A Regulatory Perspective on Assessing Critical Quality Attributes

Patrick Lynch, Ph.D.

OBP/CDER/FDA

CASSS Midwest Discussion Group

Assessment of Criticality of Quality Attributes for Biotherapeutics

October 20, 2016, St. Louis, MO

2

Disclaimer

This presentation reflects the views of the author and should not be construed to represent FDA’s

views or policies

www.fda.gov

3

Sources of Regulatory Information on Critical Quality Attributes (CQAs)

• ICH Q7: Good Manufacturing Practice for API

– Application of CQAs to process validation

• ICH Q8(R2) and ICH Q8(R2) Annex: Pharmaceutical Development

– Definition and development guidance for CQAs

• ICH Q9: Quality Risk Management

– Quality risk management considerations applicable to CQA selection

• ICH Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnology/Biological Entities)

– CQAs in manufacturing development

www.fda.gov

4

Presentation Overview

• Defining critical quality attributes (CQAs)– Types of CQAs

• Assessing criticality of quality attributes– Enhanced approaches

• Applying CQAs in process characterization and validation studies

• Applying CQA understanding in the overall control strategy– Timing of CQA development

www.fda.gov

5

Definition of a 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)—Pharmaceutical Development

www.fda.gov

6

Overview of CQAs in Manufacturing Process Development

www.fda.gov

Process CharacterizationCQAs

Identify quality attributes that impact potency, PK/PD,

immunogenicity, or safety? (i.e. affect the drug recipients)

Understanding functional relationships between

process and CQA provides for an “enhanced approach”

Understanding CQAs helps define an

appropriate process

Control Strategy• Release testing• Stability testing• In-process control

testing (IPC)• Control of material

attributes• Control of process

parameters (PP)

7

Different Groups of CQAs

www.fda.gov

• Contaminants

– Adventitiously introduced material (e.g. virus, bacteria, endotoxin)

• Drug product (well-established CQA)

– Protein concentration, pH, visible and sub-visible particles, osmolality, appearance, excipients, etc.

• Process-related impurities

• Product-related variants

“In the case of biotechnological/biological products, most of the CQAs of the drug product are associated with the drug substance and thus are a direct result of the design of the drug substance or its manufacturing process.”—ICH Q11

8

Process-related impurities

www.fda.gov

• Raw Materials

– Cell culture media components

– Chemical reagents (e.g. reducing agents)

• Cell substrate-derived impurities

– Host cell proteins (HCP) and DNA

• Downstream-derived impurities

– Leachables (e.g. Protein-A)

9

Product-related Variant Heterogeneity

Including, but not necessarily limited to…

• Size-related variants– Aggregates– Fragments

• Charge-related variants– Deamidation– Isomerization

• Glycosylation variants– Afucosylation– Galactosylation– High mannose– Sialylation

• Oxidized variants– Methionine, Tryptophan residues

• Sequence variants• Disulfide linkage variants

www.fda.gov

Chirino, A.J., and Anthony Mire-Sluis. 2004. Nat. Biotech. 22:1383-1391

10

Regulatory Expectations to Identify CQAs

www.fda.gov

• The structural and functional complexity of biotechnology proteins makes identification of product CQAs challenging as a large number of attributes need to be assessed. However…

– At a minimum, manufacturing development should include “[Identification of] potential CQAs associated with the drug substance so that those characteristics having an impact on drug product quality can be studied and controlled”—ICH Q11

– Expect some information at Phase I with continued refinement during development

11

Assessing Criticality of Quality Attributes

www.fda.gov

• Attribute criticality is determined based on impact to safety and efficacy

• CQA assessments should consider what’s known about the impact (or lack thereof) of a particular attribute on the following parameters:– Biological activity– Pharmacology (PK/PD)– Immunogenicity– Safety

• Sources information to assess impact of CQA on potency, PK/PD, immunogenicity, and safety can include:– Prior knowledge (e.g. platform knowledge)– Published information– Non-clinical data– Clinical data

