Quality by Design 2023-24

research
center
pharmaceutical
engineering
I 3 i I ¢
be = : LE
K1 Competence Center - Initiated by the Federal Ministry of Transport, Innovation

and Technology (BMVIT)
a Das Land >| SFG[ peg and the Federal Ministry of Science, Research and Economy
(BMWFW). pflTy 12 HELM
8% FFC Steiermark EN Sebi Funded by the Austrian Research Promotion Agency (FFG),
Land Steiermark and the Styrian Business Grazm a Fhabal /
Promotion Agency (SFG).

aflTy
Table of content
= Introduction = Lipid nanoparticles & mRNA
= Future of manufacturing = Purification and franctionation in up-
= Quality-by-design and economy and downstream processing
= Quality-by-Design (QbD) in = Parenteral dosage forms

pharmaceutical sciences = Lyophilized dosage forms
= Statistical tools used in QbD = Cell and Gene Therapy (CGT)
= Design of Experiments (DoE) = Medical devices and combination
products
= Process Analytical Technology (PAT)
= QbD for special dosage forms = Conclusion

research
center
pharmaceutical
engineering
Introduction
Introduction
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL

REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
ICH HARMONISED TRIPARTITE GUIDELINE
PHARMACEUTICAL DEVELOPMENT
Q8(R2)
“It is important to recognize that quality cannot be tested into products, i.e.,
quality should be built in by design.”
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pharmaceutical T U
=E engineering G razm
Introduction
Product development cycle
| Stage 1 | Stage 2 | Stage 3 | | Staged

| Drug discovery | Preclinical | IClinical trials I | FDA review
EE ffm I
i bo |
Po Phase 1 Po |
1] 20400 volunteers Phase 3 - 1
1g! 1,000-5,000 volurtesrs H i
E =
nds 5 H FD&
Camp zu Bm —
| = rug
Phase 2 bo i
100-500 volunteers
EN SE I ee I J
| io Do |
[™ 6.5 years bold 7 years # l4+— 1.5 years —»
Source: Pharmacedtical Ressanch and Manufasiurars of amar.
Drug characterization
& optimization Preformulation
——
(enabling F, MST, PIC)
Formulation and process

< >
development Manufacturing transfer
TREE)
research
[| = [i ily & &
Introduction 0 ~
Drug
Development
path
EEE ERENT |
LEE EE EEN]
Screening (10,000 molecules)
EERE EEE EEE RRR]
EE EE EE EE EE EE
FEE RFR RE FARRER REE
FE EE ERE ERE
LE EY FEE EEE EEE EEE]

EERE EE EE EEE EN]
EEE EEE]
FEEF FTA EERE
IEE EEE EEE
CEE
yor 1 medicinal product
0 5 years 10 years 15 years 20 years 25 years

patent expiry SPC (supplementary protection
certificate) max. + 5 years
research
pe »
=E pharmaceutical We make tomorrow's drugs possible.
engineering G razm
HB NME Biologic == Percent biologics FDA approvals 1998 - 2022
45 60%
Number of FDA approvals

Percent biologics
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 201 2012 2013 2014
2015 2016 2017 2018 2019 2020 2021 2022*
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pharmaceutical T U
Introduction
2022 figures of FDA approvals
= The traditional drug development and product portfolio continues to change

towards smaller
patient populations with unmet medical needs
Orphan Drug
Approvals
Fast Track Breakthrough Therapy Priority Review Accelerated Approval
CDER identified 21 of the CDER identified 6 of the

37 (57%) drugs approved ~~ 37 (16%) novel drugs as
CDER identified 13 of the
20 (54%) of CDER's 37 CDER designated 12 of

37 (35%) novel drugs of
novel drug approvals the 37 novel drugs (32%) in 2022 as Priority Review.
Accelerated Approvals.
were for rare or orphan as Fast Track. 2022 as Breakthrough
diseases. Therapies.
hitps://www.fda.gov/imedia/164429/download?attachment wht | Bo as)

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Introduction
= Newly approved drugs by the FDA 2015-2019
Drug approved from year 2015 — June 2020
80
70 = Till June 2020 » 2019
“2018 "2017
60
"2016 n2015
Number of drugs approved

—
=]
Cancer caer cores os tend Infections a C Re . re mong Miscellaneous

» 2015 14 5 10 1 4 1 8 0 2
2016 4 3 2 1 “ “ 1 2 1
w2017 12 7 1 8 5 3 1 5
#2018 17 6 7 1 1 9 0 0 8
2019 11 10 8 0 5 3 2 3 6
® Till June 2020 11 3 1 0 1 3 1 2 3
Disease/Disorder
Introduction
Changing drug research and approval portefolio
Oncology
34%
59 % der Neuzulassungen 2022 sind Biopharmazeutika? Other 28%]

Anteill Biopharma-
Biosimilars
65 63
. 50 > > Meta . \
47 = 27 26 RR
Infectious [ I Immunity
disease 1%
9%
Hematology
9%
FDA approvals 2022 by

therapeutic class
2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022
Biopharmazeutika: Senior et al Nature 41:174-82 (2023)
I Originale [I Biosimilars Chemische und sonstige Medikamente
BCG & VFA: Medizinische Biotechnologie in Deutschland 2023
TREE)
Introduction
Changing drug research and approval portefolio
Gesamtzahl der zugelassenen und im Markt verfugbaren Produkte nach Wirkstoffart?
3 6 3 398
13 10 em
Veranderung
2021-2022:
+36 (+10 %)
[8 Neuzulassungen 2022
I Vor 2022 zugelassen
Rekom- Impf- Insuline Genn- Enzyme Wachs- Andere Gen- Wachs- Inter- Epoetine Ge-
Andere Gesamt
binante stoffe? nungs- tums- Hormone thera- tums- ferone schlechts-

Antikorper? modula- faktoren peutika hormone hormone
toren
BCG & VFA: Medizinische Biotechnologie in Deutschland 2023

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Introduction
ALLOCATION OF R&tD INVESTMENTS BY FUNCTION (%)
14.7 Pre-human/
R&D spendings Pre-clinical

per phase
Oren
9.0 Phasel
11.5 Phasell
The cost of 49.2 Clinical Trials
researching and
developing a new
chemical or
biological entity was
estimated at €1,926
: Clinical Trials
28.7 Phaselll
4.9 Approval
12.9 Pharmacovigilance
million ($2 ) 558 (Phase IV) Source: PARMA, Annual Membership

million in year 2013 Survey 2022 (percentages calculated from
. 2021 data; total values may be affected by

dollars) in 2014 18.2 Uncategorized
rounding)
DiMasi et al, Journal of Health Economics, January 2016 mflaTy [A Fe)!

aflTy
Introduction
What is quality?
= The standard of something as measured against other things of a similar kind; the
degree of
excellence of something.
= General excellence of standard or level.
What is design?
= A plan or drawing produced to show the look of function or workings of a

building, garment, or
other object before it is made.
= The art or action of conceiving of and producing a plan or drawing of something

before it is made.
research
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B pharmaceutical U
engineering Grazm
Introduction
What is Quality by Design (QbD)?
= A concept introduced to the pharmaceutical

industry about 20 years ago
ear
-
armaceutical |
engineerin Graze
Introduction
Initiate
Quality Risk Management Process
Risk Identification
SCIENCE MEDICINES HEALTH
& EUROPEAN MEDICINES AGENCY
Risk Analysis
Risk Evaluation
“Quality by design is an approach that aims to
unacceptable
ensure the quality of medicines by employing
vg. . . Risk Reduction

statistical, analytical and risk-management
Risk Acceptance
methodology in the design, development and
manufacturing of medicines”
Review Events
TREE)
aflTy
Introduction
& EUROPEAN MEDICINES AGENCY
= “One of the goals of quality by design is to ensure that all sources of

variability affecting a
process are identified, explained and managed by appropriate measures”
= “Quality by design centers on the use of multivariate analysis, often in

combination with modern
process-analytical chemistry methods and knowledge-management tools to enhance the
identification and understanding of critical attributes of materials and critical
parameters of the
manufacturing process”
hy
aflTy
Introduction
r /A\ EUROPEAN MEDICINES AGENCY
= In March 2011, the European Medicines Agency (EMA) and the United States Food and
Drug
Administration (US FDA) launched, under US-EU Confidentiality Arrangements, a joint
pilot
program for the parallel assessment of applications containing Quality by Design
(QbD)
elements
= The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) participates as an

observer.
hy
Future of manufacturing
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American Pharmaceutical Review - November 2004
= ...a] ing for > 20

en he toon cee The Concept of
a Pharmaceutical Quality
DOI 10.1007/512247-015-9215-8 Janet Woodcock M.D.
REVIEW ARTICLE Acting Deputy Commissioner for Operations

Food and Drug Administration
Modernizing Pharmaceutical Manufacturing: from Batch

to Continuous Production
Sau L. Lee + Thomas F. O'Connor - Xiaochuan Yang - Celia N. Cruz -

Sharmista Chatterjee - Rapti D. Madurawe + Christine M. V. Moore -
Lawrence X. Yu + Janet Woodcock
TREE)
= Starting more than 100 years ago...
Traditional manufacturing
was dedicated to achieve the
desired high pharmaceutical
product quality in terms
reproducible performance
Traditional and stability. It was assured
Manufacturing by 3 consecutive batches
meeting the set specification
before “freezing” the process
TPT 200-300 days . oo

Past 2010 > 2015
TPT Throughput Time Pharmaceutical Manufacturing
TREE)
aflTy
= With regard to efficiency the St. Gallen Report concluded in 2006
« There is no clear understanding in the industry about their cost structure in

manufacturing
- 83 % of the companies expect increasing heterogeneity in customer demand
« Low Overall Equipment Efficacy (OEE) correlates with increasing number of unit
operations (much higher efficiency with standard equipment)
- Importance of employee training in cost efficiency

- Short cycle times are of critical importance for manufacturing flexibility
- High quality today achieved by “good inspection” rather than a “good process”
- High inter-correlation of each element in integrated systems causes unplanned

maintenance, work-in-progress stocks and rejections
- Operational improvement programs must focus on the entire manufacturing process

- R&D is key in designing the efficient product and process
Operational Excellence in the Pharmaceutical Industry — St Gallen Report (2006) phy

= With regard to efficiency the St. Gallen Report concluded in 2006

« There is no clear understanding in the industry about their cost structure in
manufacturing
- 83 % of the companies expect increasing heterogeneity in customer demand
| ow Overall Fauinment Ffficacvy (OFF) correlates with increasing number of unit

There is no clear understanding in the industry
about their cost structure in manufacturing

TT TT TY OTT TT To OU OT Oo OT OT Troe IT TT oT Ta TOO TOT TT TO TO Ter OTTO IT TY
TT 7ST TITTY
- High quality today achieved by “good inspection” rather than a “good process”
- High inter-correlation of each element in integrated systems causes unplanned

maintenance, work-in-progress stocks and rejections
- Operational improvement programs must focus on the entire manufacturing process

- R&D is key in designing the efficient product and process
Operational Excellence in the Pharmaceutical Industry — St Gallen Report (2006) phy

aflTy
The model to estimate Cost of Good Sold (COGs)
COGs = (Daily Dose x Bulk Cost) + Formulation cost x 100

Daily Selling Price
Formulation costs: Excipients + drug
Bulk cost: Overheads
This assumes that overheads are shared equally across all products
manufactured in one plant.
hy
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pharmaceutical T U
= Cost structure of pharmaceutical manufacturing per unit operation
- GMP space
+ Number of surrounded equipment Other costs (R&D etc);
. Energy 11.49% |
- Solvent/water/detergence Ee |
- HVAC Cost for |
- Validation/qualification propery & plant NR
) QA/QC/QDD Costs for I | vainly related
- Operators/planning machines & oot | to drug substance
- Cleaning/waste direct
- Maintenance Labour costs;
11.90%
* Yield losses
* Inventory/JIT implication
« Depreciation
- Equipment effectiveness (utilization time)

- Safety stocks
Operational Excellence in the Pharmaceutical Industry — St Gallen Report (2006)

platy, [A Ea)
Indirect
Material costs;
438%
= Cost structure of pharmaceutical manufacturing per unit operation
GMP space
Number of surrounded equipment Other cons RAD ec)

E 1
lventwal Each unit operation adds significant

‘overhead’ costs to manufacturing.
Validation/d UammCauor
QA/QC/QbP a NN
Direct
Material costs;
41.92%
Operatals/f Sharing the total plant overheads equally

across all products is highly misleading.
Mainly related
| to drug substance
\intenance Chou coms
11.90%
ld losses be]
Inventory/JIT implication Labour costs;
. . 12.44%
Depreciation
Equipment effectiveness (utilization time)

Safety stocks
Operational Excellence in the Pharmaceutical Industry — St Gallen Report (2006)
Indirect
Material costs;
438%
why
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pharmaceutical T U
= There is an increasing awareness of the cost drivers in pharmaceutical

manufacturing
« Energy costs
Cycle times (Work in progress, inventory, stock...)
Cost for capital

GMP space (4.000 — 12.000 $ / m?)
Ecological costs (waste, CO,, etc)
Historical Energy Costs for the U.S. Pharmaceutical Industry
Distribution of energy use in the pharmaceutical

industry
Overall Plug loads and | Lighting Heating, Ventilation
(100 %) processes and air
conditioning
(HVAC)
Total 100 % 25% 10 % 65 %
R&D 30 % Equipment GLP
Manufacturin | 50 % Processes GMP
g
Galitsky et al 2006 TREE)

aflTy
Energy Utilization index across 3 different pharmaceutical manufacturing

plants [kWh/m?/y]
Formulation unit 1 Formulation unit 2 Formulation unit 3
White Gray Black White Gray Black White Gray Black
6513 4032 69 4050 1526 122 8759 1490 225
Witty said in the interview with the Times he expects the GSK energy bill
to rise 20% to 30% next year.
Probing every possible cost-savings opportunity, GSK is considering

removing its factories from the local power Grid to supply its own
energy more cheaply.
Andrew Witty, September 2011
Zhang 2009 nfhTy

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Commitments of the pharmaceutical industry in times of climate change
a
oP
: oF &
&° A 4® Ww oo et EA av © & oo a
EE I RR PR CPUC i ER Cpe
i ro a 2018 2015 2015 2019 2016 2016 2008 1 2019 nm 2020 2019 1 2017
0
; | L| i
030 1
20%
0%
30 2030
aon 00
’ 202
0 2030 2030
S0% 030 2035 2030 2040
60% 2030
FE FF OF
2030
709%
HW Scope 1+2
MW Scope 3
Hl Interim target (142)
MW Interim target (3)
80%
00%
Percentage reduction in GHG emissions
100%
2050 2025 2025 2027 2030
Bl, BMS, Eli Lily and Viatris do nat commit to reductions in GHG emissions
specifically
GHG, greenhouse gas
Commitments to percentage greenhouse gas (GHG) emission reduction in scope 1, 2,

and 3 emissions
by a range of target years by 16 pharmaceutical companies that made them
Booth et al Int. J. Environ. Res. Public Health 2023, 20, 3206. platy, [A
MANNE
Ea)
aflTy
= Work in Progress (WIP) depends on

« the number of unit operation
- the number of components

~25 days (VAR = 0.24)
iy “RE
= Safety stocks depends on HOW EE —

« Complexity of manufacturing =r
- the supply chain - ~12 dy (VAR = 0.5) ~ Pm
» 3 party involvement [4 EE EE Pr
. Cycle times I - vatve-acding activities (e.g. unit operations) 8
+ 46 calendar days for raw materigls L/S wees wn mmister I =.
25 calendar days for WIP Le —=
91 calendar days Finished Goods Inventory

162 calendar days of total cycle time
< 6 calendar days of this cycle time (3.7 %) is related to value

added
Cogdill et al J Pharm Innov (2007) 2:38-50 platy,

= Overheads associated with inventory carry includes items such as

expiration loss, cost of facilities, insurance, paperwork, transportation,
physical handling, spillage/damage and theft/pilferage
= Applies to any incoming good including WIP and safety stocks
= Estimated at 20 — 25 % on the costs of the component
= Weighted average cost of capital (WACC) is a company- specific measure of the

cost of internal
allocation of capital
= Estimated to be 7.5 %
= Cost for safety stocks (example) annual turn over $ 240 mio N- YW WwW - ©
= Safety stock (10 batch)~ $ 60 mio ©

= $ 4.5 mio cost for safety stock/year
May Jun Jul Aug Sep Ot Muy Dex: Jan Fats Blur
ze =022 ET nee Fee
Tne FLEES zazz 02g =0Ty 2023 FLEE
Cogdill et al J Pharm Innov (2007) 2:38-50;

https://pwc-tools.de/kapitalkosten/en/healthcare-pharmaceuticals/ ny,
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= Overall Equipment Effectiveness (OEE) depends on
- the number of unit operations Key Pharmaceutic A world-class

«+ their process uniqueness performance al industry manufacturing
- Low OEE has a low amortization and poor ROI [Ll (2005) plant
OEE (%) 30 92
Cycle times (h) 720 8
= OEE is impacted by
- Stoppages and breakdowns
. Unplanned maintenance Planned production time
- Down times and set up times rerio = Availabity

+ Inter-correlation with other a li a)
Plant operating time
rocess parts Se Speed > Reduced speed Performance

Pp Pp Net operating time be P)
Productive eNEIRY R Rejected material = Quality

time loss Startup loss (@))
IBM The metamorphosis of manufacturing 2005; Aigner et al 2017 nally A SE)

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center
pharmaceutical T U
= Traditional manufacturing moved to lean manufacturing
Lean manufacturing
involves never ending efforts
to eliminate or reduce waste
or any activity that consumes
resources without adding
value in design,
manufacturing, distribution,
and customer service
LEAN Manufacturing Processes.
Traditional
Manufacturing
TPT 200-300 days TPT 100-150 days oo

Past 2010 > 2015
TREE)
BE == T
=E aceuical U
engineering Grazm
= Operational excellence drives lean manufacturing
Lean manufacturing have been introduced into the pharmaceutical manufacturing over
the
past decade to increase effectiveness and efficiency
« Areview of the outcomes between 2004 — 2009 were disappointing
. 1
Muneantncs_J TALE Smid | [endef Lt
— Con J tC Us
(ar | ot (7
ert open Total Productive Maintenance (TPM)
Total Quality Management (TQM)
Just-In-Time (JIT)
Standardised Standardised Standardised

equipment processes replenishement
Stable running machines Low inventory
Self-directed High continuous Low abseentism & Flexible

teams improvement rates fluctuation workforce
acuewJopsad jeuonesadp
Effective Management System
Stages of Operational Excellence
Friedli et al J Pharm Innov 2010

aflTy
Results of operational excellence and lean manufacturing efforts
- Unplanned maintenance increased from 25 % to 33 %

- Use of new technology remains very low 58 % vs 57 % considered new technology
+ Rejection rate of finished products went down from 1 % to 0.74 %,
- Supplier complaints rise from 1 % to 2.4 % (raw material turn-over increased from
4 to 5
times/year), while pull production increased from 44 % to 59 %
- Set up time went up from 79 min to 93 min

- Cycle times from weighing to packaging increased from 22 days to 22.7 days
- Order fulfillment (right quantity & quality) remained at 95 %
- Lay-out optimization decreased from 68 % to 57 % impacting product flow and tact

(complexity
of material handling & storage as well as process interruptions)
« Pharmaceutical manufacturing still struggles with effectiveness and can not focus
on efficiency
Friedli et al J Pharm Innov 2010 platy, [A Ea)

aflTy
Conclusion
= “The US pharmaceutical industry could be wasting more than $50bn (€39bn) per year
in manufacturing costs due to inefficient processes.” (Macher and Nickerson 2006)
= “Manufacturing defects in fact account for almost three-quarters of all drug

recalls.”
(Dean, Bruttin and van Dyck, April 2005 (Source: U.S. Food and Drug Administration
Enforcement Reports, 2000 —2004).
| Cc seareh
aceuical T U
=E engineering Grazm
= There is an emerging challenge of falsified medicines and drug shortage

worldwide,
including Europe and USA
Figure 1: The areas in which medicine shortages are most

18 + commonly reported: the percentage of 607 respondents
16,(33.3%) who reported shortages for antimicrobial agents,
16} oncology medicines, emergency medicines,

14 | cardiovascular medicines and anaesthetics
12,(25.0%)
12 H11,(22.9%)
10 + 57% y
5 ] 0.4%)
3 i 3%)
1 LE > 30° ”
Africa North | and Asia a

America Central
America
oN A 0
Prevalence of incidents involving health damage due

to falsified medicines by region (n, %). Total number Antimicrobials Oncology
Emergency Cardiovascular Anaesthetics
of incidents is, n = 48. Source: EAHP 2014.
Rahman et al Trop Med Int Health 23: 1294-1303 (2018) pity = at)!
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= Benchmarking to other industries the pharmaceutical industry was definitive an

underperformer
Traditional
Manufacturing
LEAN Manufacturing
Continuous Manufactiiving
TPT 200-300 days TPT 100-150 days TPT << 10 days
Past 2010 > 2015
Trout & Bisson 2009 TREE)

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= Medical advances drive treatment towards personalized drug products and

healthcare
interventions and hence towards (mass)customization
Volume per
mode 1955 ¢ Dose by Different

) number of mini-tableted
mini-tablets drugs
Customized
Modules Personalized
Modules
Personalized
Production
2 mg mini-
br
Og,
“etio,, 1850 tablets
Va riety Fig. 2. Personalized products may consist of three types of modules.
Fig. 1. Historical manufacturing paradigm volume-variety relationship.
Berry et al J Manufact Systems 32: 404— 411 (2013) platy, [ Ea)

research
center a . -
pharmacevtical TU We make tomorrow's drugs possible.
= The majority of future new drugs are orphan drugs (defined as: USA: <1/200.000
people;
EU: < 10.000 people in Europe)
FA =
30
2014 2015 2016 2017 2018 2019 2014 2015 2016 2017 2018 2019
Il Non-orphan new active substances [lll Orphan
Source: IQVIA analysis: FDA CDER, EMA NCEs 2019 data

