Establishing and Applying Critical

Quality Attributes During the

Product Development Lifecycle

ISCT Liaison Meeting

October 19, 2016

Tom Finn, Ph.D.

Product Reviewer
Office of Tissues and Advanced Therapies
FDA/CBER

www.fda.gov 1
 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

2
Definition:
“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

Specification:
Parameter/test Assay Criterion

14 day culture, aerobic and

Sterility No growth
anaerobic

3
 Definition:
“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
of the DS and DP.”

- ICH Q6B and Q11

CQA
Full product specifications
characterization

4
The more reflective CQA are of clinical safety
and efficacy, the easier it is to evaluate the
consequences of a manufacturing change

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

Research Preclinical Phase I Phase II Phase III BLA

Preclinical efficacy

Potency

Clinical efficacy

• 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.
5
Lot release tests exist to set expectations for
adequate product safety and quality
Lots that don’t meet these cut-offs should not be distributed and used

Sterility Viability

Endotoxin Identity

Mycoplasma Purity

Visual Potency
appearance

6
Lot release specifications are at the center of many
product areas and are interrelated.

It is important to choose them carefully and apply them

where needed 7
 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
or manufacturing
experience CPP
• CPPs are controlled and
monitored to confirm that
the quality attributes of
the product are
maintained or improved
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CQA and CPP are used together to help ensure
quality and manufacturing consistency
Acceptance
criteria for Action limits
source for specific
material steps

Criteria for
intermediates Equipment
performance
In-process
criteria

FP Release Process
criteria limits

Process Parameters have boundaries within which a given process

yields an expected result that is defined in terms of CQAs
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 Typical early product development approach
Initial product characterization Adjustments to specifications
based on preclinical data

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

•Tumorigencity GMP
•Proof of concept Further refinement
•Toxicity of specifications
•Biodistribution during trials

Conduct pivotal
Manufacture lots animal
for clinical trial safety and POC
Initial specifications & GMP studies
manufacturing process

• 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
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 Factors important for establishing
CQA and CPP
• 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

11
 Perform the right level of product
characterization to ensure product quality
Too much?
Tc9 Th9
Th22 Th3
CD8 CD69
Treg
CD8
iTrg Too little?
CD3 CTL
CD4 CD3 Th1
CD25 CD3
Th17
CD45 Th2
TEM
CD4 Th9
TCM NK Treg Tr1

Determining the right level is not easy!

12
 Focus on critical quality attributes

Too much
emphasis on a
single attribute

Impractical

Appropriate attributes, Appropriate attributes,

criteria too low appropriate criteria
13
 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

14
Consider assay variability and “worst case”
in designing assays and setting criteria
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:
• Different QC analysts • Different interpretation of
• Different batches of reagents procedures due to vague
• Different equipment SOPs
• Samples held for different • Subjective parameters (such
lengths of time as flow cytometry gates,
background cut offs, dilutions,
etc.)

Assay variability can confound efforts to demonstrate

manufacturing consistency, comparability, or stability.
15
CQA and CPP are not meant to be static- they should
be continually evaluated and revised as needed
• 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

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!

16
Major manufacturing changes

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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
or critical materials
• Qualification & validation

18
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”

19
 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 20
As important as lot release specifications
are, they alone only provide a partial
assessment of quality

Depending on the It is important to

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

21
 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 22
CQA are often used as goalposts
Goalpost Applications for lot release
• Establish a lower limit for key
attribute
• Maximum limit of an impurity
• Establish an allowable range

23
 Size matters
There are advantages to targeting narrow versus wide tolerances for
specifications
Narrower tolerances make it easier to assess comparability

Goalpost Narrow tolerances Wide tolerances

Need to have a very good Difficult to rely on just lot release

understanding of your specifications to show consistency and
process and product, with comparability
sufficient control points
24
 CQA as a goalpost
When a product has substantial inherent variability you need to
consider what you are targeting

You should aim like this… Not this…

25
Each CPP If CPP are
should have appropriate and
it’s own target the process is
consistent, then
the same target
will be hit each
time

Source Intermediate Intermediate Final

material product

26
 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?

27
 Additional thoughts
• 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

28
 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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 Take home messages
• 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
www.fda.gov 30
 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
or by calling (240) 402-8361

OTAT Learn Webinar Series:

http://www.fda.gov/BiologicsBloodVaccines/NewsEv
ents/ucm232821.htm

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Phone: 301-827-3821

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