Regulatory Perspectives on Analytical Method Transfer for

Biopharmaceutical Products

Ramesh Potla, Ph.D.Office of Biotechnology Products

OPQ/CDER/FDACMC Strategy Forum

January 23, 2017

1LL

2

The views and opinions expressed should not be used in place of regulations, published FDA guidances, or discussions with the Agency.

Disclaimer

3

Scope

Current expectations about the site transfer of validated non-compendial analytical methods

4

Outline

• Definitions

• Regulatory Framework

• Points-to-Consider– Risk Considerations– Transfer Approaches– General Considerations (Number of Lots, Analysts, Types

of Samples etc.)

• Case Studies

4

5

Definitions

6

Analytical Method Transfer: Definition

A documented process that qualifies a laboratory (the receiving laboratory) to use a validated analytical test procedure that originated in another laboratory (sending laboratory), thus ensuring that the receiving laboratory has the procedural knowledge and ability to perform the transferred analytical procedure as intended.

Adapted from USP <1224> Transfer of Analytical Procedures

7

Regulatory Framework

8

Method Lifecycle(borrowing from process validation)

8

Stage 1 – Assay Design: The assay is defined during this stage based on knowledge gained through development activities.

Stage 2 – Assay Qualification: During this stage, the assay design is confirmed as being capable of producing reproducible results suitable for the specified purpose. Scientifically sound work in progress.

Stage 2 ½ - Formal Assay Validation Study: The assay is tested against specific acceptance criteria set to verify that the performance characteristics of the final method are suitable and reliable for the intended applications.

Stage 3 – Continued Assay Verification: Ongoing assurance is gained during routine production that the assay remains in a state of control. (system suitability, assay suitability, trending of results, OOS, etc.)

Adapted from Sarah Kennett

9

Requirement for Validated Assays• 21 CFR 211.165“The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with ….”

• 21 CFR 211.194(a)(2)“[The firm] shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliabilityas applied to the product tested ….. The suitability of all testing methods used shall be verified under actual conditions of use.”

10

Requirement for Validated Assays

Adapted from FDA Guidance on Analytical Method Validation (2015)

• 21 CFR 314.50(d)(1) and 314.94(a)(9)(i)Each NDA and ANDA must include analytical procedures necessary to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product.

• 21 CFR 601.2(a) and 601.2(c)Each BLA must include a full description of the manufacturing process, including analytical proceduresthat demonstrate the manufactured product meets prescribed standards of identity, quality, safety, purity, and potency.

11

ICH Recommendations for Validated Assays

• At the time the application is submitted to the regulatory authorities, applicants should have validated the analytical procedures uses in the specifications.– ICH Q6B

• Analytical methods should be validated…– ICH Q7

12

Post-Licensure Change Requirements

12

Modification of any particular test method or manufacturing process or the conditions under which it is conducted…shall be permitted only under the following conditions• The applicant presents evidence…demonstrating that the

modification will provide assurances of the safety, purity, potency, and effectiveness of the biological product equal to or greater than the assurances provided by the method or process specified…

• 21 CFR 610.9(a)

This means that re-validation (sometimes partial revalidation) is likely to be necessary and the change has to be reported and often needs to be approved.

Adapted from Sarah Kennett

13

Points-to-consider

14

Risk Assessment Considerations

A risk-based approach should be used to determine the totality of evidence needed to demonstrate a successful method transfer.

15

Risk Assessment ConsiderationsSome of the factors to consider in the risk-based analysis include (but are not limited to):

• type of method being transferred (e.g., qualitative or quantitative) • method’s intended use (e.g., identity, purity/impurity, potency, etc.) • method capability • past method performance • type of test samples being included (e.g., in-process control samples, drug

substance, and/or final drug product) • nature of differences associated with the method transfer and their impact

on the overall method performance, product quality, safety and efficacy • criticality of the product quality attribute towards safety and efficacy• product therapeutic window/index

16

Transfer Approaches

17

Analytical Method Transfer: Approaches• Comparative testing: Both originating and receiving

labs participate in method transfer exercise. Results are compared to pre-defined acceptance criteria.

• Co-validation: The receiving laboratory participates in the initial method validation activities.

• Method validation or revalidation: Complete or partial validation is performed by the receiving laboratory.

• Transfer waiver: Not applicable to non-compendial analytical test methods for biologics

18

Transfer of Non-Compendial Methods

• The purpose of method transfer exercise is to demonstrate that the performance of the method is similar between the sending and receiving laboratories

• The Sponsor should perform a comparison of results from samples tested during the re-validation (full or partial validation) at the receiving laboratory with data generated at the sending laboratory (comparative test data and/or historic data) to ensure a consistent measure of product quality attributes at both test sites

19

Transfer of Compendial Methods

• Data demonstrating successful transfer of compendial methods are generally not required to be submitted as supplements to a BLA or amendments to an IND.

• Transfer of compendial methods is annual reportable

• In cases where the method transfer involves modifications to the compendial methods, the modified methods should be regarded as non-compendial methods and the transfer of the modified methods should be submitted under appropriate reporting categories to a BLA or an IND

20

General Considerations

21

Method Transfer

21

• Two or more laboratories participate in the transfer protocol.

