Embed Size (px)
Citation preview
Workshop Session 3 Questions
1
•How would a control strategy look different in a traditional submission vs a QbD submission? How would parameters that are not specified in the license be handled and what will be the agency involvement?•Are there additional considerations beyond criticality of a given attribute that factor into the control strategy development?•Are Expanded Change Protocols (eCP) and EU Post Approval Change Management Protocols (PAMP) the same? If not, what are the key differences?
2
Antibody Process Platform
Antibody Process Platform
Critical Quality Attributes
Key PerformanceIndicators
Illustrate Relationship of Process to Product
Critical Material Inputs
Critical Process
Parameters
Key Process Parameters
Target Product Profile
Target Product Profile
Control of Critical Inputs and Process Parameters
Design Space
Ensure Control ofCritical Outputs
Vaccine
Slide from Lynne Krummen (Genentech)
3
Example: Vaccine Protein Fragmentation
Fragment 1
Fragment 3
Fragment 2
Intact Protein(Immunogenic)
ImmunogenicNon-immunogenic
Non-immunogenic
4
Is Fragmentation a CQA?
Impact: 8 (medium)Literature identifies potential impact of fragments (decreased immunogenicity)
Green: low impactYellow: medium impact
Category
Risk Assessment
Impact on Efficacy Impact on Safety
Immunogenicity Toxicity
Literature or similar products
Available literature on potential impact
Info on potential impact based on similar products
Laboratory experienceTest fragments and fragment enriched samples
to assess impact
Non-clinical experience Assess impact in animal models
Clinical experienceEfficacy and safety results from clinical study 8 4
5
Process Capability
Immunogenicity operating space
Both processes result in a product with a highly consistent fragmentation profile
Fragm
ent 1
Fragm
ent 3
Fragment 2
6
Control Strategy
Fragmentation
Impacted by
Production scale up X
Manufacturing site
Cell Line XRaw materials Production bioreactor X Harvest Cation exchange chromatography XAnion exchange chromatography X Nanofiltration Low pH inactivation X Hydroxyapatite chromatography Formulation
Criticality of attributes
Controls
Raw material control Process clearance capability Critical operational parameters X Procedural controls Process validation In-process control X Lot release testing X Stability testing X Characterization testing X
7
Risk Analysis (Likelihood)
Manufacturing process consistently produces material that is well within the range of the prior product knowledge
Vaccine processes result in products with different proportions of the same fragments having similar safety and efficacy
In this case, fragments have low impact if they are controlled within a range
Therefore, the likelihood of adverse effect occurrence due to variation in fragmentation proportions is very low
8
Overall Process Risk Minimized
Ris
k in
dex
Raw
mat
eria
ls
Pro
duct
ion
Bio
reac
tor
Har
vest
Cat
ion
Exc
hang
e
Ani
on E
xcha
nge
Nan
ofilt
ratio
n
Low
pH
Inac
tivat
ion
Hyd
roxy
apat
ite
For
mul
atio
n
Raw
Mat
eria
l Con
trol
Pro
cess
Cap
abili
ty
Ope
ratio
nal P
aram
eter
s
Pro
cedu
ral C
ontr
ols
In-P
roce
ss C
ontr
ols
Lot R
elea
se T
estin
g
Sta
bilit
y T
estin
g
Cha
ract
eriz
atio
n T
estin
g
0
0.5
1
1.5
2
2.5
3Aggregate
Fragment
Deamidation
HCP
Insulin
Glycosylation
DNA
#REF!
9
July 2010
Where Innovation Operates
ManagementConsultants
Quality by Design
VACCINE-BASED CASE STUDY
Sam VenugopalPrincipal
T +1 650.864.3522F +1 650.967.6367M+1 408.396.9649
444 Castro StreetSuite 400Mountain View, CA 94041U.S.A.
www.prtm.com
John BerridgePharmaceutical Ccnsultant
T + 011447971324939
Bracklyn, St. Clare RoadWalmerDeal CT14 7QB
10
Questions for discussion
What challenges would there be to justifying the described immunogenicity design space?
What studies would be needed for a therapeutic protein to justify an immunogenicity “design space”, where immunogenicity is undesirable?
11
Questions for discussion
QbD has several elements that can be applied across multiple product types and associated systems. What are the essential components of QbD that can be applied most generally?
What elements of QbD appear to be the most difficult/costly/time consuming?
How are companies making decisions over how much, if at all, QbD will be applied to a particular product, especially considering early phase, late phase and licensed products?
Global acceptance of QbD by regulators is one barrier to the implementation of QbD on a holistic basis. How are companies managing with global filings? What other concerns do companies have in implementing QbD?
Apart from process and product, on what other applications can QbD have an impact?
