Regulatory Perspectives on Advanced Analytical Methods used for Control of Biopharmaceutical Products

Sarah Kennett, Review Chief Division of Biotechnology Review and Research I

Office of Biotechnology Products OPQ/CDER/FDA

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AT Europe March 20, 2015

Disclaimer

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

Overview Survey of methods used in biotechnology product

specifications

Method lifecycle -examples of method validation/transfer/change issues

Other questions and issues related to the use of methods utilizing advanced technologies

Conclusions

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Quality The suitability of either a drug substance or a drug

product for its intended use. This term includes such attributes as the identity, strength, and purity.

Critical Quality Attribute (CQA) A physical, chemical, biological or microbiological

property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

ICH Q8(R2) 4

Analytical methods used in QC labs • Data from currently marketed products regulated under

BLA by the Office of Biotechnology Products – Products withdrawn from the market are not included. – Protein products regulated under NDA are not included. – Missing data for 4 products.

• Total of 98 protein products surveyed (approved 1965-2015)

• Focus on capillary electrophoresis as an advanced

analytical technique (relative to SDS-PAGE and IEF)

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Use of CE in QC labs CE-based method included in release/stability specifications:

44 products

No CE-based method for release/stability: 54 products

45% of specifications for current OBP regulated

BLA products include a CE-based method.

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Use of CE in QC labs Products approved in the last 5 years CE-based method included in release/stability specifications:

24 products

No CE-based method for release/stability: 17 products

59% of specifications for OBP regulated BLA products approved in the last 5 years include a

CE-based method. (35% in previous years)

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Use of CE in QC labs Types of methods CGE (SDS/LDS) 34 products

cIEF/icIEF 12 products

CZE 6 products (charge, identity, other)

CE glycosylation 6 products

There are as many as 3 types of CE in a single set of specifications.

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Methods used in QC labs CGE (SDS/LDS) 34 products SDS-PAGE 49 products

cIEF/icIEF 12 products IEX (WCX, SAX) 38 products IEF 21 products RP-HPLC 43 products HIC 5 products

SEC (GPC, GF) 83 products

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Advanced analytical technologies can include standard methods using -modern detection systems -innovative equipment -current software -novel reagents -alternate sample prep

Use of MS in QC labs Mass Spectrometry was identified in the specifications of 2 products. -identity -oligosaccharide

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Use of CE in QC labs CE is included in the specifications for OBP regulated BLA products marketed by 23 companies.

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Expectation that the use of advanced analytical techniques will continue to grow -Control -Characterization

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Biosimilars - EMA and Health Canada Guidances (draft) • Given the complexity of the molecule and its inherent

heterogeneity, the set of analytical techniques should represent the state-of-the-art. It is the duty of the manufacturer to demonstrate that the selected methods used in the comparability exercise would be able to detect slight differences in all aspects pertinent to the evaluation of quality.

• The product-related substances and impurities in the similar biological medicinal product should be identified and compared to the reference product using state-of-the-art technologies.

• …state-of-the-art analytical technologies … these process-related impurities should be confirmed by appropriate studies (which may include non-clinical and/or clinical studies).

• The product can be well characterized by a set of modern analytical

methods.

Biosimilars - US Guidance for Industry: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product Draft guidance 2012

• Advances in analytical sciences (both physicochemical and biological) enable some protein products to be characterized extensively in terms of their physicochemical and biological properties.

• A meaningful assessment as to whether the proposed biosimilar product is highly similar to the reference product depends on, among other things, the capabilities of available state-of-the-art analytical assays to assess, for example, the molecular weight of the protein, complexity of the protein (higher order structure and post-translational modifications), degree of heterogeneity, functional properties, impurity profiles, and degradation profiles denoting stability. The capability of the methods used in the analytical assessment, as well as their limitations should be described by the applicant.

• In addition, the use of complementary analytical techniques in series, such as peptide mapping or capillary electrophoresis combined with mass spectrometry of the separated molecules, should provide a meaningful and sensitive method for comparing products.