• Consider all potential CQAs for analysis– Show your thinking

12

Further Studies to Assess CQAs

www.fda.gov

• In some cases, additional studies can help confirm attribute criticality or address “gaps” in knowledge regarding CQA impact on potency, PK/PD, immunogenicity, safety

• Examples of Additional Studies:– Isolation or enrichment of product-related variants:

• Assessment of variant impact on in vitro bioactivity

• Assessment of variant impact on FcRn binding (to provide additional understanding of impact on PK)

• Assessment of variant impact in vivo by animal studies or clinical experience (e.g. clearance of a particular variant in animal studies)

13

Managing Uncertainty

www.fda.gov

Is the picture of all product quality

attributes complete?• Product

characterization

Is there sufficient data to understand how each critical quality attribute will impact safety and efficacy?

14

CQA Evaluation by Risk Assessments

www.fda.gov

“The identification of CQAs for complex products can be challenging. Biotechnological/biological products, for example, typically possess such a large number of quality attributes that it might not be possible to fully evaluate the impact on safety and efficacy of each one. Risk assessments can be performed to rank or prioritize quality attributes.”—ICH Q11

• For enhanced approaches, CQA identification is generally more systematic and detailed

• These CQA assessments involve use of formal risk assessment tools and CQA “scoring”

• Preference is for CQA scoring to address impact (severity) and uncertainty with regards to biological activity, PK/PD, safety, and immunogenicity

15

Example of a CQA Risk Assessment (Impact)

www.fda.gov

Example from CMC-Biotech Working Group (CMC-BWG) consortium, A-Mab Case Study.

16

Example of a CQA Risk Assessment (Uncertainty)

www.fda.gov

Example from CMC-Biotech Working Group (CMC-BWG) consortium, A-Mab Case Study.

17

CQA Risk Assessment Scoring Summary

www.fda.gov

• Risk scores (= Severity x Uncertainty) provide information for each quality attribute against each parameter (biological activity, PK/PD, safety, immunogenicity)

• Criticality assigned taking into consideration on overall risk prioritization scoring

• Different types of risk assessment tools are sometimes used to evaluate CQA priority (ICH Q9)

• CQA risk assessments can help focus the control strategy

– Well thought-out justifications are important

18

Review Expectations for CQA Risk Assessment

www.fda.gov

CDER Manual of Policies and Procedures (MAPP) 5016.1—Applying ICH Q8(R2), Q9, and Q10 Principles to Chemistry, Manufacturing, and Controls Review:

• The reviewer should evaluate each risk assessment presented in an application• The reviewer should take a scientific and risk-based approach when reviewing the

application:• The reviewer should evaluate the risks to product quality and the ability of

the control strategy to suitably control the risks. The reviewer may choose to conduct an independent formal risk assessment using the tools provided in ICH Q9 to aid this evaluation.

What is the regulatory perspective on CQA Risk Assessments?

19

Examples of CQA Review Considerations

www.fda.gov

1. Incorrect assessment of quality attributes in the risk assessment

– Example: Risk assessment does not evaluate all potential in vivo mechanisms of action of the protein

20

Examples of CQA Review Considerations

www.fda.gov

2. Underestimation of criticality of attribute because process capability or detectability were included in the CQA risk assessment

– Example: Impurity (e.g. HCP) considered non-CQA because of process clearance• HCP and other impurities can have a direct impact on overall safety,

efficacy, and immunogenicity profile of the product

– May need to revisit such “cleared” or “undetectable” CQAs in event of process change, technology transfer, analytical methodology change, etc.

21

Examples of CQA Review Considerations

www.fda.gov

3. Underestimation of the impact of an attribute because the risk assessment relied heavily on the lack of a clinical impact, but the product lots used clinically contained very low levels of the attribute

– Most clinical studies are not designed to look at impact of low-level variants on immunogenicity and safety

– In some cases, more information from literature may help justify immunogenicity and safety scoring

22

Examples of CQA Review Considerations

www.fda.gov

4. Lack of assessment of attribute interactions

– Example: Oxidation may not directly impact biological activity, PK/PD, immunogenicity, or safety, but does it affect other attributes that do directly impact these parameters? (e.g. aggregation)

