Code of federal regulations

1. CODE OF FEDERAL REGULATION
(CFR)
PRESENTEDBY
ADITYAMADHUKARPATIL
M PHARM 1ST YEAR
PHARMACEUTICS DEPARTMENT

2. CONTENTS
• HISTORY
• DEFINATION
• 21 CFR, PART 210 AND 211- AN OVERVIEW OF THE
REGULATIONS

3. HISTORY
US FDA
FEDERAL AGENCY OF USA
FDA ensures the quality of drug products by carefully monitoring
drug manufacturers' compliance with its Current Good
Manufacturing Practice (CGMP) regulations.
 The CGMP regulations for drugs contain minimum requirements for
the methods, facilities, and controls used in manufacturing,
processing, and packing of a drug product.
The regulations make sure that a product is safe for use, and that it
has the ingredients and strength it claims to have.

4. Formed in June 30 , 1906 (111 yrs)
Founders : Theodore Roosevelt , Harvey Washington Wiley.
Headquarters : white Oak Campus , 10903 New Hampshire Avenue ,
Silver Spring , Maryland.
Executive agency
Scott Gottlieb , Commissioner of Foods and Drugs.
Parent Agency
Department of Health and Human Services.

5. FDA IN INDIA
• FDA opened the India Office in New Delhi in 2008, to ensure that
food and medical products exported from India to the U.S. are safe,
are of good quality, and are effective.
• FDA’s goals in India are to obtain information to help make better
regulatory decisions about the products from India that are being
developed and exported for the U.S. market. This includes medical
products being reviewed for marketing authorization in the U.S.,
and the safety assessment of products that are already on the U.S.
market. In addition, the India Office helps verify that foods being
imported into the U.S. are safe.

6. FDA activities in INDIA include:
• Conducting inspections of medical products and foods facilities that
export to the U.S.
• Engaging with Indian regulatory authorities to build confidence in each
other and develop quality standards
• Partnering with Indian counterpart agencies on bilateral initiatives
• Assisting and training Indian regulators, Indian pharmaceutical and foods
industries and stakeholders on developing and maintaining the quality,
safety and effectiveness of medical products and foods
• Building and strengthening relationships with the government of India by
supporting the mission of the U.S. Embassy

7. MISSION
• FDA is responsible for protecting the public health by
assuring the safety, efficacy and security
• FDA is also responsible for advancing the public
health by helping to speed innovations that make
medicines more effective, safer, and more affordable
• Help the public get the accurate, science-based
information they need to use medicines and foods to
maintain and improve their health.
• FDA also has responsibility on tobacco products to
protect the public health and to reduce tobacco use
by minors.

8. FDA
ORGANIZATION
Centre for
Drug
Evaluation
and
Research
Centre for
Biological
Evaluation
and
Research
Centre for
Devices
Radiological
Health
Centre for
Food Safety
and Applied
Nutrition
Centre for
Tobacco
Products
Centre for
Veterinary
Products
National
Center for
Toxicological
Research

9. What does FDA Regulates ?
Foods, including:
• Dietary Supplements
• Bottled Water
• Food Additives
• Infant Formulas
Drugs, including:
• Prescription Drugs (both brand-name and generic)
• Non-prescription (over-the-counter) drugs
Biologics, including:
• Vaccines
• Blood and Blood Products
• Cellular and Gene therapy products
• Tissue and Tissue products
• Allergenic extracts

10. Medical Devices, including:
• Simple items like Tongue depressors and Bedpans
• Complex technologies such as Heart pacemakers
• Dental devices
• Surgical implants and Prosthetics
Electronic Products that give off radiation, including:
• Microwave ovens
• X-ray equipment
• Laser products
• Ultrasonic therapy equipment
• Mercury vapor lamps
• Sunlamps

11. Cosmetics, including:
• color additives found in makeup and
other personal care products
• skin moisturizers and cleansers
• nail polish and perfume
Veterinary Products, including:
• livestock feeds
• pet foods
• veterinary drugs and devices
Tobacco Products, including:
• cigarettes
• cigarette tobacco
• roll-your-own tobacco
• smokeless tobacco

12. FDA does not regulates :
Advertising
The Federal Trade Commission is a federal agency
that regulates many types of advertising. The FTC
protects consumers by stopping unfair, deceptive or
fraudulent practices in the marketplace.
Alcohol
The Department of the Treasury’s Alcohol and
Tobacco Tax and Trade Bureau regulates aspects of
alcohol production, importation, wholesale
distribution, labeling, and advertising.

