QbD for Sterile Products

Tim Lukas
Pfizer
1. Introduction to the QbD framework/requirements
2. The Need, Value and Demand for QBD
3. QbD demands Expert Design & Detailed Assessment
4. QbD Product Development for Liquid Products A Chronological
staged progression (colour coded)
Presentation interspersed with anecdotes
Presentation interspersed with questions
Presentation augmented with some product examples
5. Conclusion
6. Acknowledgements
7. Glossary of Terms
Content
2
The Framework of QbD
Process Analysers
E
n
a
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l
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r
s
:

P
A
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Design of Experiments
Multivariate Analysis
Process Modelling
Science
Quality Risk Management
Knowledge Management
Quality Quality
Target Target
Product Product
Profile Profile
Product Product
& Process & Process
Dev Dev
(CPP) (CPP)
Design Design
Space Space
- -
Quality
Target
Product
Profile
(QTPP)
CPPs
Design
Space
Pharmaceutical Quality System
Control
Strategy
Continuous
Improve-
ment
Product & process
development
U
n
d
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r
p
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b
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CQAs
3
Quality By Design for Parenterals
With Reference to Other Liquid Products
QbD requires
1. Understand current standards and requirements for a quality product
2. Apply knowledge from design/development/manufacture of past
products, understanding susceptibilities and minimising sensitivity in
prototype design
3. Understand the specific properties and challenges of your candidate
4. Select the best, robust development option
5. Conduct systematic evaluation of product attributes & sensitivity
resulting from change in components, composition, process/
equipment, testing, storage, stability and use
6. Secure appropriate formulation, primary pack, process, storage and
use
4
Quality By Design For Parenterals
With Reference To Other Liquid Products
5
Approach similar when applied to Parenteral/liquid systems
.
Opportunity to note specific considerations of liquids formulators
(renaissance in liquids work associated with Paediatric guidance)
.
Drawn extensively from industry (EFPIA) thinking about QBD
.
Highlight some general and specific examples from industry
.
A work in progress. QBD should and is evolving.
Development Issues - The Need for QbD
6
Muddling through with best guess formulations highlighted
the need for Quality By Design
Flawed strategy with increasing analytical scrutiny and specifications shaped
around batch data
o Are three batches representative or unrepresentative!
o The less effort in control the broader the specification?
o The more diligent the team the tighter the controls
(but the less to worry about)
Move away from reactive issues driven formulation fixes with the use of testing
to check if quality is present
Embrace certainty through preparation of quality products
Composition, formulation, process & controls integrate and dictate the only
outcome, the Quality Product
o Confidence in product
o Freedom from pass/ fail testing worries
o Opportunity to eliminate release testing?
Regulator and Innovator demand. (Generics next?)
7
The Value Of QbD : Structured, Systematic
And Professional Product Development
8
Quality By Design =
Designing In Quality Then Confirming By Assessment
QBD - too often the focus is work confirming robustness. The implicit
assumptions
o Only possible if you designed the right formulation in the first place
o You cant map an operating space if you are at the edge of failure
Late characterisation of product is a high risk strategy with major consequences.
(Inheriting a licensed in product) If there is little operational space, options are
limited
o If possible - manage the product youve got and build in the best controls. Appreciate
there may be manufacture, stability, batch failure and recall issues. (costly in money,
manufacture slots, opportunity, reputation, sales)
o If possible renegotiate the product profile (hit in differentiation & sales)
o Start the formulation and design process again with improved knowledge
o Get a better candidate!
Give yourself every chance of succeeding
o Select the right molecule and properties to fit the known broad robust design space
o Explore and understand product performance so you can define product robustness
and centre within design space as the most robust/forgiving product process and
presentation
o Have time for iteration/response to knowledge/findings
9
Quality Design & Development
10
Design
11
Define candidate properties that permit progression
Facilitate fast low risk development and enable access
And utilisation of institutional knowledge and capabilities
Access prior knowledge of candidate/series/moiety
Conduct pre-formulation studies. Define formulation
and process options offering robustness
Scope formulation and process options. Identify
opportunities and flaws. Select the lead likely to be
viable, robust and straightforward to develop.
Define product attributes delivering safety efficacy
quality and performance for this therapy.
