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Presentation: Consultation on "Guidance on variations to biologicals included in the Register"

TGA presentation: Biotherapeutics Association of Australasia 2016 AGM, TGA Workshop & Education Session

1 November 2016


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  • Presented by: Mat Adams, Biological Science Section, Scientific Evaluation Branch, Therapeutic Goods Administration
  • Presented at: Biotherapeutics Association of Australasia 2016 AGM, TGA Workshop & Education Session, Canberra
  • Presentation date: 13 October 2016
  • Presentation summary: An overview of the open consultation on "Guidance on variations to biologicals included in the Register" including a summary of major changes from the previous version of the guidance.


Consultation on "Guidance on variations to biologicals included in the Register"

Dr Mat Adams
Departmental Officer, Biological Science,
Scientific Evaluation Branch, TGA

Biotherapeutics Association of Australasia 2016 AGM, TGA Workshop & Education Session, 13 October 2016

Slide 1 - Consultation on draft guidance

Slide 2 - Major changes from previous version of guidance

  • The new draft guidance includes several major changes since last version presented at the previous BAA meeting (October 2015)
  • Many of these changes are to align terminology and processes with other sections of the TGA or to align with specific terminology in the Therapeutic Goods Act and Regulations
  • Presented in a web-compatible format to improve navigation and help in determining the category of variation which applies to your application

Slide 3 - Major changes from previous version of guidance

  • A variation is now defined as changes to "matters that would have been relevant to the decision to include the biological in the ARTG"
    • Previously defined as "changes that have the potential to affect the quality, safety and/or efficacy of the good"
  • Variation categories now defined as Major, Minor and Self-assessable variations
    • Previously Category A (Major variation) / Category B (Minor variation) / Category C (low-risk variation)
  • Improved guidance on Safety-related changes (made under s9D(3AA))
  • Improved separation of variations made under s9D of the Act versus "separate and distinct goods" made under s32DD of the Act.
    • Described as "New biologicals based on a parent (already approved) biological"

Slide 4 - Workshop (1)

Please raise issues as the various sections of the guidance are raised:

  • Varying biological entries on the ARTG
    • Definition of a variation as "matters that would have been relevant to the decision to include the biological in the ARTG".
  • Determine if the change would have been relevant to the inclusion decision
    • Twelve questions to help determine if the change is a variation
    • "Yes" to any question means the change is likely to be a variation and require pre-approval

Slide 5 - Workshop (2)

  1. Affect compliance with a standard?
  2. Alter a critical in-process control or release specification?
  3. Have the potential to alter the justification used to support a critical in-process control or release specification?
    1. Justification can be by reference to limits set down in a standard, international guidance, process validation or from published literature.
    2. When information becomes available that alters the appropriateness of the justification, this could impact on the initial decision to accept the specification
  4. Nullify or invalidate previous validation studies?
    1. A manufacturing process or method needs to be supported by current validation studies submitted and accepted by TGA.
    2. Re-validation should occur and data be submitted if the changed process or method is not supported by current studies.
  5. Alter a manufacturing process or test method, including changes to infectious disease test kits?

Slide 6 - Workshop (3)

  1. Alter a critical material that affects the critical quality and safety parameters?
    1. defined as supplies or reagents that come in direct contact with the cell or tissue during any stage of manufacture, such as primary containers or collection kits.
  2. Introduce a new manufacturing site or change the scope of activities performed at a current manufacturing site?
  3. Involve generation of a new Master Cell Bank or Working Cell Bank?
  4. Alter the formulation or composition of the finished product?
  5. Alter the approved risk-benefit profile?
  6. Alter the intended clinical use or therapeutic indication?
  7. Alter the intended clinical use/therapeutic indication (including safety-related changes)?

Slide 7 - Workshop (4)

  • Determine if the change is a correction to your ARTG entry
    • Changes made under s9D(1)
    • Process better described
  • Determine the variation category
    • Separate and distinct goods
    • Safety related changes
    • Other changes
  • Determine if the change creates a separate and distinct good
    • Class 1/2 and Class 3/4 biologicals have different requirements
  • Determine if the change is safety-related
    • Adding a warning or precaution; reducing patient population

Slide 8 - Workshop (5)

  • Other changes with potential to impact quality, safety and efficacy
    • Self-assessable variations
    • Defined self assessable variations with conditions
      • Infectious disease test kit change
      • Reduction in shelf life or shipping timeframes
      • New manufacturing site
      • Donor selection criteria change (more stringent)
      • Critical material change
      • In-process or release specification change (more stringent)
      • Variation previously approved for another biological

Slide 9 - Workshop (6)

  • Determine the supporting document requirements
  • Submit your application
    • Multiple variations in a single application
    • Multiple products
    • Multiple ARTG entries
  • Prepare and submit your cover letter and supporting documents
  • Pay your application fee
  • Screening of your application
    • 15 working days
  • Pay your evaluation fee

Slide 10 - Workshop (7)

  • Evaluation of your supporting documents
    • Timeframes
  • Making a decision on your application
    • One decision made, not all changes may be approved
  • Implement the change
  • New biologicals based on a parent biological
    • s32DD changes
    • Submitted as a new application in Business Services
    • Evaluated and fees applied in a similar fashion as variations

Slide 11 - ?????

Slide 12 - Variations to biologicals


  1. Move to make self-assessable variations 'notifications'
    • Under MMDR recommendations
    • Can be implemented immediately following notification
    • Following review of the change TGA could reclassify the change if it requires evaluation
  2. Changes impacting multiple facilities or rolled out nationally
    • e.g. DRAI, changes at testing facilities
    • TGA still needs to recover cost of processing the change
    • Change alters documents submitted from each facility
    • Still legal obligation for each bank to notify TGA of the change in an application (with associated application fee)
    • Ability to waive or reduce evaluation fee
    • Other options moving forward

Slide 13 - Variations to biologicals


  1. Approval of 'process' rather than 'individual criteria'
    • e.g. Epidemiological situations, Compliance with TGO 88 9(13)
    • Need TGA to agree that the decision-making process is sufficiently robust
    • For example, AATB Standards

Slide 14 - Compliance

  • Still a lot of confusion around what changes need to be notified to TGA
  • Following completion of the consultation keen to work with the Sector to continue education and improvements
  • Need to review compliance in a collegiate manner
  • E.g. TGA is aware of changes to test kits utilised by a number of the national testing facilities
    • Only some Sponsors have submitted variations for these changes

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