13. Consumer Products
The Consumer Product Safety Commission (CPSC)
works to ensure the safety of consumer products such
as toys, cribs, power tools, cigarette lighters,
household chemicals, and other products that pose a
fire, electrical, chemical or mechanical hazard.
Drugs of Abuse
The Department of Justice’s Drug Enforcement
Administration(DEA)works to enforce the controlled
substances laws and regulations of the United States,
including as they pertain to the manufacture,
distribution, and dispensing of legally produced
controlled substances.

14. Meat and Poultry
The U.S. Department of Agriculture's Food Safety
and Inspection Service regulates aspects of the
safety and labeling of traditional (non-game) meats,
poultry, and certain egg products.
Pesticides
The Environmental Protection Agency (EPA)
regulates many aspects of pesticides. EPA sets limits
on how much of a pesticide may be used on food
during growing and processing, and how much can
remain on the food you buy.

15. Vaccines for Animal Diseases
The U.S. Department of Agriculture’s Animal and
Plant Health Inspection Service (APHIS), Center for
Veterinary Biologics, regulates aspects of veterinary
vaccines and other types of veterinary biologics.
Water
The Environmental Protection Agency(EPA) regulates
aspects of drinking water. EPA develops national
standards for drinking water from municipal water
supplies (tap water) to limit the levels of impurities.

16. FDA Advisory Committee.
• Advisory committees provide FDA with independent advice from
outside experts on issues related to human and veterinary drugs,
vaccines and other biological products, medical devices, and food.
• In general, advisory committees include a chair, several members,
plus a consumer, industry, and sometimes a patient representative.
Additional experts with special knowledge may be added for
individual committee meetings as needed. Although the committees
provide advice to the agency, FDA makes the final decisions.
• The final regulations published in the Federal Register (daily
published record of proposed rules, final rules, meeting notices,
etc.) are collected in the CFR.

17. DEFINATION
The Code of Federal Regulations(CFR) is an annual codification of
the general and permanent rules published in the Federal Register
by the executive departments and agencies of the Federal
Government.
The Code of Federal Regulations (CFR) is available:
As an electronic configuration, free of charge, on the GPO's Federal
Digital System (FDsys), maintained by the U.S. Government Printing
Office.
As paper publications, by full set subscription or individual copy
purchase, from the Superintendent of Documents, or at any Federal
Configuration Library.

18. The CFR is divided into 50 titles representing broad
areas subject to Federal regulation.
Each Title is divided into chapters that are assigned to
agencies issuing regulations pertaining to that broad
subject area. Each chapter is divided into parts and
each part is then divided into sections -- the basic unit
of the CFR.
The purpose of the CFR is to present the official and
complete text of agency regulations in one organized
publication and to provide a comprehensive and
convenient reference for all those who may need to
know the text of general and permanent Federal
regulations.

19. Section 21 of the CFR contains most regulations pertaining to food
and drugs. The regulations document the actions of drug sponsors
that are required under Federal law.
• 21 Code of Federal Regulations Part 210. Current Good
Manufacturing Practice in Manufacturing Processing, packing, or
Holding of Drugs.
• 21 Code of Federal Regulations Part 211. Current Good
Manufacturing Practice for Finished Pharmaceuticals.

20. 21 CFR , PARTS 210 AND 211
AN OVERVIEW OF THE REGULATIONS

21. Part 210
• Status of the regulations – 210.1
– Regulations set forth are “minimum” requirements!!!!
– Covers manufacturing, facilities and controls for
• Manufacturing, processing, packaging or holding of a drug product
– Failure to comply will render the drug to be adulterated
• The person who is responsible for the failure to comply shall be subject to
regulatory action

22. Part 210
• Applicability – 210.2
• Applies to drug products for human use

23. Part 210
•The Definitions – 210.3
•This is a critical section – understand
the definitions, learn these or you
will fail!
•Here are some:
• Act means the Federal Food, Drug and
Cosmetic Act

