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CASSS LATIN AMERICA 2019

CMC FORUM LATIN AMERICA 2019REGULATIONS OF POST APPROVAL CHANGES IN BIOTHERAPEUTICS- GLOBAL DEVELOPMENTS AND OPPORTUNITIES FOR THE REGION

CASE STUDY – How can we use the WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products in real life examples?

C. Mota- March 2019

CASSS Meeting Latin America © 2018

CASE STUDY DESCRIPTION

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General Case:

- Addition of a new drug substance manufacturing site.

- Analytical release testing

- Change in scale

Multiple changes: Involving various combinations of individual changes, may be submitted in the same supplement.

The MAH should clearly specify which supporting data support which change.

If the recommended reporting categories for the individual changes differ, the

submission should be in accordance with the more restrictive of the categories.


How to classify the change according to WHO guideline?

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DESCRIPTION OF CHANGE

CONDITIONS TO BE FULFILLED

SUPPORTING DATA

REPORTING CATEGORY

1. Change to a drug substance manufacturing facility:

A. Replacement or addition of a manufacturing facility for the bulk drug substance or any intermediate

None 1-4,6-8

Major

1-3 1-8 Moderate

Conversion of a drug substance manufacturing facility from single-product to multi-product

4 9,10 Moderate

Deletion of a manufacturing facility or manufacturer of an intermediate drug substance or bulk

5,6 None Minor



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SUPPORTING DATA

REPORTING CATEGORY

8. Change in scale of the manufacturing process:

a. At the cell culture stage 3,9-11 2,3,5-7,9,11 Moderate

b. At the purification stage 1,2,4,6 2,5-7,9,11 Moderate



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SUPPORTING DATA

REPORTING CATEGORY

18. Change affecting the quality control (release and stability) testing of the drug substance, involving the following:Note: Transfer of testing to a different facility within a GMP-approved site is not considered to be reportable change but is treated as minor GMP change and is reviewed during inspections.

a. Transfer of the quality control testing activities for a non-pharmacopoeial assay to a new company not approved in the current marketing authorization or license, or to a different facility within the same company

None 1,2 Moderate

1-3 1,2 Minor

b. Transfer of the quality control testing activities for a pharmacopoeial assay to a new company not approved in the current marketing authorization or license

None 1,2 Moderate

1 1,2 Minor


GMP

Manufacturing SiteInformation

Validation

Comparability

SUPPORTING DATA for CHANGE No. 1

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Evidence of GMP compliance of the facility

Name, Address and Responsibilities of the proposed facility.

Summary of the process validation studies and results

Pre-change and post-change drug substance with respect to physicochemical properties, biological activity, purity, impurities and contaminants as appropriate. Nonclinical and/or clinical bridging studies may be required if the quality data alone are insufficient to establish comparability..


Supporting Data Change No. 1

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Batches

Comparative test results do not need to be generated concurrently, relevant historical testing results are

acceptable.

Matrixing and Bracketing, use of smaller scale batches, or fewer than 3 batches may be acceptable where

justified and agreed with the NRA

3 consecutive commercial-scale batches of the pre-change and post-change

Description and summary of in-process control and release testing results as quantitative data in

comparative tabular format

Stability Comparative pre-change and post-change test results for the manufacturer’s characterized key stability indicating attributes for 3 commercial-scale drug product batches, produced with the proposed changes and stored under accelerated conditions for a minimum of 3 months

Test results that cover a minimum of 6 months in real-time/real temperature conditions should also be provided. A

possibility of 3 months of real time data could be acceptable if properly justified

.Matrixing and bracketing, the use of smaller-scale batches and /or the use of fewer than 3 batches for stability testing may be acceptable where justified and agreed by the NRA

Real time stability studies to confirm the full shelf/life hodl/time under its normal storage conditions and to report if

any failures in the ongoing long term stability studies.

Updated post-approval stability protocol


SUPPORTING DATA Change No. 8 Conditions

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3. There is no change in the drug substance impurity profile outside of the approved limits

9. The change is not expected to have an impact on the quality, safety or efficacy of the final product

10. There is no change in the proportionality of the raw materials (i.e. the change in scale is linear)

11. The change in scale involves the use of same reactor (does not involve the use of a larger bioreactor)


Flow Diagram

Characterization and testing

Validation

Comparability


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Flow diagram (including process and in-process controls) of the proposed manufacturing process(es) and a brief narrative description

If the change results in an increase of the number of population doublings or subcultivations, information of the characterization and testing of the post-production cell bank for recombinant product.

Process validation results

Pre-change and post-change drug substance with respect to physicochemical properties, biological activity, purity, impurities and contaminants as appropriate. Nonclinical and/or clinical bridging studies may be required if the quality data alone are insufficient to establish comparability..

Documents provided for change No. 1


Supporting Data Change No. 8

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Batches

Comparative test results do not need to be generated concurrently, relevant historical testing results are

acceptable.

Matrixing and Bracketing, use of smaller scale batches, or fewer than 3 batches may be acceptable where

justified and agreed with the NRA

3 consecutive commercial-scale batches of the pre-change and post-change

Description and summary of in-process control and release testing results as quantitative data in

comparative tabular format

Stability Comparative pre-change and post-change test results for the manufacturer’s characterized key stability indicating attributes for 3 commercial-scale drug product batches, produced with the proposed changes and stored under accelerated conditions for a minimum of 3 months

Test results that cover a minimum of 6 months in real-time/real temperature conditions should also be provided. A

possibility of 3 months of real time data could be acceptable if properly justified

.Matrixing and bracketing, the use of smaller-scale batches and /or the use of fewer than 3 batches for stability testing may be acceptable where justified and agreed by the NRA

Real time stability studies to confirm the full shelf/life hodl/time under its normal storage conditions and to report if

any failures in the ongoing long term stability studies.

Updated post-approval stability protocol and stability commitment

Documents provided for change No. 1


Information

GMP


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Information demonstrating technology transfer qualification

Evidence that the new company/facility is GMP-compliant

CASSS Meeting Latin America © 2018 12

Approval Time

As one of the changes is considered Major, then the marketing authorization holder should submit and receive a notification of approval from the NRA before implementing the change.

The real approval time range from:

Months 3 6 9 12 15 18 21 24 27 30

Approval in US and EU

Approval time for PAC could be from 3 months up to 24 months or more in some countries1

1. IFPMA- Supply Chain Post Approval Change: Global ComplexityContributing to Delayed Patient Benefit


• Many countries have strong regulations for approval of new biotherapeutic products

• Regulation for approval of post approval changes is not available in some countries

• The WHO Guideline is a comprehensive document that can help NRA’s and Industry in submitting and supporting documentation for post approval changes

• Variations occurs simultaneously and over time can potentially generate stock out situations.

• Regulatory convergence could help to avoid stock out situations

• All stakeholders should work together to keep products in the market for the patients

Conclusions

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References: Guidelines on procedures and data requirements for changes to approved biotherapeutic products- WHO/BS/2017.2311

CASSS Meeting Latin America © 2018 14

Thank you to my AbbVie colleaguesThat helped me with the information of this case study.