Post-Notice of Compliance (NOC) Changes – Quality Guidance 

From Health Canada

Overview

The Post-NOC Changes: Quality guidance assists sponsors with the classification of quality changes made to a new drug that has received a Notice of Compliance (NOC). It also provides sponsors with recommendations on the data to support a change which would be considered sufficient to allow a determination of the impact of the change on the quality of the new drug as it relates to safety, efficacy and/or effective use of the new drug.

Please note, Health Canada has taken a first step to simplify market access for non-prescription drugs. For more information visit, Non-prescription Drug Action Plan. 

Who this guide is for

• Sponsor filing a submission with quality changes post authorization
• Health Canada employees who are processing and screening submissions submitted for a quality change.

In this guide

View complete guide

Download PDF (1,426 KB, 269 pages)

• 1. Introduction
  • 1.1 Objectives
  • 1.2 Scope and application
  • 1.3 Background
• 2. Guidance for Implementation
  • 2.1 Reporting categories
    • 2.1.1 Level I - Supplements (major quality changes)
    • 2.1.2 Level II - Notifiable Changes (moderate quality changes)
    • 2.1.3 Level III - Annual Notification (minor quality changes)
    • 2.1.4 Level IV Changes - Record of Changes
• 3. Documentation
  • 3.1 General information
  • 3.2 Supporting data - Level I and Level II changes
  • 3.3 Supporting data - Level III changes
  • 3.4 Supporting data - Level IV changes
  • 3.5 Comparative studies
    • 3.5.1 Comparative in vivo studies
    • 3.5.2 Comparative in vitro studies
  • 3.6 Stability Testing
  • 3.7 Pharmaceutical development and quality by design
  • 3.8 Consistency lot testing
  • 3.9 On-site evaluation (OSE)
  • 3.10 Multiple changes
  • 3.11 Interchangeable pharmacopoeial texts
• 4. Appendices
  • Appendix 1: Quality Post-NOC Changes (human pharmaceuticals)
    • 3.2.S Drug substance
      • 3.2.S.1 General information
        • 1. Change in the name of the drug substance
      • 3.2.S.2 Manufacture
        • 2. Replacement or addition of a manufacturing site and/or manufacturer
        • 3. Deletion of a manufacturing site or manufacturer for the starting material, intermediate, or drug substance
        • 4. Change in the manufacturing process
        • 5. Change in the batch size for the drug substance or for a continuous process
      • 3.2.S.3 Characterisation
      • 3.2.S.4 Control of the Drug Substance
        • 6. Change in the standard claimed for the drug substance
        • 7. Change in the specification for the drug substance to comply with an updated Schedule B pharmacopoeial monograph
        • 8. Change in the specification for the drug substance involving test and acceptance criteria
        • 9. Change in the specification for the drug substance involving analytical procedures
      • 3.2.S.6 Container Closure System
        • 10. Change in the primary container closure system(s) for the storage and shipment of the drug substance
      • 3.2.S.7 Stability
        • 11. Change in the re-test period (or shelf life) for the drug substance
        • 12. Change in the labelled storage conditions for the drug substance, involving: addition/deletion of a cautionary statement or relaxation/tightening of a temperature criterion
        • 13. Change to the post-approval stability protocol or stability commitment
    • 3.2.P Drug Product
      • 3.2.P.1 Description and Composition of the Drug Product
        • 14. Addition of a dosage form or strength
        • 15. Change in the composition of a solution dosage form
        • 16. Change in the composition of an immediate release dosage form including film- coating, colours, flavours and printing inks
        • 17. Change in the composition (qualitative or quantitative) in the release controlling agent of a modified release dosage form
        • 18. Change to product markings, involving a change in embossing, debossing, or engraving (except scorelines/break lines) (e.g., plain tablet to engraved, engraved to plain, change in engraving) or a change in imprinting (e.g., plain tablet/capsule to imprinted tablet/capsule)
        • 19. Change in scoring configuration
        • 20. Change in shape or dimensions of tablets, capsules, suppositories or pessaries
        • 21. Change in diluent
      • 3.2.P.2 Pharmaceutical Development
        • 22. Change in the approved design space
      • 3.2.P.3 Manufacture
        • 23. Replacement or addition of a drug product manufacturer / manufacturing site
        • 24. Change in the batch size for the drug product
        • 25. Change in the drug product manufacturing process
        • 26. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates
        • 27. Change in the approved protocol for process validation and/or evaluation studies