* The majority of pharmaceutical manufacturing is still mass manufacturing based on

batch
processes, while other industries have moved to mass customization using continuous
processing
= Regulatory agencies, including the FDA, EMA and PMDA support the adoption of CM
for
pharmaceutical production based on science- and risk-based approaches.” S. Lee, FDA
Deputy Director & Emerging Technology Team Chair, March 2017
* The selection of the manufacturing process is based on three major components

that need to
be addressed in the pharmaceutical industry
Manufacturing costs : :
Development costs & Lifecycle /service
* Component
* R&D expenses costs

costs
* Pr n * Supply chain
oduct and Plant & Supply
process operational costs
development P * Market costs
costs
= Product & process complexity is 0

already determined by the early Material properties, o Process.
and late stage product characteristics, g[ characteristics,
development functionalities £ mechanistic,
2 ang © trajectory,
= QbD aims to understand the jerzaliby = variability
multifactorial interdependence S
between materials and processes Formulation Process
to mitigate the risk development development
= Preferably, QbD should determine Product characteristics
the formulation and process with and performance
the least risk and prevent ,over-
engineering consistent &

- reproducible
4EEERRAT i)
BE == T
=E aceuical U
engineering Grazm
= FDA recognizes that CM is an emerging technology that Quality Considerations
can enable pharmaceutical modernization and deliver fri .
potential benefits to both industry and patients. or ontinuous

= CM can improve pharmaceutical manufacturing by, e.g. Manufacturing
an integrated process with fewer steps and shorter Guidance for Industry
processing times; smaller equipment footprint; enhanced
development approach (e.g., QbD) and use of PAT and
models; enabling real-time product quality monitoring; DRAFT GUIDANCE

and providing flexible operation to allow scale-up, scale- ER Fog
down, and scale-out to accommodate changing supply pe Tl Cs bin
demands. = rs: === = = : 4
= FDA expects that adopting CM for pharmaceutical For question eganding ti drut
document contact (CDER) Sau. Loe a 101-796-2903
production will reduce drug product quality issues, lower February 2019
manufacturing costs, and improve availability of quality U5. Departmeet of teak sad
Maman Services
medicines to patients Comer for Bra vai nd Rr (DER
February 2019
Pharmaceutical Quality CMC
Pharmaceutical Quality Manufacturing Standards (CGMP)
TREE)
aflTy
Definitions
Continuous Manufacturing: An integrated process that consists of a series of two or

more unit-
operations. In such a process, the input material(s) are continuously fed into and
transformed
within the process, and the output materials are continuously removed from the
system
Advanced manufacturing: is a systematic predictive framework of methodologies than

enable the
optimal implementation and control of a manufacturing process
Batch: A specific quantity of a drug or other material that is intended to have

uniform character
and quality, within specified limits and is produced according to a single
manufacturing order
during the same cycle of manufacture
Residence Time Distribution (RTD): A probability distribution that describes the

amount of time a
mass or fluid element remains in a process
Control Strategy: A planned set of controls, derived from current product and
process
understanding that assures process performance and product quality
Continued Process Verification: Assurance that during routine production the

process remains in
a state of control
TREE)
ear
-
armaceutical | | U
engineerin Graze
= Continuous manufacturing have been installed in nearly all major pharmaceutical

companies
= Main continuous manufacturing line suppliers are GEA and Bohle
https://www.continuous-
production.com/continuous-manufacturing
https://www.gea.com/en/news/insights/2
018/from-batch-based-to-continuous-
manufacturing.jsp
aflTy
FDA STATEMENT
FDA statement on FDA's modern approach

to advanced pharmaceutical manufacturing
f share | 9 Tweet | in Linkedin Email =~ & Print
For Inmediate Release: ~~ February 26,2019
Statement From: Commissioner of Food and Drugs - Food and Drug Administration
Scott Gottlieb M.D.
Director - Center for Drug Evaluation and Research
Janet Woodcock M.D.
Continuous manufacturing advantages from early to late stage development &
manufacturning
= Process development according to QbD principles enabled with limited drug

substance
= Support fast track development programs through early finalization of formulation

and
processing
= Product consistance throughout the clinical and commercial manufacturing
= Avoidance of product and process scaling up phase
= Highly consistant product quality and performance through continuous close loop
monitoring
= High flexibility in manufacturing scale and ,batch size"
= Ease of manufacturing transfer for commercial manufacturing or supply chain
= Smaller manufacturing footprint, equipment, capital cost and utility requirements

= Real-Time-Release Testing (RTRT)
aflTy
Continuous manufacturing disadvantages from early to late stage development &

manufacturning
= Continuous manufacturing line accessability and capital investment
= Thorough product and process understanding (QbD) to be generated during early

development
(incl. a number of DoEs)
Identification and implementation of control strategies (temporary)
Extensive cleaning and cleaning validation program
Availability of the required skills (temporary)
Limited regulatory guidance (temporary)

research
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pharmaceutical T U
Comparison between a batch and continuous manufacturing processing
~1kg scale :
mmm 4 Define pivotal formulation at small scale
Start Pivotal ® _gsyq scale
Studies m—- ~.50kg scale Possible formulation

E—r.
le 1 modification
Commercial
Final Formulation (BE if needed) ® SMMerLss
10-30kg/hr
—. # Define final formulation on commercial scale
Start Pivotal
Studies * 10-30kg/hr
Establish QbD design space around target
Ready to Manuf. Commercial DP #
nN
—-
J
'®
-
—
-—
ve
O
10- 30kg/hr - Commercial Production
Patricia Hurter, et. al. “Implementing Continuous Manufacturing to Streamline and

Accelerate Drug Development” AAPS
NewsMagazine, August 2013, pp. 15-19.
TREE)
aflTy
Stages of data transformation on the path to
Data are transformed from raw realizing Industry 4.0
signals captured from a system to full

digital maturity. Data are initially
collected from a manufacturing Industry 4.0

process, then organized by data
digitization and analysis as Big Data Actionable
into information, then synthesized into insight Digital Maturity
knowledge by the meaning discerned 4 KNOWLEDGE A soe
via artificial intelligence, and finally to weaning Artificial Intelligence
actionable wisdom attained through
. . . vo. INFORMATION Organized
the combined insights of digital pales Big Data/
maturity Data Digitization

DATA Signals
Data Collection
Arden et al Int J Pharm 602 (2021) 120554 plu [A Fe)!

research
center
pharmaceutical T U
A cyber-physical system (CPS) for pharmaceutical manufacturing in Industry 4.0
a] - Th any I.
I
I
I
~ Supplier Inventories Public Health Emergencies oo’
~ | [)
I
I
I
~ -
-
. ~< “> 2 i
~ -
Hes ’
Control ~ -
Service BS a Energy Dashboard Production Dashboard
> ~~ _ Network! ” &
~ etwor -
Modeling i | ” 1] |
= « wi. Hei) a s
ar Simulation ~ ”- La =
Mgmt 2 b Process Monitoring
gm = info no Do
y - od -
info po eg ~~ -i (S]
-— ” / ~ ~ a
a» Sf 7 \ = Yu —
-
ir R a Pd / \ 8 ie tie La
PT ih ” 7 / \ ~ ~ ay
i - \ ~ ES B 7%
Feeding PAT AS i 3 / =X VS a 7% Real-Time
Coating PAT Release

Testing
Dall
In-Process Testing
Arden et al Int J Pharm 602 (2021) 120554 aiTy

Quality-by-Design (QbD) and economy
Considerations for continuous manufacturing

= Evaluation of different manufacturing processes
= Factors to calculate process chain costs
Equipment-related cost Product-related cost Site-related cost
Investment cost [€] Economic life [year] Footprint [m?]
Depreciation [€/year] Power consumption [kW] Energy cost [€/kWh]

Imputed interest rate [%] Material cost [€/kg| Room cost [€/year]
Maintenance cost [€/year] Throughput [kg/h] Labor cost [€/h]
Imputed interest [€/year] QA costs [€/kg] Site-related overheads [€/m?]
Operating hour [h/year]
Aigner et al Chapter 14 in: Continuous Manufacturing of Pharmaceuticals 2017 hu

research
center
pharmaceutical T U
Evaluation of different manufacturing processes
- . Detailed evaluation and . .

Early decisionmaking (scope of the decision-making peaieddesnandnstalaton = |) the
early stages
. Phamaceutical company .
Pharmaceutical company expand sippler Phamaceutical company product and process
specific assumptions
not sucessful recycle have to be made,
© ifnot successful recycle which might require
qualitative and semi-
: : : : quantitative validation
Technical Does the Assessment of cost Final decision for The evaluation is finished
and the process
feasibility and risk investment look | oc 5 phasic the process to will be designed,
installed and validated
assessment promising atthe | oqion of the progress further for the planed process
Many options are first glance process {dominated by
evaluated (dominated by economic
technical considerations)
» Basic considerations)? | * Only processes

assozement of : with high chance « The decision is
expected costs * Process with too] of success should mainly cost } } } }
« Evaluate risk for Oh isk willbe | be svaluatedin driven = Aigner, |, Hsiao, W-K.,
Dujmovic, D.,
differant excluded detail « If costs are too Stegemann, S. Khinast, J. Methodology
production ~~ *!froneofthe | «Space demand high for all for economic and technical
comparison of
routes options is found | and production ~~ processes then continuous and batch
processes to
«Find possible kely to succeed) location should the evaluation enhance early stage
decision-making. In:
knock—_out thenideaneed | be ficed has to be Continuous Manufacturing of
Easy to be * CAPEX and OPEX recycled Pharmaceuticals, Eds: Kleinebudde, P,,
« Basic process reconsidered can be estimated Khinast, J., Rantanen, J. pp 485-505.

John
planning Wiley & Sons Ltd. (2017)
Aigner et al Chapter 14 in: Continuous Manufacturing of Pharmaceuticals 2017 platy,

a Ea)
research
center
pharmaceutical T U
Considerations for continuous manufacturing Oto of ayte bodies ant

Evaluation of the sytem boundaries and performance '
targets (manufacturing efficiency) is specific for a Hodeing of ihe process chains
product and include: Y
Performing technical feasibility and risk
» Chosen production capacity of the plant i"
« Analysis of the process in comparison to alternatives Busiuntion of Sis success
pylons
‘
* Long term production planning Calculation of the process chain costs, cost
comparison and interpretation
+ Supply chain forcast y
Technology economic profiing and
« Number of shifts ST
Performing scenario, sensitivity and
uncertainty
Methodology for evaluating process chains in early stage development
Aigner et al Chapter 14 in: Continuous Manufacturing of Pharmaceuticals 2017 phy [A

Ea)
BE == T
=E aceuical U
engineering Grazm
Considerations for continuous manufacturing [ Secondary Manufacturing
Modeling of the process chain includes: Bentng || Gransaton | 5] Dying [| Benang |]

Tseng [of coasng
«Unit operations
+ Main and auxiliar equipment for process Main and Overall

integration auxiliar Equipment
equipment effectiveness
- Batch size or throughput rate

Plant operating time
«Overall equipment or processing times

Persie
i — . ~
a Speed Reduced speed

Net operating time — Hm. He =p
Productive Jel ll Rejected material =H
time loss ll Startup loss
Aigner et al Chapter 14 in: Continuous Manufacturing of Pharmaceuticals 2017 phy

[ Fe)!
research
center
pharmaceutical T U
Considerations for continuous Product-related criteria Biopharmaceutical

performance
- Regulatory compliance and clearance
man ufa cturin Jd Dosage form size, shape and presentation
; . oy ern ; Solid state of the API

Performing a technical feasibility and risk stability and shelf life
assessment include Impact on pharmaceutical packaging
Process-related criteria Number of unit operations

+ Calculated risk associated with a product product yl or ciicncy
or process to not meet desired targets Fonmerctal avatlabiliy of process equipment
- Done based on criteria specific, predefined Robusnes
risk scores for unknowns Costrelated criteria Equipment costs
Depreciation
Direct material costs (e.g., API and excipients)
«Weighing factors are being used to based Utility costs (e.g., energy, water and
HVAC)
on the importance of a criteria Direct labor costs
Major criteria for feasibility and risk assessment
Aigner et al Chapter 14 in: Continuous Manufacturing of Pharmaceuticals 2017 phy [A

Fe)!
=E
research
center
pharmaceutical
engineering G razm
Evaluation of the process options is derived from the

feasibility and risk assessment
- Establish the required equipment including auxiliar

and control (PAT) tools
- Calculate the direct and indirect costs for materials

and manufacturing
- Simulation and estimation of approximate direct and

indirect costs using e.g. flow sheet modeling
+ Process simulation to based on prior knowledge
«Cost calculation based on different models (e.g.

Product costing with activity unit) and equipment cost
calculations based on exisiting knowledge and
factors (e.g. Total planned cost estimate, Lang factor)
Aigner et al Chapter 14 in: Continuous Manufacturing of Pharmaceuticals 2017 hu
Evaluation of the process options
Establishment of an equipment portfolio
'
Identification and analysis of relevant cost
categories and factors
Modelling and simulation of the processes
Check of technical feasibility and efficiency
Deriving heuristics for cost estimates

y
Calculation of the equipment costs
| EE)
=E
research
center
pharmaceutical
engineering G razm
Technology-Economic profiling for the

manufacturing process decison
«The highest scored process can be derived from

the process evaluation sheet summarzing all
results
«For further precision, Sensitivity and Uncertainty

analysis can be performed as well as laboratory
scale test runs to narrow down certain
assumptions and predictions
Labomtory -scale analysis, feasibility studies, test uns with

pilot -scale equipment sto
Start 1: Definition of rank criteria and

risk profile elements
Start 2 : Definition of quantitative and/or
Start 3 : Definition of weighting factors?
Aigner et al Chapter 14 in: Continuous Manufacturing of Pharmaceuticals 2017
nihTy,
[A 2)
[l=
p=]
research
center
pharmaceutical
engineering
Grazm
Process Evaluation
Risks
Fl
Thermal degradation of the &F1
RZ
Regulatory requirements
R3
Freedam ta operate (infringing valid intellectual property rights of
ET
Solid state of the API
RS
Stability ! shelf life of the product
Kannziele
Gewicht [=10
Gewicht [je=100)
Roller Compaction
Bewertung Comments
BewerntungComments |BewertungComments
RISK
ak
ak
ak
ak
ak
ak
ak
RISK
RISK
RISK
RISK
BewertungComments
Bewertung Comments
ok
ak
ak
ak
ak
ak
ok
ok
ok
ok
ok
ok
63.19 61.13 41.32 49.08 47 84

100 2 5 3 4
K maschine costs 30 10 years 25.44 23.38 [ 22.24 30.00 29.17
KT process costs [Total aber 10 Years) 625 630 T15 530 545
KA overhead [maschine costs] £ [25
2__|Qualitative Direct Costs 30 wo] | 975] | 97s | 225] | 3.75]
2.1 | Material costs 12.00 40 0 =] | =] | R00]
2.2 [Direct labor costs 3.00 30 a | 5.00] [| 5.00] | 5.00]
2.3 [Storage 1.50 5 1 0.75 0.75
2.5 [Ukiity costs 1.50 5 0 | - | - | - [ -
2.6 [QAKC costs E.00 20 1] 1] - [1] -
B Qualitative process and product property ranking 19.33
1 Product 20 100
11 Similarity with the existing dosage 0 eo)
) farm and composition 4.00 4.00
12 [Dosage form size and shape 5.00 30
1.53 [Flow ability 5.00 30 | -
14 | Stability 4.00 20 | 2ET7]
2 [Process 20 B.67]
May. throughput of commerziallu- em)
21 ) A - 30
available unit operations 5.00
2.2 |Footprint 2.00 10
55 GMP -confarmity of the process 10 ue
) equipment 2.00 0.ET
Robustness [process
24 understanding & cantral] 5.00 a0 IN
2.5 | Type of process [semi continous, 4.00 20 133 1.33 |
BE == T
=E aceuical U
engineering Grazm
Portable
Skid-mounted equipment
High Small autonomous POD’s

Modularity Rapid deployment & Re-deployment
Multiple configurations, Rapid ulti-company POD* farms
Fy . process/product changeover,
= Miniature g
Fol ccept next-gen’ technologies
9S small footprint Enable portable design
ro Reduced energy consumption P g
3 Enable modularity
<C
od , Im TT TT TTT
> Continuous manufacturing I Transformational |
= Variable lot size for demand-based supply. [ I
= Same equipment at multiple scale | development, I
« _. . . 1 O
© Enable miniaturization manufactu ring &
— Iu hf
Low
Established —) Current state of the art ——————————) Future/Emerging
* POD: Point of Distribution
Phil Nixon (Pfizer) AAPS Ardenhouse Conference March 16-18, 2015 wiTy [A Ca)
research
center
I [] 1B engineering Grazm
State of the art continuous manufacturing lines
e.g. ConsiGma 25 e.g. ConsiGma CDC

Modular manufacturing suite which can be Direct compression line equipped with
Lighthouse
equipped with blending, milling, wet/dry Probe (Fibre optic probe (Reflectant (UV-
VIS-NIR),
granulation, compression, coating
scattering, raman, fluorescence, video imaging)

research
center
pharmaceutical T U
The ConsiGma 25 is equipped with a variety of PAT tools for online control of the
CQA and CPP
Basic PAT measurement - x 0 . ~

. Powder Feed Factors)
. Liquid addition (mass & density)
. Torque measurement
. Product Temperature/drying curves
. i et t at
. Differential Pre er
. ts
i
Continuous manufacturing lines are installed at Pfizer Groton, Vertex and others
why | Lo a)
Quality-by-Design (QbD) in pharmaceutical
sciences
QbD in pharmaceutical sciences
Foundation of the Quality-by-Design as manufacturing science
The basic concept starts with a definition of who the users will be and need, what
this means for the product design and how this can be converted into a reproducible
product quality PROCESS

FEATURES
FEATURES
agape
FEATURES™
Fig 1-10d
Fig 1-10¢c
NEEDS
2
Ane :
Fig 1-10a
Juran JM (1992), Juran on Quality By Design, Bass J Ed. Ty

aflTy
Foundation of the Quality-by-Design as manufacturing science
This translates into a Targeted Product Profile (TPP), the Critical Qualiy
Attributes
(CQA), the Critical Process Parameter (CPP) and the Design Space in which product
quality is guaranteed
Design
Space
CQAs
CQAs +»
TPPs
TPPs »
Patients
Juran JM (1992), Juran on Quality By Design, Bass J Ed. Ty

Cc research
center
pharmaceutical T U
[=] engineering G razm
Quality Process
. Target Design
Foundation of the Produc Space
Profile (optional)
Quality-by-Design as
manufacturing science
Initial Risk
Assessment
(RA) to identify
Critical Quality
Attributes,
Extend RA
fo priorit
potential
CPPs to study,
ISPE PQLI Guide, 2011 (Pharm. Eng. (2010),30(2),1-6 Lo CREE)

ear
-
armaceutical | | U
engineerin Graze
Formulation Transferred to
Developmen Manufacturing
Laboratory Pilot plant
Formulation and (process)
Formulation, process,
specification, QC frozen
already fixed Transferred to Transferred to

launch site manufacturing
site
Continuous
a
improvement
TREE)
research
center
pharmaceutical T U
Q8 Pharmaceutical Development May 2006
+ Quality by Design
Q8 R1 Pharmaceutical Development Nov 2007

+“ Annex to ICH Q8 (practical guidance)
Q8 R2 Pharmaceutical Development Nov 2009

“+ Annex to ICH Q8 (suggested contents for the 3.2.P.2)
Q9 Quality Risk Management June 2006

+ Integrated Risk management system
Q10 Pharmaceutical Quality System May 2007
+ Integrated quality management system
Q11 Development and manufacturing of drug substances May 2012

+ Application of Q8-10 to drug substance
Q12 Technical and regulatory considerations for life cycle management Sept 2014
The regulatory Framework
s+ Framework to facilitate life cycle management
Q13 Continuous Manufacturing of Drug Substances and Drug Products Nov 2022
yy [) Ea)
Critical Quality Attribute (CQA)
A physical, chemical, biological or microbiological property or characteristic that

should be within an appropriate
limit, range, or distribution to ensure the desired product quality for the
finished product
Critical Material Attributes (CMA) often refers to CQA of excipients

Critical Process Parameter (CPP)
A process parameter whose variability has an impact on a critical quality attribute

and therefore should be
monitored or controlled to ensure the process produces the desired quality
Quality by Design (QbD)
A systematic approach to development that begins with predefined objectives and

emphasizes product and
process understanding and process control, based on sound science and quality risk
management
Target Product Profile (TPP)
A prospective summary of the quality characteristics of a drug product that ideally

will be achieved to ensure the
desired quality, taking into account safety and efficacy of the drug product
TREE)
ICHQS8
“Critical sources of variability that can lead to product failures should be
identified, appropriately understood,
and managed or controlled.”
ICHQ9
“Quality risk management is a systematic process for the assessment, control,
communication and review of
risk to the quality of the drug product across the product life cycle.”
ICHQ10
“Systematic approach to acquiring, analyzing, storing and disseminating information
related to products,
processes and components across the product life-cycle.”
ICH Q 9 defines quality as:

“...the protection of the patient by managing the risk to quality should be
considered of prime importance.”
ICH Q 8 R2 defines quality as:

“In all cases, the product should be designed to meet patients’ needs and the
intended product
performance.”
TREE)
management
Opportunities to impact
risk using quality risk
Process
Materials
Facilities
Manufacturing
Distribution
Q9
Patient
G.- Claycamp, FDA, June 2006
J)
Target Profluct Profile
Drug substance properties; prior knowledge
Proposed formulation and manufacturing process

(Risk Identification)
Cause and effect process

(Risk Analysis)
Risk-based classification
(Risk Evaluation)
bd
Proposed Parameters to investigate (e.g. by DOE)

(Risk Reduction)
— | TT
FORMULATION PROCESS DESIGN _ |

DESIGN SPACE CONTROL STRATEGY SPACE BY UNIT
(Risk Reduction) OPERATION
TREE)
Relative prevalence of papers
according to the studied
factors: = [I
= Formulation Attributes (FAS)

= Process Parameters (PPs)
= both (FAs + PPs)
Studied Parameters
3
wm
Bw
1%
rhe 4
Na.
60%
(n=36)
FAs + PPs
0 5 10 15 20 25 30 35 40
. Number of papers
[percentages are calculated with reference sid
to the total number of papers (n = 60)]
Grangeia et al EJPB 147 (2020) 19-37 phy

Oil-in-Water (o/w)
Emulsification-Solvent
= Relative prevalence of the Evang

Manufacturing Unit Hot Melt Extrusion (13)
Operations reported in the
research papers included in
this review
Powder Blending E11 at

Dry Granulation rr] brie |
Wet Granulation 1 rie
5 10 15 20 25
Manufacturing Unit Operations
Number of papers
Grangeia et al EJPB 747 (2020) 19-37 ihTy iz =)
42%
(n=25)
30
aflTy
Risk Assessment
= Risk assessment consists of the identification of hazards and the analysis and
evaluation of
risks associated with exposure to those hazards (as defined below).
= Quality risk assessments begin with a well-defined problem description or risk

question.
= When the risk in question is well defined, an appropriate risk management tool
and the types
of information needed to address the risk question will be more readily
identifiable.
= As an aid to clearly defining the risk(s) for risk assessment purposes, three
fundamental
questions are often helpful:
1. What might go wrong?

