving the possible failure of a drug productto meet any of its specifications and, for such drug prod-ucts, a determination as to the need for an investigation

in accordance with Section 211.192. Such proceduresshall include provisions for review to determine whetherthe complaint represents a serious and unexpected adversedrug experience which is required to be reported to theFood and Drug Administration in accordance with Section310.305 of this chapter. (b) A written record of each com-plaint shall be maintained in a file designated for drugproduct complaints. The file regarding such drug productcomplaints shall be maintained at the establishment wherethe drug product involved was manufactured, processed,or packed, or such file may be maintained at anotherfacility if the written records in such files are readilyavailable for inspection at that other facility. Writtenrecords involving a drug product shall be maintained untilat least 1 year after the expiration date of the drug product,or 1 year after the date that the complaint was received,whichever is longer. In the case of certain OTC drugproducts lacking expiration dating because they meet thecriteria for exemption under Section 211.137, such writtenrecords shall be maintained for 3 years after distributionof the drug product.

1. The written record shall include the followinginformation, where known: the name andstrength of the drug product, lot number, nameof complainant, nature of complaint, and replyto complainant.

2. Where an investigation under Section 211.192is conducted, the written record shall includethe findings of the investigation and followup.The record or copy of the record of the inves-tigation shall be maintained at the establishmentwhere the investigation occurred in accordancewith Section 211.180(c).

3. Where an investigation under Section 211.192is not conducted, the written record shallinclude the reason that an investigation wasfound not to be necessary and the name of theresponsible person making such a determina-tion. (43 FR 45077, Sept. 29, 1978, asamended at 51 FR 24479, July 3, 1986.)

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Section 211.204, Returned Drug Products, states that:Returned drug products shall be identified as such andheld. If the conditions under which returned drug productshave been held, stored, or shipped before or during theirreturn, or if the condition of the drug product, its container,carton, or labeling, as a result of storage or shipping, castsdoubt on the safety, identity, strength, quality, or purity ofthe drug product, the returned drug product shall bedestroyed unless examination, testing, or other investiga-tions prove the drug product meets appropriate standardsof safety, identity, strength, quality, or purity. A drug

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product may be reprocessed provided the subsequent drugproduct meets appropriate standards, specifications, andcharacteristics. Records of returned drug products shall bemaintained and shall include the name and label potencyof the drug product dosage form, lot number (or controlnumber or batch number), reason for the return, quantityreturned, date of disposition, and ultimate disposition ofthe returned drug product. If the reason for a drug productbeing returned implicates associated batches, an appropri-ate investigation shall be conducted in accordance withthe requirements of Section 211.192. Procedures for theholding, testing, and reprocessing of returned drug prod-ucts shall be in writing and shall be followed.

Section 211.208, Drug Product Salvaging, statesthat: Drug products that have been subjected to improperstorage conditions including extremes in temperature,humidity, smoke, fumes, pressure, age, or radiation due

to natural disasters, fires, accidents, or equipment failuresshall not be salvaged and returned to the marketplace.Whenever there is a question whether drug products havebeen subjected to such conditions, salvaging operationsmay be conducted only if there is (a) evidence from lab-oratory tests and assays (including animal feeding studieswhere applicable) that the drug products meet all appli-cable standards of identity, strength, quality, and purityand (b) evidence from inspection of the premises that thedrug products and their associated packaging were notsubjected to improper storage conditions as a result of thedisaster or accident. Organoleptic examinations shall beacceptable only as supplemental evidence that the drugproducts meet appropriate standards of identity, strength,quality, and purity. Records including name, lot number,and disposition shall be maintained for drug products sub-ject to this section.

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Vol 2 - Handbook of Pharmaceutical Manufacturing Formulations Uncompressed Solid Products (Volume 2 of 6)/1747_C02.pdf 2 Compliance Program Guidance Manual for FDA Staff: Drug Manufacturing Inspections


A primary mission of the Food and Drug Administration(FDA) is to conduct comprehensive regulatory coverageof all aspects of production and distribution of drugs anddrug products to assure that such products meet the501(a)(2)(B) requirements of the Food, Drugs and Cos-metics Act. The FDA has developed two basic strategies:

1. Evaluating through factory inspections, includ-ing the collection and analysis of associatedsamples, the conditions and practices underwhich drugs and drug products are manufac-tured, packed, tested, and held

2. Monitoring the quality of drugs and drug prod-ucts through surveillance activities such as sam-pling and analyzing products in distribution

This compliance program is designed to provide guid-ance for implementing the first strategy. Products fromproduction and distribution facilities covered under thisprogram are consistently of acceptable quality if the firmis operating in a state of control. The Drug Product Sur-veillance Program (CP 7356.008) provides guidance forthe latter strategy.



The goal of this programs activities is to minimize con-sumers exposure to adulterated drug products. Under