      • 3.2.P.4 Control of Excipients
        • 28. Change in the source of an excipient from a vegetable source, synthetic source, or non-TSE (e.g., animal) to a TSE risk (e.g., animal) source, or from a TSE risk (e.g., animal) to a different TSE risk (e.g., animal)
        • 29. Change in the source of an excipient from a TSE risk (e.g., animal) source to a vegetable or synthetic source
      • 3.2.P.5 Control of Drug Product
        • 30. Change in the standard claimed for the drug product (e.g., from a House Standard to a Schedule B pharmacopoeial standard) or change in the specification for the drug product to comply with an updated Schedule B pharmacopoeial monograph
        • 31. Change in the specification for the drug product tests and acceptance criteria
        • 32. Change in the specification for the drug product, for analytical procedures
      • 3.2.P.7 Container Closure System
        • 33. Replacement or addition of a primary container closure system
        • 34. Change in the package size
        • 35. Change in qualitative and/or quantitative composition of any primary or functional secondary container closure component
        • 36. Change in the specification for a primary or functional secondary container closure component where there is no other change in the container closure system
      • 3.2.P.8 Stability
        • 37. Change in the shelf life for the drug product
        • 38. Change in the labelled conditions for drug product, or reconstituted/diluted product
        • 39. Change to the post-approval stability protocol or stability commitment
  • Appendix 2: Quality Post-NOC Changes (Veterinary Drugs)
    • 3.2.S Drug Substance
      • 3.2.S.1 General Information
        • 1. Change in the name of the drug substance
      • 3.2.S.2 Manufacture
        • 2. Replacement or addition of a manufacturing site and/or manufacturer
        • 3. Deletion of a manufacturing site or manufacturer for the starting material, intermediate, or drug substance
        • 4. Change in the manufacturing process for the drug substance or intermediate
        • 5. Change in the batch size for the drug substance
        • 6. Change in the controls for the materials used in the manufacture of the drug substance
      • 3.2.S.3 Characterisation
      • 3.2.S.4 Control of the Drug Substance
        • 7. Change in the standard claimed for the drug substance
        • 8. Change in the specification for the drug substance to comply with an updated Schedule B pharmacopoeial monograph
        • 9. Change in the specification for the drug substance involving test and acceptance criteria
        • 10. Change in the specification for the drug substance involving analytical procedures
      • 3.2.S.6 Container Closure System
        • 11. Change in the primary container closure system(s) for the storage and shipment of the drug substance
      • 3.2.S.7 Stability
        • 12. Change in the re-test period (or shelf life) for the drug substance
        • 13. Change in the labelled storage conditions for the drug substance, involving: addition/deletion of a cautionary statement or relaxation/tightening of a temperature criterion
        • 14. Change to the post-approval stability protocol or stability commitment
    • 3.2.P Drug Product
      • 3.2.P.1 Description and Composition of the Drug Product
        • 15. Addition of a dosage form or strength
        • 16. Change in the composition of a solution dosage form
        • 17. Change in the composition of an immediate release dosage form (other than a medicated premix)
        • 18. Change in the composition of a medicated premix dosage form
        • 19. Addition, deletion or replacement of microtracer used in a medicated premix
        • 20. Addition, deletion or replacement of carrier used in a medicated premix
        • 21. Change in the composition in the release controlling agent of a modified release solid oral dosage form
        • 22. Change to product markings, involving a change in embossing, debossing, or engraving (except scorelines/break lines) (e.g., plain tablet to engraved, engraved to plain, change in engraving) or a change in imprinting (e.g., plain tablet/capsule to imprinted tablet/capsule)
        • 23. Change in scoring configuration
        • 24. Change in shape or dimensions of tablets, capsules, suppositories, or pessaries
        • 25. Change in diluent
      • 3.2.P.2 Pharmaceutical Development
        • 26. Change in the approved design space
      • 3.2.P.3 Manufacture
        • 27. Replacement or addition of a drug product manufacturer / manufacturing site
        • 28. Change in the batch size for the drug product
        • 29. Change in the drug product manufacturing process