• A sufficient number of representative samples should be used including forced degradation samples or samples containing product-related impurities where appropriate.

• Accuracy and precision should be evaluated, “especially with regard to assessment of interlaboratory variability.”

Adapted from FDA Guidance on Analytical Method Validation (2015)

22

Examples of Critical Assay ParametersTested During a Method Transfer Exercise

23

Number of Lots

• No universal expectations on the number of lots needed

• Depends on the intended use of the analytical method

• For a method transfer exercise, evaluation of multiple replicates from one lot is usually enough as to not add manufacturing variability into the determination of assay performance

• In other instances, it may be necessary to use more than one lot to demonstrate that a method is suitable for analysis of a different sample or impurity concentration.

24

Types of Samples

• Test samples included in the method transfer exercise should be chosen based on the method’s intended use.

• Examples include:- Reference standards- Stressed samples- Spiked samples

25

Number of Analysts

• At the minimum, two analysts at the receiving laboratory should perform the test.

• Determination of intermediate precision should include multiple analysts (e.g., two) performing the test on multiple days, using separate sample preparations and/or equipment.

26

System Suitability Acceptance Criteria

• System suitability acceptance criteria for transferred assays are generally the same between the sending and receiving laboratories.

• In cases where there are differences in system suitability acceptance criteria between the sending and receiving laboratories, the differences should be evaluated to ensure that the system suitability at the receiving laboratory provides sufficient control over the function of the assay.

27

Method Transfer Acceptance Criteria• Pre-defined acceptance criteria for method transfer exercises are

generally established based on a risk assessment, assay capabilities, previous validation data, historical data from an internal control (e.g., reference standard), previous method transfers, and the intended statistical methodology.

• The FDA reviewer evaluates the data generated during the method transfer, and not only the acceptance criteria, to determine whether the method transfer was successful.

• For a method transfer to be considered successful, both system suitability results and the test sample results must pass the pre-defined protocol acceptance criteria, which should be appropriate for the purpose of method transfer.

28

Reporting Analytical MethodTransfer Data to the Agency

• The sponsor should report the results of a successful non-compendial method transfer and receive approval prior to releasing commercial drug product from a new test site. The sponsor should submit the method transfer results as either a CBE-30 or a PAS based on the potential impact of the method transfer to product quality, safety, or efficacy.

• In OBP, the results to support the transfer of the majority of analytical methods are typically submitted as a CBE-30. However, transfer of some high-risk assays, such as potency assays, should be submitted as a PAS. This is particularly important for products for which the dosing is based on the potency.

• The transfer of compendial tests (e.g., pH testing) is annual reportable.

29

Case Studies

30

Prior Approval Supplement (PAS) – adding a new site for drug substance manufacturing and quality control testing.

Transfer of several stability-indicating purity (CEX-, SEC-HPLC, SDS-PAGE) and potency assays was found unacceptable.

The transfer exercise did not include appropriate aged or spiked samples to demonstrate that the transferred methods are capable of detecting and quantifying impurities at comparable levels between the sending and receiving sites.

The Sponsor withdrew the addition of new test sites for purity and potency assays.

Method Transfer: Case Study#1

31

Method Transfer: Case Study#2Host Cell DNA by qPCR method – both original validation and method transfer reports were submitted in the original BLA submission.

The product was made in NS0 cells and the method transfer was performed using inappropriate samples (CHO DNA).

The Sponsor was asked to remove the additional testing site from the BLA application.

32

Method Transfer: Case Study#3No direct comparison to the originating lab for most assays transferred.

For some methods (e.g., CZE for glycans), the electropherogram profile was compared to the example included in the method SOP. However, the specifications also include quantitative criteria.

For one quantitative method, the receiving lab results for one sample (mean) were compared to the historical originating lab results for “the same sample material.” It is not clear what the originating lab sample material was or if it is relevant to use as a comparator (e.g., if the receiving lab sample was generated using a new manufacturing process).

This is not sufficient to support transfer.

33

Method Transfer: Case Study#4RP-HPLC Assay for Protein Content: The Sponsor provided accuracy and precision data in the transfer report

Data provided failed to demonstrate assay precision. Two of the three HPLC instruments used in transfer exercise failed system suitability at least once. Also failed the assay acceptance criterion for analyst differences (acceptable difference - ≤ 5%; result – 13%)

The Sponsor was asked to perform complete validation of the RP-HPLC method at the receiving site, and to demonstrate that the newly validated method provides comparable and meaningful results.

34

Conclusions• The goal of a method transfer exercise is to ensure

continuity in the validated state of the transferred analytical method at the receiving laboratory.

• Use a scientifically sound risk-based approach to determine the totality of evidence needed to demonstrate a successful method transfer.

• Continued method verification as part of the firm’s quality system facilitates accurate and reliable performance of the transferred method at the receiving laboratory on a routine basis.

3535

Acknowledgements• Susan Kirshner• Sarah Kennett• Rashmi Rawat• Qing Zhou• Deborah Schmiel• Frances Namuswe• Leslie Rivera Rosado• Maria Cecilia Tami• Other OBP colleagues

3636

Thank you!