24. Part 210 – Definitions Cont.
• Batch
• A specific quantity of drug/material intended to have uniform character and
quality produced under a single manufacturing order form during the same
cycle of manufacture.
• Component
• Any ingredient intended for use INCLUDING those that may not appear in
such drug product

25. Part 210 – Definitions Cont.
• Drug Product
• Finished dosage form
• Fiber
• Any particulate with a length at least 3x its width
• Active ingredient
• Any component intended to furnish pharmacological activity

26. Part 210 – Definitions Cont.
• Drug is defined by the Act as any compound that has effect in the
diagnosis, cure, mitigation, treatment or prevention of disease or to
affect the structure or function of the body of man or animals
• In-process material
• Any material fabricated, compounded, blended or derived for use in the drug
product.

27. Part 210 – Definitions Cont.
• Manufacture, processing, packing or holding includes
• Packaging and labeling, testing and quality control of drug
products
• Quality Control
• Any person or unit designated by the firm to be responsible
for duties relating to QC
• Representative Sample
• Samples drawn on rational criteria intended to accurately
portray the material being sampled

28. Part 211
• This is the “meat” of the regulations
• There are 11 subparts (identified by letters from A through K)
• Covers all sections of operations
• Designed to be all encompassing (general) – DON’T expect too many
specifics
• The goal is to tell you what to do, not how to do it!

29. Subpart A – Part 211
• General Provisions
• 211.1 – Scope
• 211.3 – Definitions
• Scope
• Minimum requirements
• Applies to drugs for human use
• Definitions
• Those set forth in 210.3 are applicable

30. 211.22
• Responsibilities of QC unit
• Shall be a quality control unit
• They shall have the responsibility and authority to
approve or reject all components, containers,
closures, in-process materials, packaging material,
labeling and drug products
• Authority to review production records
• If errors have occurred, that they have been fully
investigated

31. 211.22
• The QC unit shall have adequate laboratory facilities
• They shall have the responsibility for
approving/rejecting all procedures or specifications
impacting the quality of the drug product
• Responsibilities shall be in writing and shall be
followed

32. 211.25
• Personnel qualifications
• Everyone shall have the education, training and experience to do their
jobs
• Everyone who supervises those people shall have the education,
training and experience to assign functions to provide assurance for
drug quality
• There shall be an adequate number of qualified personnel

33. 211.28
•Wear clean clothing and protective
apparel
•Practice good sanitation and health habits
•Limited access areas
•If you are sick – do you belong in the
area?

34. 211.34
• Consultants
• Shall have sufficient education, training and experience to advise on
the subject matter
• Records maintained stating the name, address and qualifications of
consultants

35. Subpart C – Part 211
• 211.42 Design and construction features
• 211.44 Lighting
• 211.46 Ventilation, air filtration, air heating and cooling (HVAC)
• 211.48 Plumbing
• 211.50 Sewage and refuse
• 211.52 Washing and toilet facilities
• 211.56 Sanitation
• 211.58 Maintenance

36. 211.42
• Any building shall be maintained to facilitate cleaning, maintenance
and proper operations
• Adequate space
• Operations performed in defined areas
• Receipt, storage, holding, etc.
• All operations
• Penicillin operations in separate area

37. 211.44 and 211.46
• 211.44 – Lighting
• Adequate lighting provided
• 211.46
• Adequate ventilation
• Adequate equipment for control of environment – micro, dust, air-
pressure
• Air filtration provided

38. 211.48 - Plumbing
• Potable water supplied under continuous positive pressure
• System free of defects
• Potable water meeting EPA requirements (40 CFR, Part 141)
• Drains of adequate size
• Air break provided or back-flow prevention

39. 211.50 and 211.52
• 211.50 – Sewage and refuse
• Dispose of trash, sewage and other refuse in a safe and sanitary
manner
• 211.52 – Washing and toilet facilities
• Adequate washing facilities provided
• Hot and cold potable water
• Soap and detergent
• Air dryers or single-service towels
• Easy access to working areas

40. 211.56 Sanitation
• Facilities maintained in a clean and sanitary condition
• Free of rodents, birds, insects
• Shall be written procedures on cleaning schedules, methods,
equipment and materials
• Shall be written procedures for rodentcides, insecticides, fungicides.
• Prevent contamination