Build in realistic commercial differentiation and utility
Scope Product Options
Select and define lead
Quality target product
profile
Knowledge Gathering
Molecule properties
Quality gate
Assess
12
Evaluate the product experimentally based on Risk Analysis.
Define fundamental performance indicators. Model predict &
confirm quality & robustness experimentally. Establish robust
product & process and any sensitivities requiring attention
Product and Process
Risk Assessment
Experimentation and
Predictive modelling
Control Strategy
Continuous
improvement
Final Positioning
and lock down
Accept product and position it in the design
space based on deep product understanding
Successful Risk assessment. Successful Product. Now optimise
manufacturing efficiency based on batch data. Establish
flexibility to manage minor changes
Define control based on product/process knowledge and any
sensitivities. Establish PARs, design space and response
and any PAT approaches
Apply expert & organisational wisdom. Conduct Failure Mode Effects
Analysis on the product & process. Identify high risks, potential
cause & effects & likely critical process parameters & risk mitigation
The Quality Target Product Profile
Requires Care And Understanding

Careful negotiation, defines the formulation challenge
and the ease of delivery
Encompasses the needs of regulators, users,
patients, marketeers and manufacturing
No requests that undermine quality or hamper
development unnecessarily
Adapts to challenges in product development revising
non-essential features of the product profile
Critical
Accurate
Realistic
Evolving
13
14
Understand what is
necessary to satisfy the regulators, patients
sufficient to provide differentiation
possible to simplify development and manufacturing
The Quality Target Product Profile
Requires Care And Understanding
Quality Target Product Profile
15
Quality Target Product Profile
16
Prioritising within the Product Profile
17
The Quality Target Product Profile Dictates
The Product Design Requirements
18
Anecdote The Product Profile
Dictates Design And Development Work
19
Product Example : Dectomax
20
Question/Calculation
The Poiseuilles equation states
Q = ! r
4
"P/8 L or more usefully "P= 8 L Q / ! r
4

o !P is the pressure drop
o L is the length of pipe
o is the dynamic viscosity
o Q is the flow rate
o r is the radius
Also force x distance = work done = pressure x area
This relates the force of injection and the pressure exerted to get the injection to
flow to the properties of the fluid and the pipe along which it flows.
J Pharm pharmaco 1979 v31 p497 500
Int J pharmaceutics v 36 (1987) p141 145
A prototype formulation can just be injected under field conditions. Unfortunately
formulation requirements dictate that its viscosity is increased four fold. What can
you do to the dosing system to offset the increased force of injection? Explain in
quantitative terms design options for syringe and needle.
21
Candidate Selection
Molecule + right properties = Development Candidate
Example molecule Symplain
Weak base, pKa ~9.5
Key properties
Solubility must support dose at
some useful pH (3 9)
Stability must support a
solution presentation
pH/stability sensitivity
manage from pH 3 4.5
Manageable Oxidation risk
Manageable thermal lability
Benchmark vs prior knowledge
and experience
22
Understand Candidate Solubility
Define pKa
Predict solubility using
Henderson Hasselbalch
equation. Confirm exptlly
Measure intrinsic solubility
using thermodynamic stable
form of free acid/free base.
wrong form=wrong solubility
Free acid/free base ppts when
free unionised [D] exceeds
saturated solubility in the [D
+
]/
[D] equilibrium. This pptn
event defines the maxm
solubility at any pH. It defines
the [D
+
] ceiling
Ionised form ppts in
combination with a
counterion.
Profile solubility of
thermodynamically
stable salt forms of
interest.
Different salt
counterions have
different plateau
solubilities --------
Dont create wrong salt
form in situ
Amorphous forms may
precipitate/salt out at
extreme pH & high
concentrations
Understand any
counterion (Cl
-
) Ksp
value sensitivity
Dont formulate buffer
back at high pH where
[D] can supersaturate
Cosolvents raise intrinsic
solubility, prevent free base
pptn so higher salt solubility is
accessible.
23
Question/Calculation
Calculate key points and sketch the pH solubility profile of candidates A to F
using the equation provided for a free base pH = pK + log10 [S
0
]/([S
T
]
[S
0
])
Candidate pKa Intrinsic Solubility(pH) Comments
solubility(4C) 3 3.3 3.7 Viable?
