IQ Consortium White Paper: Expectations for Phase-AppropriateDS and DP Specifications for Early-Stage Protein TherapeuticsCorné J.M. StroopMSD, Oss, the Netherlands

Who is the IQ Consortium?• The International Consortium for Innovation and Quality

in Pharmaceutical Development (IQ) is a technically focused organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader R&D community

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Specification Working Group• Members include representatives from 14 companies• Early phase specification strategies were the first focus

• Manuscript published Juliana Kretsinger, et al., Journal of Pharmaceutical Sciences (April 2019) 108, 1442-1452

• Second effort is underway to define strategies for setting patient focused commercial specifications• Manuscript has been drafted and is under review within the

group

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Acknowledgements

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Name Company_Name Early Specs WG Commercial Specs WGAthena Nagi Merck X XLuca Benetti Merck X

Bill Egan GSK Vaccines X XBruno Figueroa Pfizer X

Neha Frantz Biogen X XMartin Gastens AbbVie X X

Scott Hart BMS XWayne Kelley GSK X XBob Kitchen Pfizer X

Juliana Kretsinger Lilly X XElena Luganovski Daiichi-Sankyo X X

Eduard Luss Vertex X XSuzanne Mercorelli Merck X X

Shawn Novick Seattle Genetics X XBarbara Rellahan Amgen X XDaisy Richardson Merck X XMargaret Ruesch Pfizer XClemens Stilling UCB X XDaniela Stranges GSK Vaccines X X

Corné Stroop MSD X XJohn Stults Genentech X

Ann Subashi Pfizer XWeijie Wang Incyte Corporation X X

Ping Yin Vertex X X

Intercompany Survey• Survey was prepared to gather information about current

early-phase specification practices and sent to all IQ consortium members in 2017

• 14 questions focused on specifications for first in human (FIH) clinical trial materials

• 20 responses were received • 3 responses across all vaccines provided a limited dataset

• Full survey results are provided as supplemental material to the article

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White Paper• Purpose: establishing phase-appropriate DS and DP

specifications for FIH clinical development of biologics • Context: Phase I, with focus on mAbs and ADCs, but general

principles may be applied to other protein therapeutics• Introduction:

• Platform approach using prior knowledge• ICH Q6B (“Specifications: Test Procedures and Acceptance Criteria for

Biotechnological / Biological Products”) does not provide specific guidance for FIH-stage biologic specifications.

• Outcome of a survey conducted among participating member companies and additional discussion

• Unique characteristics may justify a different limit, excluding tests, or including additional tests 6

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Use of Platform Specifications

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Question 2: Do you utilize platform/template specifications to guide establishment of required test methods and specification acceptance criteria for early phase projects on the follow molecule types?

~80% use platform

specifications

Survey Results• Leverage published guidance for safety criteria, such as

calculation of criteria for DNA or endotoxin based on the highest dose.

• Majority (18/20) reported use of CQA assessment with a varying level of influence (limited due to limited product-specific information).

• Information from stressed and accelerated stability studies (19/19), toxicology assessment batches (18/19) and large scale representative development batches (17/20) are weighted more heavily than small scale representative batches.

• Varying practices regarding the setting of specification acceptance criteria before or after testing of the initial GMP clinical batch.

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Compares to reference• Compares to reference is most frequently used as a criteria for

identity testing• Detailed criteria vary and are typically listed in the method• Definition of compares to reference/standard acceptance criteria:

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Answer Choices Responses

Not applicable 1

Qualitative comparison of the retention/migration time 11Quantitative comparison of the retention/migration time with numericalcriteria 10

Qualitative comparison of the peak profile 12Qualitative comparison of the peak profile with specific peak information toevaluate 8

Quantitative comparison of the area for specific peaks with numericalcriteria 5

Quantitative comparison of the profile based on elution order and/ornumber of peaks 5

Case by case approach, as the type of criteria for each molecule will vary 7

Total Respondents 20

“Report Results”• 60% frequently (plus 20% sometimes) use “report results” as

acceptance criteria for charge heterogeneity• About half (55%) indicated they have implemented changes to

specification strategies based on recent regulatory feedback. The most common change (11/17) was addition of criteria that previously had “report results” as platform.• 25% had not changed strategies, despite feedback• Continue to use “report result” for assessing charge heterogeneity,

glycosylation, or excipient content, but seldom used CQAs

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Survey Results• Revision of specifications prior to PhIII is an expectation for

most respondents (17/19).• Additional characterization testing of clinical batches is

common• Some characterization results may be in regulatory submissions,

but not all characterization testing and results are included

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White paper

• Kretsinger, J., Frantz, N., Hart, S.A., Kelley, W.P., Kitchen, B., Novick, S., Rellahan, B., Stranges, D., Stroop, C.J.M., Yin, P., and Gastens, M.H.,Expectations for Phase-Appropriate Drug Substance and Drug Product Specifications for Early-Stage Protein Therapeutics, Journal of Pharmaceutical Sciences (April 2019) 108, 1442-1452

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White paper outline

• Introduction• Results of Survey• Template Specification

Proposal • mAb and ADC examples

• Justification of Specifications• Report results• Compares to reference• Characterization testing

• Conclusion

• Approach is to define minimal requirements. • More tests or tighter criteria

may be standard at some companies, but the white paper focuses on aligned minimal requirements

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Table 3 Specification for mAb Drug Substance (IND table S.4.1-1)Quality Attribute Analytical Procedure5 Acceptance Criteria

Identity List out method type (e.g.