41. 211.58 Maintenance
•Facilities shall be maintained in a
good state of repair

42. 211.63 and 211.65
• 211.63 - Equipment shall be of appropriate design, adequate size and
suitably located to facilitate operations, cleaning and maintenance
• 211.65 – Equipment constructed to not be reactive with product
• Lubricants/coolants shall not come into contact with product to alter
their quality

43. 211.67
• Equipment and utensils cleaned, maintained and sanitized often
enough to prevent contamination and malfunctions
• Written procedures for cleaning and maintenance of equipment and
utensils used within the manufacturing process arena
• Maintenance, cleaning, sanitizing and inspection records

44. 211.68
• Automatic, mechanical and electronic equipment, computers, etc.
used in the manufacturing realm shall be routinely calibrated,
checked and inspected per a written program with retained records of
calibrations, inspections, etc
• Change controls, input/output verification, back-ups

45. 211.72 Filters
•Shall not release fibers into drug products
• If fiber releasing filters are necessary
• Additional filtering using 0.22 micron max
porosity
• 0.45 if manufacturing conditions so dictate
• Use of asbestos-containing filter is allowed
only after proving to FDA safety or
effectiveness is not compromised

46. 211.80 - General
• Written procedures for receipt, sampling, approval, rejection, etc
• Handle and store to prevent contamination
• Bagged or boxed items shall be stored off of the floor and be
adequately space for cleaning and inspection
• Each container of items will be ID’d with code for each lot received
and status (quarantined, approved, rejected)

47. 211.82 – Receipt/Storage of untested items
•Perform visual inspection for correctness of
items, damage, contamination, etc upon
receipt
•Items will be quarantined until inspected
and released

48. 211.84 – Testing and Approval/Rejection
• Each lot must be held until QC release
• Sampling based upon appropriate criteria
• Samples
• Cleaned where necessary
• Obtained in a way to prevent contamination
• Sterile equipment when necessary
• No compositing of subdivided samples
• Samples ID’d with lot #, container, date, etc
• Containers must show samples were taken

49. 211.84 – Testing and Approval/Rejection (con’d)
• Sample testing
• Conduct at least one identity verification
• Test components for conformity to specifications (C of A is OK)
• Test containers and closures for conformity to specifications (C of T is OK)
• Microscopic test of components if appropriate
• Establish contamination spec if item subject to contamination
• Conduct microbiological tests on items that microbiological contamination is
objectionable

50. 211.84 – Testing and Approval/Rejection (con’d)
• Any lot of components, drug product containers or closures that
meets appropriate specifications of identity, strength, quality, purity
and related tests may be approved and released for use. Any lot of
such material that does not meet such specifications shall be rejected

51. 211.86 and 211.87 and 211.89
• 211.86 - Use of approved components, etc
• Use FIFO when possible (1st in - 1st out)
• 211.87 – Retesting of approved components, etc
• After storing for a long time
• After exposure to air, heat or other conditions that may adversely affect
quality
• 211.89 Rejected components, etc
• ID and quarantine to prevent use

52. 211.94 Drug Product Containers and Closures
• Shall not be reactive, additive or absorptive as to adversely effect
product
• Provide protection from external factors that could contaminate or
deteriorate drug
• Clean and suitable for use (sterilize, etc)
• Written standards, test methods to be followed (includes cleaning,
sterilization and non-pyrogenation)

53. 211.100 Written procedures; deviations
• Have written procedures for production and process controls to
ensure drug products have specified identity, strength, quality and
purity. Approval by QA/QC unit
• These procedures shall be followed and the execution of production
and process control functions shall be recorded at time of
completion. Deviations shall be recorded and justified.

54. 211.101 Charge-in of Components
• Each batch formulation should attempt to make 100% of specified
active ingredient
• When a component is transferred to a non-original container, it shall
indicate
• Name, item code
• Receiving or control number
• Weight or measurement in new container
• Batch for which component was issued including name, strength and lot
number

55. 211.101 Charge-in of
Components (con’d)
• Supervision of weighing operations
• QC released component
• Weight or measurement is correct per batch record
• Containers are properly identified
• Each component added to a batch will have verification by a second
person

56. 211.103 Calculation of Yield
• Actual yields and percentages of theoretical yields shall be
determined at the end of each appropriate phase of production.
Calculations will be verified independently by a second person