– In some cases, more information from literature may help justify immunogenicity and safety scoring

23

Applying knowledge of CQAs in Process Characterization and Validation

www.fda.gov

Process CharacterizationCQAs

Identify quality attributes that impact potency, PK/PD,

immunogenicity, or safety? (i.e. affect the drug recipients)

Understanding functional relationships between

process and CQA provides for an “enhanced approach”

Understanding CQAs helps define an

appropriate process

Control Strategy• Release testing• Stability testing• In-process control

testing (IPC)• Control of input

material attributes• Controls for unit

operations• Monitoring program

24

Manufacturing Process

www.fda.gov

ICH Q7—Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients:

The critical parameters/attributes should normally be identified during the development stage or from historical data, and the ranges necessary for the reproducible operation should be defined. This should include:

• Defining the API in terms of its critical product attributes;• Identifying process parameters that could affect the critical quality attributes

of the API;• Determining the range for each critical process parameter expected to be

used during routine manufacturing and process control

25

Linking Material Attributes and Process Parameters to CQAs

www.fda.gov

• Process characterization studies provide information on the impact that different manufacturing process parameters and material attributes have on product CQAs.

• In more traditional approaches, per ICH Q11 “material specifications and process parameters ranges can be based primary on batch process history and univariate experiments.”

• For enhanced approaches, preliminary risk assessments and small scale univaritate and multivariate (DoE) studies are used to systemically assess impact on CQAs.

26

A Good Process Characterization Study Linking CQA to CPP and Material Attributes will…

www.fda.gov

• Include thorough information on the initial risk assessments performed (and the results) to justify parameter inclusion or exclusion from DoE studies

• Assess process parameter ranges that are broad enough to assure identification of CQA impact

• Discriminate between a statistically significant change to a CQA vs. one that is practically meaningful (e.g. change from 0.1% to 0.2% may be significant, but is it meaningful?)

• Use qualified or validated methods to assess CQAs

• Use small scale studies that are qualified as representative of the full-scale process

• Assess all CQAs and directly link them to unit operations

27

Applying knowledge of CQAs to Control Strategy

www.fda.gov

Process CharacterizationCQAs

Robust product understanding through CQA assessment, coupled with CQA-linked process understanding allows for:• More meaningful and efficient testing strategy• Flexibility in operating ranges and broader CQA acceptance criteria • More flexible control strategy

Control Strategy• Release testing• Stability testing• In-process control

testing (IPC)• Control of input

material attributes• Controls for unit

operations• Monitoring program

28

Timing of CQA and Process Development

www.fda.gov

351(a), New Biological Entity

• CQAs identified during development• Expect some CQA information by Phase I (particularly CQAs that

impact safety)• CQAs refined during process characterization• CQAs well-understood and confirmed during process validation• Refinement of CQAs is a continuous process

ICH Q7—Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients:

Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.

29

CQA Development for Expedited Programs

www.fda.gov

• Products on accelerated regulatory review pathways (e.g. Breakthrough Therapies) are still subject to statutory requirements• Including process validation requirements applied

under 21 CFR parts 210 and 211• Per ICH 7, API is defined in terms of its “critical quality

attributes”• Thorough and early knowledge of CQAs is important to

mitigate risk• Consider front-loading CMC development of products

intended for accelerated pathways

30

Take Home Points

www.fda.gov

• Information on product CQAs is expected– Include explanations of your thinking

• Criticality of quality attributes is evaluated in terms of safety and efficacy for the patient, independent of process or analytical capabilities

• CQA evaluations and risk assessments are appropriate to prioritize CQAs for further study and justify proposed control strategies– Increased understanding can facilitate increased flexibility

• Understanding of CQAs is needed for process validation

• CQAs are continually evaluated as product and process understanding increases

31

Acknowledgements

www.fda.gov

• Laurie Graham, OPPQ/CDER/FDA

• Maria-Teresa Gutierrez-Lugo, OBP/CDER/FDA

• Christopher Downey, OBP/CDER/FDA

• Juhong Liu, OBP/CDER/FDA