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Method Lifecycle Development SOP System suitability Sample, etc. acceptance Qualification Validation Transfer Change to a new method or change to current method

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Why are these assays used?

Specifications- release/stability In-process controls Characterization Comparability Investigations-deviation/event Development-process/product Reference Standard Qualification Cell Bank Qualification

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What Needs to be Considered Throughout the Method Lifecycle Development SOP System suitability Reference materials Qualification Validation Transfer Change to a new method or change to current method During all lifecycle activities, it is crucial to think about all the different uses of the method and all aspects of the method life-cycle. Would QbD be useful?

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Specifications- release & stability In-process controls Characterization Comparability Investigations-deviation/event Development-process/product Reference Standard Qualification Cell Bank Qualification

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Quality by Design (QbD)

A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

ICH Q8(R2)

The QbD concept is to enhance understanding of a product and process starting at the development stage. A product is designed to meet a desired clinical performance, and the process is designed to consistently deliver that product. The process is continually monitored and updated to assure product quality.

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Quality Target Product Profile (QTPP) A prospective summary of the quality characteristics of a drug product

that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.

Design Space The multidimensional combination and interaction of input variables

(e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.

ICH Q8(R2)

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Quality by Design (QbD)

≠

Design Space

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QbD Approach (pharmaceutical development)

CQAs

QTPP

Design Space

Control Strategy

Process Validation

Monitoring/Continual Improvement

Risk Assessment Product and Process

Characterization CPPs

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QbD for Analytical Methods Are QbD principles applicable/useful for analytical methods?

QTPP → Target Method Profile CQA → Critical Method Attribute CPP → Critical Method Parameter

Risk Management: Use of risk management tools for analytical development

Control Strategy: System suitability, assay/run/plate acceptance

Continual Improvement: Yes- FDA supports improvement of methods and movement to superior methods.

Require Understanding

of Method, Product,

and Product Control Strategy

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QbD for Analytical Methods, cnt. Design Space?

The multidimensional combination and interaction of input variables (columns, reagents, suppliers) and method parameters that have been demonstrated to provide assurance of quality.

Is this similar to developing and validating a method with significant

robustness included in the validation?

OR

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QbD for Analytical Methods, cnt. Design Space?

The multidimensional combination and interaction of input variables and methods that have been demonstrated to provide assurance of quality (e.g., interchangeable methods used with the knowledge that all necessary attributes can be detected/quantified/identified equally well using any method).

-The TMP, CMAs, CMPs would be extremely important.

-Careful consideration of lifecycle elements (development, SOP, validation) AND uses (QC release/stability, in-process testing, characterization) become critical.

-The concept seems possible. However, discussing with the appropriate regulatory agencies would be recommended!

-Remember that testing by another method is not an acceptable route to obtaining a passing result when a failing result was obtained using the initial method.

Use of Advanced Techniques in QC labs Challenges Issues Questions (Really not different from any other methods!)

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Method Lifecycle Management • FDA Validation Guidance intended to compliment ICH Q2(R1) • BLA submissions should include:

– A full description of analytical procedures – Data to establish that the methods “meet proper standards of accuracy and reliability

and are suitable for their intended purpose”

• Validation should be performed under an approved protocol following cGMP and should include predetermined acceptance criteria

• Validation typically includes: – Specificity – Linearity – Accuracy – Precision (repeatability, intermediate precision, and reproducibility) – Range – Quantitation limit – Detection limit – Robustness (data can also come from development studies)

• Compendial methods should be verified for suitability

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Method Lifecycle Management Method Change/Transfer • Lifecycle Management

– Trend analysis – Appropriateness of method and new technologies should be evaluated over

lifecycle – Samples should be archived

• Analytical Method Comparability Studies – New method equal or superior to original method – New method is not more susceptible to matrix effects – Stability indicating properties should be evaluated

• Analytical Method Transfer Studies – 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 – Also see USP<1224> Transfer of Analytical Procedures

Draft Guidance for Industry: Analytical Procedures and Methods Validation for Drugs and Biologics, CDER, CBER, FDA, February 2014

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Example: Method Transfer Recommendation on inspection - CZE method (similar issues with

other): • Transfer included a statistical justification for the acceptance

criteria, but only acidic variants had established transfer criteria. • The inspection discussion included that testing of only typical release

samples and assessing only acidic variants may not demonstrate true equivalence between the transferring and receiving labs.