2. What is the likelihood (probability) it will go wrong?
3. What are the consequences (severity)?
Initial Risk Assessment
: Basic risk management facilitation methods ~~ |] TA

ao |
. Process mapping
— provides a clear and simple visual

representation of involved steps
— facilitates understanding, explaining and

systematically analyzing complex processes
and associated risks
— a pre-requisite for the use of some other

methods (e.g. FMEA)
sieving
Tabletting :
¥ Air
& | Fiuidized Bed
Dryer
Granulation Air
Magnesium Blending
“ Stearate
L en
i in
J ff Fa )
il. | coo
fi EE | ¥| oo g| Packaging
ITs >) Coating
research
center
pharmaceutical
engineering G razm
Initial Risk Assessment
= Basic risk management facilitation LSM | ote | wey | [eatin
SprayRate “" Redrying—g Pa » \

methods Pan Speed—, Time Temp— \ \
] ] ] Gun Distance—=\ wee wr — Seen sze—\ ther —3\
= Cause and effect diagrams (Ishikawal/fish remparsmue—\ AxFim—d\ ED samsior—A
ALOMIZING AN Prassure—, Shock Cycle—»\ Mi Speed—>\ Methog—\
\ 3 y y | Tablet
bone 4 4 J— 4 Hardness
Operator—¥% Precompressng—v)/ Naer—¥ ginstar SF 55
»/ if / A i [// /
= How to perform? rovome—y/ ton Camry —,
oy. Mechs 74
) ) Opeaior—/ Fandichoend:—ly Tomp—/ process c of avons / / /
— Define and agree a precise problem mmey esses WT iay—
« ” . / D om Spray Patte - / // /
statement (put as “head” of fishbone) Tooing—v/ rs —/ Memon 7//[
ant Feed 4 SE rs. // y
; “ Factors Frame / NERS LOD
— Evaluation “What could be the [Compressing |= +++ wr J
roblem’s causes?” in the main “bones Endpoint lee 5
P A
of the diagram” ..// [Granulation]
Time
— Evaluation of root causes of each bone
TREE)
research
center
pharmaceutical T U
IPO Diagram for the Granulation Process
u Controllable Parameters
IPO diagrams ii
HERE .
input—process—output (IPO) [8 Hel o| [2l8le] | [Ele
model, or input-process- HEHEHE EHR [El EH
output pattern can be used to SLE aaa ele el ale _
ear Granu rocess
o-_
structure the risk assessment all DE
regarding CMA and CPP Sodium starch glycolate 1. Material Transfer [Granule
uniformity
Pazopanib
Paovidone 2. Preblend (Granule water content
Water 3. Water Spray (Granule porosity
Raw material supplier 4. Wet Massing [Granule shape
Solution Pump ls Wet Milling (Granule density
6. Transfer to fluid bed dryer (Granule size distribution
3 ¥
I}
sls
gE
oe
2l=|g
s|Z|E
wl E [=]
HEE
Bl=l=
TREE)
aflTy
= Failure Modes and Effects Analysis (FMEA) is a systematic, proactive method for
evaluating a
process to identify where and how it might fail and to assess the relative impact
of different
failures, in order to identify the parts of the process that are most in need of
change.
= There are Seven Steps to Developing an FMEA:

1. FMEA Pre-Work and Assemble the FMEA Team
2. Path 1 Development (Requirements through Severity Ranking)
3. Path 2 Development (Potential Causes and Prevention Controls through Occurrence
Ranking)
4. Path 3 Development (Testing and Detection Controls through Detection Ranking)
5. Action Priority & Assignment
6. Actions Taken / Design Review
7.Re-ranking RPN & Closure
why
FMEA framework and structure to determine the risk
Function or
Failur Potential Potential D i
Process ailure otentia SEV otentia OCC etection DET RPN
Type Impact Causes Mode
Step
What are the
: : existing
a _ |Whatisthe 1, What |How controls that
outline Describe |impact on the : ) How :
: severe is | causes the| frequently | either prevent ._.. | Risk
function, what has | key output : : easyisit| . .
: : the effect [key input |is this the failure priority
step or item | gone variables or .__|to
to the to go likely to | from occurring number
being wrong internal : detect?
: customer? | wrong? occur? or detect it
analyzed requirements? )
should it
occur?
yy [) Ea)
research
center
pharmaceutical T U
Excipient Quality-by-Design Pre-work
"Excipient risk factors” and "key excipient properties” should be identified as

pre-work to the RFT Risk Assessment. This spreadsheet can be used for this
activity.
The excipient risk factors and key properties will be used as "process parameters”
in the standard RFT Risk Assessment spreadsheet.
‘They are to be inserted under the appropriate focus areas (e.g. at the lubrication
step for a lubricant)
Instructions for using this spreadsheet
1. Assume that the current formulation is fixed.
2. Using the template create a separate sheet for each excipient in the
formulation. Clearly identify the specific grade and supplier of each excipient.
3. For each excipient fill out columns B, C and D to clearly identify the
"excipient risk factors” and "key excipient properties”. See below for scoring
matrix.
4. For the key properties assume that these will vary only within normal ranges
(e.g. the excipient will meet its release specs before being used to make the
product)
4. Key properties should be assessed with the intended processing pathway in mind
(e.q.. direct compression, dray granulation, etc)
6. If desired alternate grades or sources of excipients can be assessed using

additional sheets. This is optional, but may be needed for some products.
If vou need help, contact Bruno Hancock in Groton or Craig Bentham in Sandwich.
Good luck!
iExcipient risk factors
Score Definition
1 Low risk. Very low probability of this factor being a problem. Risk is very
easily mitigated.
3 Moderate risk. Low probability of this factor being a problem. Risk is easily
mitigated.
5 Medium risk. May impact key product attributes or manufacuring process. Risk can
be managed using standard approaches (eg. specifications, IPCs)
Ni High risk. Risk factor is likely to impact product performance (eq. dissolution)
or manufacturing process. and will require a control strategy.
10 Very high nsk. Risk factor is likely to impact safety or efficacy of product if
not adequately controled. Likely requires aggressive risk management approaches.
‘Key excipient properties
Score Definition
1 Based on literature data or documented Pfizer experience, normal variation of
this property is very unlikely to the drug product quality, its performance or its
manufacturing process.
3 Based on general scientific principles or literature data, normal variation of
this property is unlikely to impact the drug product quality, its performance or
its manufacturing process.
5 Based on literature data, normal variation in this property could impact the
guality of the drug product. its performance or its manufacturing process.
i Based on experience with other Pfizer products, normal variation in this property
is likely to impact the the drug product quality, its performance or its
manufacturing process.
10 Based on experience with this specific Pfizer product. normal variation in this
property is known to impact the drug product guality or performance.
hy
r Cc research
center
=E engineering
pharmaceutical
aflTy
Each excipient property is then assessed for its
If yes, / importance. In this example it is assumed that a direct

Normal ry eon fabletting process is being used for the
property Key SCO
Excipient property range property? |(1,3,5{7,10) |Notes Unit Measurment Technique
Purity 99.0-101.0 N % HPLC assay
Residual Solvents <5 ppm N Zz % wiw GC headspace analysis
Polymorph/Form Monohydrate N % XRPD or other
% Crystallinity Conforms N / Ifitis a "key" property | |% XRPD or other
Moisture Content <5% Y 7 the pone ascore to] [9% wiw KF titration
Particle Size Distribution (D10, D50, D90, D4 3 eic) D50=25-45um Y D its importance
micron Laser diffraction
Particle Morphology N - Image analysis
Particle Aspect Ratio N = Microscopy
True (absolute) Density 1.52-1.53 N kg /m*3 Pycnometry
Bulk/Tapped Density N kg /m"3 USP method
Specific Surface Area <2.0 N m"2/kg Nitrogen sorption
Viscosity = N cP Rheometer
Powder Flow FFC=8.0-10.0 Y 10, Flow function| Shear cell
Powder Compaction = N \ Max. tensile 9 Compaction simulator
Lubrication Properties N TBD TBD
Disintegration Performance N minutes USP method (no discs)
Other TBD TBD
“N
The properties list should be edited as appropriate for each excipient.
The high scoring properties (7's and 10's)

are also copied over to the Risk
Assessment spreadsheet as "process

parameters" in the appropriate focus area
The measurement techniques

columns should be updated as
the list of properties is modified.
research
center
pharmaceutical T U
= Understanding the variability of materials & processes is key for consistent

product quality
Raw material quality history
Principal Component
Analysis (PCA) of NIR
data for different batches
of the same “quality” of
raw material supplied
from two different
vendors.
0.30
Lor
86 10854 uA a AA% 171
14240, 156189 10. +
289 go = it
L A1p8 168 4,
0.20
0.10 20 4
se
161
11]
Note that all batches comply with pharmacopoeia standards!
+ J. Vessman, Pharm. Anal., Overview, in Encyclopedia of Anal. Sciences, Academic

Press Limited, 1995, p. 3807.
+ O. Svensson, M. Josefson, EW. Langkilde, Applied Spectroscopy, 51 (1997) 1826-
1835.
TREE)
research
center
pharmaceutical T U
= The QbT knowledge space is very limited and excipients batches outside the tested
space
might fail
Raw material quality QbT
0.30
The 3 excipient
batches tested in ICH
Lor
0.20
28 a
aE isp Gi are good
0.10 499 82 2 =
_ 0.00 A QbT
i Ens gg A187 .
or / pa 3 Batches out of this
156 alge
02 Vendor 1 =... - range are unknown
5 115%
122
11]

1835.
TREE)
research
center
pharmaceutical T U
= The QbD knowledge space is broad including the point of failure
aterial quality : QbD

Measuring the breath
: A A 47 | . gn -
5 sant : a = of specifications
0.20 3 ) — : Te gr confirm suitable
8610954 ase C,H TL 143 As 2
M183 a0 Droet8g aay. TT a 4 wok ranae
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= TE wt bD
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0.20 ndor 1 131 - g go failure
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research
center
pharmaceutical T U
— Emmy
= The significant difference between QbT and QbD

4 SS QbD
/ ~
So Knowledge space
28 :
10854 afos. °°
88s" A
142; 156189 4g pm
107111
£559 A
198.2
QbD
Design Space
12]
0.10
0.20 . 5 QbT
Tested Space
~ ~ 7’
~ — »

1835. oo
platy, [A 4EEERRAT i)
research
center
pharmaceutical T U
QbD as an enabler of continuous manufacturing
= The difference between standard test data and QbD data based on capsule weight
distribution
Size 1 Overall - WGT - TRF method
Size 1 Overall - WGT
Target
LSL Target USL

Process Data | Overall Capability
LSL 71 | Pp 2.76
Target 76 PPL 2.53
uUsL 81 I PPU 2.99
Sample Mean 75.5844 | ppk 2.53
Sample N 84 | Cpm 2.27
StDev(Overall) 0.604108 |
Process Data
Representative sample and determine

the average weight of 100 capsules.
Stegemann et al PharmSciTech 15(3) 542-549 (2014)
Overall Capability
LSL 71 Il 1.07
Target 76 0.98
usL 81 1.16
Sample Mean 75.5836 0.98
Sample N 8404 1.04
StDev (Overall) 1.55376
Individual weight across 8500
capsules across a batch
SESEAEH
D)
aflTy
Design Space concept
Knowledge Space
Flexible |
Design Space
OPERATIONAL
FREEDOM
Control Space
Control Space
Limited
hy
aflTy
Relative prevalence by RA Tools * Ishikawa Diagram

Failure Mode & Effects Analysis (FMEA)
» Risk Estimation Matrix (REM)
* Preliminary Hazard Analysis (PHA)
CR Matrices [1] 2% * Input Process Output (IPO)

| oh Diagram and Critical Relationship (CR)
IPO Diagram (a=1) Matrices
0
ria [ID - i
reve
res |
Ishikawa Diagram [| —_— o
0 2 4 6 8 10 12
Number of papers
Grangeia et al EJPB 147 (2020) 19-37 phy
Reported RA tool
Example: twin-screw wet-granulation and continuous fluid-bed drying

process
= Risk assessment of process-units twin-screw wet-granulation and continuous

fluid-bed drying
= subsequent design of experiment testing of factor-response relationships to

identify and quantify critical process parameters in regard to dried granules’
critical quality attributes moisture content (LOD) and particle size distribution.
Drying air outlet

Wet granule IAL
inlet
ta
» |
a
CA I corer, EEN oorvoverts, NNN corvowvety, INN AONGRE,
»
= Vibrational drying bed
Aedes =) - J
hl
| 3
Pauli et al J Pharm Innov 13:247-60 (2018)
Dry granule
outlet
nihTy,
fe hy
[A Ea)
research
center
The drying models can be divided into two major

categories: and the Arrhenius concepts
= the equilibrium model assumes heat transfer limitation

between the drying air and the particles
= the Arrhenius considers that the drying process is

governed by the evaporation rate
There are channels in the air flow, reducing the overall solid
surface area and making the liquid diffusion from the pores
to the surface a macroscopically significant step
= above a critical moisture content (XC) the drying rate (RV)

is independent of the actual moisture (X)
= Below XC, the liquid is transferred to the surface of the

particles from the inner pores first and then is evaporated,
which translates to a moisture content-dependent drying
rate
Domokos et al Powder Technol 388: 70-81 (2021)
Particle level
The solid’s bed

A Liquid diffusion
Drying air to the surface
flowing in
channels Heat transfer
between the
(Aggregated) phases
wet solids being

on the belt
Evaporation (mass & heat transfer)
Macroscopic level L,
Wet particles *
PU
—_—
H? ©
rrrrrrrrrtrnd
Drying air, adjustable flow rate and temperature
The main effects considered in the drying

model in macroscopic scale and the level of
particles
TREE)
research
center
pharmaceutical T U
Process Parameters
+ Room Temperature N
+ Relative Humidity
+ Room Airflow \
. . - + Cooling Water Temperatura Powder Feeder. MN
Fishbone Diagram for twin- for TSG « Pouder Feed Refs ~~ \ | Mould Pump
. » Cooling Water Flow Rate + Feeding ww do 2 |
screw wet-granulation , rom Building to TSG "Feeding Mode (Volumetric, Gravimerio)
|
. . . = * Agitator- | Screwspeed AN |
listing all conceivable EIT * Hopper Rofl Frequency \ * Operator
AN Twin Screw Granulator — \ People
process parameters and N > Strow ton tpeed 198. \
. . ~. » Barrel Temperature TSG Te
material attributes that could aN " Transter Presaure from TSG 10 FBD
potentially vary over the \. \, .
. Fa 7!
course of production J A
Granules —_— J . /
» Abrasiveness/ Cormosiveness J + Type of Granulator fi
{Wear & tear on Equipment) + Screw Configuration A
{ + Response Time Joh
a /| + Cooling Efficiency /
-— ! + Pipe Diameter from TSG to FED ! \
Pre-Blend ore blend Water Content (LOD) / | + Metal Composition (Screws and Barrel)
/ "J tenth
+ Preblend Panicle Size Distribution (PSD) / = Runtime Py . iJon whi
» Pre-blend Blend Uniformity (BU) / Granulation Liquid _— / Rune ol Tubing
+ Pre-blend Flowability « Temperature of Water Powder Feeder — / : :
» Pre-blend Pour-8Tap Density / « Type of Powder Feeder / Calibration Frequency
» Pre-blend Water Uptake Capacity! / « Hopper Capacity /
Wettability / s Hopper Shape f
Materials + Feeding Screw Design /
« Gear Bax Speed /
# Agitator Design /
+ Calibration Frequency /
Ti ——t—
L Ryhmse Time Machine
Pauli et al J Pharm Innov 13:247-60 (2018) nfhTy [A Fe)!

=E
research
center
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engineering G razm
Fishbone Diagram for

continuous fluid-bed drying
listing all conceivable process
parameters and material
attributes that could
potentially vary over the
course of production
Inlet Air Temperature
Inlet Air Humidty
Drying Air Flow Rate
Drying Time (Rotor Speed)
Filter Blowing (Duration/ Interval! Pressure)

Preheating Conditions
Chamber Fill Mass (=Fluid-Bed Height)

Discharge Air Pressure
Process Parameters
+ Room Temperature
* Relative Humidity
- “ » Operator
Environment AN People
a h
~~. ™~ ha
~~ “ aN
\. ™ iCQAs:
— - - x LOD
~~
, PSD
7 ~
~ yd
Materials Machine
+ Wet Granules PSD s Type of Dryer
+ Wet Granules Moisture Content + Bottom Plate Porosity
+ Wet Granules Density « Exhaust air filter Cartridge Type/ Porosity
+ Wet Granules Morphology + Qutlet Chute Diameter
+ Wet Granules Stickiness ¢ Dead Volume in the Chambers
+ Wet Granules Temperature + Runtime

nihTy,
| EE)
research
center
pharmaceutical T U
Definition of potentially critical material attributes (pCMA) and potentially

critical process parameter (pCPP) including the justification
Category Factor Decision Justification

Environment Room temperature nCPP Tightly controlled by room control (21 +6 °C);
also,
TSG and FBD have internal heating/cooling elements
Relative humidity pCPP Relative humidity of environment defines dryer inlet .
humidity, which could influence drying behavior Risk Assessment
Materials Temperature of granulation liquid nCMA Processed at room temperature =»
low probability that outcomes TSWG-
significant variations occur. Also, TSG
is heated individually FBD.docx
Pre-blend LOD pCMA Can vary with varying batches of drug product and
excipients or with relative humidity. Potential
influence on drying behavior
Process parameters TSG barrel temperature pCPP Problems with cooling/heating unit
could change
granulation behavior
Transfer pressure TSG to FBD nCPP Low probability of occurrence
Machine Runtime pCPP Potentially critical > investigate
Type of granulator nCPP Low probability of occurrence
People Operator nCPP Only trained operators allowed (GMP)
Pauli et al J Pharm Innov 13:247-60 (2018) nfhTy,

research
center
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= Summary of potential critical process parameters and potential critical material

attributes for
continuous twin-screw wet-granulation and fluid bed drying as identified during
risk
assessment
= Definition of the range to be investigated
# Factor Abbrev. Factor Factor type* Range to investigate (— to +) Unit

01 Solid feed rate SFR pCPP Q 2-4 kg/h
02 Liquid feed rate LFR pCPP Q 0.65-1.15 kg/h
03 Screw speed TSG Ss pCPP Q 200-400 pm
04 Barrel temperature TSG BT pCPP Q 3040 °C
05 Dryer rotation speed FBD DRS pCPP Q 8-16 ph
06 Drying temperature FBD DT pCPP Q 70-90 °C
07 Drying air flow rate FBD DAV pCPP Q 80-110 m'/h
08 Room relative humidity N/A pCPP U Monitored SerH
09 Pre-blend LOD N/A pCMA uU Monitored %
10 Runtime of equipment NA pCPP - Monitored** h
*#¢, quantitative factor; U, uncontrolled factor

*#*Runtime was assessed prior to screening DoE trials to avoid biased results
Pauli et al J Pharm Innov 13:247-60 (2018) platy, [A Fe)!

research
center
pharmaceutical T U
= What are these typical material attributes, process parameter and quality
attributes to be
considered
Input material attributes Process parameters Quality attributes
Blending/mixing
* Particle size * Type and geometry of mixer * Blend uniformity
* Particle size distribution * Mixer load level * Potency
* Fines/oversize * Order of addition « Particle size
* Particle shape * Number of revolutions (time and speed) * Particle size

distribution
* Bulk/tapped/true density * Apitating bar (on/off pattern) * Bulk/tapped/true

density
* (Cohesvefadhesive properties * Discharge method * Moisture content
* Electrostatic properties * Holding time * Flow properties
* Moisture content * Environment temperature and RH * (Cohesive/adhesive properties

* Powder segregation
.
Electrostatic properties
Yu et al AAPS J 16 (4): 771 (2014) phy

=E
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center
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engineering
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Input material attributes
Process parameters
Quality attributes
Particle/granule size
distribution
Fines
Particle/granule shape
Bulk/tapped/true density
Adhesive properties
Hardness/plasticity
Viscoelasticity
Brittleness
Elasticity
Solid form/polymorph
Moisture content
Granule porosity/density
Size reduction/comminution
Ribbon milling
Ribbon dimensions
Ribbon density
Ribbon porosity/solid fraction
Impact/cutting/screening mills
Mill type
Speed
Blade configuration, type, orientation

Screen size and type
Feeding rate
Fluid energy mill
Number of grinding nozzles

Feed rate
Nozzle pressure
Classifier
Granule/ribbon milling
Mill type
Speed
Blade configuration, type, orientation

Screen size and type
Feeding rate
Yu et al AAPS J 16 (4): 771 (2014)
Particle/granule size distribution
Particle/granule shape
Particle/granule shape factor
(e.g., aspect ratio)
Particle/granule density/Porosity
Flow properties
API polymorphic form
API crystalline morphology

Cohesive/adhesive properties
Hardness/Plasticity
Viscoelasticity
Brittleness
Elasticity
=E
research
center
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engineering
aflTy
Process parameters
Quality attributes
Fines/Oversize
Particle shape
Hardness/plasticity
Viscoelasticity
Brittleness
Elasticity
Moisture content
Wet granulation
High/low shear granulation
Type of granulator (High/low shear, top/bottom drive)
Fill level
Pregranulation mix time
Granulating liquid or solvent quantity
Impeller speed. tip speed, configuration, location, power

consumption/torque
Chopper speed. configuration, location, power consumption

Spray nozzle type and location
Method of binder excipient addition (dry/wet)
Method of granulating liquid addition (spray or pump)

granulating liquid temperature
granulating liquid addition rate and time
Wet massing time (post-granulation mix time)
Bowl temperature(jacket temperature)

