Small yields: Process yields 200 to 300 mL. Stability in small scale representative container .. Total volume needed for routine, accelerated and stress is ~ 32 mL. Analytical development: Genomic Titer (ddPCR) = 0.3 mL, CCIT 2 vials, Potency 0.3 mL , SDS-PAGE 0.1. No sterility. Basically 2 vials for each time point, plus 2 for CCIT and 1 for reserve. 1 mL fill.
Process Validation & Regulatory Strategies for Fast-track and Breakthrough Therapies
Process Validation & Regulatory
Strategies for Fast-track and
March 20, 2018
– FDA’s Expedited Pathway Designations
– Breakthrough Therapy (BT) Designation by Therapy
– Expedited vs Traditional Development Program Timelines
– Common Challenges for Breakthrough Therapy Products
– Common Process Development Challenges for BT Products
– Common Analytical Challenges for BT Products
– Common Manufacturing Challenges for BT Products
– Key’s to a Successful Regulatory Strategy
– Understanding Scientifically Complete CMC Sections
• Process Validation
– Keys for Successful Validation
Primary focus of presentation will be on Breakthrough Therapies
FDA’s Expedited Pathway Designations
BT Designation by Therapy
(1) Hemophilia, Cystic Fibrosis, etc.
(2) 10 for Hepatitis C
(3) PTSD, Depression, GVHD, Peanut Allergy, etc.
Expedited vs Traditional Development
Traditional BLA /NDA
Phase 1 Clinical Study
Several months 2
Decision on BT Application N/A
EOP 1 Meeting Confirms
Breakthrough Therapy Status 6 months N/A
Phase 2/3 Clinical Study
Phase 2: Several Mo. to 2
Phase 3: 1 to 4 years 2
NDA/BLA Preparation 6 months
NDA/BLA Review 6 months 10 months
Development Timeline ~ 5.2 years 1
~7.4 years 1
Breakthrough Therapy designation accelerates a CMC program by almost 2 years.
Common Challenges for Breakthrough
• Small Yields
• Limited Time Impacts Development
– Process Design (Stage 1 of PV)
– Analytical Method Development and Validation
– Ability to gain detailed process understanding and experience
• Quality Programs Must Be Accelerated
– Material Qualification Programs
• Traditional Paradigm for Financial Investments
• “Phase Appropriate” GMPs
– There are approximately 2 fewer years for product development,
so commercial GMPs need to be implemented sooner
• Change Management is a Challenge
– Must be able to demonstrate comparability to initial process
CASE STUDY – Gene and Cell Therapies
Common Process Development Challenges
for BT Products
– Critical Quality Attributes: These need to be established earlier on to
begin Process Design activities, which is challenging when analytical
methods might not be adequately developed / qualified.
– Change Management: Breakthrough Therapy designation typically
based on ‘Phase 1 Process’ - therefore scale-ups and formulation
changes must be minimized for Phase 2/3.
– Process and Analytical Comparability: Comparison of process used
in Phase 1 Clinical Trial (e.g. Breakthrough Therapy process/material)
and proposed commercial process (e.g. scale-up), and plans to
establish analytical comparability with potentially under-developed
– Process Validation Approaches: Lack of material or batches to
perform typical ‘process design studies’ e.g. viral clearance, filter
validation, residual or impurity profiling studies including bioburden,
etc. The number of available validation lots before filing of NDA/BLA
may be less than the typical 3-5 lots.
Common Analytical Challenges for BT
– Stability: Limited material and limited lots available to propose shelf-life.
– Reference Standard Program: Typically companies start with interim
standard and then establish commercial reference standard. But,
methods need to be validated sooner so commercial reference standard
can be established sooner.
– In-Process and Release Specifications: Volumes for USP methods are
a challenge. For example, 100 mL needed for pre-filtration bioburden,
when process only yields 200 mL.
– Finished Product Control: Some of the finished product tests take a
long time. BT product might expire before that time (e.g. Sterility).
– Justification of Specifications: Traditionally more batches and
statistical analysis (e.g. 95-99% tolerance interval) are desired. BT
products have very limited number of batches therefore limited knowledge
of process and analytical variability.
– Method Development: Limited time to develop challenging methods
such as infectious titer and potency.
Common Manufacturing Challenges for BT
• Contract Manufacturing: Because a non-traditional and
compressed development approach is taken for many activities,
CMOs feel the risk of manufacturing and non-compliance is on
them, not the Sponsor.