        • 30. Change in manufacturing process of a veterinary medicated premix (e.g. from regular powder to granulated form or/and vice versa)
        • 31. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediate
        • 32. Change in the approved protocol for process validation and/or evaluation studies
      • 3.2.P.4 Control of Excipients
        • 33. Change in the source of an excipient from a vegetable, synthetic source, or non-TSE (e.g., animal) to a TSE risk (e.g., animal) source, or from a TSE risk (e.g., animal) source to a different TSE risk (e.g., animal)
        • 34. Change in the source of an excipient from a TSE risk (e.g., animal) source to a vegetable or synthetic source
        • 35. Change in the analytical test method of an excipient in a medicated premix to comply with an updated version of a Schedule B pharmacopoeial monograph
      • 3.2.P.5 Control of Drug Product
        • 36. Change in the standard claimed for the drug product (e.g., from a Professed to Schedule B pharmacopoeial standard) or change in the specification for the drug product to comply with an updated Schedule B pharmacopoeial monograph
        • 37. Change in the specification for the drug product tests and acceptance criteria
        • 38. Change in the specification for the drug product, for analytical procedures
        • 39. Change of specification for a veterinary drug product used in food producing animals
      • 3.2.P.7 Container Closure System
        • 40. Replacement or addition of a primary container closure system
        • 41. Change in the package size
        • 42. Change in qualitative and/or quantitative composition of any primary or functional secondary container closure component
        • 43. Change in the specification for a primary or functional secondary container closure component, involving deletion, replacement or addition of a test or; relaxation or tightening of an acceptance criterion
      • 3.2.P.8 Stability
        • 44. Change in the shelf life for the drug product
        • 45. Change in the labelled storage conditions for the drug product or the diluted or reconstituted product
        • 46. Change to the post-approval stability protocol or stability commitment
        • 47. Change in the stability protocol or the shelf life for a medicated premix
        • 48. Change to the post-approval stability protocol or stability commitment of a sterile veterinary drug used as euthanasia drug or an ear implant for bovine and ovine species
      • 3.2.R.2 Devices
        • 49. Change of an approved device used for administration a veterinary drug
        • 50. Significant change to a device used in administration of an extended release veterinary drug
        • 51. Minor changes to a device used in administration of an extended release veterinary drug
  • Appendix 3: Quality Post-NOC Changes (biologics)
    • 3.2.S Drug substance
      • 3.2.S.1 General information
        • 1. Change in the name of the drug substance
      • 3.2.S.2 Manufacture
        • 2. Change to a drug substance manufacturing facility
        • 3. Modification to a facility involved in the manufacture of a drug substance
        • 4. Change to the drug substance fermentation process
        • 5. Change to the drug substance purification process
        • 6. Change in scale of the manufacturing process
        • 7. Introduction of reprocessing steps
        • 8. Change in the parameters of an approved holding step or addition of a new holding step
        • 9. Change in the auxiliary materials/reagents of biological origin
        • 10. Change in the specification for the materials
        • 11. Change in raw materials testing site
        • 12. Changes to the cell banks
        • 13. Changes to the seed banks
        • 14. Change in cell bank/seed bank manufacturing site
        • 15. Change in cell bank/seed bank testing site
        • 16. Change in cell bank/seed bank qualification protocol
        • 17. Change in product-contact equipment/material used in the drug substance manufacturing process
        • 18. Change in the controls (in process tests and/or acceptance criteria) applied during the drug substance manufacturing process or on intermediates
        • 19. Change in in-process controls testing site
        • 20. Change in the approved design space, involving
      • 3.2.S.3 Characterisation
      • 3.2.S.4 Control of the Drug Substance
        • 21. Changes affecting the quality control (QC) testing of the drug substance (release and stability)
        • 22. Change in the standard/monograph (i.e. specifications) claimed for the drug substance
        • 23. Change in the specifications for the drug substance to comply with an updated Schedule B pharmacopoeial standard/monograph
        • 24. Change the control strategy of the drug substance
        • 25. Change in the drug substance release or shelf life specifications.