A 5.7 5 g/ml
B 6.3 1 g/ml
C 5.7 1 g/ml
D 6.3 5 g/ml
E 6.7 5 g/ml
F 6.7 1 g/ml
Discuss their relative merits as injectables providing a dose of 2mg/ml.
What specification needs to be set to maintain solubility at 4C?
24
Anecdote: Desperate Measures To Achieve Objectives.
A Price Worth Paying?
In formulation design
*GRAS = Generally Recognised As Safe
Development speed and certainty if you stick with precedent.
Novel excipients bring many challenges.
Developing design and understanding space from scratch.
Examples - the Cyclodextrins,
Hydroxypropyl beta cyclodextrin(HPBCD) and
Sulphobutylether beta cyclodextrin, sodium salt (SBECD)

Pharmacopoeial Precedented
Unprecedented
GRAS* &
qualified
25
Check degradation mechanism and specific
sensitivity
o pH and H+/OH- catalysed
o Metal ion catalysed
o Oxidation/light
o Thermal lability
Measure small degradation change & [D]
f

~[D]
i
. [D] constant, degradation rate then D
independentpseudo zero order. Typically
small change during shelf life.
Arrhenius predictions to aid with shelf life
prediction. ASAP evaluation providing
degradation profile is representative.
Confidence that 4C or lyophile options will
support candidate
Exploration of a pH range to support a
specification and match with solubility
requirement
Understand Candidate Stability
Arrhenius ln k = ln A E
a
/RT
ln k = ln A E
a
/RT + B(%RH)
ASAP
(Accelerated Stability Assessment Programme)
K. Waterman
Pharm Res 24 780 (2007)
26
Question/Calculation
Stability calculation using ASAP.
Implications of a shift in equilibrium moisture content by applying
ASAP
Exploit short term, high temperature, high moisture, stress stability
conditions in which small amounts of degradation occur
Application valid if degradation is mirrored qualitatively across the
temperature range
(iso-conversion conditions).
27
Question
The Stokes Einstein (Smoluchowski relation) applies to the diffusion of
spherical particles through liquid with low Reynold number
D = k T/6"#r
An intermolecular diffusion controlled reaction between drug and excipient is threatening shelf
life. If the viscosity (#) of the product shifts during storage it could threaten product shelf-life.
A polymer in the formulation also degrades by hydrolysis during sterilisation. Excipient
polymer viscosity depends on excipient quality control and is molecular weight dependent.
What are the implications for the definition of polymer quantities in the formulation and
polymer quality assurance?
Consider how much would viscosity have to vary as a result of sterilisation to compromise
stability?
What are the implications for excipient quality, molecular weight and formulation
concentration/overage in the formulation?
How much of a viscosity increase is needed to improve stability in initial design?
28
Anecdote Ensure You Have Adequate Stability For The
Proposed Use And Pack
Candidate instability in alcohols/water
Most formulation/solubilisation options excluded
Move to GRAS listed aprotic solvents could achieve satisfactory stability
and performance
Allowed development of topical prototype formulations, stable in glass
vials.
Topicals needed to be cheap and packaged at low cost in plastic tubes
Moisture transmission through plastic tubes undermined stability
Packaging and moisture control costs undermine viability of a cheap
frequently used product
Packaging needs to be an integral part of the product profile
Costs are a key concern in generic and Animal Health markets
29
Pet endectocide
Topical Spot on
Monthly dosing
Single use tube
Easy dosing to pets
Polypropylene plastic
tube?
Product Idea: Spot On
!
Learning
Packaging challenge costs
preclude development
Alternative candidate and
formulation work required
Product profile, pack
requirements and
deliverables shape product
viability and development
Triglyceride
Formulation
Free from water and
alcohols
Solution
Isopropyl acetate solvent
Volatile loss & moisture
ingress modelling
Moisture activity/Chemical
stability predict shelf life.
Special tube and Al blister
costs prohibitive
Identify alternative series
with improved stability
Challenge
Low cost
Limited solubilisers
Avoid volatile alcohols
Stabilisation against hydrolysis
Satisfactory stability in glass
vials
Stop moisture ingress through
plastic tubes and Al blisters
30
Scope Product Options
What formulation options have a track record of success?
Which formulation excipient options are understood and compatible with
my candidate?