Product temperature
Post mixing time
Pump Type: Peristaltic, Gear type
Granulating liquid vessel (e.g. pressurized, heated)
Fluid bed granulation
Type of fluid bed

Inlet air distribution plate
Spray nozzle (tip size, type/quantity/ pattern/configuration/position)

Filter type and orifice size
Endpoint measurement
(e.g.. power consumption, torque,

etc.)
Blend uniformity
Potency
Flow
Moisture content
Particle size and distribution
Granule size and distribution
Granule strength and uniformity
API polymorphic form
Granule brittleness
Granule elasticity
Yu et al AAPS J 16 (4): 771 (2014)
__ EL
=E
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center
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engineering G razm
Process parameters
Quality attributes
Fill level
Bottom screen size and type
Preheating temperature/time
Method of binder excipient addition (dry/wet)

Granulating liquid temperature
Granulating liquid quantity
Granulating liquid concentration/viscosity

Granulating liquid holding time
Granulating liquid delivery method
Granulating liquid spray rate
Inlet air, volume, temperature, dew point

Atomization air pressure
Product and filter pressure differentials

Product temperature
Exhaust air temperature, flow
Filter shaking interval and duration
Yu et al AAPS J 16 (4): 771 (2014)
nihTy,
fe hy
[ Fe)!
=E
research
center
pharmaceutical
engineering G razm
Process parameters
Quality attributes
* Particle size, distribution
* Fines/oversize
Particle shape
+ Electrostatic properties
* Hardness/plasticity
L
Viscoelasticity
¢ Brittleness
* Elasticity
+ Solid form/polymorph
* Moisture content
Drying
Fluidized bed
Inlet air volume, temperature, dew point

Product temperature
Exhaust air temperature, flow
Shaking interval and duration
Total drying time
Type of tray dryer
Bed thickness/tray depth (depth of product per tray)

Type of drying tray liner (e.g., paper, plastic,
synthetic fiber, etc.)
Quantity carts and trays per chamber
Quantity of product per tray

Drying time and temperature
Air flow
Inlet dew point
Vacuum/microwave
Jacket temperature
Condenser temperature
Impeller speed
Bleed air volume

Vacuum pressure
Microwave power
Electric field
Energy supplied
Product temperature
Bowl and lid temperature
Total drying time
Granule size and distribution

Granule strength, uniformity
Flow
Moisture content
Residual solvents
API polymorphic form or transition

Purity profile
Moisture profile (e.g. product

temperature vs. LOD)
Potency
Yu et al AAPS J 16 (4): 771 (2014)
nihTy,
=E
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center
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engineering
aflTy
Process parameters
Quality attributes
Particle size, distribution

Fines/oversize
Particle shape
Hardness/plasticity
Viscoelasticity
Brittleness
Elasticity
Roller compaction/chilsonation
Type of roller compactor
Auger (feed screw) type/design (horizontal,

vertical or angular)
Deaeration (e.g., vacuum)
Auger (feed screw) speed
Roll shape (cylindrical or interlocking).
Roll surface design (smooth, knurled, serrated,

or pocketed)
Roll gap width (e.g., flexible or fixed)
Roll speed
Roll pressure
Roller temperature
Fines recycled (yes or no, # of cycles)
Yu et al AAPS J 16 (4): 771 (2014)
Ribbon appearance (edge attrition,

splitting, lamination, color, etc.)
Ribbon thickness
Ribbon density (e.g., envelop

density)
Ribbon porosity/solid fraction

Ribbon tensile strength/breaking
force
Throughput rate
API polymorphic form and transition

=E
research
center
pharmaceutical
engineering
aflTy
Process parameters
Quality attributes
Fines/oversize
Particle shape
Hardness/plasticity
Viscoelasticity
Brittleness
Elasticity
Extrusion-Spheronization
Type of extruder (screw or basket)
Screw length, pitch, and diameter
Screw channel depth
Screw blade configuration
Number of screws (single/dual)
Die or screen configuration (e.g., radial or axial)
Die length/diameter ratio
Roll diameter (mm)
Screen opening diameter (mm)
Screw speed (rpm)
Feeding rate (g/min)
Type and scale of spheronizer
Spheronizer load level
Plate geometry and speed
Plate groove design (spacing and pattern)
Air flow
Residence time
Yu et al AAPS J 16 (4): 771 (2014)
Extrudate
Density
Length/thickness/diameter
Moisture content
API polymorphic form and transition

Content uniformity
Throughput
Pellets after spheronization
Pellets size and distribution
Pellets shape factor (e.g. aspect

ratio)
Bulk/Tapped density
Flow properties
Brittleness
Elasticity
Mechanical strength
Friability
=E
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center
pharmaceutical
engineering
aflTy
Process parameters
Quality attributes
Fines/oversize
Particle shape
Melting point
Density
Moisture content
Hot melt extrusion

Screw design (twin/single)
Screw speed
Screw opening diameter (mm)
Solid and liquid feed rates
Feeder type/design
Feed rate
No. of zones
Zone temperatures
Chilling rate
Yu et al AAPS J 16 (4): 771 (2014)
Extrudate density
Length/thickness/diameter
Polymorphic form and transition
Content uniformity
Throughput
research
center
pharmaceutical T U

Tabletting
* Particle/granule size * Type of press (model, geometry, number of stations) *

Tablet appearance
and distribution * Hopper design, height, angle, vibration * Tablet weight

* Fines/oversize * Feeder mechanism (gravity/forced feed, shape of wheels, * Weight
uniformity
* Particle/granule shape direction of rotation, number of bars) * Content
uniformity
* (Cohesive/adhesive * Feed frame type and speed * Hardness/tablet breaking force/
properties * Feeder fill depth tensile strength

¢ Electrostatic properties * Tooling design (e.g.. dimension, score configuration,
* Thickness/dimensions
* Hardness/plasticity quality of the metal) ® Tablet porosity/density/solid
fraction
* Bulk'tapped/true density * Maximum punch load * Friability
* Viscoelasticity * Press speed/dwell time * Tablet defects
* Brittleness * Precompression force * Moisture content
* Elasticity * Main compression force * Disintegration
* Solid form/polymorph * Punch penetration depth * Dissolution
* Moisture * Ejection force
* Dwell Time
Yu et al AAPS J 16 (4): 771 (2014) phy

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Encapsulation
* Particle/granule size and * Machine type * Capsule appearance

distribution * Machine fill speed * Weight
* Fines/oversize * Tamping Force * Weight uniformity
* Particle/granule shape * No. of tamps * Content uniformity
* (Cohesiveladhesive properties * Auger screw design/speed * Moisture content
* Electrostatic properties * Powder bed height * Slug tensile strength
* Hardness/plasticity * Disintegration
* Bulk/tapped/true density * Dissolution
* Viscoelasticity
* Brittleness
+ FElasticity
+ Solid form/polymorph
+ Moisture
Yu et al AAPS J 16 (4): 771 (2014) phy

=E
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center
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Process parameters
Quality attributes
Tablet dimensions
Tablet defects
Hardness/plasticity
Density
Porosity
Moisture content
Pan coating
Type of pan coater (conventional or side-vented)
Pan (fully perforated or partial perforated)
Baffle (design, number, location)
Pan load level
Pan rotation speed
Spray nozzle (type. quantity, pattern, configuration,
spray pattern)
Nozzle to bed distance
Distance between nozzles
Nozzle orientation
Total preheating time
Inlet air flow rate, volume, temperature, dew point

Product temperature
Individual nozzle spray rate
Total spray rate
Pattern air pressure
Exhaust air temperature, air flow
Total coating, curing time and drying time

Yu et al AAPS J 16 (4): 771 (2014)
Coating efficiency
Core tablet weight before and after

preheating
Moisture (gain/loss) during

preheating
Environmental equivalency factor

Coated drug product (e.g., tablet or
capsule) appearance
% weight gain
Film thickness
Coating (polymer and /or color)

uniformity
Hardness/breaking force/Tensile
strength
Friability
Moisture (gain/loss) during overall

process
Residual solvent(s)
Disintegration
Dissolution
Tablet defects
Visual attributes
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center
pharmaceutical
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Process parameters
Quality attributes
Tablet dimensions
Tablet defects
Hardness/plasticity
Density/porosity
moisture content
Fluid bed coating

Type of fluid bed coater
Fluid bed load level
Partition column diameter
Partition column height
Number of partition columns
Air distribution plate type and size
Filter differential pressure
Filter shaking interval and duration
Spray nozzle (type, quantity, pattern, configuration)
Nozzle port size
Total preheating time
Spray rate per nozzle
Total spray rate
Inlet air flow rate, volume, temperature, dew point
Product temperature
Exhaust air temperature, air flow
Total coating, curing and drying time
Yu et al AAPS J 16 (4): 771 (2014)
Coating efficiency
Core tablet weight before and after

preheating
Moisture (gain/loss) during

preheating
Environmental equivalency factor

Coated drug product (e.g, tablet or
capsule) appearance
% weight gain
Film thickness
Coating (polymer and /or color)

uniformity
Hardness/breaking force/tensile
strength
Friability
Moisture (gain/loss) during overall

process
Residual solvent(s)
Disintegration
Dissolution
Tablet defects
Visual attributes
research
pe »
engineering G razm

Laser drilling
* Size/dimensions + Conveyor type * Opening diameter (internal and
* Polymer type + Conveyor speed external)
membrane thickness Laser power * Depth
* Number of pulses * Shape of the opening
* Type(s) of lens(es)
* One or two sided
* Number of holes
Yu et al AAPS J 16 (4): 771 (2014)

research
a
pharmaceutical T U
= Finally each material attribute and process

parameter must be seen in the entirety of the
manufacturing process
= This also include the interconnecting steps

and processes of unit operations
Critical
Parameters
Inbet air dew point (moisture)

Irdst sir temperature
Init air flow
In process
Process Step controls
Formulation Moisture
(e.g. Fluid bed Control
granulation’ “| Particle size
drying) Density
2 - Tablet physical
Compression and chemical
properties
Film Coating Tablet weight
Process gain Tablet
appearance
Pan rotation speed
nihTy,
[E)
aflTy
The Target Product Profile (TPP) defines the:
Physicochemical attributes of the desired drug product

v' dosage form
v' dosing regimen that achieves a predefined clinical result
v" pharmacokinetics (PK) bioequivalence
v' efficacy and safety profiles
v' product identification (tablet size, shape, and color)
v" product stability

vo...
= [Intended patient population
v" “In all cases, the product should be designed to meet patients’ needs and the
intended
product performance.” (Q8(R2))
vo.
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Target Product Profile (TPP)
* Describes all the desired product

attributes and performance criteria
* Set the objectives for the product

development scientists
* In the majority of cases the desired

dosage form is already mentioned
(Tablet)
* Only very few consider ,special

populations” in the TPP for NCE
* Required pediatric formulations

have to be derived from the
standard adult form
Indication
Product
Target populations
Target countries
Clinical efficacy
Microbiologic
efficacy
interactions
Formulations and
dosage
Stability
Total cost per

patient
Minimum essential
Treatment of HIV-negative chikiren aged 6-24 months and

adults with diarrhea due to Cryptosporidium hominis or
Cryptosporidium parvum infection
Single agent or combination drug regimen

Note that the risk of resistance is unknown and may require
combination therapy
Children ages 6-24 months with diarrhea due to

cryptosporidiosis
immunocompetent adults with diarrhea due to

cryptosporidiosis
Countries that have been shown to have significant endemic

cryplosporidiosis or that contribute heavily to the diarrhea
burden in children
Superiority to nitazoxanide in malnourished children
Equivalent to nitazoxanide in immunocompetent adults
Superiority to nitazoxanide in mainourished children
Equivalent to nitazoxanide in immunocompetent adults

Active against both C. hominis and C. parvum
Safe in patients >6 months old
SAE rate <5% by Common Terminology Criteria for AEs;

AEs > Grade 2 no more than 30%
No unmanageable drug-drug interactions

Oral; maximum 3x/day for 14 days; liquid formulation or
compatible with hydrodispersible tablet or granules appropriate

for children available
+2 years in Zone IVb (30°C 75% humidity)

$US2.00
AE, adverse event, SAE, severe adverse event
doi: 10.137 1joumal. patd. 0003967 1001
Ideal
Treatment of children > 1 month old and adults, including HIV-

positive patients, with diarrhea due to cryptosporidiosis. Curative
for additional diarrheal pathogens, and safe for use in syndromic
treatment of diarrhea
Single agent therapy
Children ages 1-24 months with diarrhea due to

cryptosporidiosis
Immunocompromised patients with diarrhea due to

cryplosporidiosis
Note that immunocompetent and immunocompromised patient

populations may require distinct therapies
Countries accounting for 90% of morbidity and mortality due to

diarrhea
Cessation of diarrhea within 2 days in well nourished, HIV-
negative children
-80% efficacy in all patient populations
Elimination of the effects of Cryptosporidium infection on

malnutrition
Elimination of fecal parasite shedding within 2 days of starting

therapy for all patient populations
Sale for syndromic treatment of diarrhea in patients >1 month

old
No drug-related SAEs by Common Terminology Criteria; minimal

drug-related AEs
No CYP3A4 inhibition; no interactions with antiretroviral drugs
Oral liquid or hydrodispersible tablet or granules given as a

single dose
Minimal or no food effect

-3 years in Zone IV
<$SUS0.50 (approximate total cost of nitazoxanide 100 mg/5 mi

liquid formulation in India)
Defining a Target Product Profile
= Example: Sakura Tablet - Japanese Mock File
Target Product Profile-Element
Target
Strength and dosage form
Immediate release tablet containing

30mg of active ingredient
Specifications to assure safety and

Efficacy during shelf life
Assay, Uniformity of Dosage Unit

(content uniformity) and dissolution
Description and hardness
Robust tablet able to withstand

Transport and handling
Appearance
Film-coated tablet with a suitable

Size to aid patient acceptability and
compliance.
Total tablet weight containing
why

= Example: ACE-Tablets — Pharmaceutical Development Case Study, CMC-IM Working
Group
TargetProductProfile-Element Target
Dosage form Tablet, facilitating patient's

compliance; appropriate size, single
Tablet dose
Specifications to assure safety and Identity, assay, appearance,
efficacy Chemical and microbiological purity,

dissolution, content uniformity
CCS Adequate protection from moisture

vapor, protection through
distribution
why

= Example: Tablets — EFPIA Mock P2
Target Product Profile-Element
Target
Description Round normal convex uncoated tablet

Identification Positive
Assay 20mg 5% active at time of manufacture
Degradation products
Qualified meeting ICHQ3B and Q6A

criteria
Dissolution
Immediate release
Uniformity of dosage units
Meets pharmacopoeial acceptance

criteria
Microbiological limits
Meets pharmacopoeial acceptance

criteria
why
EE)
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center
pharmaceutical T U
Quality Target Product Profile = quantitative surrogate of TPP parameters within a

certain range
to achieve product quality as outlined in TPP (example)
Target Product Profile-Element Target Associated Quality Attribute

Strength and dosage form Immediate release tablet Containing 30mg of -In vivo
performance
active ingredient -Dissolution
Specifications to assure Assay, Uniformity of Dosage Unit (content -Assay
Safety and efficacy during uniformity) and dissolution -Degradation
Shelf life -ContentUniformity
-Chemical/physical
stability
-Dissolution
Description and hardness Robust tablet able to withstand -Friability
Transport and handling
Appearance Film-coated tablet with a suitable size to aid -Appearance
patientsacceptability and compliance. Total
tablet weight containing 30mg of active
ingredients is 100mg with a diameter of 6mm
platy, [) {Ray i)
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Quality Attribute Target
Dosage form Tablet, maximum weight 200mg
Potency 20mg
Pharmacokinetics Immediate release (T in 2h)
Appearance Tablet conforming to description shape and size
Identity Positive for acetriptan
Assay 95-105%
Impurities ACE12345 NMT 0.5%; other Imp. NMT 0.2%, total NMT 1%
Water NMT 1%
Content Uniformity Meets USP
Resistance to Crushing (Hardness) 5-12 kP
Friability NMT1.0%
Dissolution Consistent with immediate release, e.g. NLT75% at 30mins

Disintegration NMT 15 mins
Microbiology If testing required, meets USP criteria
why
Criticality Assessment of Quality Attributes

= It is the potential impact of product quality attributes on safety and efficacy
that defines criticality
= Quality Attributes from the TPP have to undergo a risk/criticality assessment

(acc. ICH Q9) to
define Critical Quality attributes (CQAs), i.e. elements of the TPP that may be
important to
Safety & Efficacy of the product used to focus further product and process
development
= Attributes already established as regulatory requirements (ICH Q6) can be

regarded as CQAs
per se without prior criticality determination (i.e. testing (control) is a
regulatory requirement and
thus no criticality determination has to be performed) standard quality attributes
(SQAs)
Specification: Test Procedures and Acceptance Criteria for New Drug Substances and
New Drug Products:
Chemical Substances Q6A
General: Appearance, |dentification, Assay, Impurities
Tablets: Dissolution, Disintegration, Hardness/Friability, Uniformity of dosage

form
Parenterals: Uniformity of dosage units, pH, Sterility, Endotoxins, Particulate,

Matter, Particle size distribution
= Critical Quality Attributes as the Foundation of QbD

= Evaluation by Risk Assessment
Ranking | Severity Probability

1 NON CRITICAL NO OCCURRENCE
No damage to patient/full therapeutic effect
2 MEDIUM CRITICAL POSSIBLE
Reversible damage/weakened therapeutic effect OCCURRENCE
3 HIGH CRITICAL DEFINITE
Dead or permanent injury/no therapeutic effect OCCURRENCE
RPN = Severity x Probability

Total RPN > 3 = critical
=E
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center
pharmaceutical
engineering
aflTy
Example
Quality What might go wrong? | SEVERITY PROPABILITY RPN
Attribute (Failure mode) What are the consequences? What is the Risk
q likelihood? Assessment
Identity API has not the required MEDIUM CRITICAL POSSIBLE 2x2=4
chemical structure or solid | The desired Safety and Efficacy | OCCURENCE CQA
State form profile is not delivered

Assay The wrong dose is delivered | HIGH CRITICAL POSSIBLE 3x2=6
to the patient No or weak therapeutic effect OCCURENCE CQA

Dissolution Does not comply with the HIGH CRITICAL POSSIBLE 3x2=6
requirement for an Therapeutic effect OCCURENCE CQA
immediate release tablet

Assay Free Fatty | FFA content too high due to | HIGH CRITICAL POSSIBLE 3x2=6
Acids (of an iv stress during production Weak therapeutic effect OCCURENCE CQA
emulsion)
Peroxide level Higher peroxide level due to | HIGH CRITICAL DEFINITE 3x3=9
stress during production OCCURENCE CQA
nfhTU [) Ea)
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pharmaceutical T U
What is the Impact that ---- will have on purity? 1) minimal ~~ 9) significant
What is the Probability that variations in — willoccur? 1) unlikely ~~ 9) highly
likely
What is our Ability to Detect a meaningful variation in ------ at a meaningful
control point? 1) certain ~~ 9) unlikely
Unit Operation Parameter Comments
Distillation performed under vacuum, at low

temperature, minimizing risk of hydrolysis
Higher water = higher degradation
In process control assay should ensure detection and

Higher temperature = higher degradation
Temperature alarms should enable quick detection
and control
Distillative Solvent Switch Temperature / Time, etc.
Distillative Solvent Switch Water content at end of Distillation

/ Crystallization (Crystallization Feed)
Crystallization -- AP| Feed
Solution Feed Temperature
Crystallization — API Feed Longer time = higher degradation
Addition Time Detection of prolonged addition time may occur too

Solution .
late to prevent some degradation
— This parameters cannot impact impurity rejection,

Crystallization Seed wt percentage since no rejection of hydrolysis degradate
occurs.
Crystallization Antisolvent percentage This parameters cannot impact impurity
rejection,
(charge ratio) since no rejection of hydrolysis degradate occurs.
a a ture is | hthatnod dati ill

Crystallization Crystallization temperature Tempera ure is low enough that no
degradation wi
Crystallization Other crystallization parameters These parameters cannot impact

impurity rejection,
since no rejection of hydrolysis degradate occurs.
TREE)
aflTy
The acceptable variability in critical product quality attributes must be

established!
= This assessment would consider, e.g., previous clinical exposure of the product,
nonclinical
(animal) studies, in vitro biological activity assay, an understanding of the

molecule’s action
and manufacturing capability
= Set the acceptable specifications for raw materials and process variables that
lead to the
desired finished product quality attributes
why
research
center
pharmaceutical T U
* QbD is “the multidimensional combination

and interaction of input variables (e.g.
material attributes) and process
parameters that have been demonstrated
to provide assurance of quality.”
Granulation &
Milling
Blending & Final

Blending
Pre-blending
Compression Film-Coating
Screan Size
Impeller Speed
Init Air Flow
Atom. Pressure
Pan Speed
* The least components and unit operations

to achieve the desired TPP targets:
Granulation Particle
Pre-Blend Uniformity Sin Distribution
g
8
zl
i
20
T1
Excipient Functionality
v" the lower the risk
Excipiant Grade
v" the higher the manufacturing efficiency
v' the less complex supply chain

Physical Compatibility
Chamical Compatibility
Van Buskirk AAPS PharmSciTech 15:665 (2014) LEE)

Optional feeders for more
- . TLV lubricant)
- Science and model based formulation and V ww
Enablers for continuous manufacturing
process development (QbD) Feeder W

«Capable to accomodate for the product and wv Contional)
process variables |
+ Closed loop PAT enabled control of the CQA ml)
and CPP Slender; 1

« Data processing and process adjustment y ro pr
G |
within the design space ranulator |_

9) r==zzzl_ Dryer)
=== Dry Granulation
=== Wet granulation
~=- Direct Compaction
—— Common processing steps
I
Roller “==cccca== : '
Compactor 1 =
. I Op 3
Mit Coater
(optional) Dissolution
mE == T
=E aceuical U
engineering Grazm
Inflow
Continuous manufacturing principles
Blending/mixing depends on various factors that

need to be investigated to establish the ,design
spaces”: materials
Measured
= Material properties 3 [a
S| materials
= Process parameter we
conditions properties
¢ Flow rate L Blend Ratios stig

