Bioanalytical Community

Greetings to the bioanalytical community, 

Hope to hear some feedback or insights on this topic: 

In a late-stage phase 3 trials we often need to supply multiple lots of GMP drugs (mAbs in this case) to the clinical sites. What is the standard practice to show lot to lot comparability in the sense of bioanalytical assays? Is it necessary to perform bridging experiments for all the lots used in the clinical study or a CMC issued comparability report would suffice? It may be necessary to bridge the LBA-based PK assays, but what about MSD-based ADA assays? Is it necessary to relabel the new lot of the drug since they are used as reagents and not the actual analytical target? We are committed to perform what is required but curious to see what the current standard practice is. 

Thanks in advance. 

Best, 

Yu-Lu 

Hi Yu-Lu, are you referring to comparing reference standard (RS) used for PK bioassay with drug substance (DS) administered to study patients? The short answer: it depends on the manufacturing process. RS used for pivotal trials may still be the same RS batch initially derived from CMC Tox batch (most likely), or it could be derived from GMP batch (a possibility). DS used for Ph3 will be derived from subsequent generations(s) of GMP batch obtained using different manufacturing process due to a scale-up. We think the following makes sense, let me know if you agree:

1.      Receive RS and CoA from CMC and use the same RS for validation and Ph1

2.      After launching a DS derived using a new process (after Ph1), receive the new DS and CoA from CMC. Then compare (bridge) the new DS and existing RS in the PK assay format as follows: bioanalytical evaluation should be carried out with QCs from the original material and the new material prior. Do this bridging only once. 

3.      If the bridging is successful, keep using the original RS lot. If it fails, a new lot of RS may be prepared by CMC using the current GMP batch.

4. For ADA, bridging is done at each subsequent re-labeling even when RS lot is the same.

Greetings to the bioanalytical community, 

Hope to hear some feedback or insights on this topic: 

In a late-stage phase 3 trials we often need to supply multiple lots of GMP drugs (mAbs in this case) to the clinical sites. What is the standard practice to show lot to lot comparability in the sense of bioanalytical assays? Is it necessary to perform bridging experiments for all the lots used in the clinical study or a CMC issued comparability report would suffice? It may be necessary to bridge the LBA-based PK assays, but what about MSD-based ADA assays? Is it necessary to relabel the new lot of the drug since they are used as reagents and not the actual analytical target? We are committed to perform what is required but curious to see what the current standard practice is. 

Thanks in advance. 

Best, 

Yu-Lu 

Hi Anna, 

Thank you so much for your response! 

Overall your approaches align with our practices and we appreciate your feedback! 

For the sake of analytical discussion, we are debating on the practicality of bridging for ADA assays. Several reasons are debated, just to name a few below: 

1. Logistically difficult to maintain the same labelling efficiency which may lead to slightly different NC signal. 
2. Do we need to reestablish the cut point? 
3. ADA is a semi-qualitative assay. 
4. New lot of TA already passed CMC QA and passed PK bridging.
5. If we have 5 different lots of the CMC material for a large ph3 study, are we expected to execute bridging for all five lots for both PK and ADA assays? 

All comments welcome, thanks in advance! 

Best, 

Yu-Lu

Hi Yu-Lu, are you referring to comparing reference standard (RS) used for PK bioassay with drug substance (DS) administered to study patients? The short answer: it depends on the manufacturing process. RS used for pivotal trials may still be the same RS batch initially derived from CMC Tox batch (most likely), or it could be derived from GMP batch (a possibility). DS used for Ph3 will be derived from subsequent generations(s) of GMP batch obtained using different manufacturing process due to a scale-up. We think the following makes sense, let me know if you agree:

1.      Receive RS and CoA from CMC and use the same RS for validation and Ph1

2.      After launching a DS derived using a new process (after Ph1), receive the new DS and CoA from CMC. Then compare (bridge) the new DS and existing RS in the PK assay format as follows: bioanalytical evaluation should be carried out with QCs from the original material and the new material prior. Do this bridging only once. 

3.      If the bridging is successful, keep using the original RS lot. If it fails, a new lot of RS may be prepared by CMC using the current GMP batch.

4. For ADA, bridging is done at each subsequent re-labeling even when RS lot is the same.

Greetings to the bioanalytical community, 

Hope to hear some feedback or insights on this topic: 

In a late-stage phase 3 trials we often need to supply multiple lots of GMP drugs (mAbs in this case) to the clinical sites. What is the standard practice to show lot to lot comparability in the sense of bioanalytical assays? Is it necessary to perform bridging experiments for all the lots used in the clinical study or a CMC issued comparability report would suffice? It may be necessary to bridge the LBA-based PK assays, but what about MSD-based ADA assays? Is it necessary to relabel the new lot of the drug since they are used as reagents and not the actual analytical target? We are committed to perform what is required but curious to see what the current standard practice is. 

Thanks in advance. 

Best, 

Yu-Lu 

Hi Anna, 

Thank you so much for your response! 

Overall your approaches align with our practices and we appreciate your feedback! 

For the sake of analytical discussion, we are debating on the practicality of bridging for ADA assays. Several reasons are debated, just to name a few below: 

1. Logistically difficult to maintain the same labelling efficiency which may lead to slightly different NC signal. 
2. Do we need to reestablish the cut point? 
3. ADA is a semi-qualitative assay. 
4. New lot of TA already passed CMC QA and passed PK bridging.
5. If we have 5 different lots of the CMC material for a large ph3 study, are we expected to execute bridging for all five lots for both PK and ADA assays? 

All comments welcome, thanks in advance! 

Best, 

Yu-Lu

Hi Yu-Lu, are you referring to comparing reference standard (RS) used for PK bioassay with drug substance (DS) administered to study patients? The short answer: it depends on the manufacturing process. RS used for pivotal trials may still be the same RS batch initially derived from CMC Tox batch (most likely), or it could be derived from GMP batch (a possibility). DS used for Ph3 will be derived from subsequent generations(s) of GMP batch obtained using different manufacturing process due to a scale-up. We think the following makes sense, let me know if you agree:

1.      Receive RS and CoA from CMC and use the same RS for validation and Ph1

2.      After launching a DS derived using a new process (after Ph1), receive the new DS and CoA from CMC. Then compare (bridge) the new DS and existing RS in the PK assay format as follows: bioanalytical evaluation should be carried out with QCs from the original material and the new material prior. Do this bridging only once. 

3.      If the bridging is successful, keep using the original RS lot. If it fails, a new lot of RS may be prepared by CMC using the current GMP batch.

4. For ADA, bridging is done at each subsequent re-labeling even when RS lot is the same.

Greetings to the bioanalytical community, 

Hope to hear some feedback or insights on this topic: 

In a late-stage phase 3 trials we often need to supply multiple lots of GMP drugs (mAbs in this case) to the clinical sites. What is the standard practice to show lot to lot comparability in the sense of bioanalytical assays? Is it necessary to perform bridging experiments for all the lots used in the clinical study or a CMC issued comparability report would suffice? It may be necessary to bridge the LBA-based PK assays, but what about MSD-based ADA assays? Is it necessary to relabel the new lot of the drug since they are used as reagents and not the actual analytical target? We are committed to perform what is required but curious to see what the current standard practice is. 

Thanks in advance. 

Best, 

Yu-Lu