What are the chemical stability risks real or apparent, significant or
manageable?
What are the physical stability risks and constraints?
Disproportionation, sedimentation, viscosity, particulates, pack
interactions, leachables/extractives?
Avoid the issues and pick a viable option. Give yourself a hope of a
sensible fishbone diagram analysis later
31
Composition of Symplain Citrate Injection
(1) Equivalent to 0.5 mg/ml or 2.5 mg/vial of symplain, based on a theoretical potency factor of 73.5% for the citrate salt. Actual
weight may vary according to the potency of lot used.
(2) Reflects nominal fill weight. An appropriate overfill is included to ensure labeled extractable volume.
(3) If needed, added as a ~ 0.1 M solution in WFI.
32
Selecting The Appropriate Composition

Component Comments
API Company standard. Appropriate quality controls special care with final
crystallisation solvent, endotoxins, impurities & particulates
Sodium Citrate Buffer precedent at satisfactory pH. Avoid buffer at extreme pH. Ensure no pack
interaction. No disproportionation risk with API. Buffer pKa position.
Sodium Chloride Tonicity appropriate. No issues/challenges with sterilisation.
Beware common ion effect if appropriate.
HCl Risk/challenge of pH drift during manufacture or in the product. pH adjustment
in manufacture aided by buffer if present
NaOH Risk/challenge of pH drift during manufacture or in the product. Worry about
introduction of ash if used in large quantities. (Salt purification aid)
Anti-oxidants Precedent, chemical compatability, Control at end of shelf-life
Preservatives Precedent at level, appropriate performance at required pH, chemical stability/
compatability. AET criteria met.
Polymers Source, synthesis, peroxides and impact on stability.
Robustness to sterilisation. Viscosity and ease of filling
Packaging Available, proven, stability established, already in use, stock item, already
validated in use, compatible with formulation. Leachables, ab/adsorption.
33
Question/Calculation
A drug, di sodium salt of Molecular Wt 446 Dalton is crystallised. It has solubility of 4.46 mg/ml. Calculate
its solubility product. What solubility suppression is observed in isotonic saline?
How does dissolution rate change under sink conditions moving from water to isotonic saline? Consider the
implications for formulation design and manufacturing.
When calculating Ksp, make sure you have the right equation
D
2-
+ 2 Na+ ! Na
2
D K
sp
= [Na]
2
[D]
Even if the drug has good solubility the effect of the solubility product will be marked because of the square
relationship for Na+.
A drug salt of molecular weight 446 has a solubility of 4.46 mg/ml. Solubility is 0.01M
K
sp
= 0.01 x 0.01 x 0.01 = 1.0 x 10
-6
M.
Isotonic saline contains 150mM Na
So K
sp
= 1.0 x 10
-6
= 150 x 10
-3
x 150 x 10
-3
x [D]
Drug solubility = 4.44 x 10
5
M = 17.8 gA /ml. A 250 fold drop which will impact dissolution
Saline is not a good choice of tonicity adjuster
34
Buffer Question
How effective is my formulation buffer? How much do I need in my system?
(IUPAC approach)
We normally consider pH change after a change in H
+
. So how much acid or base
generating degradation will prompt a change in pH in my system?
A 100mM buffer system is formulated optimally around its pK
a
of 5. During
formulation storage the pH shifts from pH 6 to pH 4. (Best case and broad pH
specification enabled)
What acid concentration is generated during the experiment?
If 100mM buffer shifts from pH 6 to pH 4
A
-
/HA ratio changes from 90.9/9.09 to 9.09/90.9 an 81.8% change.
81.8% acid is associated to form HA and 81.8 mM H
+
is consumed.
(fractionally 0.41 = buffer capacity out 1 pH unit from the pK)
This approach, calculating across a significant pH shift as occurs experimentally, is
consistent with the IUPAC definition of buffer capacity. J. Chem. Ed 74 937 (1997)
How much buffer will you need at which pH condition?
35
Buffer Calculation
A compound (MWt 250 Da) formulated at 10 mg/ml has good solubility in
the pH range 3 to 7 & good pH stability in the range 4.0 5.8. During
degradation H+ ions are generated. After 2 years shelf life H+ generated
is 1% of drug load.
Proposed regulatory pH specification is 4.0 5.7.