      • 3.2.S.5 Reference Standards or Materials used to release the Drug Substance
        • 26. Change the reference standards from pharmacopoeial to House
        • 27. Change the reference standards from House/Professed to pharmacopoeial
        • 28. Qualification of a new lot of reference standard against the approved reference standard (except for a bacterial or viral vaccine, bacterial toxin or blood product)
        • 29. Qualification of a new lot or reference standard against the approved reference standard for a bacterial or viral vaccine, bacterial toxin or blood product)
        • 30. Change to reference standard qualification protocol (except for a bacterial or viral vaccine, bacterial toxin or blood product)
        • 31. Change to reference standard qualification protocol for a bacterial or viral vaccine, bacterial toxin or blood product)
        • 32. Extension of the reference standard shelf-life or retest period
      • 3.2.S.6 Container Closure System
        • 33. Change in the primary container closure system(s) for the storage and shipment of the drug substance
        • 34. Change in the supplier for a primary container closure component
      • 3.2.S.7 Stability
        • 35. Change in the shelf life for the drug substance or for a stored intermediate of the drug substance
        • 36. Change in the post-approval stability protocol of the drug substance
        • 37. Change in the labelled storage conditions for the drug substance
    • 3.2.P Drug Product
      • 3.2.P.1 Description and Composition of the Drug Product
        • 38. Change in the description or composition of the drug product
      • 3.2.P.1 Description and Composition of the Drug Product: Change to an adjuvant
        • 39. Change involving a chemical/synthetic adjuvant
        • 40. Change involving a biological adjuvant
      • 3.2.P.1 Description and Composition of the Drug Product: Change to a diluent
        • 41. Change to diluent
      • 3.2.P.2 Pharmaceutical Development
        • 42.Change in the approved design space
      • 3.2.P.3 Manufacture
        • 43. Change involving a drug product manufacturer/manufacturing facility
        • 44. Effect on the existing drug products in a drug product manufacturing facility involving introduction of a new product or change in concurrence
        • 45. Change in the drug product manufacturing process
        • 46. Change in the controls (in-process tests and/or acceptance criteria) applied during the drug product manufacturing process or on intermediates
        • 47. Change in in-process controls testing site
      • 3.2.P.4 Control of Excipients
        • 48. Change in the standard/monograph (i.e. specifications) claimed for the excipient
        • 49. Change in the specification for the excipient to comply with an updated Schedule B pharmacopoeial standard/monograph
        • 50. Change in the specifications used to release the excipient
        • 51. Change in the source of an excipient from a vegetable or synthetic source to a human or animal source that may pose a TSE or viral risk
        • 52. Change in the source of an excipient from a TSE risk (e.g., animal) source to a vegetable or synthetic source
        • 53Replacement in the source of an excipient from a TSE risk source to a different TSE risk source (e.g., different country of origin, different animal species)
        • 54. Change in manufacture of a biological excipient
        • 55. Change in supplier for a human plasma-derived excipient
        • 56. Change in supplier of an excipient of non-biological origin or of biological origin
        • 57. Change in excipient testing site
      • 3.2.P.5 Control of Drug Product
        • 58. Changes affecting the quality control (QC) testing of the drug product (release and stability)
        • 59. Change in the standard/monograph (i.e. specifications) claimed for the drug product
        • 60. Change in the specifications for the drug product to comply with an updated Schedule B pharmacopoeial standard/monograph
        • 61. Change the control strategy of the drug product
        • 62. Change in the drug product release or shelf-life specifications
      • 3.2.P.6 Reference Standards or Materials
        • 63. Change the reference standards from pharmacopoeial to House
        • 64. Change the reference standards from House/Professed to pharmacopoeial
        • 65. Qualification of a new lot of reference standard against the approved reference standard
        • 66. Qualification of a new lot of reference standard against the approved reference standard for a bacterial or viral vaccine, bacterial toxin or blood product
        • 67. Change to reference standard qualification protocol
