Risked-Based Development and CMC

Question-Based Review:
Asking the Right Questions for Process
Understanding, Control and Filing

Kenneth R. Morris, Ph.D.

Department of Industrial and Physical Pharmacy
Purdue University

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 
max1, [ 0.5−0.01( MP − 25 )−log K ] 
 10 ow


 Relationship to human intestinal fraction absorbed, FA, to the

absorption parameter, Π , of the ‘rule of unity’
 Variability is the Enemy

Variability

RM Input Process Product

b l e !l!e!
a D
var
i
I X
s
Et ab ???
Fju
Ad

You CANNOT have a constant output from a

fixed process and variable input - KRM

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?

 What’s the 1st API question you’d want

the answer to if designing a DF or in
evaluating the appropriateness of the
selected API attributes?
 The 2nd ?, etc…
 The development scientist and the
regulator are asking many of the same
questions.
1st principles API and Excipient Selection Rationale

e
tim
 API

SOLID/CA? LIQUID/CA? SEMISOLID/CA? BIOLOGICAL/CA?

DF

SOLID LIQUID SEMISOLID INHALED

OTHER CAPSULE TABLET

CYCLE ON DATA
RISK ASSESSMENT
WET GRAN DRY GRAN DC

PS SHAPE MECH

ID CAs
 API

SOLID/CA? LIQUID/CA? SEMISOLID/CA? BIOLOGICAL/CA?

CRYSTAL AMORPH

P’MORPH HYDRATE OTHER

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)?

Possible PCCPs based on the RMs?

Possible PCCPs from Process Model?

What is the model for the process? From RM

CA
selection
What Processes are viable?
What Process is consistent with the RM CAs based DF?
An Example: Q6A polymorph decision tree

 This is great. If you understand the solid state and no

polymorphs are formed, you’re done!
 If there are forms, they must be understood, e.g.:
What are the relative stabilities of low energy forms?
 These are the “right” questions for scientist and regulators
 An
Example
con’t: Q6A
polymorph
decision
 We’re OK at first but when considering the product the logical
1st question should be: tree
Based on what is known about the material AND the process,
what if any changes in form would be EXPECTED?
 If the answer is none based on the scientific understanding,
then a confirmatory test during development should suffice
 Otherwise, the next question should be:
Is the observed change the Expected one?
What was the rationale for selecting the processing step
responsible for the change?
 Then we’re back to the tree
 An
Example
con’t: Q6A
polymorph
decision
tree
 Here it might be reasonable to be asked:
Does the performance testing relate to the performance of
interest?
 If the answer is yes based on the scientific understanding,
then we’re back on track
 A next question might be: based on the understanding of the
form’s behavior what would the expect trend in transformation
be?
 An Example con’t: Q6A
polymorph decision tree

Does the observed change correspond to an

understood and expected transformation?
 If not, the system is not as well understood as
thought!
One Example:
Mechanical Properties as a CA, the Hiestand Indices
-The Bonding Index for the survival of strength after
decompression:

BI = tensile strength/hardness = σT/H (>0.005)

- The Brittle Fracture Index measures the ability of a material to

relieve stress by plastic deformation around a defect:

BFI = tensile strength of a compact with a defect/without

= 0.5[(σT/σTo )-1] (<0.20)

-The Strain Index measures the relative strain during

decompression after plastic deformation:

SI = Hardness/Reduced Modulus of Elasticity = H/E’

Hiestand, E., Rationale for and the Measurement of Tableting Indices, in Pharmaceutical Powder Compaction
Technology, G. Alderborn and C. Nystrom, Editors. 1996, Marcel Dekker, Inc.: New York
Rowe, R.C. and R.J. Roberts, Mechanical Properties, in Pharmaceutical Powder Compaction Technology,
G. Alderborn and C. Nystrom, Editors. 1996, Marcel Dekker, Inc.: New York.
Phenacetin - fracture on
decompression the importance of BI

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

BI = tensile strength/hardness = σT/H (>0.5x10-2 )

 Erythromycin - fracture on ejection
the importance of the BFI

BFI = 0.7 (High)

BFI = 0.5[(σT/ σTo )-1] (<0.20) BI = 0.03 (High)

Courtesy of Greg Amidon, Pfizer, SI = 0.04 (High)
Previously Presented at AAPS 2002
or U.of Mich. Solids course
 1.0

0.9

0.8
Brittle
0.7 BFI = tensile strength of a
Fracture

Brittle Fracture Index

0.6 compact with/without a
Index of defect = 0.5[(σT/ σTo )-1]
Excipients at 0.5
(<0.20)
a solid 0.4

fraction of 0.9 0.3

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.

Effect of the Addition of a Non-brittle Material to a Brittle Drug

(Methenamine, Flurbiprofen, Drug X (Pfizer))
1.0

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.

log(Hmix ) = log(HC2 /HC1 )*(%C2/100) + log(HC1 )

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

Production - Scale Product

up/down/same performance

Sensor development What variables

and refinement should be important?

What variables are

measurable?
PCCPs and Scale up with Monitoring
The basic approach is captured as two simple process
understanding (i.e. PAT) premises:
1. PCCPs are preserved throughout scale-up
► the magnitude of the responses may not scale
directly, but the variables being monitored
reflect the “state” of the process
1. Monitoring material properties makes scaling
less equipment dependent (as opposed to only
monitoring equipment properties)
► equipment differences (scale and type) may
have an effect, however, differences in the
material should reflect significant changes in
the PCCPs
Equipment:Chilsonator IR220 (Fitzpatrick)
CDI-NIR; Texture Analyzer 3 point beam bending
E = F l3/ 4ξ h3b
Roll speed: 4 - 12 rpm
VFS Speed: 200 rpm
HFS Speed: 30 rpm
Roll Pressure: 6560
Average NIR Spectrum (n = 13)
0.6 Gupta, et.al., in press, J.Pharm.Sci.
MCC compacts
Roll
VFS Speed: 194 - 197 rpm Speed
0.5 29 - 30 rpm
HFS Speed: (rpm)
Roll Gap: 0.031 - 0.038"
0.4 Roll Pressure: 6551 lb/in 4
NIR Absorance

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

VFS Speed: 200 rpm

0.35 HFS Speed: 30 rpm
Roll Pressure: 6560 lb/in
Dry
Slope of NIR Spectrum

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"

linear function of the 14 Roll Pressure: 6551 lb/in

Force at break (N)

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

1000 Increaing Roll Speed

Day1

800
Day2
Dry
Granulation
Particle Size (0m)

d90
600

400
by Roller
d50
Compaction
200 d10

Gupta, et.al, in press, J.Pharm.Sci.

0
3 4 5 6 7 8 9 10 11 12 13
Roll Speed (rpm) Avicel® PH-200 Milled Compacts
1200
Increaing Roll Speed

 The particle sizes of d90 Day1

1000
Day2

the milled material 800

Particle Size (¬m)

is also manifest in 600

d50

the slope of the NIR 400

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

 Similar trends (as seen before) were observed for Thickness,

Width, Force at break and Young’s Modulus
Gupta, et.al, in press, J.Pharm.Sci.
 Speeds
0.40
6 8 10 12 4 6 8 10 Roll
30 30 30 30 20 30 40 50 HFS
200 200 200 200 100 150 200 250 VFS
0.36
Slope of NIR Spectrum

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)

On-line vs. Off-line Slope

Data and Post Milling PS
Gupta, et.al, in press, J.Pharm.Sci.
 0.32 Red Symbols: No Vacuum .

Blue Symbols: 0.31 Bars Vacuum

Slope of NIR Spectrum

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