Internal specification is set at pH 4.3 to 5.5
This ensures supplies in the field always have robust stability.
Manufacturing and pH testing variation means we make the supplies at
pH 5.2 (worst case 0.2 unit variation in manufacture/testing)
After manufacture supplies start life at pH 4.9. At end of shelf life, the
final pH in the sample on stability should not drop below 4.5 (allows for
expt error).
How much (what is the minimum) buffer that will manage a pH drift from
4.9 to 4.5 on stability? If possible pick acetate buffer pK 4.75. (optimal
buffer) Calculate the molarity required for this buffer system?
36
Question/Calculation
Drug molarity in solution is 10/250 = 0.04 M H
+
generated on stability = 0.04/100 = 4 x 10
-4
M
pH = pK

+ log
10
[A-] / [HA]
At the starting pH 4.9 = 4.75 + log
10
[z] / [B - z]
where Buffer Molarity is unknown B
0.15 = log
10
[z] / [B - z] 1.4125 = z/(B-z) B = 1.708 z
At the final pH 4.5 = 4.75 + log
10
[y] / [B - y]
-0.25 = log
10
[y] / [B - y] 0.5623 = y/(B - y) B = 2.7782 y
H
+
generated on stability = 0.04/100 = 4 x 10
-4
M

However the acetate concentration decreases during the stability pH drift from x to y moles/litre,
therefore y = z 4 x 10
-4
moles/litre.
So B = 2.7782 ( z - 4 x 10
-4
) B = 2.7782 [( B/1.708) - 4 x 10
-4
]
2.7782 x 4 x 10
-4
= ((2.7782/1.708) - 1) B 1.11 x 10
-3
= 0.6266B

So minimum buffer molarity M = 1.77 m M In this case a low level of buffer would be
appropriate minimum if this was the only acid generating mechanism.
Getting the buffer quantity low is particularly important if working at extreme pH.
37
Anecdote: Preservatives/AET and CDs
Cyclodextrins (CDs) are useful solubility enhancers. The beta cyclodextrins used
pharmaceutically consist of seven ! 1,4 linked gluco-D-pyranose units in a ring
creating a torus shape. Moieties of similar size to substituted phenyl groups bind into
the central cavity. This enhances solubility.
Each of the seven sugars has three potential sites of chemical substitution in the 2,
3 and 6 positions making a maximum theoretical degree of substitution (DS) of 21.
Two beta CDs have been used parenterally.
Encapsin Hydroxypropyl " cyclodextrin (HPBCD)
Captisol Sulphobutylether " cyclodextrin as its sodium salt (SBECD)
These can be used to aid solubility.
Useful reference on Cyclodextrins (CD)
Mark E Davis, Marcus E Brewster in Nature Reviews Drug Discovery 3 1023 -1035
38
Unfortunately the CDs also include most of the preferred preservatives
which have a favourable structure for inclusion.
There is competition in solution which means less CD is available to dissolve
drug. Preservative is associated with CD increasing the formulation
requirement. This makes multi-dose products containing CD difficult to
preserve.
When formulating
find preservatives with minimal inclusion
find conditions where sufficient preservative is free to pass
the Anti-microbial Effectiveness Test (AET)
ensure sufficient drug is included to achieve necessary solubility
These are complex challenging systems with a complex design space.
(eg.Cerenia)
39
Anecdote: Preservatives/AET and CDs
Question/Calculation
A Pharma Co. is considering developing a single dose CD formulation using
HPBCD (Encapsin) as an alternative to its current SBECD (Captisol)
formulation which contains 5mg/ml drug P(M Wt 500 Da) in a 4.326% SBECD
solution. If the association constant for the free base drug is
K= 2000 dm
3
mol
-1
in SBECDNa (DS=6.3, Av. MWt 2163 Da) and
K= 670 dm
3
mol
-1
for free base drug associating in HPBCD (DS= 4.5, Av M.Wt
1396) then.
P + CD ! PCD K = [PCD]/[P] [CD]
1. Calculate for the 5mg/ml formulation how much drug is included in SBECD
in percentage terms.
2. What quantity of drug is free in solution?
3. If you swap to HPBCD how much is needed?
4. What is the particle number in solution for the formulations and how much
NaCl should be added to achieve appropriate tonicity?
