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CMC Strategy Forum 2013 15-16 July 2013

A Global Reference Standard Program for Biotech Products

by Anne Munk Jespersen & Kirsten Byrialsen,


Agenda

• Global expectations

• The internal reference standard system

• Shifts

• The global demand - How can we comply?

Slide no 2

Global expectations

CMC Strategy Forum 2013 Slide no 3 15-16 July 2013

Borrowed from CASSS, CMC Strategy Forum overview 2013

Scenario A: An in-house primary RS is established

Content (mg) • Primary RS:

• Preferably defined based on total protein determined by an absolute method (Kjeldahl, Elemental Analysis or Amino Acid Analysis)

• If required in addition corrected for related impurities from the HPLC assay method

• If possible a mass balance is performed as confirmation

Potency (units) • The definition of the unit

depends on the product and the history of the products

• For a completely new product an activity of 1 unit/mg could be used


Scenario A: An in-house secondary RS (working standard) is established

Content (mg) • HPLC assay against

in-house primary RS

Potency (units) • If no well defined specific

activity, potency assay against in-house primary RS

• If well defined specific activity, potency is defined from content determination of biologically active components


Specifications are set on

the 95% confidence interval of the mean value

Scenario A: In-house RS program - Test of continued suitability for use

• In-house primary and secondary RS are followed in stability:

• Followed at storage temperature

• Calibration data used as time zero

• Sampled typically using ICH Q1A frequency

• Parameters relevant for the content and potency values are followed

• Oldest representative RS lot followed for as long as necessary to support final shelf life period (can be 20 years or more)


Scenario A: In-house RS program Stock is low and a new RS lot is prepared

New primary RS lot • Content: New determination

by absolute method

• Potency:

• If specific activity is well defined, potency is defined from content determination of biologically active components

• If specific activity is not well defined, potency is determined against old PRM

• New ID and purity tests

• Comparison with old primary RS by ID and assay methods

New secondary RS lot • ID, content and potency (if

relevant) determined against in-house primary RS

• If specific activity is well defined, potency is defined from content determination of biologically active components

• Comparison with old secondary RS by the assay methods


Scenario A: In-house RS program Control of shifts due to replacement of RS lots

Content control • “Content control” is a

calculated value giving the difference in content value a sample obtains if it is measured against the old and new secondary RS lot

Potency control • “Potency control” is a

calculated value giving the difference in potency value a sample obtains if it is measured against the old and new secondary RS lot


For new secondary RS the study contains:

Primary RS

Old secondary RS

New secondary RS


What is a shift? Visualisation of consequence of shift

Sample Peak area:100,000

Old calibration study Peak area old RS: 100,000 Ξ 1.48 mg

New calibration study Peak area old RS ~ new RS: 100,000 = 1.45 mg

Consequence: The declared content on the sample in theory shifts 2% down from 1.48 mg to 1.45 mg, plus the uncertainty of the measurement of the sample.

1.48 mg 1.45 mg

Slide no 9

Peak area (signal)

Peak area (signal)

Peak area (signal)


Why shifts can be a challenge

• We can never reduce the shifts to zero due to uncertainty

• Important that DS and DP specifications leave room for shifts due to replacing RS batches (often not the case) – otherwise stability studies are a great challenge

Slide no 10


Uncertainties related to the certified value

• The quality of the RS batch with regard to production, handling, stability, homogeneity - between containers and within containers

• Qualification of participating laboratories:

• Variations due to the analytical assay procedure

• Training of personnel

• Data treatment e.g. data exclusion and rounding of results

Slide no 11


Designing the optimal calibration study

• Factors to take into consideration: • training of personnel and detailed written procedures for sample

treatment

• analytical method

• calibration study run over a longer time

• written procedures for exclusion of data

• only rounding of end results

• Reduce the uncertainty by repeating the factors with the highest variance the most

• This will ensure a more realistic uncertainty on the certified value with a smaller shift when changing batches

Slide no 12

The uncertainties can be reduced but not eliminated

Conclusion on shifts

• Shifts will occur however good we design our calibration studies due to uncertainty

• There should to be room for the unavoidable shifts in the drug substance and drug product specifications

• It is important to have as large RS batches as possible so batches are changed as seldom as possible


Scenario B: External RS is available

• If only one external RS is available

• No in-house primary RS necessary

• External RS used as primary RS

Scenario B is often only the situation for a very short time before next scenario appears:

Scenario C: More than one external RS available



Scenario C: Several external RS available. Which one gives your product the

“true” value? Due to uncertainty when establishing the different Pharmacopoeias RS, there will be systematic differences in measurement of products against the different RS

Slide no 15

PhEur Rus. P

JP

CP

IP

Bra. P

WHO USP


Scenario C: Why will there be systematic

differences when measuring products against the different external RS?

