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Question-Based Review:
Asking the Right Questions for Process
Understanding, Control and Filing
OPS-SAB
July 20th , 2004
Current vs. QBD Desired State
Companies may or may not have Companies include needed
info but it’s not always in the filing
data with filing and could
Reviewers must go through cycle
share it prior to the filing
of info requests and questions
Companies may or may not have Companies include the
clear scientific rationales for data analysis to produce
choices but are not always meaningful summaries and
sharing it.
scientific rationales
Reviewers must often “piece
together” data and observations Reviewers assess the
to discover the rationale for a rationales and summarized
spec, method, formula, process, data presentations as
etc.
satisfactory or not
Reviewers are analyzing the data
they often must tease out of the
company
Risk Based Development: a simple concept
1. Use sound scientific principles in Associated regulatory
the design of the DF and Process question rationale?
2. Identify the critical attributes (CAs)
for the raw materials
3. Identify the process critical control
points for the processes (PCCPs)
4. Employ the proper analyses and
PAT concepts for process
understanding and control
5. Tie it all together with the
appropriate informatics to feed the
information forward and backwards
for QbD and continuous
improvement and innovation =
reduced risk
Risked Based Development - RBD
RBD is all about “feeding forward” (after Ali Afnan)
1. Exploring the characteristics of the RMs, and
possible variability in RM and processing that are
expected to impact on required DF performance
1. Deciding on a DF based on #1 (+ business case) and
selection of possible processes
2. Deciding what data are necessary to access the
probable success of #2 (1st,principles, lit, DOE)
3. Collect and analyze the data (here comes PAT)
Gap analysis - refining models as development
proceeds
1. Continuous improvement
Example: Solid Oral Dosage Forms
Does it
work?
Can we
make it?
How realistic is RBD?
As all good pharm. Scientist/Engineer know:
• A formula without a process is (e.g.) a pile of
powder
Even during API characterization, developing a
formula implies an expected DF and process or
range of choices (e.g., you don’t use compaction
aids for lyophiles)
So API characteristics are among the 1st
information you need to feed forward
So what’s different about the new GMP?
Models, data, and informatics – the process!
Accessing solubility impact
at preformulation:
Yalkowsky’s Modified
Absorption Parameter
(QSAR & Combinatorial Science, 22,
247-257 2003)
K ow
Π=
O Lumen
K ow
Π=
4 Dose
max1, [ 0.5−0.01( MP − 25 )−log K ]
10 ow
Variability
b l e !l!e!
a D
var
i
I X
s
Et ab ???
Fju
Ad
Adapted from Rick Cooley, Eli Lilly, and Jon Clark CDER-FDA
Example: CMC-API Selection
Rationale/Process for DF Development
How do you know what questions to ask?
e
tim
API
DF
CYCLE ON DATA
RISK ASSESSMENT
WET GRAN DRY GRAN DC
PS SHAPE MECH
ID CAs
API
CRYSTAL AMORPH
DECISION TREE,
e.g. Q6A
CLASSIFI-
STABILITY
MICRO- Or New
CATION MERITICS
Process Design/Selection Rationale
OPT
ID PCCPs
Revise
Amount of
data needed-DOE?
Data Treatment for Fit?
Response Factor(s)?
BFI = 0.4
BI = tensile strength/hardness = σT/H (Moderate)
(>0.5x10-2 )
BI = 0.005 (Low)
Courtesy of Greg Amidon, Pfizer,
Previously Presented at AAPS 2002 SI = 0.013 (Low)
or U.of Mich. Solids course
Courtesy of Greg Amidon, Pfizer, Previously
Bonding Index of: Presented at AAPS 2002 or U.of Mich. Solids course
Excipients Drugs
0.025
0.040
0.035
0.020
0.030
Bonding Index
Bonding Index
0.025 0.015
0.020
0.010
0.015
0.010
0.005
0.005
0.000 0.000
Su
SD se
Ca
Hy
MC tose
MC
MC
Ma
As
cro
PN
PN
PN
Ac
PN
PN
Flu
d.
SO
La
C
n
p
eta
nit
U-
U-
U-
U-
U-
La
r bi
irin
c
PH
PH
PH
4* H
A
ol
E
C
D
cto
mi
p.
10
10
10
2O
n.
se
0.9
0.8
Brittle
0.7 BFI = tensile strength of a
Fracture
0.2
0.1
0.0
Sorbitol
SD Lactose
MCC, med, RM
MCC, coarse
Croscarmellose
Povidone
Ca SO4 di-H2O
MCC, medium
Corn Starch
Sucrose
Mannitol
Hydrous Lactose
Courtesy of Greg Amidon, Pfizer,
Previously Presented at AAPS 2002
or U.of Mich. Solids course
Courtesy of Greg Amidon, Pfizer, Previously Presented at AAPS 2002 or U.of Mich.