        • 68. Change to reference standard qualification protocol for a bacterial or viral vaccine, bacterial toxin or blood product
        • 69. Extension of the reference standard shelf life or re-test period
      • 3.2.P.7 Container Closure System
        • 70. Modification of a primary container closure system
        • 71. Addition of a secondary container closure system
        • 72. Change from a reusable container to a disposable container with no changes in product-contact material (e.g., change from reusable pen to disposable pen)
        • 73. Change from approved single-dose container to multi-dose container
        • 74. Deletion of a container closure system
        • 75. Change in the supplier for a primary container closure component
        • 76. Change in the specifications used to release a primary or functional secondary container closure component
      • 3.2.P.8 Stability
        • 77. Change in the shelf life for the drug product
        • 78. Change in the post-approval stability protocol of the drug product
        • 79. Change in the labelled storage conditions for the drug product or the diluted or reconstituted product
  • Appendix 4: Quality Post-NOC Changes (Schedule C Drugs)
    • 3.2.S Drug substance (Kits/radiopharmaceuticals containing drug substance of chemical origin)
      • 3.2.S.1 General information
        • 1. Change in the name of the drug substance
      • 3.2.S.2 Manufacture
        • 2. Replacement or addition of a manufacturing site and/or manufacturer
        • 3. Deletion of a manufacturing site or manufacturer for the starting material, intermediate, or drug substance
        • 4. Change in the manufacturing process for the drug substance or intermediate
        • 5. Change in the batch size for the drug substance
        • 6. Change in the controls for the materials used in the manufacture of the drug substance
      • 3.2.S.3 Characterisation
      • 3.2.S.4 Control of the Drug Substance
        • 7. Changes affecting the quality control (QC) testing of the drug substance (release and stability)
        • 8. Change in the standard claimed for the drug substance
        • 9. Change in the specification for the drug substance to comply with an updated Schedule B pharmacopoeial monograph
        • 10. Change in the drug substance release or shelf-life specifications involving test and acceptance criteria
        • 11. Change in the specification for the drug substance involving analytical procedures
      • 3.2.S.6 Container Closure System
        • 12. Change in the primary container closure system(s) for the storage and shipment of the drug substance
      • 3.2.S.7 Stability
        • 13. Change in the re-test period (or shelf life) for the drug substance
        • 14. Change in the labelled storage conditions for the drug substance, involving: addition/deletion of a cautionary statement or relaxation/tightening of a temperature criterion
        • 15. Change to the post-approval stability protocol or stability commitment
    • 3.2.S Drug substance (Kits/Radiopharmaceuticals containing drug substance of biological origin)
    • 3.2.P Drug product (Kits/Radiopharmaceuticals containing drug substance of either chemical or biological origin)
      • 3.2.P.1 Description and Composition of the Drug Product
        • 1. Addition or modification of radioactive strength
        • 2. Change in the formulation of a kit or radiopharmaceutical
        • 3. Change of a radioisotope either for reconstitution of a kit or preparation of a radiopharmaceutical
      • 3.2.P.2 Pharmaceutical Development
        • 4. Change in the approved design space
      • 3.2.P.3 Manufacture
        • 5. Replacement or addition of a drug product manufacturer / manufacturing site
        • 6. Deletion of any drug product manufacturer / manufacturing site
        • 7. Change in the batch size for the drug product
        • 8. Change in the drug product manufacturing process
        • 9. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates
        • 10. Major change to the following process validation protocols used during the manufacture of the kit, reconstituted final product or radiopharmaceutical: introduction of product into an approved mutli-product facility, protocol for the cleaning of equipment
      • 3.2.P.4 Control of Excipients
        • 11. Change in the standard/monograph (i.e. specifications) claimed for the excipient
        • 12. Change in the specification for the excipient to comply with an updated Schedule B pharmacopoeial standard/monograph
        • 13. Change in the specifications used to release the excipient
        • 14. Change in the source of an excipient from a vegetable or synthetic source to a human or animal source that may pose a TSE or viral risk.