40
Question/Calculation
1. [P] = 5g/L /500 Da = 0.01M [SCDNa] = 43.26g/L / 2163 = 0.02M
P + CD ! PCD K = [PCD]/[P] [CD]
0.01-x 0.02 x x K = x/ (0.01 x)(0.02-x)=2000
x
2
61x + 0.4 = 0 X = [61 (61
2
1.6)
0.5
]/2 = 0.006558 M
0.006558 x100%/0.01 = 65.58%
2. 0.01 0.006558 = 0.003442M or 0.3442 x 5mg/ml = 1.721mg/ml
4a. Particle number = [P] + [CD] + [PCD] + [Na]
= 0.003442 + 0.013442 + 0.006558 + (0.02 x 6.3) complete dissociation
= 0.1494M, approximately half the 300mM requirement
Suggests that 0.45% NaCl would be a useful additive to adjust tonicity
41
Question/Calculation
3. P + CD ! PCD K = [PCD]/[P] [CD]
0.003442 R 0.006558 670 = 6558/(3442 . R)
R = 0.0028437 = free CD
T (Total CD) = R + [PCD] = 0.0028437 + 0.006558 = 0.0094017M

0.0094017 x 1396 Da = 13.1248g/L 1.312%
4a. Particle number = [P] + [CD] + [PCD]
= 0.003442 + 0.0094017 = 0. 012844M,
very little of the 300mM requirement has been used.
(300 12.8) / 300 x 0.9% ~ 0.9% NaCl
Standard adjustment is reasonable
42
Product And Process Risk Assessment
Weve done our best to design the product
What are the implications for future development?
Are there any things we have overlooked?
Have we designed something sensible we can work with and manufacture
as standard?
Where should we focus our efforts in ensuring success and a problem free
product throughout its commercial life?
Have we a clear dispassionate rationale for what we are and are not going
to do?
Avoid being dismissive based on false presumptions of a track record of
success with a particular process
Collate organisational knowledge and exploit individual expertise (science
based decisions, not a democracy avoid non expert decision skew )
43
Typical Manufacturing Process
44
Derivation Of Quality Attributes From The Quality
Target Product Profile
45
Initial Risk Assessment: Based On
Prior Knowledge Applied To Qas
DP Quality
Attributes derived
from TPP
Drug Product Manufacturing Unit Operations/
Variables
Components
Mixing,
holding
Filtration
(in-line)
Filling
Stop-
pering
Capping
Steam
Sterilization
API
attributes
Stopper / glass
attributes
Appearance
Identity
Assay
Impurity
Sterility
Endotoxins
pH
Particulate Matter
Extractable volume
O
2

in headspace
C/C Integrity
Osmolality
Low risk or no impact on quality attributes
Potentially high risk to quality attributes
46
Initial Risk Assessment: Documenting Rationale For High/
Low Risk Areas
47
Recognising Potential Contributors
To Chemical Instability
Prioritise experiments, investigate significance, address &/or control
48
Anecdote : Packaging And Leachables And Control
Of Excipients
It is easy to view the formulation as a separate entity to the
excipients and packaging supplies that are integral to its
performance Dont
These components and their interaction with the product need to
be considered.
Changes can have disastrous consequences. (our knowledge
base is not that broad, supplier understanding is also limited)
The fishbone diagram makes you think actively about your system
and not drift into problems
49
Product : Phosphate Prodrugs
50
Experimental and Predictive Modelling
Many questions are raised by the risk assessment process.
Experience helps you focus effort on the big risks
If there is a concern only data will reassure colleagues and regulators that
the product is robust
Develop experimental designs that capture interdependence through the
manufacturing process
Modelling helps avoid the completion of obvious experiments.
Modelling helps you investigate and design experiments and avoid the
unnecessary process work.
Modelling helps you harness knowledge from multiple previous products
rather than focus on 1 or 2 batches of this product.