57. 211.105 Equipment Identification
• All containers, processing lines, major equipment used during
production shall be identified to indicate contents of batch, and
phase, if necessary
• Major equipment shall be uniquely identified and shown in the batch
record to indicate the specific equipment used

58. 211.110 Sampling and testing of
in-process materials and drug products
• Procedures shall indicate in-process controls and tests in order to
validate performance and monitor output, including
• Tablet or capsule weight variation
• Disintegration time
• Adequacy of mixing to assure uniformity
• Dissolution time and rate
• Clarity, completeness or pH of solutions

59. 211.110 Sampling and testing of
in-process materials and drug products
• In-process specifications shall be consistent with final specifications
• In-process materials tested for ID, quality, strength and purity and be
accepted or rejected by QC
• Rejected material shall be quarantined in order to prevent use in
manufacturing

60. 211.111 Time Limitations
• When appropriate, time limitations for completing each phase shall
be established. Deviation from time limits is acceptable if quality is
not compromised. Deviations shall be documented and justified

61. 211.113 Control of microbiological contamination
• Appropriate written procedure for preventing microorgansims in drug
products not required to be sterile
• Appropriate written procedures for preventing microorganisms in
sterilized drug products. These procedures shall include any
sterilization process

62. 211.115 Reprocessing
• Written procedure describing a system for reprocessing non-
conforming batches and steps taken to ensure reprocessed batches
conform to standards and specs
• Reprocessing will not occur without review and approval of QC

63. Subpart G – Packaging and Labeling Control
• 211.122 Materials examination and usage criteria
• 211.125 Labeling issuance
• 211.130 Packaging and labeling operations
• 211.132 Tamper-resistant packaging requirements for
OTC human drug products
• 211.134 Drug product inspection
• 211.137 Expiration dating

64. 211.122 Materials examination
and usage criteria
• Written procedures for receipt, ID, storage, handling, sampling,
testing, etc. There will be sampling and examining of materials
• Materials not meeting specifications will be rejected.
• Records for each shipment will be retained (receipt, examination and
accept/reject)
• Labeling materials for each product will be stored separately. Access
limited to authorized personnel

65. 211.122 Materials examination
and usage criteria (con’d)
• Destroy obsolete and outdated materials
• Gang printing is prohibited unless differentiated by size, shape or
color
• Cut labeling
• Dedicate lines to each product and strength
• Use electronic equipment to perform 100% inspect – or –
• 100% visually using 2nd person to verify
• Printing devices will be monitored

66. 211.125 Printing Issuance
• Must use strict control when issuing
• Compare issued materials to master
• Reconcile quantities (used+returned=issued)
• All excess materials with lot number will be destroyed
• Returned materials shall be stored in a way to prevent
mix-ups
• Procedures will detail control of issuance

67. 211.130 Packaging and
Labeling Operations
• Physically or spatially separate materials to prevent mix-ups or cross-
contamination
• Set aside filled but unlabeled product. ID group to prevent
mislabeling
• Manufacturing history of product must be available via lot or control
number
• Batch record must reflect examination for correctness of labels
• Packaging and labeling facilities must be inspected before and after
labeling operations and reflected in batch record

68. 211.132 Tamper-Resistant Requirements for OTCs
• All OTCs for retail sale except for throat lozenge, dermatological,
insulin and dentifrice products must be tamper-resistant else
considered adulterated
• Tamper-resistant products have one or more barriers or indicators
that show visible evidence of breached integrity
• Two-piece hard gelatin capsules require two tamper-resistant packaging
unless capsules are sealed by a tamper-resistant means
• A minimum of one tamper-resistant feature is required even for sealed, two-
piece gelatin capsules

69. 211.132 Tamper-Resistant Requirements for OTCs
• Prominent statement indicating to consumer the tamper-resistant
feature and will still be visible if the feature is breached or missing
• “Request for Exemption from Tamper-Resistant Rule” petition
• Name of drug product or drug class
• Reason for exemption
• Alternatives or step taken for reducing tampering
• Other information justifying an exemption

70. 211.132 Tamper-Resistant Requirements for OTCs
(con’d)
• OTCs subject to NDA requirements and must notify FDA of packaging
changes
• This section does not affect any requirements for “special packaging”
under the Poison Prevention Packaging Act of 1970

