Improvements to Commercial Reference Standards › › resource › resmgr › CMC_N… · Case Study III: Primary Reference Standards A few years ago, Biogen Idec made a decision

Improvements to Commercial Reference

Standards

Stacey Traviglia, Ph.D.

Associate Director, Analytical Technology

Biogen Idec, Research Triangle Park, NC

16 July 2013

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Outline

• Drivers for Implementing Improvements to Commercial Reference Standard Programs

• Case Studies

– Batch Selection Criteria for Commercial Programs

– Managing Implementation of Improvements to the RS Qualification Protocol

– Primary Reference Standards

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Drivers for Implementing Improvements to

Commercial Reference Standard Programs

• Minimize drift when moving from one reference standard to another

• Implement a primary reference standard (PRS) to last the lifetime of the commercial program as the calibrator for working standards: compare PRS→ A, PRS → B, PRS → C, PRS → D

and not A → B → C → D

• Update specifications and implement new analytical technologies for further characterization during qualification studies

Case Study I: Batch Selection Criteria for RS

• TRUE or FALSE?

– Any Commercial Batch that meets release

test specifications is suitable for a Reference

Standard

• Minimizing Drift

– Selection of a drug substance batch near the

manufacturing mean will reduce the risk for

product quality drift

• Also ensures the reference standard is suitable for

its intended use

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• A risk evaluation was conducted to establish batch

selection criteria used to identify an appropriate drug

substance batch to be qualified as a reference standard

• First identified the use of the reference standard in all

drug substance and drug product testing

– Where RS is used as a calibrator, assay control or system

suitability control

• Established batch selection acceptance criteria for those

release tests that use the reference standard as a

comparator, especially the Bioassay

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• Batch selection criteria were created for

the following subset of attributes:

– Biological Activity

• Is the only assay that uses RS in a way that has

quantitative implication and could have something

to do with a drift

– Mass

– Impurities (oxidation, clips)

– Glycan Structures

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• Historical commercial DS manufacturing data (14 years and 623

batches) were used to establish the mean and SD for batch selection

criteria

• Reference standard batch selection acceptance criteria was

established based on ± 1 standard deviation of the historical

manufacturing mean (Note the ± SD is based on the data available)

• Upon selection, a batch was qualified via a pre-defined reference

standard qualification protocol

• Batch selection criteria for future reference standards will be

established using the most up-to-date dataset available to determine

the manufacturing mean and standard deviation

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Case Study II:

Improvements to the Qualification Protocol

The following improvements were made to the qualification

protocol:

• Updated acceptance criteria

– Report results to numerical limits

– Adjust limits based on additional data

• Added Batch Selection Criteria

• Implemented new analytical technologies

– Differential scanning calorimetry

• Melting points comparable to reference standard

– Analytical ultracentrifugation

• Monomer Sedimentation coefficient comparable to reference standard

– Hydrogen Deuterium Exchange Mass Spec

• Comparable to reference standard

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Case Study II:


Lessons learned • Changing the filed qualification protocol and

implementing a new RS at the same time

caused some headaches

– Did not receive regulatory approval of the new

qualification protocol by the time the expiry old RS

was reached and new one needed to be put in place

– After receiving FDA and EMA approval and new RS

was to be implemented, ROW filings lagged, creating

out-of-compliance in ROW countries with the filed

qualification protocol

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Case Study II:


Work-around • Used existing stability data to extend the expiry

of the current RS until approval was received

• Tracked inventory carefully to ensure we didn’t

run out while waiting for approval

• Assessed the new RS against the old

qualification protocol criteria and documented

the conformance of the new RS against the old

qualification protocol to ensure ROW compliance

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Case Study III: Primary Reference Standards

A few years ago, Biogen Idec made a decision to

implement primary references standards for new programs

• For a new commercial product, Biogen Idec establishes

a primary reference standard (PRS) in order to ensure

that the quality of the commercial product is consistent

with that of the clinical material, and to avoid drift in

product quality over time

• Working reference standards (WRS) are established for

routine release and stability testing of drug substance

(DS) and drug product (DP)

• The WRS is qualified against the PRS, and stability

monitoring is performed for both the PRS and WRS

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The Primary Standard (PRS)…

• is the “gold standard” representative of molecule,

process, formulation, and clinical experience

• will not be used for routine release and stability testing

once the first working standard has been qualified

• is used to qualify all future working reference standards

– minimizing drift of reference standards over time

• is intended to last the lifetime of the program, however, a

new primary would be established if

– major formulation or process change

– low inventory

– stability issues


Question: When do we implement a PRS?

