A Risk-Based Approach to the

Implementation of a Control
Strategy for Advanced Therapy
Medicinal Products
Darius Pillsbury – Senior Consultant
 The Knowledge Doubling Curve:
“Before the 20th century, human knowledge doubled
every century. By the 1950s, it doubled every 25 years.
Today, it is doubling about every 13 months.”

• Source: Thoughts on the future of human knowledge and machine intelligence

- London School of Economics and Political Science
AGENDA

Level Set: Quick Intro to ATMPs and

the Process Validation Lifecycle
Risk-Based Approach to Process
Qualification (Stage 2)
Unique Challenges and Considerations
for ATMPs
Advanced Therapy Medicinal Products
ATMPs
o Gene Therapy Medicinal Products: healthy gene is packaged within a
delivery system (a “vector”) that is administered to patient leading to a
therapeutic, prophylactic, or diagnostic effect.

o Cell Based Advanced Therapy Medicinal Products: contain cells that have
been manipulated to change their biological characteristics or cells not
intended to be used for the same essential functions in the body.

o Tissue-engineered products: contain cells or tissues that have been

modified so they can be used to repair, regenerate, or replace human
tissue
Advanced Therapy Medicinal Products

Direct administration of gene

Deliver targeted gene to cells ex-vivo by
using viral (e.g., AAV) or non-
physical, chemical or viral (pictured) and
viral (e.g., lipid nanoparticle
infused into the patient.
delivery system
 Advanced Therapy Medicinal Products
987+ companies developing ATMPs worldwide
1,066 clinical trials underway (thru 2019)
Source: Alliance of Regenerative Medicine

“The activity reflects a turning point in the development of these technologies and their
application to human health. It’s similar to the period marking an acceleration in the
development of antibody drugs in the late 1990s, and the mainstreaming of monoclonal
antibodies as the backbone of modern treatment regimens.”
– Scott Gottlieb, ex-FDACommissioner in 2019
 Advanced Therapy Medicinal Products
Some examples of Gene Therapy Products that have been approved:

Glybera – uniQure (first gene therapy for an inherited disease approved in

Europe in 2012, subsequently pulled from market in 2017)
• Treats lipoprotein lipase deficiency (ultra rare disease)

Zolgensma (onasemnogene abeparvovec-xioi) - Novartis / Avexis

• Treats infant spinal muscular atrophy (SMA); approved in 2019
• EMA Conditional approval (May 2020)

Luxturna (voretigene neparvovec-rzyl) – Spark Therapeutics

• First medicine approved for an inherited genetic disorder in 2017 by
FDA
• Treats biallelic RPE65 mutation-associated retinal dystrophy
 Advanced Therapy Medicinal Products
Recent Ex-vivo Autologous Cell Therapy products approved by the FDA:
Kymriah (tisagenlecleucel) – Novartis
Approved in 2017 by FDA
Treatment of patients up to 25 years age for r/r B-cell acute
lymphoblastic leukemia

Yescarta (axicabtagene ciloleucel) – Kite Pharma (Gilead)

Approved in 2017 by FDA
Treatment for adult patients with relapsed, refractory diffuse large
B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma

Zynteglo (Autologous CD34+ cells encoding BA-T87Q-globin gene) –

Bluebird bio -- Approved in 2019 by FDA
Treatment for B-thalassaemia (TDT) = patients cannot make enough
haemoglobin thus are anemic (patient age: 12 years and older)
 Process Validation Lifecycle Approach
Clinical & Regulatory Pathway

Phase II Phase
Early Product Pre- Phase I BLA /
Development Safety/ III Post-Marketing
Clinical MAA

PRODUCT DISCONTINUATION
Safety Dose Efficacy

Process Validation Lifecycle Stages

PROCESS CONTINUED PROCESS

PROCESS DESIGN QUALIFICATION VERIFICATION
(Stage 1) (Stage 3)
(Stage 2)

Phase Appropriate Quality Systems

Pre-GMPs / Apply GLPs cGMPs: Quality Assurance (Phase-Appropriate Systems)

Product/Process Knowledge and Risk Management

 Process Validation Lifecycle Approach
CONTINUED
PROCESS PROCESS
PROCESS
DESIGN QUALIFICATION
VERIFICATION
(Stage 1) (Stage 2)
(Stage 3)
Process and product Stage 2A is the qualification of On-going monitoring of the process
knowledge are explored to GMP manufacturing systems control strategy through the
establish a control strategy (facility/utilities/equipment); manufacture of commercial product
for manufacture. The Stage 2B is the Process lots. Continual process
product control strategy is Performance Qualification improvement based on monitoring.
defined. (PPQ) based on the process
control strategy.