71. 211.134 Drug Product Inspection
• Packaged and labeled product should be final inspected to assure
correct labeling
• A sampling of units shall be collected and inspected for correct
labeling
• Results of inspection shall be recorded in batch record

72. 211.137 Expiration Dating
• Expiration date determined by stability testing
• Related to storage conditions on labeling determined by stability
testing
• Products to be reconstituted must have an expiration date for both
reconstitution and unreconstitution
• Expiration dates must be on labeling

73. 211.137 Expiration Dating (cond’)
• Homeopathic drugs are exempt
• Allergenic extracts labeled “No U.S. Standard of Potency” are exempt
• New products for investigational use are exempt provided they meet
stability specifications in their clinical investigations
• OTCs are exempt if labeling does not have dosage and are stable for
three years

74. 211.142 Warehousing
• Drug products must be quarantined prior to QC release
• Storage conditions must not affect drug products adversely (light,
temperature, humidity)

75. 211.150 Distribution
• Oldest products are distributed first. Deviation is permitted if it is
temporary and appropriate
• System must be in place to readily recall distributed product if
necessary

76. 211.160
• Specs, standards, sampling plans, test procedures and
any changes will be reviewed by the quality unit
• Deviations recorded and justified
• Lab controls – scientifically sound
• Determine conformance to specs
• Components
• In-process
• Sampling
• Calibration done

77. 211.165
• Each batch shall meet final specs prior to release
• Lots free of objectionable microorganisms
• Sampling and testing described in SOPs
• Accuracy, sensitivity, specificity and reproducibility of test methods
established and documented
• Lots not meeting spec are rejected

78. 211.166
• Stability shall be done
• Results shall be used to determine storage conditions
and expiry dates
• Written program includes:
• Sample size, test intervals
• Storage conditions
• Reliable, meaningful and specific test methods

79. 211.170
• Reserve samples shall be taken
• Representative of each lot
• Twice the quantity for full battery of tests
• Final product
• API

80. 211.173 and 211.176
• 211.173 Lab animals maintained and controlled
• 211.176
• Penicillin controlled in separate facility

81. 211.180 General Requirements
• Retain docs at least 1 year after the expiry date or
certain OTCs, 3 years after distribution
• All docs shall be readily available for review
• Docs can be copied
• Data shall be evaluated at least annually
• Procedures established to assure that management are
notified of investigations, recalls and FDA issues

82. 211.182 and 211.184
• 211.182 - Records of major equipment cleaning,
maintenance (except routine) and use shall be
documented
• 211.184 – Records shall be made on components,
containers, closures and labeling
• Name of supplier, supplier lot #, receiving code and date
received
• Results of tests, individual inventory

83. 211.186
• Master records maintained
• Made by one person and checked by another (prepared, dated,
signed – full signature)
• Name & strength, dosage form
• Name and weight measure of API, total weight of each dosage unit
• Complete list of components
• Accurate statement of weights, reasonable variations
• Theoretical reconciliation

84. 211.188
• Batch records maintained for each lot
• Include
• Dates
• Who did the work?
• RM lot #
• Weights used
• Any test results
• Inspections
• Yields
• Specimens of labeling
• Sampling performed
• Any investigations made

85. 211.192
• Records reviewed by the quality unit
• Issues resolved
• Investigations performed
• “The investigation shall extend to other batches … that may have
been associated with the specific failure or discrepancy”

86. 211.194
• Lab records include complete data from all tests
• Description of sample received
• Statement of each method
• Complete record of all data – graphs, charts
• Initials of person doing test and dates
• Initials of person checking and dates
• Calibration data maintained
• Stability records maintained

87. 211.196 and 211.198
• 211.196 - Distribution records maintained – who, where, what,
quantity
• 211.198 – Complaint files maintained
• Investigations performed
• Include name of product, lot number, name of complainant, nature of
complaint, reply

88. 211.204
• Returned products identified and held
• If conditions of return or storage are in doubt,
investigation is warranted
• Procedures shall be in writing

89. 211.208
• Product subjected to improper storage conditions due to disaster or
accident shall not be salvaged
• Unless,
• Tests can show everything is OK
• Evaluation of conditions indicates product was not exposed to such harsh
conditions