Lean what 21 CFR Parts 210 and 211 are and how you an implement these regulations in your organization. For more information and tips on compliance go to http://compliance-insight.com/fda-gcp-and-gmp-training/21-cfr-210-211/

1. 21 CFR, Parts 210 and 211
An Overview of the Regulations

2. 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

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

4. 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

5. 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

6. 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

7. 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.

8. 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

9. 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!

10. 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

11. 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

12. 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

13. 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

14. 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?

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 211.58 Maintenance
• Facilities shall be
maintained in a good state
of repair

23. 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

24. 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

25. 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

26. 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

27. 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)

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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)

34. 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.

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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

51. 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

52. 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

53. 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

54. 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

55. 211.142 Warehousing
• Drug products must be quarantined prior
to QC release
• Storage conditions must not affect drug
products adversely (light, temperature,
humidity)

56. 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

57. 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

58. 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

59. 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

60. 211.170
• Reserve samples shall be taken
• Representative of each lot
• Twice the quantity for full battery of tests
• Final product
• API

61. 211.173 and 211.176
• 211.173 Lab animals maintained and
controlled
• 211.176
– Penicillin controlled in separate facility

62. 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

63. 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

64. 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

65. 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

66. 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”

67. 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

68. 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

69. 211.204
• Returned products identified and held
• If conditions of return or storage are in
doubt, investigation is warranted
• Procedures shall be in writing

70. 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

71. The End
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