Difference: 0.005 mg drug/mg ”as is” ~ 0.5%

is" as" drug/mg mg 0.936

100

%03.0%41.0%71.5%100

100

%30.0%100

is" as" drug/mg mg 0.941

100

%03.0%50.0%12.5%100

100

%31.0%100

Pharmacopoeia 2

Pharmacopoeia 1

100

%%%%100

100

%%100 RSROIWIis" as" drug/mg mg

Due to uncertainty e.g. when establishing two Pharmacopoeias RS using same principle, systematic differences will appear when measuring a product against the two RS. See imagined example (same RS lot used):

Scenario C: The in-house primary RS again relevant, why?


• Due to the difference when measuring against the different Pharmacopoeias RS

• Due to the need for a consistent measurement of products

• Due to larger shifts when external RS replace lots

In-house secondary RS measured against in-house primary RS or USP RS

(Source: USP PF 34(2), Uncertainty Statements Regarding USP Reference Standards by K. Byrialsen et al.)

Scenario C: The in-house RS traceability to external RS

• The in-house primary RS is traceable by comparison to relevant Pharmacopoeias RS

• The in-house secondary RS is calibrated against the in-house primary RS


Secondary RS

Primary RS (100,0%)

Pharmaopoeia 3

Pharmaopoeia 2

Pharmaopoeia 1

Pharmaopoeia n

102,0%

100,0% 101.0% 99,5%

Pharmaopoeia n Pharmaopoeia

n Pharmaopoeia n Pharmaopoeia

n

98,0% 101,0%

99.6% 101,0%

Example values for comparison of content

The only monographs on recombinant Glucagon are USP, Ph.Eur and BP. The monographs and RS are harmonized and shared between USP and Ph.Eur and BP refers to the Ph.Eur RS => one RS value

Scenario C: Situation where harmonized Ph.Eur and USP RS are available -> Scenario B

CMC Strategy Forum 2013 15-16 July 2013 19

Ph.Eur

USP


Scenario C: External RS available The Somatropin WHO IS story

• For many years ago no monograph nor external RS defined in mg was available on recombinant Somatropin

• Each Somatropin manufacturer defined their own mg of Somatropin ->

• Somatropin products were shown to contain up to 25% different amount of human growth hormone with same label claim

• Manufacturers of Somatropin agreed to work on a harmonization initiative together with WHO (NIBSC), Ph.Eur., USP and JP


Scenario C: A Somatropin WHO IS was established

• At the same time it was shown that the size-exclusion HPLC could be used as a replacement for the bioassay -> the HPLC assay method was harmonized

• The WHO reference standard was defined in mg

• A conversion factor between mg and IU was defined giving a well defined specific activity (if the specific activity was not well

defined there could just be two separate traceability chains)

• The labelling was changed from IU to mg simultaneously by all manufacturers (the labelling could have stayed in IU and the

same procedure still followed)


Scenario C -> Scenario B: The Somatropin WHO IS defined in mg & IU WHO is acknowledged as a primary reference standard with regard to pharmacopoeia potency reference standards. This is also applied to the Somatropin traceability system in mg.

Slide no 22

WHO Somatropin

International Standard

Ph.Eur

USP

JP Secondary

RS

Pharmacopoeia n Pharmacopoeia

n Pharmacopoeia n Pharmacopoeia

n Pharmacopoeia n Pharmacopoeia

n


Conclusion: How can the Global challenges be handled?

• Preferred: • One international reference standard defined in IU and mg

• Pharmacopoeias harmonized with regard to monographs and RS

• Known uncertainties on the Pharmacopoeia RS aiding the demands for traceability

• Real life: • If no international or harmonized RS: A large stock of in-house

primary RS stable for as many years as possible and traceable to relevant external RS

• Reduce uncertainty during calibration to minimize the shifts to the unavoidable shifts

• Room for the unavoidable shifts in the product specification limits

• Worst case: • Introduce correction factors

• Change product specifications

• One specification, but different RS and fillings for different regions

Slide no 23


Future

• Harmonized monographs and RS with stated uncertainty, and an International WHO defined both in IU and mg

Slide no 24

Acknowledgements

• Niels Zeuthen, Statistician, Principal Scientist, Diabetes

• Ulla Riber, Senior Project Manager, Diabetes

• Andrew Chang, Exec. Dir. Global Regulatory Affairs



Thank you for your attention

Questions or comments?

Slide no 26

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