Impella speed 5 al “v
[1] [kx
= Blender design a
. . . . Avice] —» £€— APAP 0s
« Impella design configuration (design of blades, bn] — 04
= 03
blade angle, number of blades) Za ] l
«+ Blender/mixer angle = r
. [\] 100 200 300
« Weir o wo [® Impeller Speed (RPM)
{a} Schematics of the experimental set-up for mixing in Gericke continuous mixer,
(b) Effect of impeller speed on blend uniformity (RSD.
Portillo et al Powder Technol 182, 368 (2008); Vanarase et al Powder Technol 208,
26 (2011); Vanarase et al Powder Technol 246, 63 (2013) WHTY [A Ea)
Statistical tools used in QbD
aflTy
Statistical tools in QbD

= Typically, only a few process disturbances or independent process changes
routinely occur, and
the hundreds of measurements on the process variables are only different

reflections of these few
underlying events
= Principle Component Analysis (PCA)
= Soft Independent Modeling of Class Analogy (SIMCA)

= Partial Least Squares Regression (PLS)
= Response Surface Methodology (RSM)
= Response Contour Plot
= Experimental Design (Design of Experiments (DoE)
= Regression Analysis
= Coefficient plot
why
research
center
pharmaceutical T U
Statistical analysis from a historical set of data or data from a Design of

Experiments (DoE)
can be used for:
+ Product development (product & process design)

- Generate process understanding (product improvement)
+ Process monitoring and control
1. Definition of product CQAs
2. Formulation and process design to meet Pe Product and process design
* LVM Fedback/Feedforward controllers
: ti itoring of th '
8: Confinuous monitoring of fhe : ¢ LVM Predictive Control
the product CQAs e LVM inversion

Process = nderstandin PR 3. Understanding relations between raw
* UNepreTeion o materials, CPPs and product CQAs
parameters
fie —— i
!'14. Identification and control of disturbances | ee
H : a ' Process monitoring and control
. raw materials, process conditions !
! ( P ) - « Multivariate statistical process control (MSPC)
i ' I ———-%e Raw material acceptance regions
|
i
I
]
|
Tomba et al. Int J Pharm 457: 283-297 (2013) fly [A SE)

aflTy
Block diagram representation of the use of a latent variable regression model
(a) for product property prediction - product development (product & process
design)
a USE OF DIRECT MODEL
Process
parameters
Raw materials
properties
model > oroperges
Raw materials
fractions
Product property prediction
Tomba et al. Int J Pharm 457: 283-297 (2013) lly

(b) for product design (by model inversion) - process understanding, monitoring &
control
b MODEL INVERSION
Process
parameters
Raw materials
product
Raw materials gp model properties
fractions
Product design

(c) for process design (by model inversion) - process understanding, monitoring &
control
c MODEL INVERSION
Process
parameters
Raw Material
properties ~~! inverse Desired
¢— product
Raw material ___—p| Model properties
fractions
Process design

aflTy
Principle Component Analysis (PCA)
= PCA is a mathematical procedure that transforms a large set of variables into a

lower
dimensional set of new variables designated as principal components
= PCA is an exploratory analysis technique which, depending of the analysis

objective,
can be used on its own to look for features/patterns/clusters in the data
= The philosophy behind PCA: in any data set it is likely that the key information
is
contained in some dominating sources of variability other than typical variability
(e.g.
noise in the measurements)
= Each of these new variables, typically called principal components (PC) but also
sometimes referred to as latent variables (LV), is a linear combination of the
original
variables
= The first principal component to be extracted is that which captures the highest
amount of variability in the data set and each subsequent component to be obtained
is that which captures the highest amount of the residual variance
Ferreira & Tobyn Pharm Dev Technol 2015;20(5):513-27 yy [A Le)

aflTy
Summary and meaning of key PCA model outputs
Variance explained
This value tells how much of the total variance included in the data set (or in
each individual
variable) is explained by the model (or each individual principal component). It is
a measure of how
well the model fits the data. It can be expressed as a number between 0 and 1 or a
percentage.
Scores plot
The scores of a sample in a principal component is the projection of that

sample/observation in the
principal component. This plot will most commonly be shown as the scatter plot of
the scores of the
samples on two components and is used to inspect the relationship between samples
by looking at
their relative positions in the scatter plot. This type of plots is commonly used
to identify clusters
(groupings), atypical observations and trends.

aflTy
Loadings plot
The loading of an original variable in a principal component is a measure of how

much that variable
has contributed to that component. Variables with high (positive or negative)
loadings have a strong
contribution for that component. As for the scores plot, it's usual to see scatter
plots of two
components. The relative position of each original variable in the loadings plot
can tells us about
how they relate to one another. For a better understanding of which measurements
are driving the
trends/groupings seen in the scores plot, the scores and loadings plot need to be
examined in
conjunction (sometimes the scores and loadings plots are superimposed in a biplot).
Hotelling’s T?
Diagnostic statistics that measures the distance from the sample to the centre of
the model.
Samples with high Hotelling’s T2 are different from all the other samples and can
have a large
influence in the model obtained.
Ferreira & Tobyn Pharm Dev Technol 2015;20(5):513-27 aiTy

aflTy
Residuals
Diagnostic statistic that gives a measure of the lack of fit of the model to each
sample. It measures
the distance between the sample and its projection on the model. Samples with high
residuals are
poorly explained by the model

Principle Component Analysis (PCA) x ind ty from (xy, xs. x4)

= For a sample of mean centered and scaled measurements SE TN
with n observations on k variables, X, the principal components » ~~ ~~ f from (xz.
)
are derived as linear combinations t; = Xp; in such a way that WT TNT ee ee
subject to the eigenvector |p] = 1, the first PC has the grrr mere ib
maximum variance, the second PC has the next greatest Principal components (PCA)
variance and is subject to the condition that it is uncorrelated

with (orthogonal to) the first PC, etc
a
£3
L ]
[ ]
[ ]
-
-
L ]
[ ]
0
(a) Simple interpretation of PCA and dimensionality reduction. The
®
principal components t1 and t2 use the correlation of five variables and 2 °%e
Observations —»
break the process in two orthogonal events. The first principal g Te

component corresponds to the event that affects the largest number of 5 |. Ct
variables, the second to the event that affects the next number of A
variables, and so on. (b) These components can be plotted against each ' i ®
other. A five-variable system is projected onto a two-dimensional plane. ®
(b)
wiTy
research
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pharmaceutical T U
From data table to variable space
One object in
Var. 3 3-variable space
Variables p (e.g., wavenumbers)
\
\
=
/
/
/
Samplel Abs.1.1 Absl.2 Absl.3 Absl.4
Sample2 | Abs.2.1 Xn P
Data + Noise
Sesser ee
ppp pp—p—" Jp ———
Sample3 Abs.3.1
BEES,
\ /
Nog
A
S
™
[\S}
Sampled Abs.4.1
Objects n (e.g., samples)

Var. 1
The whole table yields a swarm of points in variable space.
TREE)
The basic idea behind Multivariate Analysis is that the number of underlying
factors acting
on a system is much smaller than the number of measurements taken on the system.
(1) Looking for the mean

mean
vag, 3 \
vars \a ® . (2) Mean centering
var. 3,
Each of the points represents a

sample that is measured e.qg., at
three different wavenumbers.
var. 2
var. 1
« var. 1
s (3) Unit variance scaling
aflTy
Residual
variance is The first principal component (PC1)
var. 3 bk
2 ri med is set to describe the largest
analysis variation in the data, which is the
same as the direction in which the
Feiancecl tie ) points spread most in the variable
scores (coordinates PC (t « )
of the lines) is 1 (812 1 space
maximised "o
Pa 2 The Score value (ti1) for the pointiis
the distance from the projection of

the point on the 1st component to
SS the origin
PC1 hence is the first latent variable
he *) 1
var. in a new coordinate system that
describes the variation in the data
TREE)
aflTy
var. 3
The second principal component
(PC2) is set to describe the largest

variation in the data, perpendicular
(orthogonal) to the 1st component
The Score value (ti2) for the pointiis

the distance from the projection of
the point on the 2nd component to
the origin
PC2 hence is the second latent

variable in a new coordinate system
that describes the variation in the
data
hy
aflTy
var. 2
The loading (p) describes the original variables importance

for respective PC. This is the same as the similarity in
direction between the original variable and the PC.
The loading (p) is described as the cosine of the angle

between the original variable and the PC.
hy
aflTy
Principal Components (PC)

Main data variations, also known as ,latent variables, ,factors® and ,eigenvectors”
Scores (T)
Map of samples: Projected locations of objects onto the PCs
Loadings (P)
Map of variables: Correlation between variables (regression of Xon T)
Residuals (E)
Error. The data can be devided into structure and residual (noise): X = Xstructure
+ E
Variance
Residual variance — variance remaining in E
Explained variance — The % variance explained by Xstructure
Model Equation: X = TPT + E = structure + noise

SIMCA : Soft Independent Modeling of Class Analogy:
= based on using separate bilinear modelling
= Individual data class models are often PCA models
= A complete SIMCA model usually consists of several PC-models one for each class
Data mining
(with PCA)
1.) Training stage
=) data mining, e.g. PCA
2.) Classification stage

=) Testing the model
hy
| EE)
=E
research
center
pharmaceutical
engineering G razm
@® Unknown sample 4
Each group model is optimized

regarding:
-> number of PCs
-> data pretreatments (MSC,

normalisation, derivatives)
-> wavenumber range (p variables)
Group 2
Individual PCA model
“eq |, mean
Euclidean distance /| ‘a
Individual PCA model %
Group 3
Individual PCA model
TREE)
aflTy
1.) Calibration
Independent variables Dependent variables

(e.g., NIR spectra) (Reference values)
2.) Prediction
For future predictions a new set of X-measurements (e.g., spectra)

Is used to predict Y-values (e.g. concentration)
hy
Partial Least Squares regression (PLS)
= PLS also known as projection to latent structures, is the most commonly used
multivariate regression
method
= PLS is particularly useful to generate calibration models that allow the

prediction of outcomes of
expensive and/or time consuming measurements using other cheaper and/or faster
techniques
= This technique is used to find relationships between two blocks of data (often
referred to as independent
variables or X and dependent variables or Y)
= PLS regression is also a projection technique and as such is related to PCA in

the sense that each block
of data is decomposed
= In PCA the principal components are sequentially extracted to maximize the amount
of variance in
the data captured by each component, in the PLS regression the correlation between
X and Y is
taken into account and the principal components will be selected as the directions
that explain the larger
amount of variance in X which is directly related with variance in Y
Ferreira et al Pharm Dev Technol (2014) aTy [A Ea)

Summary and meaning of key PLS model outputs
Variance explained (R2) in Y
This value tells how much of the total variance included in the dependent variable
(Y) is explained by the
model. Provides an indication of how well the model fits the training set.
Variance predicted (Q2) in Y
This value tells how much of the total variance included in the dependent variable
(Y) is predicted by the
model according to internal validation. Provides an indication of how well the
model predicts new data and
thus gives a more realistic assessment of the model predictive ability when applied
to new samples.

aflTy
Root mean square error (RMSE)
Compares predicted and measured values (for the dependent variable) and gives a
measure of how
well the model is able to explain/predict the dependent variable (higher error %4
poor model). The
RMSE can be calculated for the calibration (RMSEC), cross-validation/internal
validation (RMSECV)
or external prediction (RMSEP).
Regression coefficients
The PLS model can be represented as a multiple regression equation (Y 7 b0 + b1x1 +

b2x2 +. . )
where b1, b2. . . represent the regression coefficients for each variable over all
model components.
The scaled regression coefficients reflect the relative importance of the variables
to the model and
can be used to assess which are the original variables with a stronger relationship
with the
dependent variable (Y).
Variable Importance for the Projection (VIP)

The VIP plot summarizes the importance (weight) of each original variable in the
regression model

Depending on the intended use of the model, different effort will be applied to its
validation but
it's advisable as a minimum to perform an internal validation (also known as cross-
validation)
This procedure involves sequentially removing samples from the data set,
calculating a model
with the remaining samples and applying that model to the samples set aside to
obtain a
prediction — this provides an indication how robust the model is to predict new
samples
MVA methods are empirical or “data-driven” i.e. they make no use of previous
information or a
priori system knowledge and instead focus on extracting the “hidden” information
contained in
large/complex data sets
The power of MVA resides in the fact that it enables understanding the
relationships in the data
and generation of knowledge even in the absence of fundamental/mechanistic
understanding
it is important to ensure that the data included in the analysis provides a good
representation of
the expected system variability and large amounts of data may be required to have
confidence
that the relationships identified are representative
Ferreira et al Pharm Dev Technol (2014) aTy [A Ea)

research
center
pharmaceutical T U
Partial Least Squares Regressions (PLS)
A connection between an independent variable matrix X, and a matrix Y

of M dependent variables y shall now be established, similar to PCA
4 X3 Y;
Variables p= 3 Y Response m = 1 REE CTP
X3 be - ed 1 -& 1 7 ha 4 ’ Tea +
— = 3 “4 re 0) ef EE a
i » ® . ES a aL 7,
NIT a TREN
Bo SIN
LH P A RAN
/ — : ) )Y *
X | \
2 \ \
X,
X=TPT+E andY=TQT+F
Scores (X-scores: T, Y-scores: U) > Map of samples: Projected locations of objects

onto the model PCs.
Loadings (X-loading: P, Y-loadings: Q) > Map of variables: Describing relationships

between either X- or Y-variables.
Loading Weights (X-loading weights: W) = Describes relationships between X and Y
variables.
Residuals (X-residuals: E, Y-residuals: F) = Error.
TREE)
The effect of introducing a second PLS component can also be illustrated by looking
at
the residuals after PLS comp. 1 and PLS comp. 2 > the residuals f2 (after PLS comp.
2)
are smaller than f1 (after PLS comp. 1)
AY A
X ‘
3% i A :
\ Q 4 \
" a _ # PLS comp.1 \ .
9 ¥ \ . ny
PLS comp.2 ‘ p \ Optimal number of PCs = 3
w » a’® & \
y /
oa lo" ©
Q —~ >
o A. X,
| | 1 ra |
| | >
) PCo PCi1 PC2 PC3 PCq4 PCs
Number of PCs
Soft Independent Modelling of Class Analogy

(SIMCA)
= SIMCA is a disjoint classification algorithm.
= In SIMCA each class of samples is modelled

separately using PCA.
= A PCA analysis is performed on each class,

represented by the samples in the training set
belonging to this class.
= Based on this analysis, boundaries around the

class are defined based on two spatial distances
(Euclidean and Mahalanobis distances).
= The selection of the number of PCs to be taken

into account to define the boundaries for each
class is based on a cross-validation procedure
A
A
pc Class 2
L J . —
—~% \ Aa Te ~
| 8 . La 2)
| oi ol d, d NN oe NN PC;
\o ® Bat CB . «
lo ¥, —
\ H \ (2)
\ a d, PG,
Class 1 > A,
A (1)
ALA axA PC]
SC
A; Class 3
The data obtained from experiments designed to detect the relationships between
operating
variables and CPPs of the process, in order to guarantee the CQAs are statistically
modelled
Response surface DoEs are empirical models for the approximation of the underlying
unknown
physical mechanisms that are supposed to have generated the experimental data
A statistical model fits the data, as shown:
y= bp + b1x1 + by x3 + baxy + ba x5 + bsx1%2 +£
where y is a CPP (i.e., a product temperature), x; are the operating variables

(i.e., impella
speed), € is a random error assumed to follow a Gaussian distribution, and b; are
model
parameters. The terms x? allow the evaluation of a quadratic impact of the
operating variable on
the CPPs, and the term x,x, allows the test for an interaction between operating
variables
The objective is to estimate the b; parameters from experimental data which best
predict the
CPP values from observed operating variable values
TREE)
Response Surface Methodology (RSM)
= The response surface applied for

optimisation of the experimental values of
previously identified significant experimental
factors can be visualised graphically.
= The function f (x7, x2) can be plotted against

the levels of x7 and x2. Three-dimensional
graphs show the response surface from the
side and are called response surface plots.
= Sometimes it is less complicated to view the

response surface in two-dimensional graphs
(contour plots) that show contour lines of x7
and x2 pairs which have the same response
value y.
2 D plot
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= Data
preprocessing — Co oo oo
filtering of Model Building and Calibration Process-Monitoring
irrelevant features (esian of Experiment (DoE) Model building MVBATN, 4 \
. ne 100% B : =< - he
— Baseline » | Lp BR 3 ,
correction, E | cc PI AD) !
SNV, MSC, |<£ [camo] ” . = :
Derivatives = \ 100% A 100% C Unscrambler J
< lll ph Re) ——==T2to=-==v
etc. g | 3 ~
* Model Building: £ | LERUMETRICS £5 1 MODDE [<,~] J SIMCA |
Qualitative (e.g., | & AN Ms company | €Y/ J \/ 4000
PCA), Neg mm = Am m mmm mmm mmm mmm mmm mma Nm mmm =
Quantitative (e.g., Rearrangement and Consolidation ' )
PLS, PLS2) of Calibration data Real-time
Interpretation
TREE)
aflTy
Spectral pretreatments are applied to reduce the offset effects due to e.g.
scattering etc:
= increase the signal-to-noise ratio
= to correct for spectral interferences
Sources of spectral variations can be versatile:
= Interaction of different compounds
= Light scattering from solid samples or turbid solutions
= Pathlength variations through in-homogenously distributed or agglomerating

particles
Distortions caused by the spectrometer hardware like:

= Baseline drift
= Wavelength shifts
= Effects from detector non-linearity or stray light
= Noise coming from the detector, amplifier or analogue-digital converter
why
The Savitzky-Golay smoothing The Savitzky-Golay derivatives
= Approach fits a low-degree polynomial = The resolution enhancement makes it

easier
through the data points within the local spectral to identify weak peaks in the
spectra that are
window to derive the processed signal values not visible in the original spectra.
Lief Hi PO TURMiE] HIRED. = The main drawback of derivatives on
= A drawback is that suboptimal cut-off spectroscopic data is the loss of the

original
frequency can influence useful spectral parts, shape of the spectral curve, but
most notably,
so that the spectral resolution decreases. reduction of the signal-to noise ratio.
The Normalization Multiplicative Signal Correction (MSC) and
= Normalisation is used to compensate for Standard Normal Variate (SNV)
variations due to, for example, varying = Show very similar results whereas
especially
amount of analytes. The result is that all SNV shows good results in combination
with
spectra display a common size, so they have derivative spectra to compensate for
been normalized. variations in particle size.
aTy [) Ea)
research
center
pharmaceutical T U
NIR of Gluten and Starch
Normalization
Effect of normalization on
near-IR spectra of five
synthetic gluten and starch
mixtures. | |
860 880 900 920 940 960 980 1 000 1020 1 040
Normalize to (divide each

variape by) fhe sum of the 042 | | | 1-norm Normalization Applied
variables for the given
sample
TL
Wi = > ig 0.08 — | : : ;
7=1 860 880 900 920 940 960 980 1000 1020 1040
Frequency (1/cm)
why | Lo a)
Design of Experiments (DoE)
aflTy
What is DoE?
- Methodology to design (plan) and statistically evaluate experiments
- Set of representative experiments, in which all factors under investigation are

varied
simultaneously and systematically
- From this set, a model is derived which captures the relation between factor
settings and
experimental results (responses, e.g., CQAs, performance attributes)
Aim of DoE
« Maximizing the information content from experimental series (relationship between

inputs
and output) while keeping the number of experiments low
Benefits
= Information on relationship between inputs and output are statistically

significant and effects
of input variables on output are quantifiable
= Experimental designs for different objectives (e.g., number of variables,

screening,
optimization, formulation development)
hy
aflTy
= Low-resolution designs (lll or IV) like E,

fractional factorial design (FFD),
Taguchi design, and Plackett-Burman
design are primarily used for the
purpose of screening y
= FFDs are expressed using the notation —

XP, where X is the number of levels of 5 B)
each factor investigated, k is the
number of factors investigated, and p
describes the size of the fraction of the
full factorial used. For example, a 25-2
design is 1/4 of a two level, five factor
factorial design, which requires only 8
runs instead of full 32 runs
(©)
Fig. 5 Examples of screening designs (A) fractional factorial design, (B) Taguchi
design,
(C) and Plackett-Burman design.
hy
= The “Taguchi method” utilize two-, three-, E,

and mixed-level FFDs . This design
primarily relies on the use of orthogonal
arrays, which provide a set of well
balanced (minimum) experiments serve as H.-
objective functions for optimization. rm
Taguchi design starts with minimum of (A) (B)
three factors and produces four
experimental runs at two levels without
requisite of any center point runs.
= This design has run numbers that are a

multiple of 4. Plackett-Burman design
starts with minimum of 11 factors and
: : (C)
produces 12 experimental runs without Fig. 5 Examples of screening designs (A)
fractional factorial design, (B) Taguchi design,
requisite of any center point runs. {C) and Plackest-Burman design.
TREE)
= Response surface designs are particularly

used for optimization of the factors identified
from the risk assessment and/or screening
study. The response surface designs include
full factorial design, central composite
design (CCD), Box-Behnken design (BBD),
optimal design, and mixture designs. (A)
= CCD is considered as an augmented form of

three-level factorial design coupled with star o
points or axial points. o
= BBD is an independent quadratic design in PY

that it does not contain an embedded
factorial or FFD. In this design, the treatment

9 (C) (D) (E)
combinations are at the midpoints of edges

Fig. 6 Examples of response surface designs (A) full factorial design, (B) central
of the process space and at the center. composite design, (C) Box-Behnken design,
(D) optimal design, and (E) mixture design.
X, >
Process
- Determine influential variables (factors)
« Determine the range influential factors to optimize response
"Yq, Ys,
- Determine the range of influential factors to minimize response variability
— Improve process yield
— Reduce variability
— Reduce development time

— Reduce overall costs
aflTy
Problem definition — Steps in experimental design
1. Experimental objective: Why is an experiment done? For what purpose? What is the
desired
result?
2. (Input) factors: Variables that are changed to give different results on the
measured
responses
Responses: e.g., CQAs, performance attributes

Model: polynomial model corresponding to the objective
Design: supports the selected model, follows from the objective
oO a Aw
Worksheet: review of the actual design

Problem definition — step 1: experimental objective
I. Familiarization
ii. Screening
iii. Finding the optimal region

iv. Optimization
v. Robustness testing
vi. Mechanistic modeling
Factor 2
Factor 1
Simple factorial design
used in familiarization
Finding the optimal region
hy
Problem definition — step 2: definition of factors
= Variables that exert an influence on the system due to changes in their levels
Controlled Quantitative
Controlled Qualitative
low center high

