Quality Attributes During the Product Development Lifecycle ISCT - - PowerPoint PPT Presentation

1 www.fda.gov

ISCT Liaison Meeting

October 19, 2016

Tom Finn, Ph.D. Product Reviewer Office of Tissues and Advanced Therapies FDA/CBER

Establishing and Applying Critical Quality Attributes During the Product Development Lifecycle

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Topics

• Product terminology
• CQA and CPP and how they are

developed and used during the product lifecycle

• Considerations for demonstrating

product comparability after a manufacturing change

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“A CQA is 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)

Product Quality is defined in terms of Specifications and Critical Quality Standards and Attributes

Definition:

Parameter/test Assay Criterion Sterility 14 day culture, aerobic and anaerobic No growth

Specification:

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Definition:

specifications Full product characterization

“Specifications are critical quality standards (CQAs) that are

proposed and justified by the manufacturer and approved by regulatory authorities… Specifications are chosen to confirm the quality of the DS and DP rather than to establish full characterization, and should focus on those characteristics found to be useful in ensuring the safety and efficacy

• f the DS and DP.”
• ICH Q6B and Q11

CQA

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BLA Phase III Phase II Phase I Preclinical Research

Clinical efficacy Potency Preclinical efficacy

But efficacy data is not usually obtained until late in product development, long after CQAs have been established

• You should make use of preclinical and clinical data whenever

available to adjust CQA and CPP parameters. This is easier to do if two phase 3 studies are done- revise CQA prior to conducting confirmatory trial.

• Although not required until phase 3, we recommend you develop a

potency assay as early as possible.

The more reflective CQA are of clinical safety and efficacy, the easier it is to evaluate the consequences of a manufacturing change

Sterility Endotoxin Mycoplasma Viability Identity Purity Visual appearance Potency

Lots that don’t meet these cut-offs should not be distributed and used

Lot release tests exist to set expectations for adequate product safety and quality

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It is important to choose them carefully and apply them where needed Lot release specifications are at the center of many product areas and are interrelated.

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CQA are also fundamental to critical process parameters (CPP)

• Critical Process

Parameters (CPP) are independent process parameters most likely to affect the quality attributes of a product

• CPPs are determined by

sound scientific research

• r manufacturing

experience

• CPPs are controlled and

monitored to confirm that the quality attributes of the product are maintained or improved

CPP

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CQA and CPP are used together to help ensure quality and manufacturing consistency

In-process criteria Process limits Acceptance criteria for source material FP Release criteria Equipment performance Action limits for specific steps Criteria for intermediates Process Parameters have boundaries within which a given process yields an expected result that is defined in terms of CQAs

• Early product development and preclinical data are used to justify safety and quality of the

product for use in clinical studies

• FDA encourages continual improvements to product quality, but that must be balanced with

maintaining product consistency

• Need to be sure that preclinical testing is representative of actual clinical lots

Typical early product development approach

Initial product characterization Initial specifications & manufacturing process

Conduct pivotal animal safety and POC studies Manufacture lots for clinical trial Further refinement

• f specifications

during trials Adjustments to specifications based on preclinical data

• Tumorigencity
• Proof of concept
• Toxicity
• Biodistribution

Manufacture lots for clinical trial Conduct pivotal animal safety and POC studies

GMP or GLP GMP GMP

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• Proposed mechanism of action
• What properties or characteristics of the product (i.e.,

quality attributes) are likely to achieve the intended action in the patient?

• What manufacturing steps are critical and how would you

measure and ensure they were successful? -identify process parameters

• What safety concerns are associated with this type of

product

• What undesirable properties do you want to minimize?
• What labeling claims do you want to make based on

identified attributes and/or process parameters?

• Assay suitability & qualification

Factors important for establishing CQA and CPP

CD3 Too little? Too much?

Perform the right level of product characterization to ensure product quality

Determining the right level is not easy! CD3 CD8 CD3 CD45 Th1 Treg CD4 CD4 NK

Th2

Th9

CTL

CD8 Treg

Th3

Th17 Tr1 TEM TCM

Th9

Th22 iTrg Tc9 CD25 CD69

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Impractical Too much emphasis on a single attribute Appropriate attributes, criteria too low Appropriate attributes, appropriate criteria

Focus on critical quality attributes

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Common issues with choosing product release specifications

• Specifications not capturing key product attributes
• Criteria inconsistent with manufacturing experience
• Lack of supportive data or rationale
• Product characterization that does not take into account

cellular impurities that might interfere with the activity of the product, or present a safety concern

• Criteria set for a very wide range – could add variability

to clinical trial outcomes

• Misinterpretation or over-interpretation of data

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Assays are sometimes qualified/validated under ideal or best case conditions, and may factor only one variable at a time. This can lead to overconfidence of an assay. Real world use may involve:

Consider assay variability and “worst case” in designing assays and setting criteria

• Different QC analysts
• Different batches of reagents
• Different equipment
• Samples held for different

lengths of time

• Different interpretation of

procedures due to vague SOPs

• Subjective parameters (such

as flow cytometry gates, background cut offs, dilutions, etc.)

Assay variability can confound efforts to demonstrate manufacturing consistency, comparability, or stability.