• During the inspection, the sponsor provided data for main peak and basic peaks.

• “Strengthen method transfer policies to evaluate a wider range of samples.”

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Example: Method Transfer, cnt. Issues with additional transfers by the same sponsor: • “Transfer” is partial validation only. • No direct comparison between transferring and receiving labs. • No data to allow for a “good” indirect comparison (e.g., same

samples tested at both sites ever). • System suitability was not useful for a comparison (e.g., reference

material curves). • Potentially useful raw data were not provided.

• Development of system suitability was not for this purpose. • Specifications need to be considered. Release/stability acceptance

criteria were set using data obtained at site #1. – If data generated at subsequent sites are not equivalent, are acceptance criteria still appropriate?

• Trending – If sites do not generate equivalent data, how does product/process trending work?

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cIEF and CE-SDS assays used to control purity • Validation did not include accuracy and LOQ/sensitivity. • Precision did not include all relevant peaks/peak groups (this was

also not considered for a non-CE-based assay). • The sponsor indicated that these are not applicable based on the

intended use of the assays and that the assays are semi-quantitative; the sponsor also stated that “accuracy is not relevant.”

• The assays’ intended uses are to quantify and control specific impurities/groups of impurities. These assays should be quantitative; the proposed acceptance criteria are.

• Accuracy with respect to an accepted reference value is relevant.

• Additional validation studies were required. 30

Example: Assay Validation

cIEF and CE-SDS assays used to control purity In Addition: • Based on the data (including electropherograms), it appears that

there were some changes made to the assays during development. • The specification acceptance criteria need to be based on (and make

sense relative to) the data provided.

• The sponsor needed to clarify when during development the methods were changed (and how). Data to support the change (that the new method was “as good as” the old method) and to identify how the data from the previous versions of the assays relate to the data from the current versions of the assays were required.

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Example: Assay Validation, cnt.

Example: Method Change (post-approval)

Response to a PMC to develop quantitative method for charge variants

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Method 1 IEF

Example: Method Change, cnt. • The sponsor provided:

– Characterization - comparison of methods, including enzyme treated samples(carboxypeptidase, glycosidase), to show similarity in variants detected

– Description of method – Validation report – New acceptance criteria for release and stability – Stability data

• Real time/accelerated • Forced degradation – to show that the stability indicating properties of the

method are equivalent to or better than the current method

• This is all good!

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Example: Method Change, cnt. • Differences in pI distribution, attributed to differences in

methods, were not considered an issue by FDA. • The new method was assessed by FDA as generally being

suitable for its purpose.

However…

• Insufficient information about method was provided (although it was noted that controls and system suitability info was provided). – There were questions about critical reagent sources and stability.

• Sample stability was not evaluated (or not included). • The sponsor did not remember to update protocols that include

release testing (e.g., reference standard, WCB, reprocessing). • And -

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Example: Method Change, cnt. • The proposed acceptance criteria were determined to be

unacceptable. The proposed criteria did not provide as much control as the previous criteria.

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Main peak group makes up ~90% of the product. The proposed icIEF acceptance criteria included control only over the total percent area of the main peak group peaks. The IEF criteria included controls for band numbers and percents for peaks in different pI regions. CQAs need to be considered when determining how data should be reported and evaluated. Method 2 icIEF

(e-gram excerpt)

Main peak group

Example: Method Change, cnt. • The current method standard operating procedure, the final method

validation report, and relevant method development information were requested to allow for an evaluation of the suitability of the proposed method.

• The sponsor was requested to include the new method in the qualification protocol for the primary and secondary reference standard (with acceptance criteria suitable to prevent drift in product quality).