Stage 1: Key Output is the “Process Control Strategy”

 Process Validation Lifecycle Approach
CONTINUED
PROCESS PROCESS
PROCESS
DESIGN QUALIFICATION
VERIFICATION
(Stage 1) (Stage 2)
(Stage 3)
Process and product Stage 2A is the qualification of On-going monitoring of the process
knowledge are explored to GMP manufacturing systems control strategy through the
establish a control strategy (facility/utilities/equipment); manufacture of commercial product
for manufacture. The Stage 2B is the Process lots. Continual process
product control strategy is Performance Qualification improvement based on monitoring.
defined. (PPQ) based on the process
control strategy.

Stage 2: Goal is a “Successful PPQ campaign”

 Process Validation Lifecycle Approach
CONTINUED
PROCESS PROCESS
PROCESS
DESIGN QUALIFICATION
VERIFICATION
(Stage 1) (Stage 2)
(Stage 3)
Process and product Stage 2A is the qualification of On-going monitoring of the process
knowledge are explored to GMP manufacturing systems control strategy through the
establish a control strategy (facility/utilities/equipment); manufacture of commercial product
for manufacture. The Stage 2B is the Process lots. Continual process
product control strategy is Performance Qualification improvement based on monitoring.
defined. (PPQ) based on the process
control strategy.

Stage 3: Goal is to “Continuous Improvement”

 Process Validation Lifecycle Approach
Continued
Process
Process Design Process
Qualification
(Stage 1) Verification
(Stage 2)
(Stage 3)

[Question]
When can the Process be considered as Validated?
• Stage 1
• Stage 2
• Stage 3
 Process Validation Lifecycle
Unique Challenges for Development of ATMPs
“In manufacturing, they need to focus on producing quality products by
design in scalable processes, so that if early clinical trials are promising,
they can advance development rapidly.” -- Peter Marks, Director CBER

Critical
Quality Scale-out /
Accelerated Attributes Scale-up
Clinical Managing Regulatory
Timeline Specifications Requirements /
(RMAT, PRIME) Multiple Guidelines
Starting
Materials process
changes
 Elements of the Overall Control Strategy
Product
PROCESS Knowledge FACILITY
PARAMETERS Target Product Profile
& EQUIPMENT
and CONTROLS Quality Target Product Profile
Critical Quality Attributes

ANALYTICAL CONTAMINATION
METHODS THE CONTROLS

CONTROL
RAW MATERIALS
STRATEGY TRANSPORT/
SHIPPING
 Facilities/Utilities/Equipment
Process Control Strategy translates to Facilities/Utilities/Equipment design,
qualification, and maintenance using risk-based approach

CQA

CPP

Critical
Aspects
Apply risk assessment based on the product attributes early
– if possible, before Facility and Equipment Design.
Contamination Control Strategy
Utilities

Facility Equipment
Quality Risk
Management Microbial
and Product
Contamination
Knowledge Quality
Sources
Management
Personnel Materials

HACCP Process
 Contamination Control Strategy
Unique Challenges for ATMPs
• No terminal sterilization for cell-based products
• Aseptic manipulation of the product throughout the entirety of Utilities

the manufacturing process Facility

Equipmen
t
• Lack of dedicated viral clearance steps Microbial
• Product segregation - multiple products / patient lots / viral Contamination
Sources

vectors concurrently manufactured Personnel Materials

• One lot per one patient (autologous) thus risk of a contaminated

Process
batch is higher severity for risk assessment

EMA Annex 1 in revision – Contamination Control Strategy!

 Raw Materials Control Strategy
Risk assessment is key to develop robust control and monitoring plan
for raw materials used in the process!