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CQA and CPP are not meant to be static- they should be continually evaluated and revised as needed

Carved in stone Continually upgrading

• Changes to CQA could include either revising existing criteria, or adding or

removing a specification (as supported by product characterization data)

• But since these have tremendous impact, revise cautiously!
• Additional product characterization data may indicate a better way of

ensuring quality

• Clinical outcome data may provide clues as to what product properties are

the most important

• Additional manufacturing experience may guide CPP and CQA

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Major manufacturing changes

A little planning up front can help avoid problems later Think in advance about:

• Donor eligibility of source

material

• Cell bank qualification
• Cell bank capacity
• Logistical issues for

products with short shelf lives

• Scale up needs
• Second source for custom
• r critical materials
• Qualification & validation

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It is easier to accommodate manufacturing changes at earlier developmental stages

• Product knowledge should increase with stage of development

(identity, stability, potency, manufacturing, consistency/product comparability, etc.)

• Consider manufacturing changes that might be needed to

accommodate larger trials and commercial production

• Manufacturing changes can be implemented at any stage, but

the potential impact of a manufacturing change can increase the farther you are along in the product lifecycle. Phase 1 & 2 may be a good time to implement a major manufacturing change prior to conducting pivotal phase 3 studies. However, for these phases manufacturing is often “on autopilot”

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Phase 3 is a little like commercial manufacturing on training wheels

• Should be using as close to the commercial process as

is feasible for registration studies

• Potency should be in place
• Critical Quality Attributes (CQA) should

be identified and appropriate assays in place

• Additional stability data should be

collected

• Well defined CPPs should be in place:

Phase 3 is critical for demonstrating manufacturing consistency

• But some details are still being

worked out to prepare for commercial production

Depending on the issue or the study, there may be the need to extend an analysis to product properties beyond lot release values It is important to understand where the gaps exist so that an appropriate characterization can be done

As important as lot release specifications are, they alone only provide a partial assessment of quality

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Situations where additional product characterization and analysis may be needed

• Process qualification and validation studies (to

demonstrate manufacturing consistency)

– Additional in-process and final product attributes, yield

• Comparability studies after a major manufacturing change

(e.g. new process step, new facility, new critical reagent, etc.)

– Additional measures of identity, potency, purity, etc. – Yield

• Stability studies (not all lot release tests are stability

indicating- you need to evaluate each one)

– Genetic stability and identity of cell lines – Evaluate apoptosis in addition to viability – Additional measures of potency

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Goalpost

CQA are often used as goalposts

Applications for lot release

• Establish a lower limit for key

attribute

• Maximum limit of an impurity
• Establish an allowable range

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There are advantages to targeting narrow versus wide tolerances for specifications Narrower tolerances make it easier to assess comparability

Size matters

Goalpost Narrow tolerances Wide tolerances

Need to have a very good understanding of your process and product, with sufficient control points Difficult to rely on just lot release specifications to show consistency and comparability

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You should aim like this…

CQA as a goalpost

Not this… When a product has substantial inherent variability you need to consider what you are targeting

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Each CPP should have it’s own target If CPP are appropriate and the process is consistent, then the same target will be hit each time

Source material Intermediate Intermediate Final product

Designing meaningful comparability studies

• Perform risk assessment to establish scope- what is most likely to be

affected and to what degree?

• Consider what are the most sensitive parameters to test
• What assumptions are you making?
• Leverage what you already know from product development
• Where does known variability exist and how will you try to control for

that?

• Justify # of samples, types of samples, number of tests, and type of

analysis

• What limits does the study design place on interpretation?
• How will you analyze the data?

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• First show the current process is consistent
• Where possible use a split manufacturing

approach to factor out source material variability- this allows for a head-to-head comparison of the new method compared to the existing method

• Criteria should be predetermined
• Understand and incorporate worst case

Additional thoughts

What to include in a manufacturing change IND amendment

• Clear description of what you are changing and why
• Change control- what is the scope of the change and what was

impacted

• A summary of your risk assessment
• Whether this is intended to be a temporary fix or a long-term

solution

• Comparability study, including:

– Design of the study (with justification for sample size) – Justify relevant CQAs and test methods – Risk assessment identifying the type and level of impact – Rationale for acceptance criteria – How the study was executed – Data demonstrating an acceptable level of product comparability

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• Think carefully about what you are expecting clinically of your

product and work backwards

• Think of all the CMC parameters that are relying on CQA and

CPP and factor those into your specifications and action limits

• Reset/Refine your release specifications and your “goalposts”

after you’ve identified key sources of variability in your process and have taken steps to control them

• Choose assays that are suitable for assuring product quality, with

adequate sensitivity and specificity. Factor assay variability into your specifications

• First show your existing process is consistent, then show after a

manufacturing change your product is comparable

• CQA and CPP should be continually evaluated and revised as

needed based on multiple identified attributes and process parameters

• Manufacturing changes are inevitable, but they are easier to

accommodate early in product development, so plan ahead

Take home messages

OTAT Contact Information

For product questions please contact: Tom Finn at thomas.finn@fda.hhs.gov Regulatory Questions: Contact the Regulatory Management Staff in OTAT at Lori.Tull@fda.hhs.gov

• r by calling (240) 402-8361

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