1 batch providing success versus an accurate estimation of the boundary of
failure
51
52
Formulation Design Of Experiments
Use DOE to characterize inter-dependent and
synergistic effects of Temperature, pH, Oxygen and
Light on product stability to the point of use
pH > temp > O
2
> light
Formulation design &
controls
(Manage through
manufacture
packaging and
administration set)
Sterilization
process
(Storage and use)
Manage with
Manufacturing
controls
Terminal Sterilisation Feasibility:
Cumulative Contributions To Degradation
53
Terminal Sterilization Feasibility
Parameters:
o Set-point temperature
o Dwell time
Key requirements (CQAs):
o Sterility Assurance Level (Log Reduction $ 8)
o Degradation % 2%
Limits can be defined based on first principles:
o Sterilization theory:
o Arrhenius kinetics:
Less experimentation required
Allows non-empirical Design Space development 54
Balancing opposing effects:
sterility assurance vs chemical stability
55
Terminal Sterilization Feasibility:
Identify A Mutually Compliant Operating Solution Space For
Sal And Purity
56
Terminal Sterilisation Design Space
57
Question/Calculation
If there was an interruption to a sterilisation cyclecould your
product go through it all over again?
What would the implications be for stability?
Is there a process that is most energy efficient and shift efficient for
manufacturing, can these conditions be underwritten so flexibility
exists in operations
58
ANECDOTE:
Link Between Formulation Choice And Design Space Complexity
Formulating with Cyclodextrins. SBECD DS=6.5
CD is a heterogeneous population of cyclodextrins with different substitution
patterns (21 potential centres for substitution)
K the association constant (binding stability constant) is a population mean
K may and does vary with Degree of substitution(DS) on the CD
As DS varies moles of CD varies since CD is used as a % w/v in the
formulation
K varies with Temperature
K varies with pH
Stability depends on pH
Solubility depends on K
Chemical Stability may depend on K (steric effects)
Chemical stability depends on viscosity
Careful mapping of design space boundaries so formulation is always
robust
59
Control Strategy
If the control is needed for product quality make sure it is
developed and applied.
Develop based on previous experience in collaboration with
the manufacturing site and capabilities.
o Cant impose your aspirations.
o Build in time for introduction of new approaches
The simpler the better. Avoid complications and ambiguity.
Integrate controls with design space & specification
60
Parametric
Release For
Sterility
Risk assessment
(FMEA)
Detailed decision
tree for batch
release
61
!"#$%&& (#)*"#+&
62
Process Controls
Controls on O
2
exposure:
o Eliminates the need for an antioxidant
o Reduces degradation extending the terminal sterilisn design
space
PAT Applications:
o N
2
sparge of compounded solution (feedback control to limit
dissolved O
2
content)
o Fill weight monitoring with feedback control
o N
2
purge rate during filling (feedback control to limit O
2

headspace)
o But temperature & duration design space needed for
sterilisation
Real Time Release (RTR)
o Fill weight data in lieu of extractable volume
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Visualization Of Control Strategy
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Revised Risk Assessment
Failure Mode Effects Analysis quantifies risk and prioritizes work
Risk is manageable/acceptable after implementing the control strategy
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Revised Risk Assessment
Stopper / glass
attributes
API attributes
Steam
Sterilization
Capping
Stop-
pering
Filling Filtration
Mixing,
holding
Components Drug Product Manufacturing Unit Operations/Variables DP Quality
Attributes derived
from TPP
Osmolality
C/C Integrity
O
2
in headspace
Extractable volume
Particulate matter
pH
Endotoxins
Sterility
Impurity
Assay
Identity
Appearance
Low risk
(Originally red - Potentially Critical to Quality) Risk mitigated and/or Control Strategy implemented
Acceptable risk following implementation of control strategy
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Continuous Improvement Opportunities
Successful Risk assessment, Successful Product. Now optimise
since development provided Design space flexibility to manage
minor changes
Manufacturing understanding and efficiency based on batch
data. Identify and act on trends & knowledge to improve product
and supply for customers and efficiency for manufacturer.
Simple data review and tracking allows spot change and avoid
problems.