Temperature 35°C 40°C 45°C
Amount 249 49 6g
Speed 200 rpm | 250 rpm | 300 rpm
pH 4 6 8
Bender type A B C
Supplier DE SP BG
Catalyst Na K Ca
Surface coating PVC PvDC PP
Uncontrolled
Outside/Inside Temperature
Outside/Inside Moisture
aflTy
Problem definition — step 3: specification of responses

= Regular and derived responses
= Quantitative and qualitative responses
Problem definition — step 4: Selection of model
= Polynomial regression models
Three main types of polynomial models
Linear y = Bo + Bix1 + Baxa +... +¢ ) GR factors
2 Yorn responses
Interaction: y = Bo + B1x1 + Bax2 + B12x1x2 + ... + € Bererene. regression
coefficients
Quadratic: y = Bo + B1x1 + B2x2 + B11x12+ B22x2 2 + B12x1x2 + ... + € Brrerenene
residual
TREE)
armaceutical
py
Overview Experimental Designs
(examplary)
2k-fractional factorial
designs
Fractional factorial
designs with 2
levels per factor
Response Surface
Designs
non-linear
relationship, 5
levels per factor
Main effects (and

interactions)
Screening
Factors 3 -47
Factors 2 -7
why | Lo a)
research
center
pharmaceutical T U
= Chosen model and design to be generated are intimately linked
= The number of factors, their levels and nature (quantitative,

qualitative,...), and the selected experimental objective.
Problem definition — step 6: creation of worksheet
= WS contains the selected design as work instruction for the

EXPEIIMENLEr orto Exp ame wun oder ct ct Wegner es isin i. isla ai Cushing ssh
11 Incl - 1 5 1
2 M2 1% Incl - 5 5 1
3 | M3 16 Incl - 1 25 1
4 bd 3 Incl - 5 25 1
5 MNS 1 Incl - 1 5 3
& MB 10 Incl - 5 LH] 3
TNF & Incl - 1 25 3
a Ng E Incl - 5 zs 3
2 NS F Incl - 1 15 2
10 M10 2 Incl - 5 1% 2
1x M1 17 Incl - 3 L} 2
12 M12 4 Incl - 3 25 2
13 M13 £ Incl 3 is i
14 M14 15 Incl 3 i5 3
15 M15 1z Incl - 3 15 2
16 MIG 5 Incl - 3 i5 2
17 M17 14 (Incl 3 15 2
nihTy,
fe hy
[A Fe)!
Introduction to Full Factorial Designs
Basis for all classical experimental designs
Require relatively few runs per investigated factor
Upgrading to form composite designs used in optimization
Basis for two-level fractional factorial designs (used in screening with many
factors)
2 — 4 factors; with many factors switch to fractional factorial design
average A B Cc AB AC BC ABC
+ - - - + + +
Design * rT
: : + + + +
22 two-level design in 2 factors . oo. . )
2° two-level design in 3 factors > ) \ ) .
32 three-level design in 2 factors + + + +
+ - + + - +
+ + + + + + +
research
center
B pharmaceutical
engineering Grazm
Regression analysis — the Summary of Fit plot
= R2 goodness of fit. how well the regression model fits the raw data (0 — 1)
= Q2 goodness of prediction: estimation for the predictive power of a model (-~ —

1)
= Model validity: right type of model (> 0.25) '*
= Reproducibility: replicate error (> 0.5)
0gT
0g +
041
021
0o-
CA,
|
RZ
[wy
Model Validity
Reproducikility
why | Ls
)))
research
center
pharmaceutical T U
Model interpretation — Coefficient plot
= Regression coefficients incl. confidence

intervals
= Size of confidence intervals depending on:
(i) experimental design,

(il) goodness of the regression model
(iif) number of degrees of freedom
= Main effects and interaction terms
CoeliC 51 |(RibFor)
DV MVA3 M1 (PLS)
CoefCS[Comp. 1){(RibPor)
06
0s
04
03
oz
01
on
01
-02
03
-04
05
06
or
-08
3
RP
RS
HFS
True
Dikarrotrbr
Var D (Prmary)
SINC AS « 11 - FUSES 181548 AM
Coefficient plot for the six variables included in model 1
TREE)
research
center
pharmaceutical T U
Use of model — Response contour plot
« Making predictions
1 2 3 4 5 Bb
Lower Upper
1 400 50 100 5,83455 5,65142 6,01767
2 400 40 100 | 6,04054 5,82333 6,2577
3 400 50 110 6,24454 6,02739 6,4617
4 400 40 110 6,546594 6,28749 6,8064
5
%0 55 B00 BS VO V5 80 85 90 895
aflTy
Systematic characterization of raw materials, processes and the corresponding

product quality
= Design of Experiments (DoE) (Umetrics MKS MODDE)
= Systematic parameter variation to develop a Design Space (DS)
= Estimation of the impact of external influences
usstigaton TRIGIDD PLA corp = geen d

Pict of Pimple ators Foy ena sade (us Carver 4a es
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eat EL ¢ wu mn wl 2a ass ge -
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: 15 ah 28 28 AF 4b 4d 82 AE 6p mE TB
i il
Experimental Design Reproducibility Process Understanding
TREE)
research
center
pharmaceutical T U
= NIR spectroscopy for monitoring the powder-blend composition and identification

of the mixing end-
point.
= Three different fill levels were studied with either acetyl salicylic acid (ASA)
or agglomerated a-lactose
monohydrate (LM) on top
Experimental setup with a four-bladed mixer PLS Models for blend quality monitoring
p= 3K a) £3 y = 0,9996x + 0,0206 b) Ee | v=0.050x + 0.2053
acirolide statistical spectral [fi eg| RTOS Fem 08s
ixi data analysis |:'V =" Zig
mixing device r 7 Ba §
= 8 38
four blade [fiber optical z . 29
impeller probe 2 ®
2 \ A _ Fotrtoi.o.i. Jot
\ = 4 [+ 0 20 40 a0 BO 100 o 40 45 50 55 BD
- «l / Nominal API Content [% w/w] Nominal API Content [% w/w]
component A ; 3
(ASA or LM) = PLS Models for nominal ASA content:
component B PerkinElmer Preprocessings: SNV and 4th order baseline correction
(LM or ASA) FT-NIR Spectrometer400 Model: 0-100% - RMSEP 2.97 % (11 fractions)
Static sample size ~ 6 mm? (Penetration depth 0.3-0.5 mm, Spot Model1: 40-60% -
RMSEP 2.08 % (13 fractions)
size 4 mm), Integration time = 0.3 s, Impeller speed = 4 rpm 10 spectra recorded
from each fraction
TREE)
research
center
pharmaceutical T U
= Simultaneous NIR monitoring of powder blending dynamics at different positions
= In-line measurements at critical positions like corners
= Spatially-resolved investigation of mixing dynamics Unprocessad NIR Spectra

: =
optical fiber multiplexer =
ot .
§ =|
Be
5
8
g ©
=)
[=]
optical fiber | Sy
il i
ras 4000 5000 6000 7000 8000 ©000 10000
Wavenumbers [cm-1]
research
center
pharmaceutical T U
= Experimental investigation for setting up powder mixing include different fill

levels and
powder loading orders
= To investigate granular flow properties, compressed convective zones and dead

zones
dependent on the fill level (effective powder homogeneity)
Model
100 mm + 100 ° i
98 mm Formulation blend = Sioee Vibe A
H/D = 0.95= Z so! .
Table 1. Qs Particle Size Distribution of the Used Powders =~ '
10 2 ol
dip (pm) dsp (nm) dg (nm) I
9 d
H/D = 0.60~ 8 Acetyl salicylic acid 2524 439+9 725225 S BE
H/D=0.50= <7 a-Lactose monohydrate 76+1 1913 420+6 f: 40; ., of
2 i
H/D=0.35= <6 : 20} i
H/D=0.25= 45 8
10 mim 3
15 mm | <4 4 of!
15 mm 4
1mm L A A i a J
0 20 40 60 80 100
Observed conc. API (%)
Observed vs. predicted plot of

Schematic illustration of the blending vessel. Measurement ports the overall PLS
regression model
1-10 for the optical fibers are indicated by the arrows. The predicting the API
concentration.
dashed lines indicate the investigated fill levels. _

Scheibelhofer et al AAPS PharmSciTech 14 (1): 234 (2013) ~~ WTY [A Ea)
research
center
pharmaceutical T U
Experiment 1 Experiment 2 Experiment 3

100 Pos, 1 100) Pos. 2 100; yr
“b | A Position 2 a
3 hha 90}
= 60, "yK\, 60
£ ih LN so} | {\
g & \ 1 . . \ ! |
i o Experiments with a a
5 I different H/D ratio. The
: - ’ 0 0n.0 0 FJ
z BE Wwe Ew. starting composition is x
& 5
10 gm Po3 wf Ped always 80% LM on top of fw
eo | %| 20% ASA
conc. API (%)

8 8 8
hd
Jj
2
¥ 8 8
3 8
- :
0 o|
0 500 1000 1500 0 500 1000 1500 % 500 1000 1500
Time (s)
Seventy grams of LM was deposited on 70 g of ASA (resulting

| in H/D 0.35). The solid lines show the predicted API values,
and the transparent area represents the respective 95%
confidence interval of the prediction. Positions higher than 6
were above the powder fill level
cone. API (%)

BY o
o i=]
)
7
| 3
3 8
0 500 1000 1500 0 500 1000 1500

Time (9) Time (9)
Scheibelhofer et al AAPS PharmSciTech 14 (1): 234 (2013) phy

BE == T
=E aceuical U
engineering Grazm
solid feed | liquid barrel Dryer drying
temperature | rotation drying air
t
speed emperature
flow (DAV)
(BT) (DRS) (BT)
Fractional factorial design matrix
- - + + + - -
of performed Screening-DoE, a - : : + i + :
El X - - + S + + +
based on quantitative pCPPs me 12 - ; . ] ) ;
: ce : : El 14 5 + - + + ; +
identified during risk 5 BRL i + + i i i +
17 - * - - + + .
assessment. Factor low is om - - . - :
denoted as “-*, factor high as “+”, Ei 1 + + : + : : i
ctor high as "+7, or EE : : n : .
center point settings are “0” CE 19 + + . ; ) N N
[12 [I + - + - - + -
(13 | 2 + = + + = = +
(14 | 3 + + + - + -
(15 | 7 + = = + + + =
(16 | 8 + + + + + + +
5 0 0 0 0 0 0 0
FEE 10 0 0 0 0 0 0 0
(19 [ETS 0 0 0 0 0 0 0

research
center
pharmaceutical T U
Summary of DoE results pCPPs Response List of pCPPs demonstrated List of pCPPs and
pCMAs demonstrated
to be critical (CPPs) not to be critical (nCPPs/nCMAs)*
and pCMAs that were initially — —
LOD Liquid feed rate Relative humidity
identified by risk analysis were Solid feed rate Pre-blend LOD
. . ‘ys Dryer rotation speed Barrel temperature TSG
either confirmed to be critical Drying tem FBD Screw speed TSG
(CPPs) or downgraded to not Drying air flow FBD
oo (Runtime**)
critical (nCPPs/nCMAs) PSD (X10, X50, X90) Liquid feed rate Relative humidity
Solid feed rate Pre-blend LOD
Screw speed TSG Barrel temperature TSG
Drying temperature FBD
Drying air flow FBD
Dryer rotation Speed
(Runtime**)
*Rating of not critical is only valid within the tested ranges

*#*Runtime was demonstrated to be only critical during the first 20 min of process
ramp-up
Pauli et al J Pharm Innov 13:247-60 (2018) platy, [A Fe)!

To keep the process within the specification (granule moisture) changing the total
material
throughput mtot might be necessary
The following trial was
$EEES
DRS
DAV
predicted LOD
measured LOD
target LOD
acceptance
po
conducted: Granulation was : |

. ; target ih decrease rh by 50 % increase rh, by 50 % target m,_ |
initially started at a total material 5.2 kghh from target from target 15.2 kg/h |
- 30 1 Pa
mass flow rmtot of 5.2 kg/h and TE: Be I i ;

DRS of 17 rph and DAV of 120 |c = Hl Hj!
m3/h. Then, mtot was first _ 10977 : —
decreased and later increased [3&5 " nlf EL yr ="
by 50% from its initial setpoint umn. To 1 ! —— —
in-spec | oos! in-specy’ 00s! oos! in-specy’ 00s! in-spec
10 - 1
It was demonstrated that model- |, _ s- 74, M I * Z

based adaption of dryer rotation [2% §: ii Ni é
speed (DRS) and drying airflow 2 | i . u : :
(DAV) can control dried granules trial #
LOD within acceptance limits at

varying mtot,
research
center
pharmaceutical T U
M=1kg/h, T=30°C b) M =1 kg/h, T=50°C
Response surfaces of the split-plot — pps — pt

. . BE <2.25 Bl <2
experimental study. The settings of the re 7s
other two factors are as follows: --
(a) 1 kg/h mass flow rate — 30 °C
temperature
(b) 1 kg/h mass flow rate — 50 °C
temperature
(c) 2 kg/h mass flow rate — 30 °C
temperature --
(d) 2 kg/h mass flow rate — 50 °C = =
temperature per is
L/S = Liquid to solid ratio
Domokos et al Powder Technol 388: 70-81 (2021) phy A) SE)

Modelling roller compaction
= Roller compaction is a dry granulation technology
= The aim of this work is to reduce the material

consumption in a systematic design of
experiment (DoE).
= A mechanistic approach based on previous

models has been developed in order to replace
the experiments with higher throughput and
material consumption (high roller and screw
speeds) with model predictions
= Two models exist: (1) Screw mass flow rate

controlled or (2) gap geometry and the roller schematic of a roller compactor. [§}]
inlet funnel with
speed controlled agitator; [B3] feed screw; [E}] tamp screw; [ll}] small quantity
inlet funnel; B rollers; and (6) rotor miller. The mechanistic
model describes the region of between the rollers

Toson et al Int J Pharm X 1 (2019) 100005 phy [A Ea)
Schematic diagram of the compaction
process showing the feeding zone and the
Screw mass flow rate controlled
nip and slip regions. <b
— The powder has the maximum density yj

at the gap.
— Past the roller gap, there is a region of feeding

elastic recovery where ribbon thickness T slip region
increases while reducing the ribbon density
to its final value yk. nip region
— The mass flow can be predicted in the :

feeding zone using either the screw mass aes y
flow rate (m, ) or the gap geometry and
the roller speed (m,,). Gap geometry and the

— Experimentally, it is the throughput roller speed controlled
observed after the ribbon relaxation (m,,).
Toson et al Int J Pharm X 1 (2019) 100005 platy,

research
center
pharmaceutical T U
Full factorial DoE with 11 experimental runs
The critical process parameters are the roll speed Ng,

the gap width S, and the specific compaction force
SCF. The simulated values used the experimental runs
at low throughput (Ng level=—1) for calibration,
whereas the high the results for higher throughput Ng
levels=0 and +1) were fully predicted
roll speed gap width specific compaction force

Np (rpm) S (mm) SCF (kN/cm)
Run # Ng 5 SCF role in simulation
Level -1 0 +1 -1 0 +1 ~-1 0 +1
1 -1 -1 -1 used for calibration
TbuMCC 1 2 3 2 3 4 5 7 9 2 +1 -1 -1 fully predicted
IbuMannitol 1 2 3 2 3 4 2 3.5 5 3 -1 +1 -1 used for calibration
4 +1 +1 -1 fully predicted
. . 5 -1 -1 +1 used for calibration
Process settings used in the DoE for IbuMCC 6 +1 “1 +1 fully predicted
and IbuMannitol formulations (Ibu = 7 1 1 1 used for calibration
8 +1 +1 +1 fully predicted
Ibuprofen) 9 0 0 0 fully predicted
10 0 0 0 fully predicted
11 0 0 0 fully predicted
Toson et al Int J Pharm X 1 (2019) 100005 phy [A Ea)

research
center
pharmaceutical T U
= Experimentally observed ribbon solid fraction and the prediction error for the
IbuMCC and
IbuMannitol formulations. The predictions used the calibrated compression profile
K, y,. The
two methods to calculate the screw constant in screw-controlled mode are compared
(cg, and
Cs,). Runs marked with an asterisk (*) were used in the calibration sequence.
Run # TbuMCC IbuMannitol

Obs. yr Gap Screw cs) Screw css Obs. yg Gap SCrew Cs; Screw Css
1* 0.692 0.687 0.684 0.684 0.860 0.848 0.843 0.845

2 0.679 0.688 0.679 0.680 0.855 0.849 0.843 0.844
3* 0.646 0.651 0.651 0.651 0.808 0.816 0.818 0.819
4 0.648 0.651 0.643 0.642 0.825 0.816 0.813 0.813
5% 0.796 0.803 0.800 0.800 0.913 0.918 0.916 0.917
[3 0.793 0.803 0.795 0.795 0.903 0.918 0.908 0.909
7= 0.767 0.759 0.762 0.762 0.882 0.882 0.885 0.884
8 0.774 0.760 0.757 0.755 0.886 0.881 0.878 0.877
a 0.736 0.732 0.728 0.728 0.861 0.866 0.863 0.863
10 0.726 0.732 0.728 0.728 0.871 0.866 0.863 0.863
11 0.736 0.732 0.728 0.728 0.849 0.866 0.863 0.863
Mean “Error 0.9 0.8 0.9 0.9 1.0 1.0
Toson et al Int J Pharm X 1 (2019) 100005 TREE)

Graphical exploration around the optimal point (YR=0.725; mobs =10 kg/h) comparing
the multiple
linear regression (MLR) model based on the experimental data with the MLR model
based on the
simulated data for IbuMCC. The four experimental data points used to calibrate the
mechanistic
model are marked e S = 3mm S = 3mm $ = 4mm

— 3.0 3.0
3.0
25 2.5
2.0 + 2.0 +
Ng [rpm]
@ calibration point
1.5 prediction 1 1.5
experiment
3 pred. sweetspot
£o3 exp. sweetspot
1.0 1.0
2 3 4 5 2 3 4 5
SCF [kN/cm] SCF [kN/cm] SCF [kN/cm]
Toson et al Int J Pharm X 1 (2019) 100005

research
center
pharmaceutical T U
Screening DoE methods used in development
Definitive Screening Design [] he
=1)
Mixed-Level Fractional Factorial 2%
(L18 Hunter Design) (n=1)
: 5%
add: 7%
Two-Level Full Factorial | —
(n=15)
0 2 4 6 8 10 12 14 16
Number of papers
Screening DoE methods
Grangeia et al EJPB 747 (2020) 19-37 ihTy z =)

research
center
pharmaceutical T U
Optimising DoE methods used in development
. 2%
I-Optimal (n=1)
2 Mixed-Level Fractional Factorial 2
n=
=
= . . 3%
z Mixed-Level Full Factorial 2
| (n=2)
2 Three-Level Full Factorial [1 3%
= (n=2)
1-1)
2 Box-Behnken C1 ie
E Response Surface Method 39%
& (without details) (n=2)
. 15%
Central Composite ©=9)
0 1 2 3 4 5 6 7 8 9 10
Number of papers
Grangeia et al EJPB 747 (2020) 19-37 ihTy z =)
aflTy
Conclusion
= An iteration process for calibrating the K and yj; values, which can reduce the
material
amount required, the number of RC experiments and the material characterization

efforts at
a low software expense
= A simple method that uses the RC throughput to calculate the volume relaxation
that the
ribbon experiences after exiting the rollers and the relaxation factor (8) can be
used to
predict the throughput with an acceptable accuracy
= Based on a limited number of experiments, a design space for a broad range of

throughputs
can be predicted with a high accuracy
= |t may be used in the future as a soft sensor for RC processes operating in

continuous
manufacturing lines for in-line adjustment of throughput while maintaining the

desired ribbon
solid fraction
Toson et al Int J Pharm X 1 (2019) 100005 platy,

Process Analytical Technology (PAT)

Guidance for Industry
Design and optimization of drug formulations and manufacturing PAT — A Framework
for
es i Ie FY Jameson nod he IMTS unovative Pharmaceutical
= |dentify and measure critical material and process attributes Development,
Manufacturing,
relating to product quality and Quality Assurance
= Design a process measurement system to allow real time or

near real time (e.g., on-, in-, or at-line) monitoring of all critical
U.S. Department of Health and Human Services
attributes Food and Drug Administration

. . . Center for Drug Evaluation and Research (CDER)
= Design process controls that provide adjustments to ensure Center for Veterinary
Medicine (CVM)
— . ffic f . y. fT: 1re 0 /

control of all critical attributes Fcc AR Ncaniniory Atlas CORD)
Pharmaceutical CGMPs
= Develop mathematical relationships between product quality September 2004

attributes and measurements of critical material and process
attributes
research
center
pharmaceutical T U
= PAT is a broader field encompassing a set of Process

tools and principles to enhance
manufacturing process understanding and
control which includes process analysis,
Data
. . . : Aquisition Implementa
chemical engineering, chemometrics, & -tion
] Instrument approach
knowledge and risk management, and Control (7 »
process automation and control.
Hard (green) an Data
(green) a . d soft (blue) Processing Method
process analysis elements & develop-

Chemoma- ment
trics
TREE)
aflTy
Process Control (PC) has the goal of keeping a chemical or pharmaceutical

process within predefined boundaries with respect to predefined variables using
manipulation of certain control parameters.
PC is not to be confused with process monitoring
PC directly affects the safety and reliability of a process.
PC determines the quality of the products produced by a process.

