Analytical Control Strategies of Vaccine

Products During Product Development

Freyja Williams
Biologist
OVRR/CBER/FDA
WCBP 2016
Washington, DC
January 26-28, 2016

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 My comments are an informal
communication and represent my own best
judgment. These comments do not bind or
obligate FDA.

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 Overview

• The regulatory basis for CMC review for

products under IND
• Applying regulations to the control testing of
products under development

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 Product Quality Control

• Control the manufacturing process

– How the product is made
• Test the product throughout the process
(analytical testing)
– How the product is characterized
• Appropriate methods
• Adequately controlled

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 IND Regulations

• 21 CFR 312: Investigational New Drug

Application
http://www.accessdata.fda.gov/scripts/cdrh/cfd
ocs/cfcfr/CFRSearch.cfm?CFRPart=312

• Limited specific information regarding control

testing in the IND regulations

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 21 CFR 312.22 General principles of the IND
submission.

FDA’s primary objectives in reviewing an IND are, in all phases of

the investigation, to assure the safety and rights of subjects, and,
in Phase 2 and 3, to help assure that the quality of the scientific
evaluation of drugs is adequate to permit an evaluation of the
drug’s effectiveness and safety. Therefore, although FDA’s review
of Phase 1 submissions will focus on assessing the safety of
Phase 1 investigations, FDA’s review of Phases 2 and 3
submissions will also include an assessment of the scientific
quality of the clinical investigations and the likelihood that the
investigations will yield data capable of meeting statutory
standards for marketing approval.

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Product testing per 312.23 (7) (iv) (a)

Drug Substance requirement:

…the acceptable limits and analytical methods used to assure the
identity, strength, quality, and purity of the drug substance; and
information sufficient to support stability of the drug substance during
the toxicological studies and the planned clinical studies.

Drug Product requirement:

...the acceptable limits and analytical methods used to assure the
identity, strength, quality, and purity of the drug product; and
information sufficient to assure the product’s stability during the
planned clinical studies.

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 Stability testing in clinical studies
312.23 (7)
Chemistry, manufacturing, and control information.
(ii) It should be emphasized that the amount of information to
be submitted depends upon the scope of the proposed clinical
investigation. For example, although stability data are required
in all phases of the IND to demonstrate that the new drug
substance and drug product are within acceptable chemical and
physical limits for the planned duration of the proposed clinical
investigation, if very short-term tests are proposed, the
supporting stability data can be correspondingly limited.

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 Guidance for Industry
CGMP for Phase 1 Investigational Drugs
Phase 1 products are not subject to 21 CFR 211

However: Section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351 (a)(2)(B))
requires drugs, which include IND products, to comply with current good
manufacturing practice as follows:
A drug...shall be deemed adulterated...if...the methods used in, or the facilities or controls used
for, its manufacture, processing, packing, or holding do not conform to or are not operated or
administered in conformity with current good manufacturing practice to assure that such drug
meets the requirements … as to safety and has the identity and strength, and meets the quality
and purity characteristics, which it purports or is represented to possess.

The guidance states that adherence to CGMP during manufacture of phase 1

investigational drugs occurs mostly through:
Well-defined, written procedures
Adequately controlled equipment and manufacturing environment
Accurately and consistently recorded data from manufacturing (including testing)
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 Challenges
Developing control testing while developing the product

• Uncertainty
– Safety/Efficacy
– Critical quality attributes
– Critical process parameters
• Process changes
– Increase efficiency/yield
– Improve product quality
– Scale up
• Formulation changes
• Complexity
– Manufacturing process
– Product
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 Consequences of faulty product
testing data
• Risk to study participants, general public
• Inability to bridge across studies
• Dose, formulation, manufacturing is
inappropriate
• Failure of late phase studies due to false
assumptions
• Inability to use late phase data to support
regulatory actions

Need to repeat clinical studies

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 Product development vs analytical method
development
Phase 1 Phase 2 Phase 3

R&D Small scale GMP Scaleup Consistency lots

Process development Process qualification Continued process

verification
Scientific rationale for method. Feasibility.
Optimization. Reagent procurement.

Feasibility. Optimization. Reagent procurement.

Initial assessment of in use performance
characteristics. Preliminary system suitability
criteria. Tests directly related to safety may
require early validation.

Establishment of performance characteristics

and system suitability. Assessment of suitability
for intended use including analysis of clinical
study lots.
Fully validated. Post implementation
controls in place.
 No matter what phase

• Is the method appropriate?

– Is it the right method to measure the relevant
analyte?
• Is the method under control?
– If you ran the same sample again, would you get
the same answer?

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 Analytical Methods
Early phase methods
• Appropriate methods
– Sufficient documentation that
the method is measuring a
analyte likely relevant to the
quality of the product
• Adequate control of the
methods
– System suitability criteria
Late phase methods
• Appropriate methods
– Demonstration that the
method measures product
critical quality attribute
• Adequate control of the
methods
– Qualification/Validation
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 Changing analytical methods
• Eliminate methods that are not relevant
• Introduce new methods
• Replace methods
– New information regarding critical product
attributes
– Improved methodology available
– Existing test performance not adequate
• Precision
• Accuracy
• Ability to detect important changes in product quality
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 Potency tests (21 CFR 600.3, 610.10)
• “The word potency is interpreted to mean the
specific ability or capacity of the product, as
indicated by appropriate laboratory tests or by
adequately controlled clinical data obtained
through the administration of the product in
the manner intended, to effect a given result.”
• Translation: Every lot you release will have the
same profile as lots used in the pivotal clinical
efficacy studies

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Development of potency tests
Aspects to think about
• Critical product attributes
– Characterization of attributes
– Ability to identify subpotent lots
• Assay performance characteristics
– Accuracy/precision
– Reliability – long term assay stability
• Clinical development
– Need to bridge manufacturing among studies
• Validation
– Final test in testing laboratory
– Validation of all aspects of the test
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 Potency test development - practicalities
Cannot put subpotent lots into clinical trials

• Potency test should detect changes in product quality

– Stressed product samples
– Samples with low concentrations of antigen
– Samples with interfering moieties/inhibitors
• Changes in potency test
– Demonstrate the comparability (improvement) of the assays to
detect subpotent lots
• Test samples in both assays
– Devise strategy to bridge data across clinical studies and
potentially post licensure
• Parallel testing
• Orthogonal testing
• Additional product characterization
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 No matter what phase

• Is the method appropriate?

– Is it the right method to measure the relevant
analyte?
• Is the method under control?
– If you ran the same sample again, would you get
the same answer?

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Questions?

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