CODE OF FEDERAL REGULATION CFR.pptx

Code of federal regulations

1. CODE OF FEDERAL REGULATION (CFR) PRESENTED BY ADITYA MADHUKAR PATIL M PHARM 1 ST 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 (1 st in - 1 st 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 2 nd 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