• Practical considerations: Need a well-defined

process and sufficient material to set aside for

the RS

Our decision: just before/from PVR campaign

• Why not establish a PRS earlier?

- Small batches

- Still making changes to process

- Cost/risk: Uncertainty of an earlier program - there

are additional resources/costs for PRS

- we have RS program in place that is suitable for the

intended purpose for programs prior to PVR

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Research Reference Standard

Interim Reference Standard

Clinical Reference Standard

Primary Reference Standard

Working Reference Standard

Pre IND Phase

I Phase

II Phase III

Commercial Manufacturing

Research Reference Standard

Interim Reference Standard

GMP Reference Standard

Commercial Reference Standard

Previous Approach:

Phase-based Approach for

Reference Standard Management:



Selecting the PRS

The DS batch designated as the PRS must meet the

following general criteria for the selection:

• Manufactured during clinical supply campaign using the

intended commercial manufacturing process or during

the process validation campaign

• Batch/lot is representative of the material that is used in

Phase 3 clinical studies

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The product quality of the PRS is representative of the Phase III clinical

material and met the following general criteria:

• The primary sequence is 100% verified

• Has the correct/expected disulfide assignment, higher order

structure, post translational modifications, glycosylation, and in vitro

biological activities

• Potency/in vitro biological activity is calibrated against the

International Standard where applicable

• Biological activity within the middle range of the clinical data

• The levels of product-related substances (product heterogeneity

including glycoforms) are near the middle range of clinical data

• The levels of product-related impurities are also near the middle

range of clinical data

• The levels of process-related impurities are consistent with the other

clinical batches manufactured with the same process

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PRS Qualification

• Covered in other presentations

PRS Stability

• PRS is placed on stability: Stability indicating release tests taken

annually and characterization every four years

• Stability of the PRS is also supported by ongoing DS stability testing

• The stability specs for the PRS is established based on the DS

stability specs, except for biological activity, for which stability

criteria may be narrower than the corresponding DS specification

– This will prevent the PRS from reaching the limits of allowable product quality

and minimize drift in the RS program

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Example: Analysis was done using Stat Calc (recommended by our

statisticians based on the sample size)

• Data collected in confirmation testing of the potency std

• Tailed weighted tolerance intervals

• 95%CI, 0.9973 proportion

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N 20

Average 0.9985

Std Dev 0.0869

%RSD 8.705

PRS Stability

Specs:

62-138 MU/mL

(DS 50-160)


• Challenges

– Multiple programs transitioning at the same

time, limited RS resource and limited

supporting teams (AD, QC, Sample Control)

– Developing appropriate R&Rs for RS

Manager and support team

– Even good change is difficult and takes time,

lots of questions, discussion and agreement

(Next time should be easier!)

– Add-ons that came later in the game plan 19

Conclusions

• Even when you have a good RS program,

improvements can be made

• A lot of effort and team work was required to

make these improvements to commercial

reference standards

• Batch selection criteria, qualification protocol

updates, and PRS all work to minimize drift

when moving from one RS to another over the

lifetime of the commercial program

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Acknowledgements

• Kim Lloyd, Reference Standard Manager

• Mia Kiistala, Analytical Development CMC

• Svetlana Bergelson, Analytical Development

Bioassay

• Maureen Shreve, QC Analytical Technology

Bioassay

• Kamran Simani, Stability

• Sue Stella and Helena Madden, Regulatory

• Joe Molon, Director QC Technical Services

Documents

Improvements to Commercial Reference Standards › › resource › resmgr › CMC_N… · Case Study III: Primary Reference Standards A few years ago, Biogen Idec made a decision