Peptide Map, IEX, ICE, ELISA)

Identification confirmed

e.g. “Conforms to reference material”

Quantity Assay1

(e.g. Protein Content)

UV Not less than xx.x mg/mL or specify range

(see discussion section)

Potency 1 List out method type

(e.g. Binding ELISA)

Not less than 50% and not more than 150%

potency relative to potency of reference

standardMonomer Purity1 SEC Not less than 90.0%

Total Aggregates/High

Molecular Weight Species1

SEC Not more than 5.0 %

Purity (Reduced) 1 Reduced CE-SDS Not less than 90.0%

Total Fragments1 Non-Reduced/Reduced CE-

SDS

Report result or not more than x.x% 6

Purity (Non-Reduced) 1 Non-Reduced CE-SDS Not less than 90.0%

Residual DNA3 qPCR Not more than xx ppb

(value based on WHO limit of 10 ng/dose)2

Residual Protein A3 ELISA Not more than x ppm

Residual Host Cell Proteins3 ELISA Not more than x ppm

Additional process related

impurity (if applicable)3

List method type Not more than x ppm

Appearance/ Description1, 4 Visual Provide description (e.g. colorless to slightly

brown/yellow solution)

Charge Heterogeneity1

Main Peak

Total Acidic Variants

Total Basic Variants

List method type

(e.g. IEX, ICE)

Compares to reference

Report results

Report results

Report results

Bacterial Endotoxins1 USP <85> Not more than x.x (or x.xx) EU/mg

Total Microbial Count1 USP <61> Not more than x CFU/x mL

pH1 USP <791> Not less than x.x and not more than x.x1 Test should be evaluated for inclusion in stability studies. Microbial testing not recommended for frozen drug substance or samples held at accelerated conditions.2 Limit = 10 ng/dose ÷ (maximum clinical dose (X mg/kg) × patient mass (kg). 3 Strategy of testing process residuals as in-process controls or performing a risk assessment may be considered (see discussion/justification section) 4 For early stage products a simple description is sufficient, however, if color and clarity are assessed then an additional description is not necessary 5 USP compendia tests are listed as examples. Alternate compendia methods may be considered suitable. 6 Multiple approaches can be used to define limit, see discussion/justification section.

White paperJustification of specification discussion provides guidance regarding the basis for justifications of acceptance criteria for each test• Three categories• Additional details for some tests to aid in

understanding where molecule-specific information needs to be considered.

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White paper: Discussion Section Example

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Discussion section provides information about the possible use of non-numerical criteria, including report results and compares to reference.

White Paper: Discussion Section Example

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Scenario 1: Similar results

Scenario 2: Different results

Charge Heterogeneity:Main Peak (MP)Total Acidic Variants (TAV)Total Basic Variants (TBV)

Development55%28%17%

Clinical54%27%19%

Development55%28%17%

Clinical44%32%23%

General Considerations • Do these results accurately reflect the expected variability of the process and the method?

• Are there any additional data from development studies that should be considered?

• Does the difference in the results reflect the expected variability in the process and the method?

• Are the development lot data relevant?• What is known about the attributes that increased or

reduced in the GMP batch?Option A: Set numerical specification criteria based on the observed results from dev batch

Proposed criteria: MP NLT 50%

TAV NMT 30%, TBV NMT 22%Considerations for Option A • New batches may fail the specifications if the

criteria do not allow for process variability.• Limited stability data at the time of filing may

not allow prediction of potential changes during long-term storage.

• Setting criteria based on the limited development lot data may not be appropriate. In this case, the clinical batch would fail the proposed criteria.

• The true variability may be more or less than observed with two batches.

Conclusion for Option A • Setting numerical criteria close to the observed results has significant risk that is not warranted, when there is no link between charge variants and impacts to patient safety or efficacy

Option B: Set numerical specification criteria significantly wider than the observed results

Proposed criteria: MP NLT 45%,

TAV NMT 40%, TBV NMT 30%Considerations for Option B • The criteria are loosely based on the batch data but allow for greater process and method variability, which

reduces the potential for failing specifications.• Batches that pass the criteria could be automatically considered acceptable without further evaluation of any

differences between new batches vs. the toxicology and previous GMP batches.Option C: Set criteria as “report result”

Proposed criteria: MP Report Results, TAV Report Results, TBV Report Results

Considerations for Option C • Including the test in the specification ensures that a method has been developed and qualified, routine lot release and stability testing will be performed and the results will be trended and reported in regulatory documents

• Results from each batch are evaluated, but are not compared to any numerical specification criteria. This can allow a less biased review of the data

White paper: Discussion Section Example

Discussion section also includes information about common characterization tests.• Focus on the tests

that are performed routinely to gather data that supportfuture specifications

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