Benefits in throughput, reduced waste, downtime and lost
manufacturing capacity, eliminate systemic errors, position
optimally in specification
Understand variability in API, excipients and process
Manage change in manufacturing sites/facilities
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Product Example: Stronghold
Selamectin formulated in
Glycol ether (DPGMME)
and Propan-2-ol
Learning
Fundamental diffusion
science modelling
Primary pack controls
include the Al blister
Attention to seal quality &
control/thickness of pack
Understand IPA and
water flux
Non critical formulation
variation underwritten in
the clinic
Pet endectocide
Spot on dosing
monthly single use
easy dosing to pets
flexible plastic tube
Challenge
IPA used promotes spread
- supersaturation
- transdermal delivery
- Systemic efficacy (endos)
IPA varies provides easy dose
volume
IPA diffuses through PP tube
IPA hold up in Al blister
IPA diffusion through blister
Moisture ingress
Significant leachables
Resolution
Tube seal integrity & dose delivery
Tube thickness & diffusion
modelling and vapour steady state
Al blister design
- Limit head space
- Controlled land width & glue
- Land width seal quality/alignment
- Control Al thickness and quality
Hold strategy for tubes prior to
blistering
Pin hole He leak check, microscopy
Qualify formulation storage change
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Product Example: Slentrol
Solution in Medium
Chain Triglyceride oil
Polypropylene bottle
LDPE insert and liner
Rubber free dosing device
Weight loss in dogs
Dose on food/in mouth
Taste Acceptance
Titrating escalating dose
Daily dose regime
Easy measurement
Convenient dosing
Challenge
Oil leachables
dose titration 20 fold
(0.05 1 mg/kg)
dose target 2 100kg
Tamper evident child resistant cap
Formulation taste acceptability
through life
Consistent bioavailability
Oil compatible packaging
No confusion with syringes
preservation for in use (months)
Solution
Oily solution to meet dose titration &
bioavailability need
Non rancid oil no oxidation
Preservation achieved as is no
migration effects
3 PP bottles designed to fit
manufacturing line set up
stock item child resistant cap
purpose designed bottle insert
Bottle insert cap compatible and fits
dosing devices
Dosing devices for oil use (swelling
free)
Learning
Formulation avoids anti-
oxidant, preservation
requirements & pack impact
In use studies on device
performance and stability
Bottle insert fitting strategy
at manufacturing site
Extractives leachables with
representative material in
other standard bottles
Extractives/leachables on
device/insert (known
polymer resins)
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Conclusion
Highlighted examples of application of QbD principles in a
science-and risk-based approach to Drug Product
development
Upfront planning around a QTPP is key to success
Sensible design is essential it makes the assessment process
meaningful
Key assessment components are:
o Comprehensive risk assessment on product, components, process
o Demonstration of risk minimization approaches
o How to document risk acceptance rationale
o DoE and modeling to develop product/process understanding
o Application of DoE, Design Space, PAT, RTR, etc. for robust control
QBD is in its infancy but it is here to stay for parenteral and
liquid products
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Acknowledgements
Nancy Harper (Pfizer)
Others from EFPIAs QbD Small Molecule
Team:
Thomas Backensfeld (Bayer Schering)
Christian DeMuynck (Nycomed)
Ritva Haikala (Orion Pharma)
Heinz Wiederkehr (Roche)
Brian Withers (Abbott)
Pfizer colleagues too numerous to single out working on
Human and Veterinary Medicines over the last 25 years
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AET Anti-microbial effectiveness testing
ASAP Accelerated Stability Assessment Programme
CD Cyclodextrin
GRAS Generally Recognised As Safe
HPBCD Encapsin Hydroxypropyl " cyclodextrin
IM Intramuscular
IV Intravenous
LA Long acting
MD Multi-dose
RTR Real Time Release
SAL Sterility assurance limit
SBECD Captisol Sulphobutylether " cyclodextrin, Sodium salt
SC Subcutaneous
VM Veterinary Medicine
Glossary of Terms
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Thank You
About the Lecturer
Dr Tim Lukas is a Physical Chemist by training who has worked on
human and veterinary medicine development for more than twenty
years, based at Pfizers Global Research and Development
laboratories in Sandwich, Kent. His work has spanned discovery
support through to full development on oral, parenteral and inhaled
new chemical entities and biologicals.
Specific formulation experience includes Dectomax, Cerenia, Vfend
and Phosfluconazole injectables, and Stronghold spot on, for which he
holds the formulation patent.
Tim led the Pharmaceutical development of Slentrol oral solution,
coordinated the Pharmaceutical sciences development of the Pfizers
Veterinary Medicines Portfolio including Advastat premix, Palladia and
Trocoxil and set up Pfizers Veterinary Medicines Formulation group in
Mumbai, India.
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