• It was noted that combining the peaks in Group 2 might result in shifts

among these major isoforms not being captured by the proposed acceptance criteria. Therefore, in order to accurately control the major charged isoforms present in Group 2, the sponsor was requested to provide acceptance criteria for each peak identified in Group 2 (criteria relative to reference material might be used). 36

Example: Method Removal • Evaluated as part of a response to a PMC to set quantitative

acceptance criteria. • CEX and icIEF methods were initially included in the specification. • The sponsor provided:

– Characterization to compare peak composition (identification of variants) – Information/data to enable setting of acceptance criteria – Stability data to show that the methods are equally stability indicating

• There were differences between peak areas of CEX and icIEF (some isoforms were resolved better by one or the other); these needed to be understood to help determine if CQAs were appropriately controlled. Differences such as these should be well explained in submission and considered to ensure that acceptance criteria are set appropriately.

• The methods were used side-by-side to generate an appropriate data set for use in setting acceptance criteria.

• Acceptance criteria were set based on clinical and manufacturing experience.

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Example: Method Removal, cnt. • Regarding differences in resolution:

– icIEF allows for quantification of some isoforms not resolved by CEX. – One important isoform not as well resolved by the CE method is controlled by RP-

HPLC (also on the spec). • Acceptability was also based on identification of CQAs.

• CEX was removed because it provides redundant information. – In addition, there were consistency issues with column because the manufacturer

changed the resin, which led to a reduction in resolution and robustness. The potential for such changes and plans for identification of appropriate replacement reagents should be considered early whenever possible.

• While the proposed acceptance criteria were supposed to have been set based on clinical and manufacturing experience, the initially proposed criteria for some peaks needed to be revised to be more reflective of this experience.

• Notes were made to request an examination of the re-evaluation of acceptance criteria during a future inspection.

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Questions regulators have asked • What if the markers that are run in the sample cover up

important impurities/variants/peaks? How do you not miss peaks because they get “hidden” by the markers?

• What is the capability of CE method X and how does that compare the current method Y?

• What does the label/labeling procedure do to the sample (especially with respect to determining relative quantities)?

• The e-grams do not line up. Is there a problem with repeatability? How can you be sure that the peaks in sample 1 are the same as the peaks in sample 2? (translation: How big a difference in retention time is acceptable?)

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Questions regulators have asked • They “corrected” the peak area. How can this be okay?

{I think this was exacerbated by the sponsor’s phrasing. I had no problem explaining why this is okay –for a CE method- but wanted to point out that it’s good to read things from the regulator’s perspective before submitting them.}

• How are the mass spec data quantitative (generally with respect to post-translational modification/degradation)? Aren’t some peptides lost? Can it be validated?

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Problems/Questions identified/asked during inspections • System suitability failures

– unusually high percentage- identified

• Integration- manual versus software driven, “rules,” saving of original data and changes (data integrity)

• Critical equipment/reagents listed as “or alternative” – Need to have identified alternatives or procedure for qualification (also

necessary for introduction of new lots of some critical reagents)

• Equipment not calibrated/qualified for its purpose (e.g., heat block/thermometer used for sample prep)

• Open-ended retesting protocols – Need to have a defined number of retests/cycles allowed

• Method transfer issues (e.g., samples used and comparison performed; see example)

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Conclusions • Advanced analytical methods are used in the QC labs of many

biotechnology companies. • CE-based methods are included in a large, and apparently

growing, percent of release/stability specifications for biotechnology products.

• Many of the regulatory issues/concerns/questions regarding advanced methods used in QC labs are the same as those for other methods and can usually be resolved by the submission of appropriate data and information.

• For all methods, it is important to consider the interrelationships among different lifecycle elements and uses of the method. Doing this early is probably useful.

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Acknowledgements Ralph Bernstein Jee Chung Laurie Graham Jack Ragheb Joel Welch Additional Colleagues in the Office of Biotechnology Products

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“Why wouldn’t they be?” -The final remark by an FDA colleague at the end of a brief discussion regarding increasing numbers of CE methods included in release and stability specifications.