        • 15. Change in the source of an excipient from a TSE risk (e.g., animal) source to a vegetable or synthetic source
        • 16. Replacement in the source of an excipient from a TSE risk source to a different TSE risk source
        • 17. Change in manufacture of a biological excipient
        • 18. Change in supplier for a human plasma-derived excipient (e.g., human serum albumin)
        • 19. Change in supplier of an excipient of non-biological origin or of biological origin (excluding human plasma-derived excipient)
      • 3.2.P.5 Control of Drug Product
        • 20. Changes affecting the quality control (QC) testing of the drug product
        • 21. Change in the standard/monograph (i.e. specifications) claimed for the drug product
        • 22. Change in the specifications for the drug product to comply with an updated Schedule B pharmacopoeial standard/monograph
        • 23. Change in the drug product release and shelf-life specifications
      • 3.2.P.6 Reference Standards or Materials
        • 24. Change the reference standards from pharmacopoeial to House
        • 25. Change the reference standards from House/Professed to pharmacopoeial
        • 26. Qualification of a new lot of reference standard against the approved reference standard
        • 27. Extension of reference standard shelf life
      • 3.2.P.7 Container Closure System
        • 28. Change in the primary container closure system
        • 29. Change in the package size
        • 30. Change in the materials of construction of any primary or functional secondary container closure component
        • 31. Change in the supplier for a primary container closure component
        • 32. Change in the specifications used to release a primary or functional secondary container closure component
      • 3.2.P.8 Stability
        • 33. Change in the shelf life for the drug product such as kit, reconstituted final product or radiopharmaceutical
        • 34. Change in the post-approval stability protocol of the drug product
        • 35. Change in the labelled storage conditions for the drug product or the reconstituted final drug product or radiopharmaceutical
    • 3.2.P Drug Product (Generators)
      • 3.2.P.1 Description and Composition of the Generator
        • 1. Addition or modification of radioactive strength (total radioactivity of the generator)
        • 2. Change in the formulation
      • 3.2.P.2 Pharmaceutical Development
        • 3. Change in the approved design space
      • 3.2.P.3 Manufacture
        • 4. Replacement or addition of a generator component manufacturer/manufacturing site
        • 5. Change in the generator manufacturing process
        • 6. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates
        • 7. Major change to the following process validation protocols used during the manufacture of the generator: introduction of product into an approved mutli-product facility, protocol for the cleaning of equipment
      • 3.2.P.4 Control of Parent Radionuclide
        • 8. Change in the standard/monograph (i.e. specifications) claimed for the parent radionuclide
        • 9. Change in the specification for the parent radionuclide to comply with an updated Schedule B pharmacopoeial standard/monograph
        • 10. Change in the specifications used to release the parent radionuclide
        • 11. Addition or replacement of the source of a parent radionuclide
        • 12. Deletion of the source of a parent radionuclide
      • 3.2.P.5 Control of Generator
        • 13. Changes affecting the quality control (QC) testing of the generator
        • 14. Change in the standard/monograph (i.e. specifications) claimed for the generator product
        • 15. Change in the specifications for the generator to comply with an updated Schedule B pharmacopoeial standard/monograph
        • 16. Change in the specifications for the generator
      • 3.2.P.6 Reference Standards or Materials
        • 17. Change the reference standards from pharmacopoeial to House
        • 18. Change the reference standards from House/Professed to pharmacopoeial
        • 19. Qualification of a new lot of reference standard against the approved reference standard
        • 20. Extension of reference standard shelf life
      • 3.2.P.7 Generator Accessories
        • 21. Change in the container closure system
        • 22. Change in chromatography column and tubing
        • 23. Change in the supplier for vial, stopper, chromatography column, column tubing or elution needle
      • 3.2.P.8 Stability
        • 24. Change in the shelf life for the generator
        • 25. Change in the post-approval stability protocol of the generator
        • 26. Change in the labelled storage conditions for the generator
  • Appendix 5: Recommendations for conducting and assessing comparative dissolution profiles
  • Appendix 6: Changes to excipients
  • Appendix 7: Examples of Level IV changes
  • Appendix 8: Glossary
    • 8.1 Acronyms
    • 8.2 Définitions