# Presentation: 694085

## Comparability ExercisesLimitations for Follow-On Biologics (FOBs)The European PerspectiveChristopher J. Holloway, Ph.D., Dr.rer.hum.biol.habil.

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## Patents on many recombinant DNA products have expired, or are due to expire, sooner in Europe than in the United States
Therefore, many sponsors of FOBs have been focussing initial efforts in Europe
EMEA Scientific Advice Procedure [EMEA-H-4260-01-Rev. 2] has been used extensively to discuss requirements for FOBs
No ‘freedom of information’ on ‘Scientific Advice’, so another forum is urgently required for general scientific debate on FOBs

- Therefore, many sponsors of FOBs have been focussing initial efforts in Europe
- EMEA Scientific Advice Procedure [EMEA-H-4260-01-Rev. 2] has been used extensively to discuss requirements for FOBs
- No ‘freedom of information’ on ‘Scientific Advice’, so another forum is urgently required for general scientific debate on FOBs

## Legislative and procedural basis will differ in the US, Europe and elsewhere
BUT
The basis for approval should be similar – primarily driven by scientific considerations

Extent of non-clinical and clinical testing for approval of FOBs is contentious
This will depend on the extent to which ‘similarity’ can be proven

- BUT
- The basis for approval should be similar – primarily driven by scientific considerations
- Extent of non-clinical and clinical testing for approval of FOBs is contentious
- This will depend on the extent to which ‘similarity’ can be proven

## Consistent ‘docrine’ for biological products:
Product is inexorably linked to
Producing cell line
Specified manufacturing process
Defined scale of manufacture
Particular manufacturing facilities
Process changes require
Extensive comparability exercise
Not limited to product analysis, but also in-process data
Impact analysis required for any differences

- Product is inexorably linked to
- Producing cell line
- Specified manufacturing process
- Defined scale of manufacture
- Particular manufacturing facilities
- Process changes require
- Extensive comparability exercise
- Not limited to product analysis, but also in-process data
- Impact analysis required for any differences

## Comparability guidelines* in the EU

EMEA/CPMP/BWP/3207/Rev 1
Guideline on Comparability of Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues
EMEA/CPMP/3097/02/Final
Guideline on Comparability of Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues

* Current status; revisions under consideration

- EMEA/CPMP/BWP/3207/Rev 1
- Guideline on Comparability of Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: **Quality Issues**
- EMEA/CPMP/3097/02/Final
- Guideline on Comparability of Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: **Non-Clinical and Clinical Issues**
- * Current status; revisions under consideration

## Cases for comparability (EU perspective)

Change with no impact on quality
Change with impact on in-process controls without impact on drug substance and/or drug product specifications
Change with impact on quality criteria and no anticipated consequences on safety/efficacy
Change with impact on quality criteria and anticipated consequences on safety/efficacy

- Change with no impact on quality
- Change with impact on in-process controls without impact on drug substance and/or drug product specifications
- Change with impact on quality criteria and no anticipated consequences on safety/efficacy
- Change with impact on quality criteria and anticipated consequences on safety/efficacy

## Limitations for FOBs

“... the manufacturer, although possessing information on his own manufacturing process, would normally not have access to all necessary information that could allow comparison in terms of quality with any other products already on the market.”
“... the expression/vector system, production and purification process, facility/equipment, analytical techniques, etc. may be different from other manufacturers; the extent of the difference cannot be evaluated by the second applicant.”
“... comparison based on testing and characterisation of drug substance and drug product is not sufficient to establish all aspects pertinent to the evaluation of quality, safety and efficacy for a biotechnology-derived protein.”

- “... the manufacturer, although possessing information on his own manufacturing process, would **normally not have access to all necessary information** that could allow comparison in terms of quality with any other products already on the market.”
- “... the expression/vector system, production and purification process, facility/equipment, analytical techniques, etc. may be different from other manufacturers; **the extent of the difference cannot be evaluated by the second applicant**.”
- “... comparison based on testing and characterisation of drug substance and drug product is **not sufficient **to establish all aspects pertinent to the evaluation of quality, safety and efficacy for a biotechnology-derived protein.”

## Case study #1

| Levels of a post-translationally generated product-related speciesand the major isoform of a product expressed in a mammaliancell line following changes to cell culture media in the process |  |  |
| --- | --- | --- |
| Process | Product-related species | Major isoform |
| Process 1 |  1 % |  54 % |
| Process 2 |  1 % |  50 % |
| Process 3 |  0.1 % |  46 % |

## Case study #2

| Levels of an impurity at various stages of downstream processing, comparingthe pilot-scale process A with the commercial-scale process B. The limit ofquantification of the method at the drug substance stage is 100 ppm. |  |  |
| --- | --- | --- |
| Stage of the process | Process A | Process B |
| Conditioned medium |  10,000 ppm |  50,000 ppm |
| Column 1 eluate |  2,000 ppm |  10,000 ppm |
| Column 2 eluate |  500 ppm |  500 ppm |
| Column 3 eluate | < 100 ppm | < 100 ppm |
| Drug substance | < 100 ppm | < 100 ppm |

## Case study #3

| Results of residual host cell protein analyses conductedon drug substance using different immunoassays |  |  |
| --- | --- | --- |
| Method | Process A | Process B |
| Antibodies generated usingantigen from Process A |  100 ppm |  40 ppm |
| Antibodies generated usingantigen from Process B |  20 ppm |  80 ppm |
| ‘Generic’ host cellprotein assay |  10 ppm |  30 ppm |

## Case study #4

| Dimer levels in three batches of FOB, comparedwith three batches of the ‘original’ product(Note: formulation of FOB and ‘original’ product differ) |  |
| --- | --- |
| Batches of FOB
(“release data”) | Batches of marketed product
(after storage for some time) |
| 2.0 %     2.2 %     1.8 % | 1.6 %     2.5 %     2.2 % |
| 2.0  0.2 % | 2.1  0.5 % |

## Conclusions

Scientifically, it is difficult to conceive how the approval of FOBs can be based to any great extent on ‘comparability’
FOB sponsor has great advantages resulting form existence of marketed ‘original’ product
Indications, posology etc
Adverse effects, etc
Since FOB is derived from a ‘new’ cell line, with a different manufacturing process, possibly also different formulation, FOB has to be considered as a ‘new’ product

- Scientifically, it is difficult to conceive how the approval of FOBs can be based to any great extent on ‘comparability’
- FOB sponsor has great advantages resulting form existence of marketed ‘original’ product
- Indications, posology etc
- Adverse effects, etc
- Since FOB is derived from a ‘new’ cell line, with a different manufacturing process, possibly also different formulation, FOB has to be considered as a ‘new’ product