• Commercial Manufacturing Site: Companies typically select their
commercial manufacturing site just prior to Phase 3 , or while in
Phase 3, and perform a transfer. This has to be determined earlier
given the accelerated timelines and analytical comparability
• Material Qualification Program: A well designed material
qualification program becomes more comprehensive as a
development program progresses (See USP 1046). But in case of
BT Products, it must be implemented much sooner.
Key’s to a Successful Regulatory Strategy
• Open and transparent communication with the FDA is essential throughout
the entire approval and post-market process.
• The pharmaceutical company mindset of not wanting to further explore
certain information for fear of needing to revalidate based on those
discoveries has no place in this new reality.
• New information will be learned pre- and post-launch, and plenty of
amendments will need to be filed.
• Given the compressed development timeframes, less stability data will be
available at submission. Additional data will be submitted via amendments
during the review cycle, and in some cases, post-market.
• Launch commercial process with limited experience and optimize post-
approval–the classic three runs is not the guiding force within this construct.
• The level of flexibility regulators will extend is determined for each specific
product on a case by case basis.
– Factors taken into consideration include: riskiness of product characteristics,
seriousness of the condition and medical need, complexity of manufacturing
processes, state of the innovator’s quality system and merits of the innovator’s
risk-based quality assessment including Critical Quality Attributes (CQA).
Key’s to a Successful Regulatory Strategy,
• Evaluate ways to leverage historical development and manufacturing
knowledge to show process consistency and to ensure patient safety
and product supply are not compromised
• Have early conversations about CMC activities that may be incomplete
Process Validation, stability studies on commercial product,
manufacturing scale/tech transfer data and complete control system
• Propose use of representative pilot scale lots for stability shelf-life
• Identify alternative risk-mitigation approaches (e.g. post-marketing
commitments for process validation)
• Propose (nontraditional or novel) statistical models early for setting
• Ensure a “scientifically complete” CMC Section
• Early discussions on analytical method validation and establishment of
the commercial reference standard
Understanding “Scientifically Complete CMC
• Provide sufficient detailed information on the manufacturing process
– Cell bank manufacturing methods including a list of reagents used, descriptions
of release tests, and COAs
– Plasmid, vectors and drug product process descriptions including release tests
– Well classified process parameters (e.g. ranges for operating parameters, limits
for in-process controls and acceptance criteria for in-process acceptance criteria)
• Prioritize assays for development and validation, e.g. potency and
• Completion of (non-traditional) manufacturing process validation
• Well written comparability protocol using validated assays
• Clear description of in-process test methods, because typically they are
not filed in the Test Method Description Section. This is important
because sometimes these will take precedent over release tests, until
adequate data are available.
• Consider a post-approval product lifecycle management plan that is
included in the filing to support deferred CMC activities.
CASE STUDY – Gene and Cell Therapies
Keys for Successful Process Validation
• Critical quality attributes and process characterization work must occur
much earlier than a typical pharmaceutical development process.
• In many cases, consider broader product quality ranges for non-Critical
Quality Attributes until further manufacturing experience is acquired
• Keys to Success:
– Gaining knowledge from the product and process development- EARLY
– Understanding sources of variation in the production process - EARLY
– Determining the presence of and degree of variation - EARLY
– Understanding the impact of variation (e.g. DOE studies) on the process
and end product - EARLY
– Controlling variation in a manner aligned with Critical Quality Attributes
(CQA) and the risk a given attribute introduces to the process – EARLY
Keys for Successful Validation, continued
• Enhance analytical methods and understanding to offset more
limited process understanding and to support future comparability
work. It is extremely important to involve commercial Quality
Control representatives in the assay development design.
• Traditional Process Validation of 3 to 5 lots typically not
What to consider:
•Novel statistical models and approaches will need to be applied
in many cases. Representative samples and assays for these
models will likely need to be acquired from sources, like prior
knowledge and use of comparability protocols.
•An FDA-negotiated number of full scale PPQ batches using the
•A commitment to manufacture additional PPQ batches as a post
• Characterize the process early
• Validate methods early based on prioritization
• Initiate “Process Design” as soon as expedited designation granted
• Consider a non-standard approach to Process Validation, starting
communications with FDA about the intended approach early
• Initiate development of a regulatory acceptable Reference Standard
• Method development and validation need to be expedited
• Develop strategies to mitigate material constraints (e.g. small scale
• Comparability often does not follow standard practice
• Communicate statistical strategies to establish specifications
• Effective Regulatory Writing
• Dr. Ashley Ruth
• David Fetterolf
• Julie Spyrison
• Patrick Giljum