0.8
Brittle Fracture Index
Adding only
0.6 30% of a
non-brittle
excipient
0.4
makes the
mixture
0.2 much less
brittle.
0.0
0 20 40 60 80 100
% Drug Mixed with Excipient
Empirical Modeling of a Binary Mixture
Courtesy of Greg Amidon, Pfizer, Previously Presented at AAPS 2002 or U.of Mich.
Leuenberger and
others have 1st
principle models to
Hmix extend the
concepts (Powder
Technology 111
2000 145–153)
C1 Component C2
Risk Based Development-CMC questions
1. Use sound scientific principles in 1. Were the principles
the design of the DF and Process appropriately applied?
2. Identify the critical attributes (CAs) 2. How were the CAs
for the raw materials identified and the
3. Identify the process critical control formula designed?
points for the processes (PCCPs)
4. Employ the proper analyses and
PAT concepts for process
understanding and control
5. Tie it all together with the
appropriate informatics to feed the
information forward and backwards
for QbD and continuous
improvement and innovation =
reduced risk
ID of PCCPs
PCCP variables –
Model dev/refine
6
0.3
8
10
0.2
12
0.1
0.0
1000 1200 1400 1600 1800 2000 2200
Wavelength (nm)
0.40
Avicel® PH-200 compacts
0.30 Granulation
0.25
Roll Speed (RPM)
by Roller
y = 0.3672x + 0.1754
2
R = 0.9899
4 5 6
Compaction
7 8 9
0.20
10 11 12
0.15
0.0 0.1 0.2 0.3 0.4 0.5 0.6
2 20
Force at break/Thickness/Width (N/mm )
18 Avicel® PH-200 compacts
The strength is a 16
VFS Speed: 194 - 197 rpm
HFS Speed: 29 - 30 rpm
Roll Gap: 0.031 - 0.038"
12
density which is 10
monitored by NIR 8
y = 21.54e-0.4493x
6
Semi Empirically 4
R2 = 0.9884
F=(SNIR-0.17)/0.37 2
0
4 5 6 7 8 9 10 11 12
Gupta, et.al, in press, J.Pharm.Sci. Roll Speed (RPM)
Avicel® PH-200 Milled Compacts
800
Day2
Dry
Granulation
Particle Size (0m)
d90
600
400
by Roller
d50
Compaction
200 d10
signal (as
d10
200
predicted)
0
2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0
1 / Slope NIR Spectrum
Real-
Time
Setup
On-Line Data
0.32
Off-Line Data
0.28
0.24
0.20
0 4 8 12 16 20 24 28 32
Time (minutes)
0.30
0.28
0.26
0.24
0.00 0.01 0.02
Scale Up: 10% Tolmetin
0.03 0.04
0.05
Compacts
Force/Thickness/Width (N/mm2)
FeederSpeed / Roll Speed / Roll Pressure
50/ 8 /25 50/10/25 60/ 8 /25 60/ 6 /35 60/ 8 /35 60/10/35
Alexanderwerk’s WP 120 x 40
Formulations:100% Avicel® PH200 (MCC), 10% Tolmetin, 30% DiTab®, 60% MCC
8 Compactor settings studied prepared with and without vacuum
Gupta, et.al, in press, J.Pharm.Sci.
Risk Based Development-CMC questions
1. Use sound scientific principles in 1. Were the principles
the design of the DF and Process appropriately applied?
2. Identify the critical attributes (CAs) 2. How were the CAs
for the raw materials identified and the
3. Identify the process critical control formula designed?
points for the processes (PCCPs) 3. Ditto for PCCPs
4. Employ the proper analyses and 4. What were the bases
PAT concepts for process for the analyses
understanding and control selection?
5. Tie it all together with the 5. What are the
appropriate informatics to feed the supporting data for all
information forward and backwards of the above?
for QbD and continuous
improvement and innovation = 6. Product Development
reduced risk History
Summary: PAT, GMPs, RBD, PCCP
Asking the right questions at the right time
Feeding forward and back between disciplines
Designing the product and process against
meaningful metrics (performance, stability etc..)
• MUST start in R&D
• Development of meaningful specs
• Real time monitoring
Process understanding for quality and control
• Known functionality (i.e., models) against which
data are used to control to the mark
What do you get at each stage?
Early development – CMC go/no go decisions with
a higher level of certainty, i.e., reduced risk
Late phase development – clear formulation and
process design rationales
• Control strategies based on understanding to
reduce the risk
• Facilitation of clear regulatory queries and logical
responses
Tech transfer – more realistic processes to transfer
(Gerry Migliaccio’s “leg up”)
• Fewer “surprises” (analogous to forward pass)
• Easier approval process and inspections
Acknowledgments
Dr. Gregory Amidon – Pfizer,
Kalamazoo
CAMP – Consortium for the advanced
manufacturing of pharmaceuticals
Abhay Gupta – graduate student in
IPPH at Purdue
The Team - Headed by Jon Clark