A unique assessment employed for each of these types of materials

 Analytical Methods Control Strategy
Lifecycle approach also applies to analytical procedures through method
development, qualification/validation, and continued monitoring.
Analytical Development Challenges for ATMPs
Identity
• Complexity, variability, and stability of living
cell products
• Fast turnaround for release testing in order
Potency Purity
to meet individual patient needs
• Limited material (product in 1° containers) CQAs
for analysis/retain/retest
• Product Comparability
• Stability indicating
Dose Microbial
Product Shipping Control Strategy
Unique Challenges for ATMPs – Shipping Controls & Monitoring
Risk Assessment is crucial for developing a robust Shipping Control
Strategy
• Vein to vein (for individualized autologous therapies) –
“manufacturing” and Quality oversight start and end at the clinic
• Essential to maintain product quality throughout the process
including shipping and transport but it is commonly overlooked in
early clinical stage
• Developing technologies
• Physical shipping conditions
• Product tracking: CoI / CoC
Process Validation Lifecycle
Recent Regulatory Guidance specific to the Validation of
ATMP Processes
• FDA – 2020 Chemistry, Manufacturing, and Control
(CMC) Information for Human Gene Therapy
Investigational New Drug Applications (INDs)
• FDA – 2011 Guidance on PV – continues to
withstand the test of time…applies to ATMPs
• EMA – 2017 EudraLex Volume 4 Guidelines on
Good Manufacturing Practice specific to
Advanced Therapy Medicinal Products
 PROCESS CONTINUED PROCESS
PROCESS DESIGN
QUALIFICATION VERIFICATION
(Stage 1)
(Stage 2) (Stage 3)

Process Performance Qualification

Are we ready for Stage 2B – Process Performance Qualification?
• Process Capability Assessment

𝑆 𝑥 𝑂 𝑥 𝐷 = 𝑅𝑃𝑁
Severity x Occurrence x Detection = Risk Priority Number

• By PV Stage 2B this “process capability assessment” needs to be

primarily based on EMPIRICAL data and less human BIAS.
• Mitigations…aAre you sure you can move forward with those
HIGH/MEDIUM risks?
 PROCESS CONTINUED PROCESS
PROCESS DESIGN
QUALIFICATION VERIFICATION
(Stage 1)
(Stage 2) (Stage 3)

Process Performance Qualification

Design of the PPQ – What to Evaluate and Corresponding Acceptance Criteria?
• Critical Process Parameters and Proven Acceptable Ranges – inputs linked to CQAs
w/ PARs based on Characterization studies
• Process Performance Indicators and Operating ranges, e.g. product yield w/ ranges
based on capability analysis
• Critical Material Attributes – use multiple lots of critical materials
• In-Process Controls – verify CQAs met at critical control points
• Product (release) specifications
• Non-processing holds of intermediates – stability / microbial evaluation
• Stability – put the PPQ lots on stability
• Analytical Retains – take as many as possible and store for future use and testing
 PROCESS CONTINUED PROCESS
PROCESS DESIGN
QUALIFICATION VERIFICATION
(Stage 1)
(Stage 2) (Stage 3)

Process Performance Qualification

Regulatory Oversight FDA – 2020 Guidance is IND focused
• Process Validation [3.2.S.2.5] “We recommend that you use early stage
manufacturing experience to evaluate the need for process improvements and to
support process validation studies in the future.”
• Batch Analysis [3.2.S.4.4] – “We recommend that you retain samples of
production lots for use in future assay development, validation, or comparability
studies.”
• Control of Critical Steps [3.2.S.2.4] “The duration of production steps and hold
times should be controlled and recorded to facilitate the establishment of process
limits and to allow for future validation of each step and hold time within the
proposed limits in support of a license application.”
 PROCESS CONTINUED PROCESS
PROCESS DESIGN
QUALIFICATION VERIFICATION
(Stage 1)
(Stage 2) (Stage 3)

Process Performance Qualification

Regulatory Oversight EMA – GMPs for ATMPs
[10.3] Process Validation.
“While it is acknowledged that some degree of variability of the
finished product due to the characteristics of the starting materials is
intrinsic to ATMPs, the aim of the process validation for ATMPs is to
demonstrate that the finished product characteristics are within a given
range (in compliance with the terms of the marketing authorisation).”