PC can compensate for variations in input variables
PC can affect how efficient a process is operated.
PC has a major impact on the profitability of a company.
PC control established over 80 years in the chemical industry.
PC is new to the pharmaceutical industry
why
aflTy
Process Control is achieved by e.g. PAT
PAT is a system for designing, analyzing, and controlling manufacturing through

timely
measurements of critical quality and performance attributes of raw and in-process
materials and processes with the goal of ensuring final product quality
A mechanism to design, analyze, and control pharmaceutical manufacturing processes

through the measurement of critical process parameters (CPP) which affect product
quality attributes (CQA)
The real-time testing and adjustment based on the complete understanding of how the
components and related processes affect the final product
Nothing less than a shift in process control philosophy — replacing end of unit
operation testing with continuous, or nearly so, on-line monitoring of product
quality
why
What are the requirements for PAT
+ Robust process instrumentation with suitable analytical merits

«Optimized process integration and operation
+ Robust chemometric models or data processing algorithms

- Representative process data over time and conditions
«Autonomous process instrument control and data acquisition
* Real - time measurement assurance (i.e., smart sensing)
- Suitable information technology and automation controls infrastructure for

efficient data fusion
and archive management
- Sufficient method development, validation and ongoing compliance

«Suitable instrument validation and compliance
+ A comprehensive onsite process instrument program (metrology, instrument

maintenance,
training, sufficient on-site instrument specialist, etc
- ldentified performance metrics and continuous improvement plans

Statistical process control (SPC)
Often monitoring identified critical process parameters are considered to be assure

together with critical quality
attributes by statistical process control (SPC).
Consider. The parameters that appear to be critical in the DOE are not necessarily
the ones that will give
information about the “wellness of the process” in SPC charts.
Reason: Even though identified as important in DOE to be controlled, SPC charts on

routine data are
noncausal!
Example: Suppose that temperature is important to the yield, as determined by DOE.

This means that during
production the desired temperature profile will be regulated by the controllers.
The SPC monitoring of
temperature will provide good results.
Whereby, what is really important is how much effort the controller is putting to
maintain the temperature (how
much the valve to the cooling agent opened or closed during the reaction) .
Therefore, monitoring the controller action will provide much more information
about abnormal situations than
monitoring the temperature, although temperature was identified as critical process
parameter by DOE
aTy [) Ea)
research
center
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Process Model | [— B Process

, . | 5 arameters
= The choice of the process conditions of : ph N
the unit operation will be dictated by a ®¢ ]
(]
model that takes into account the value ~ a

input variable and calculates process
conditions such that quality IS on =11-10-8 8 7 «6 -5 -4 -3 2 -1 wr 2 34586878
9%10M1 gd
target. When the model is empirical, , SIMGAP 11 - 042008 161708 x \ 0 er
oo . Input to unit N OCs PCAs 4 -abouz006 16:
multivariate analysis can be used.
= The example here illustrates a Control strategy
feedforward control scheme for unit N using projection :
based on input information on the space Ce
“state of the intermediate product” from .
unit N1. Quality N

0 10 20 an 40 50 0 70
SIMCA-P+ 11 - 03/04/2008 16:27:11
TREE)
Traditional Process Control compared to a PAT-based Process Control
Design of manufacturing
process
Process verification
Process analyzers
Process controls
Quality assurance
Innovation in life cycle
Mainly empirical
Based on initial full-scale

batches
Mostly univariate process and

off-line material measurements
Primarily go/no go decisions
Intermediate and end product

testing of collected samples
Difficult; process is often frozen
1 Traditional approach PAT approach
Systematic understanding of
formulation and process factors
Continuous real-time process

verification
Real-time measurement of quality

and performance attributes
Process is adjusted to ensure

control of quality attributes
Ensured by the design of the

Continual improvement and

optimization possible & desired
yy [) Ea)
aflTy
PAT experience from other industries

PAT has been used by the chemical industry since mid 20 century
Core concepts in use for decades in chemical, semi-conductor, petroleum and other
manufacturing industries CPAC
+ Formalized with founding of CPAC in 1984 [a Reigat try urie rr Resize
Goal of PAC (process analytical chemistry) — supply quantitative and qualitative

information
about a chemical process
Initiated by the FDA as part of the 21st Century GMP initiative in 2001 with the
goal of
increasing productivity of pharmaceutical manufacturing
— Analytical in PAT includes chemical, physical microbiological, and/or
mathematical
analyses
- PAT is a key tool for real time process control in the QbD framework
hy
=E
research
center
pharmaceutical
engineering
aflTy
= PAT starts with the TPP, risk assessment and

QbD process to identify the critical factors for
the finished product performance
= PAT is applied as the analytical controls to

monitor the product throughout the
manufacturing to stay within the defined
boundaries
Formulation Roller
Composition) Blending | | Compaction 1 Lubrication | Compresssion
Appearance
Identity
Uniformity
Dissolution
Risk Assessment to Identify Variables Potentially Impacting

Product Quality
Theoretical Target Product Profile
Quality Target Criticality

Attribute
Dosage form Tablet, maximum weight Not applicable
200mg
Potency 20 mg Not applicable
Pharmacokinetics | Immediate release enabling Related to dissolution
Tmax in 2 hours or less
Appearance Tablet conforming to Critical
description shape and size
Identity Positive for acetriptan Critical
Assay 95 — 105% Critical
Impurities ACE12345 NMT 0.5%, Critical
other impurities NMT 0.2%,
total NMT 1%
Water NMT 1% Not critical — API not sensitive
to hydrolysis
Content Meets USP Critical
Uniformity
Resistance to 5-12kP Not critical since related to
Crushing dissolution
(Hardness)
Friability NMT 1.0% Not critical
Dissolution Consistent with immediate Critical
release. e.g.. NLT 75% at
30mins
Disintegration NMT 15mins Not critical. a precursor to
dissolution
Microbiology If testing required, meets USP | Critical only if drug product
criteria
supports microbial growth
TREE)
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center
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At-line NIR: incoming

material attributes
= Based on the identified critical
. . | C=] [=]
factors, the respective PAT tools will = | = 5 4 [Tem
. . vey NIR: granule uniformity, water T = TD xi TT T
be defined and applied within the Content 7 th
Laser Diffraction: particle size
relevant process steps distribution
NIR: blend uniformity

and water content
I STEP 5, FEEDER/BLENDER 2 [i
STEP 1, FEEDER/BLENDER 1
NIR: measures
blend uniformity
ead at
STEP 2, TWIN SCREW GRANULATOR
of
—I og ~
STEP 7, COATING
mm
Raman: Tablet coat mee Ly

thickness ey j=
®o [ y—-
a] i J Tablet Tester: Weight, Thickness, Hardness
== Finished Product Raman: API Form, Identity
TREE)
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center
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Process
analyzer
Process
= ablyir
Process stream
a
- Atdine measurement ~~ Ondine measurement Indine measurement
Sample is transferred Sample is analyzed in Sample is retuned to the Sample is

measured
into laboratory proximity of the process straam after the directly within the
process stream and measuremant process stream
disposed afterwards
Principles for process monitoring
Indirect methods
Generic sensors
= Physical (size, shape, temperature, pressure, etc.)

= Chemical (pH value, etc.)
Direct methods
* Near infrared (NIR)
— Spectroscopy
— Chemical Imaging
Raman
— Spectroscopy
— Chemical Mapping
= UV-Vis spectroscopy
= Mass spectroscopy
= (Gas chromatography
= SWAXS
= Terahertz spectroscopy
= Optical coherence
TREE)
aflTy
Spectroscopic techniques
— Infrared spectroscopy, Raman spectroscopy, nuclear magnetic resonance
spectroscopy, ...
Chemical imaging & real-time image analysis
Thermoanalytical techniques
— Differential scanning calorimetry, differential thermal analysis,

thermogravimetry, ...
X-ray diffraction techniques

— Single crystal diffraction, powder diffraction, small-angle, wide-angle, ...
Microscopy
— Optical microscopy, electron microscopy, scanning force microscopy, ...
Methods for particle analysis

— Laser diffraction, dynamic light scattering, coulter counter, ...
why
aflTy
Overview of spectroscopic techniques applied and/or investigated for pharmaceutical

applications:
= Ultraviolet-Visible Spectroscopy (UV-Vis)
= Infrared Spectrosco
P Py UV Visible Near-Infrared Mid-Infrared
= Raman Spectroscopy
= Solid-State Nuclear Magnetic Resonance | | | |
Spectroscopy (SSNMR) 50,000 25,000 14,285 4000 Zaooem1

= Time-of-Flight Secondary lon Mass
Spectroscopy (TOF-SIMS) Elemental Constituent Assay Functional Group Analysis

= Terahertz Pulsed Spectroscopy (TPS) Appearance
hy
Detector Diffuse Reflectance Qualitative Analysis
N/
e
Infrared
spectroscopy ee
Monochromator
..
Detector
Transmittance
Light Source
Chemical Properties
~
by ONAN NINN TN
Derivatized Surface,......
=E
research
center
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engineering
aflTy
Summary of Quality Features in Emerging and Established NIR Technologies
Technology Scanning Grating MEMS AOTF Tunable MEMS FTS Process

Grating and MEMS, Grating SLED/ FT-NIR
Polychromator Hadamard Rotating Disk Fabry-Perot
Quality Diode Amay Encoding
900-1700nm low
cost, 1100-2100nm 900-4500nm
medium cost, 900-2400nm | withupto 5 vis to 2300nm
1400-2400nm, with 3 different | different limited by FO
poor quality gratings gratings 800-2300nm | 1100-1850nm |coupling 700-20000nm

resolution 10 to 20 nm, 1010 20 nm,
51020 nm 128 channaols | 256 channels | 20 to 50 nm 5nm 40 cm-1 1-32 em-1

repeatability | excellent excellent good very good good short term good| excellent
stability oxceliont, with
can be very permanent
good good limited limited good alignment

reproducibility | poor, needs poor, needs poor, needs
mathematical mathematical | mathematical excellent,
treatment treatment treatment poor good good guaranteed

measurement | simultaneous,
spead good for up to 5 scans’s.,
transionts, typical up to 100 400 scans/s high froquoncy

up to 50 scans/s. | 1 scan/s. scans’s. 100 scans/s 10 scans/s. resonant scan |
modulation
photometnc
linearity stray light good good stray light good good very good
temperture good with
scale non-linoar non-linoar non-incar sonsitivo good motrology oxcollont
lineshape | poor poor poor poor good good oxcollont
size compact compact medium medium medium very small medium
cost medium low low modium madium low high
vib robust very very very good good very medium
temperature | jie affect little effect litle effect | sensitive good unkown
sensitive
We make tomorrow's drugs possible.

Averaged NIR spectra
0.6 |
0.5 NA
Absorbance (a.u.)
4000 5000
with increasing coating
thickness the absorbance end coating Identification of

intensity increases. the qualitative
and quantitative
differentiating
OM - pd wavelength
7 © uncoated
AN
begin coating
East a .
6000 7000 8000 9000 10000
Wavenumber (cm-1)
TREE)
aflTy
Attenuated Total Reflection (ATR) Spectroscopy
Sample preparation is a challenge in many traditional IR spectroscopic techniques

based on
the transmission of an IR beam through a sample. ATR is an interesting technique
requiring
minimal or no sample preparation at all.
Principle: an infrared beam is guided through a crystal by internal reflection. A

sample placed
in the evanescent field (i.e. a couple of micrometers next to the crystal)
contributes to the total
absorption of the IR beam.
ISSN
Source: Solvias
D—_
Source: PerkinElmer Source: HELLMA
hy
Raman spectroscopy
Benefits:
= Minimal or no sample preparation
= Less overlap between APIs and excipients

than with IR spectroscopy
= Complements diffraction techniques
= Often complements with IR spectroscopy;

IR-inactive vibrations can be strong in
Raman spectra and vice versa
Shortcomings:
= Small sampling area (limited by laser

beam size)
= Sample heating (depends on laser beam)
Under constant experimental conditions, the

number of Raman scattered photons is
proportional to analyte concentration
Quantitative methods can be developed with

simple peak height measurements
Multiple components in complex mixtures can

be quantified if a distinct wavelength for each
component can be identified.
When isolated bands are not apparent, advanced

multivariate statistical tools (chemometrics) e.g.,
partial least squares (PLS) can help
Fluorescence is a common interference and its

severity tends to increase with shorter
wavelengths. By using longer wavelength lasers,
many fluorescence problems can be avoided
platy, [) Ea)
= Fiber optical cables between measurement point and instrument, with a dedicated
path to
carry laser light and a separate to return the Raman signal to the spectrometer.
= Silica Raman scatter always is generated when the laser travels through fiber
optics. It will
overwhelm any analyte signal if it is not removed before the laser reaches the
sample; the
same is for case return fiber.
External PhAT Probe Head for Solid Sampling

Sampling
Raman signal Notch Filters Optic
— =A
k - ve 4 I = 6 mm
If ll Q 3mm
; Microscope
\ Spatial Samyle :
fo Filter @ (2-5 pm)
J 25cm Weeking | v
0 SET 1 ‘| -
- §:am Spot
—_— Se
Laser excitation Crating Indicator Source: Kaiser Optical Systems, Inc.
www.kosi.com
TREE)
= API and excipients distribution
= Analysis of coating defects and homogeneity
= Spatial resolution for Raman images
— 100um excitation spot size - typical spot power 100 mW

— Stage movement >1um - typical 50 ym
— Raman auto-focus for bulged surfaces - typical +/- 1 mm
Laser excitation at 785nm
Raman scattering
Raman shift [cm-1]

=
pharmaceutical T U
Chemical images filtered at significant reference peaks of

API, excipients or coatings
Reference Raman spectra of

pure substances of A, Band C
aflTy
Xray diffraction
= Principle: Observing the scattering of an X-ray beam hitting a sample as a

function of incident and scattering angle. An analysis of angle vs. intensity
provides information about the crystal structure.
= The dimension of a structure is reciprocal to the scattering angle (Bragg's law)

— Large structures (e.g. particles, pores) scatter to small angles
— Small structures (crystal lattice) scatter to large angles

2dsin® = nA
N = order of the diffracted beam

A = wavelength of the X-rays
d = distance between the planes of the

crystal lattice
0 = angle between incident ray and

scattering planes
Constructive interference Destructive interference

TREE)
aflTy
Single-crystal X-ray diffraction
= Analysis of the evenly spaced planes of a (perfect) single crystal

X-ray powder diffraction (XRPD)
= Analysis of crystalline properties of powdered solid samples

Small-angle X-ray diffraction (SAXS)
= Analysis of large structures (e.g. particles or pores) at small scattering angles

Ultra-small-angle X-ray diffraction (USAXS)
= Analysis of even larger structures possible than with SAXS

Wide-angle X-ray diffraction (WAXS)
= Analysis of small (sub-nanometer) structures at large scattering angles

Small & Wide-angle X-ray diffraction (SWAXS)
= Analysis of large and small structures at large scattering angles
why
research
center
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Small/Wide Angle X-Ray Scattering = HECUS S3-Micro
= Crystallinity
= Polymorphism =i SAXS 154
= Internal surface JTS

5 :
fnecus
VETEME SME ORAZ
a eel iMel q(VA) BET EET] FT We) Able] Adel nw

S3-MICRO 3.79A
4.384 Rmix
| Tmix
|
| 334A
[|
3.934 \
|
A
| \
-~ No {LPN k-.
Bed re WE A AB Ae AN ASN HR ES AS AY NB NA EW TRE EN ER HA eked
TREE)
Laser diffraction
= Principle: Laser light is scattered by particles suspended in a carrier gas.

particle size
(distribution) can be inferred from the diffraction pattern (i.e. intensity versus
diffraction angle)
Benefits
= Short analytical time
= High precision, robustness & reproducibility

= Wide measurement range
= Flexibility of operation using liquids

Shortcomings
http://www.malvern.co.uk/
= Particles are assumed to be spherical

= Volume diameter of non-spherical parameters is typically overestimated
= Re-scattering by other particles is neglected
research
center
pharmaceutical T U
Focus beam reflectant
= Principle: A laser beam rotates at high speed and propagates into a solution.
When the laser
hits a particle, light is scattered back and measured to give a chord length
distribution.
= The particle size distribution can be inferred from the cord-size distribution.
Cutaway of probe tip
Delacwr, Fiber Optic ©
Rotating at
& Fixed High
Velocey
. Probe al approx v Red /

45 angle io turbulent /
v well-mixsd flow
RN spc pos R.
aser Bean Is \_
Schematic of a chord length
x Scan Direction
a ep
| A
f >
N 4— Typical Paicle
|=
\ —
Chord Length
! Intensity Frofile
&
\
20 ESSEC eres | a
t >
tp ty t
A A MB
em me = r——
1 2 3 4
Source: Mettler-
ToledoApplication_note_Crystallization_Studies_on_MultiMax_with_FBRM.pdf
ED)
research
center
pharmaceutical T U
Optical Coherence Tomography Tab 1

breitbandige Tab 2 |
Measurement principle: Lichtquelle > oN
Variation of thickness
$ within a batch Tab3 ame.
Bd A | Strahlteiler Taba _a———
’ . 2 = |
al pn |
Detektor Tab.5
Referenz- A B,
spiegel
x 1
= + Oberflache 2 P(N —
Probe E—“—te— Grenz-~" & Side view .
schicht ~— aR
Position Ref, .
In cooperation with RECENDT ~piege Determined coating film thickness correlates
directly
to the optical refractive index of the material.
TREE)
research
center
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3D Image reconstruction of several OCT images
Histogram
Coating Thickness (um)
Propability Density
=]
I=
rd
~
ssao0.dbuneo)
Scanning electron microscopy (SEM)
[E)
research
center
pharmaceutical T U
Off-line | At-line | On-line | In-line

Optical microscopy X X
Electron microscopy X
Infrared spectroscopy X X X X
Raman spectroscopy X X X X
Chemical imaging X X X X
X-ray diffraction X X X X
Nuclear Magnetic Resonance Spectroscopy X X X X
Differential Scanning Calorimetry X
Differential Thermal Analysis X
Thermogravimetry X
Focused Beam Reflectance Measurement X X X X
Laser Diffraction X X X
Dynamic Light Scattering X X X
Optical Coherence Tomography X X X
platy, [) Ea)
wr T
center AA + - aro - 1
pharmacevtical U We make tomorrow's drugs possible.
Feedbackwards control Composition

analyzer/controller
2- Excipient
Example: PAT-tool:
NIR HELIOS
ee,
"eee,
..
eran,
Soa,
e,
Composition
analyzer/
transmitter
research
center Cor N N
pharmaceutical TU We make tomorrow's drugs possible.
=E engineering Grazm :
Feedforward control
Composition
analyzer/controller
1- API / excipient premix

————
LSS
2- Excipient
Composition
analyzer/
transmitter
PAT used for endpoint detection
Objective of the method
= Online API prediction
= Online moving block standard

deviation of API prediction
= Endpoint decision not on time but

based on API concetration to be
between 90 and 110 and standard
deviation of API over the last 10
revolutions below 2,5
= Stopp at defined endpoint
API [%]
Different End point settings
1000
Time [min]
—e— End point determination by
time
—=— End point determination by
homogeneity
——RSD
—=— RSD
EudraLex The Rules Governing Medicinal Products in the European Union

Volume 4 EU
Guidelines for Good Manufacturing Practice for Medicinal Products for Human and
Veterinary Use
Annex 17: Real Time Release Testing and Parametric Release
= When designing the Real Time Release Testing (RTRT) strategy, the following
minimum
criteria are expected to be established and met:
(i) Real time measurement and control of relevant in-process material attributes
and process
parameters should be accurate predictors of the corresponding finished product
attributes.
(i) The valid combination of relevant assessed material attributes and process
controls to
replace finished product attributes should be established with scientific evidence
based on
material, product and process knowledge.
(ii) The combined process measurements (process parameters and material attributes)
and
any other test data generated during the manufacturing process should provide a
robust
foundation for RTRT and the batch release decision.
aflTy
= A RTRT strategy should be integrated and controlled through the PQS. This should
include or reference information at least of the following:
quality risk management, including a full process related risk assessment, in

accordance
with the principles described in EudralLex, Volume 4, Part | Chapter 1 and Part ll
Chapter 2
change control program
control strategy
specific personnel training program
qualification and validation policy
deviation/CAPA system
contingency procedure in case of a process sensor/equipment failure
periodic review/assessment program to measure the effectiveness of the RTRT plan

for
continued assurance of product quality.
nihTy,
QbD for special dosage forms
aflTy
= Additive manufacturing is considered to be the use of computer-aided-design (CAD)

software or 3D object scanners to direct hardware to deposit material, layer upon
layer,
in precise geometric shapes. In additive manufacturing material is constantly added
to
create an object e.g. tablet (3D printing)
= |n a wider sense, 2D printing can also be considered additive manufacturing due

to the
similarities by adding drug layers on substrates
= For 3D printing, different technologies are being used for the layering process
aflTy
= Vat photopolymerisation; which is a process that utilises a light source (e.g.

laser) to
selectively cure a vat of liquid photopolymer, transforming it into a solid object.
Examples of
such are the stereolithography (SLA), digital light processing (DLP) and continuous
liquid
interface production (CLIP) technologies.
= Binder jetting (BJ); which revolves around the selective binding of solid powder
particles by
spraying a liquid agent.
= Powder bed fusion; which is a selective thermal process that involves the fusion
of powder
particles by the application of a laser or other heat source. It includes selective
laser sintering
(SLS), multi jet fusion (MJF), direct metal laser sintering/selective laser melting
(DMLS/SLM)
and electron beam melting (EBM).
= Material jetting; which is a selective technique in which liquid droplets of

materials are
deposited on a surface. These droplets spontaneously solidify (known as drop-on-
demand
(DOD)) or can be cured or fused using a UV light (known as material jetting (MJ))
or a heat
source (known as nanoparticle jetting (NPJ).
Awad et al Drug Discov Today 23(8):1547 (2018) platy, [) Ea)

aflTy
= Direct energy deposition; which is a process that selectively deposits a form of

focused
thermal energy (e.g. laser) directly onto powder particles, causing them to melt
and fuse. It
involves two technologies; laser engineering net shape (LENS) and electron beam
additive
manufacturing (EBAM).
= Sheet lamination; which compromises the bonding of materials in the form of

sheets (e.g.
cut paper, plastic or metal) to fabricate 3D objects. It is often known as
laminated object
manufacturing (LOM) or ultrasonic additive manufacturing (UAM).
= Material extrusion; which is a technology that involves the selective dispensing

of material
in a semi-solid form. This technology is further subdivided into fused deposition
modelling
(FDM), which utilises thermoplastics, and semi-solid extrusion (SSE), which
utilises gels and
pastes.
Awad et al Drug Discov Today 23(8):1547 (2018) platy,

research
pe
pharmaceutical We make tomorrow's drugs possible.
EE Kjar et al Pharmaceutics 11: 390 (2019)