Product / process knowledge – e.g., understand the Critical Material

Attributes of starting materials (i.e., the transducing vector, plasmids,
and the apheresis (for individual, autologous therapies)
 PROCESS CONTINUED PROCESS
PROCESS DESIGN
QUALIFICATION VERIFICATION
(Stage 1)
(Stage 2) (Stage 3)

Process Performance Qualification

Regulatory Oversight EMA – GMPs for ATMPs
[10.41] Validation with surrogate materials.
“The use of surrogate material may be acceptable when there is shortage
of the starting materials (e.g. autologous ATMPs, allogeneic in a matched-
donor scenario, allogeneic where there is no expansion of cells to MCB).”
“The representativeness of surrogate starting material should be
evaluated.”
Yes, you can justify the use of surrogates, however need to compare and
show that this material is representative and understand impact of any
differences observed.
 PROCESS CONTINUED PROCESS
PROCESS DESIGN
QUALIFICATION VERIFICATION
(Stage 1)
(Stage 2) (Stage 3)

Process Performance Qualification

Design of the PPQ – # of PPQ runs?
A risk-based approach should be taken to determine the number of
manufacturing runs to perform in the PPQ campaign.
What to consider?
• Capability - Understand the sources of process variability and impact on
product quality
• Process History – Failure rate? Recent process change(s)?
• Extent and relevance of process development data (e.g., process
characterization studies)
• Clinical Manufacturing experience, e.g. success rate % of mfg runs
• Complexity of the process (multiple processing equipment, equipment trains,
workstations)
 PROCESS CONTINUED PROCESS
PROCESS DESIGN
QUALIFICATION VERIFICATION
(Stage 1)
(Stage 2) (Stage 3)

Process Performance Qualification

Regulatory Oversight EMA – GMPs for ATMPs - # of PPQ runs
[10.3] Process Validation. ”It is generally accepted that, as a
minimum, three consecutive batches manufactured under routine
conditions constitute a validation of the process. An alternative
number of batches may be justified taking into account whether
standard methods of manufacture are used, whether similar products
or processes are already used at the site, the variability of starting
material (autologous v. allogenic), clinical indication (rare disease: only
few batches will be produced) .”
 PROCESS CONTINUED PROCESS
PROCESS DESIGN
QUALIFICATION VERIFICATION
(Stage 1)
(Stage 2) (Stage 3)

Process Performance Qualification

Goal of the PPQ is to show that the Process Control Strategy can provide
product with consistent quality and process performance.
• The ultimate success of the PPQ is based on the strength of the Process
Control Strategy from Process Design Stage 1.
• The PPQ is a snapshot in time. However, you will have many “headaches”
in commercialization PV Stage 3
• Batches that do not meet product specifications
• Significant process changes with many Regulatory and Product
Comparability challenges
• Thus heightened monitoring of the process (as performed during the PPQ)
should be subsequently continued through on-going monitoring post-PPQ
and into Stage 3 CPV for most ATMPs.
 PROCESS CONTINUED PROCESS
PROCESS DESIGN
QUALIFICATION VERIFICATION
(Stage 1)
(Stage 2) (Stage 3)

IN SUMMARY
✅ For ATMPs, a risk-based approach needs to be taken for the ultimate success of
the validation efforts through the lifeycle and to support successful
commercialization.
✅ This approach has many benefits including (and not limited to)…
• ORGANIZE the rapidly increasing product and process knowledge
• FOCUS on critical elements and identify risks that need to be mitigated
• IDENTIFY also what you do not know (uncertainty) and how to address
• COMMUNICATE information and data across business units and external
• READY organization ultimately for long-term successful
commercialization
Interesting Reads on Risk and Covid-19
Recent articles on managing risk and uncertainty
➢ How Military Thinking Can Improve Pharma Decision Making Under Stressful Conditions
https://www.lifescienceleader.com/doc/how-military-thinking-can-improve-pharma-decision-making-under-
stressful-conditions-0001

➢ Making Decisions In A COVID-19 World: How To Combat Stress With Quality Risk Management
https://www.pharmaceuticalonline.com/doc/making-decisions-in-a-covid-world-how-to-combat-stress-with-
quality-risk-management-0001

➢ High Absenteeism & The Production Of Medically Necessary Drugs During COVID-19
https://www.pharmaceuticalonline.com/doc/high-absenteeism-the-production-of-medically-necessary-drugs-
during-covid-0001
DARIUS PILLSBURY, Senior Consultant
e-mail: dpillsbury@valsource.com
ValSource.com
P: 610.269.2808 | F: 610.269.4069
918A Horseshoe Pike, Downingtown, PA 19335
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