=E
research
center
pharmaceutical
engineering
aflTy
Excipients most commonly used in
3D printing
4K BN ANN
I EE
Used as photopolymer
Solidifies with the action of a laser beam
Fusion
SCE EEE 2 2 BEE EERE
Konta et al Bioengin 4:79 (2017)
=
=
research
center
pharmaceutical T U
Spritam® is marketed by Aprecia Pharma using 3D-Printing Type Printer

powder bed fusion by the layer-by-layer Electrospinning Discover ¢ Evolution
. . . ve vVolu
production system. The first layer consists of Hybrid Extrusion nha d
: ) ) . GeSiM Bioscaffolder 3.2/4.2
the active ingredient and all of the excipients Bot TAZ
. Z
necessary to produce the matrix tablet. PR —————
. . A. . . . aker ca ,
Subsequently, a binder liquid is deposited for Material Extrusion ZMorph 20 SX
perfect integration and aggregation between all Solidoodle 2 Base
of the successive and identical layers. Spritam® Material Jetting 3D Systems Phenix
PXM
can be manufactured with up to 1000 mg of Binder Jetting Z Corporation Spectrum
Z510
levetiracetam. Two-Photon NanoScribe Photonic
Polymerization Professional
: Envisiontec Perfactory DSP III
ew Standard SXGA+, Kudo 3D
ht = oF watc Stereolithography Titan 1, Carbon M2
ey —Xt 3D Systems Projet 6000
Kjar et al Pharmaceutics 11: 390 (2019)
TREE)
aflTy
Feedback from FDA — Considerations
= Raw material control: printability, physicochemical characteristics, thermal

conductivity, viscoelastic
property, Print fluid characteristics (Viscosity, Surface tension, Density,
Rheology/ Viscoelastic
property)
= Process control: Identify high risk steps which may impact identity, appearance,
assay, content
uniformity, drug release, impurity level, hardness, friability, crystallinity, and
API polymorphic form.
Example of such steps could be: printing, solidification, recycling, controlling
mass & energy
transport. PAT can be used for control.
Feedback from FDA - 3DPrinted Drug Products: Typical Quality Defects
Banding: ripples on a product’s sides caused by vibration in the x-y plane during
printing
Leaning: off-axis products caused by drift in the x-y plane during printing
Warping: product distortion caused by thermal expansion or contraction
Shifting: First few layers were shifted because of base line shift during printing
Collapse: loss of porosity caused by sagging layers or excessive mass/energy input

Residuals: unbound powder or uncrosslinked monomer caused by incomplete printing
Akm Khairuzzaman (Acting Branch Chief, OPQ/FDA), USP Meeting Api 29, 2016 ally
Solvent-casting method. The ODF is preferably formulated using the solvent-casting
method,
whereby the water-soluble ingredients are dissolved to form a clear, viscous
solution.
Hot-melt extrusion . In the HME process, the API and other excipients are mixed in
a dry state, the
heating process is started, and the molten mass is extruded out of the hot-melt
extruder
Semisolid casting . In the semisolid-casting method, a solution of the water-

soluble, film-forming
polymer and acid insoluble polymer (e.g., cellulose acetate phthalate and cellulose
acetate butyrate)
and plasticizer is added. The prepared gel mass is cast into films or ribbons using
a controlled heat
source.
Solid-dispersion extrusion . The term solid dispersion refers to the dispersion of

one or more APIs
in an inert carrier in a solid state in the presence of amorphous hydrophilic
polymers using methods
such as HME.
Rolling method . In the rolling method, a solution or suspension containing the

drug is rolled on a
carrier. The solvent is mainly water and a mixture of water and alcohol. The film
is dried on the rollers
and cut into desired size and shapes.
l= =: seareh
aceuical T U
Films are prepared by extruding or casting methods
= The films can:

— contain the drug
— be neutral carriers
— provide muco-
adhesive properties
— support rapid
disintegration
— serve taste masking
Homogenizer i
} Doctor
T i ng Blade
Release
liner-Roller
= SciFLEXARRAYER S3 printing
system from SCIENION
= sciDROP PICO: piezo electric

nozzle
= Borosilicate glass nozzle with 80

um capillary orifice
Scarpa et al. Int J Pharm 523 (2017) 327-335 Ty

research
center
pharmaceutical T U
Process stage Technical issue Technical parameters modification
= 2D printing is still in its infancy,
Adoption of different ejection system

due to the complex nature NN” + Ink instability
hod KF wiser Ae Change of printer resolution
= |t consists of preparation of a Formulation Changs of pattem resolution
printable drug solution (ink) Ny ETT Ri
NY » Drop coalescence Change of drop frequency
able to form ul drop sizes
» Satellite drops formation
: Adjustment of printability parameters

+ Coffee ring effect
= The maximum amount of drug d Ink * Drug crystallisation Adjustment of solvent

evaporation rate
. . EPOSILION | o Limited drug loading T
to be pri nted on a su bstrate IS » Fast/slow solvent evaporation ~~ / Change of
ink temperature
Change of ink viscosity
<
< 25mg
; Modification of ink formulation

+[rug degradation
) Multiple printing cycles are Product PARISI LEK ERAN Ih} Check of substrate-ink
compatibility
possible, but increase db /
complexity
Change of substrate temperature
Modification of substrate formulation
<
* Drug-packaging incompatibility Deposition of substrate multilayers

* Product-packaging reactivity
Packaging
Deposition of coating layer

Change of packaging material
<
Scarpa et al. Int J Pharm 523 (2017) 327-335 wiTy [ ah)!

=
pharmaceutical T U
Listerine
SEM pictures of
= 1st column blank substrates (top to

bottom): Tesa, HPMC clear, Gelatin
clear, yMCC; 2nd column after
printing Sodium Picosulfate onto the
substrates (top to bottom) Tesa,
HPMC clear, Gelatin clear, yMCC
= 3rd column blank substrates (top to

bottom): List, HPMC opaque, Gelatin
opaque, pMCC; 4th column after
printing Sodium Picosulfate onto the
substrates (top to bottom): List,
HPMC opaque, Gelatin opaque,
pMCC.
Wimmer-Teubenbacher et al Int J Pharm 547 (2018) 169-180

Sodium Picosulfate drop deposition is highly
dependent on the physicochemical and
surface characteristics of the substrate
There is an aging effect upon storage
EN gh. Cott
SEM images of SP printed on (a) HPMC, (b) HPMCT, (c) TESA, (d) GE, (e)
GET, (f) LIST after storage at room conditions for a period of eight weeks
Wimmer-Teubenbacher et al Int J Pharm 547 (2018) 169-180
surface area [pm?]
contact angles of SP on substrates
400000
plotted against surface areas of
350000 List printed SP dots, Grubb’s outlier test
has been performed on the results
300000 + for the contact angles, error bars
are standard deviations (n=10)
250000 -
200000 7 HPMC HPMCT
oi —o—
150000 -
—8°% Ger
— yMCC
| 4
100000 Tesa FH
pMCC
50000 - s
0 T T T T T
30 50 70 90 110 130
contact angle [7]
JOR)
research
center
pharmaceutical T U
100 - 100
Dissolution performance of Sodium x; | ——* Fo.
Picosulfate (SP) printed on different $ss - 385 -
280 £80 -
substrates 275 Bs
. Comparison of drug release of 570 ——GET §7 } ——HPMCT
printed SP from the different 60 —#—-GE 60 —m-HPMC_
substrates; release from (a) Gelatin 0 20 40 60 80 100 120 0 20 40 60 80 100 120
. . time [min] time [min]
clear and Gelatin opaque films, (b) 100 - 100 -
HPMC clear and HPMC opaque
9 =
: : 90 2.00
films, (c) yYMCC and pMCC films and roel)
(d) Tesa and Listerine films; error S80 Sao.
. . = @
bars are standard deviation (n=3) 9.0 @/°
Z J ——yMCC E 70 - —t=—Tesa
60 T T T T pMCC oo | ==List
0 20 40 60 80 100 120 Can fn an ann 4s
: 0 20 40 60 80 100 120
time [min] time [min]
Wimmer-Teubenbacher et al Int J Pharm 547 (2018) 169-180 platy, [ Fe)!
research
center
B pharmaceutical
engineering Grazm
Liquid dispensing technology on a tablet core (GSK)

= The drug solubilized in a liquid is dispensed on the tablet
= The process steps and relevant controls
UV /NIR 1. Vision system, 1. Image analysis

[suspension droplet size 2. NIR Chemical
concentration] | | 2. Droplet weight Imaging
iB iB o
BN
5 =
Drug Solution or | | Low Volume | | Drying On-Line Surface
Suspension (c. 2-20ul) Analysis Coating
+ Placebo Tablets | | Dispensing Chemical | | & Printing

Imaging
TREE)
Technology equiped with
multiple PAT tools:
= 100 % viusal control of tablet

before and after manufacturing
= Wet dose position verification

= UV solution analysis
= Droplet weight check & drop

volume/dose content
= Temperature control drying

tunnel
= NIR dose position inspection

= Coating inspection
LsL 3s 43s usL Droplet

50 rere Tr TTT TT TT TT TTT TTT rrr
N= 606
300
250
g 200
E]
o
2 150
85% |= += 115%
50
0
FERRER RER fg 8 88888 8 8
© WO M~ oN ¥F © @® = oN oN ON WT © © Mm NT ©
a a S © 9 9 x= A I NG
od © © ~~ ~~ ~~ ~~ ~~ ~~~
LSL -3."S Nominal +3."S
150 :
125 va Tablet
100 N= 520
75 / 3 PpK =1.4
50 / \
™
°L
80 8 84 8 83 90 92 94 96 98 100102104 106 108110112114116 118
TREE)
Laboratory (and commercial) scale equipment (e.g. Lab Machine OPTIMA TDC125)
= Transdermal patches and Oral film strips
https: //www.optima-
packaging.com/en/machine-
solutions/lab-machine-optima-
tdc-125
=
pharmaceutical T U
= Commercial manufacturing and Packaging Line (e.g. OPTIMA TDC300)
= Transdermal patches and oral film strips

Laboratory and commercial packaging machines (e.g. Optima Life Science's rotary
4SS)
= Pouch Packaging Machine seals medical and diagnostic devices into pouches
Soft gelatin capsule (SGC) manufacturing process
The SGC process involves the preparation of a gelatin band that is passed through
die rolls in
which the shells are formed, while pumps are filling at the same time.
A SGC shell contains gelatin, plasticizer (e.g. glycerol, sorbitol) and colorants.
The shells are soft and wet after manufacturing and are dried down in drying
chambers for days
to weeks
The formulations can be hydrophilic and hydrophobic and contain ethanol, LMW PEG
(e.g.
PEG 200) and other solvents that are incompatible with liquid filled hard capsules
Migration of shell/formulation components can occur as well as solvents might

evaporate
during drying
why
research
center
pharmaceutical T U
Shell formulation
* The formulation of gelatin ribbon contains about 50 % of water upon encapsulation
= After encapsulation the capsules are dried down to a certain ,hardness”

reflecting about
8 % of water. Drying can take days or several weeks
= During drying shell and formulation components can migrate and volatile solvents
from
the formulation evaporate
= Different shell composition are being used for different formulation

characteritics (e.g.
hydrophilic, hydrophobic, etc)
Component Function Typical content (% w/w)

Gelatin Polymeric base 66.3
Glycerine/Sorbitol Plasticizer 33.0
Methylparaben + propylparaben (80/20) | Preservative 0.1
Colour Colourant 0.1
Titanium dioxide Opacifier 0.5
Water Solvent/process aid g.s. (0.7-1.3 x of gelatin)
oT)
aflTy
Soft gelatin capsules can be filled with liquids, paste, and semi solids. Typical
vehicles
used in soft capsule formulations are:
Water-immiscible volatile and non-volatile liquids such as vegetable and aromatic

oils,
aromatic and aliphatic hydrocarbons, chlorinated hydrocarbons, ethers, esters,
alcohols, and
organic acids.
Water-miscible non-volatile liquids, such as polyethylene glycols (LMW PEG), and

nonionic
surface-active agents, such as polysorbate 80.
Water-miscible and relatively non-volatile compounds such as propylene glycol (up

to ~8%)
and isopropyl alcohol, depending on factors such as concentration used and
packaging
conditions
The processing conditions of > 35°C for soft gelatin capsules should be avoided as
well as
compatibility studies with the final formulation is recommended
= Soft capsule are manufactured within the finished doage form manufacturing by
simultaneous shell formation, filling, sealing and drying
EE
Fill formulation
Shell formulation
Shell formation/filling
Fast drum drying
Final drying on trays
Counting
Packaging
Dispatching
= The most common soft gelatin (= Soft capsule manufacturing videos

process is the rotary die ict ml wk
principle
a Bact https://www.youtube.
com/watch?v=pu9bv
Product pump GICxVc
esssasese®
https://www.youtube.
com/watch?v=JvOI3
12TYmA
Gel ribbon Cooling drum
https://www.youtube.c
om/watch?v=Kht6L8v
KA-U
yy B Fe)!
aflTy
In-process controls Final controls
1. Gel ribbon thickness and uniformity 1.Sealing & leakage
across the ribbon 2. Potency and impurity content
2. Softgels seal thickness at the time of
: 3. Weight variation
encapsulation
4. Microbiol
3.Weight of the capsule fill and its variation crobiology
from capsule-to-capsule 5. Disintegration/Dissolution

4. Weight of the capsule shell and its 6. Content uniformity
variation from capsule-to-capsule 7 Water content/hardness

5. Moisture level of the capsule shell before 8
and after drying
nihTy,
Size and shape
= Determined by the die rolls
= Influenced by the fill formulation and drying
=
eo © © eo © - a
re ’s 2h * 20 wa
BY si | si | te | ze 1
| © ~ ~
& er = ~~ a DD) 4 ESS
—. — — mn " = Puiar aM nS ot »° 6 mie ott Heart Peat oft EL EE
T Bf T T
kK
Fi - ® ee oD
we Ir |
Die rolls
IRN vm VW
Oral liquid manufacturing includes:
= Dosing/feeding/metering
De-aerating
Heating/cooling
Homogenizer/Mixer “ui
Filtration
Cleaning in place | hb
Continuous or batch |
iL
—.
Yooh 3
{Smt
i
1y—
Id, 118
Suppositories are manufactured by forming the blister with the upper end open,
filling the
blister with the hot melt of the suppository formulation and sealing of the upper
end of the
blister
a. —
MN | i ded fy JE
- a
=
Lipid nanoparticles and mRNA
aflTy
MRNA vaccines — the most important launch

2020/21
= mRNA vaccines have emerged and progressed

very fast due to the immediate need in the pandemic
situation
= MRNAs are a relatively new biotherapeutic approach

in immunology
= The formulation consist of new excipients and new
manufacturing technology loses after
=
research
pe »
engineering G razm
Recruitment of immune cells & Migration of LNPs and LNP uptake and antigen
expression
to the site of administration APC to the draining lymph in cells at the injection
site and in
node draining lymph nodes
igen
presenting cell
(APC)
Draining Lymph
Node
Moderna Science Day 2020 why | Dn ana)

Chemical modification of IVT mRNA Untranslated regions
Coding region - Poly(A) tail
As native mRNAs, the inclusion of the three important domains is required:
1) the 7 methylguanosine cap (5° cap)
2) 2) the 5" and 3" untranslated regions (UTRs)
3) 3) the poly(A) tail

The 5” cap is a methylated guanosine appended at the 5" end (5° to 5 triphosphate
linkage). protects
the mRNA from degradation by exonucleases and facilitates ribosomal recruitment and
mRNA
translation. mRNA stability enhanced by the poly(A) tail, a chain of 50-100
adenosines (3” end.
Extracellular and intracellular hurdles including: i) serum ribonucleases, which

may hydrolyze RNAs;
il) non-specific interactions with serum proteins; iii) resident organ-specific
macrophages, which may
sequester mRNAs from the bloodstream; iv) the vascular endothelium; v) the cell
surface membrane;
vi) the intracellular endosomal barriers
Ibba et al Advanced Drug Delivery Reviews 177 (2021) 113930 wihTy A) SE)
l= =: seareh
sid rmaceutical TU
p=] Snaneening Grazm
Challenges in mRNA... a _
delivery : 4 3 : jr ya Immune
. Degradation by 0 TN 2 Z ga responses
extracellular NN ES NG) am\escare Expressed protein (EP) I
ribosomes
mRNA nanoconstruct
\ Secreted
i EP
Intracellular
EP
= Transfection, cellular
up-take
- (Se i
Endosomal NASINN TS ull JE RS.
clearance EP
RENN :
ysosome
= Intracellular release
Naked mRNA a
to the ribosomes SN
Endocytosis = Intracellular trafficking = Translation — Presentation
why | Lo a)
research
center
pharmaceutical T U
= Composition of MRNA vaccines

= Containing new excipients: (1) ionic lipid (2) DSPC (3) Pegylated lipids
Qualitative Composition of mRNA COVID-19 Vaccine Candidates Formulated as mRNA-

Lipid Nanoparticles (LNPs)".
Category Pfizer-BioNTech Vaccine Candidate Moderna Vaccine Candidate

Active pharmaceutical ingredient BNT162b2 RNA mRNA-1273
Lipid nanoparticle components ALC-0315 = (4-hydroxybutyl) azanediyl)bis SM-102
(proprietary ionizable lipid)
(hexane-6,1-diyl)bis (2-hexyldecanoate) PEG2000-DMG = 1-
monomethoxypolyethyleneglycol-2,3-
ALC-0159 = 2-[(polyethylene glycol )-2000]-N,N dimyristylglycerol with polyethylene
glycol of average molecular
ditetradecylacetamide weight 2000
1,2-Distearoyl-sn-glycero-3-phosphocholine 1,2-Distearoyl-sn-glycero-3
phosphocholine
Cholesterol Cholesterol
Buffer Phosphate (potassium dihydrogen phosphate, disodium Tris (tromethamine)
hydrogen phosphate dihydrate)
Other excipients Potassium chloride, sodium chloride Sodium acetate
Sucrose Sucrose
Water for injection Water for injection
3 Source: Pfizer-BioNTech: Reg 174 information for UK healthcare professionals for

COVID-19 mRNA vaccine BNT162b2 concentrate for solution for injection’ and Moderna
mRNA-1273-P301 Clinical Study Protocol.**
fe hy
[ Fe)!
Crommelin et al J Pharm Sci 110:997-1001 (2021) nly,

research
center
pharmaceutical T U
) ) Category Pfizer-BioNTech mRNA vaccine Moderna mRNA vaccine

Quantitative composition of
BionTech and Moderna SARS CoV :
. Name product BNT162b2; Comirnaty mRNA-1273
2 vaccine
mRNA dose; route of 30 pg; intramuscular 100 pg; intramuscular
= mRNA (5 cap, poly-A tail and Sa sxation
. Lipid nanoparticle 0.43 mg ALC-0315 = (4- SM-102 (heptadecan-9-yl 8-((2-
hydroxyethyl) (6-
u ntra ns ated reg ions ( U TRS) components hydroxybutyl) azanediyl)bis oxo-6-
(undecyloxy) hexyl) amino) octanoate}
Hr (hexane-6,1-diyl)bis(2- PEG2000-DMG = 1-
mo d ifi e d ) hexyldecanoate) monomethoxypolyethyleneglycol-2,3-
; Lo. 0.05 mg ALC-0159 = 2- dimyristylglycerol with polyethylene glycol of
= onic IP id [(polyethylene glycol)-2000]-N,N average molecular weight 2000
ditetradecylacetamide 1,2-Distearoyl-sn-glycero-3 phosphocholine (DSPC)
= DSPC 0.09 mg 1,2-Distearoyl-sn-glycero- Cholesterol
3-phosphocholine (DSPC)
CE 0.2 mg Cholesterol
: P EG lipid Buffer 0.01 mg Potassium dihydrogen Tris (tromethamine)
phosphate pH 7-8
" Choleste rol 0.07 mg Disodium hydrogen
phosphate dihydrate pH 7-8
= pH adjusted to pH 7-8
Other excipients 0.01 mg Potassium chloride Sodium acetate

0.36 mg Sodium chloride Sucrose
6 mg Sucrose Water for injection
Water for injection

research
pe » a
engineering G razm
= The ionic lipids is the mRNA binding and protecting excipient
Name Ionizable Lipid Structure and Theoretical pKas TNS pKa
™ Og
PL
Acuitas A9 [59] Coe 6.27
TCT
Ww
oO
5
D
CC 5
Acuitas 6.09
ALC-0315 [47] a5 a
Ho SSS
[=]
Moderna Lipid 5 [101] JS gateee 6.56
89 2 <
aL NEN (@)
Oo
o oD
S
Moderna Lipid H, SM-102 [42] SCC 6.75 o
}
=
a
Buschmann et al Vaccines 9, 65 (2021)

BNT162b2
mRNA-1273
pharmaceutical
= Functionality of the lipids
lonizable cationic lipid
PEG-lipid n~45 (PEG2000)
ALC-0315
eeso sso
SM-102
0+ CH,
Po
N n
EL VE Th Te a
ALC-0159
AAS ASAAA a
NANA
PEG-DMG
aflTy
negatively charged backbone

= The ionic lipids are optimized of the mRNA
for the mRNA
= They stabilize the mRNA and

lipophilize them
x =e]
=
SV
BY
KE] PEG-ipd [| Charged ionizable lips
$ Cholesterol || Neutral ionizable ped

f psec
Moderna Science Day 2020 mflaTy

l= =: seareh
sid rmaceutical TU
= The manufacturing process sequence
A @ Lipid mix
Cholesterol Vd PEG lipid 0] (organic) j
lonizable Phospholipid
: ee CTE FP
uh —
(aqueous)
rte
Ls
Moderna Science Day 2020 TREE)

research
center
pharmaceutical T U
= Aqueous phase is mixed with an ethanolic * E © gh. AYE ”

phase (missible, antisolvents) Lipids in ethanol HG Za 7 Bh Si
: 7 So Sak 5 : RS iain ds
= Nucleation occurs quickly during pH $ 74S Bo a Xo HH AL
. . . ET 3 a “any ANNI RS SU Pe
increase (formation of mMRNA-ionic lipid te To J, 7, QB RL
complexes) => sharp drop of MRNA and ~f YE Shel 3 ses)
Xo a SE
“Yad
ionic lipid concentration rs RIE | ES
H H 4 - Sates Ya T : H ') W - 7, ~>% Rad p Fr
= DSPC, Cholesterol, PEG-lipids assemble ~ 25 Nes er EA
around the mRNA-ionic lipid complex to
form nanoparticles in the aqueous solvent main weer are

= The microfluidic system assure a precise =a nes os
and reproducible microenvironment during
the nanoparticle formation process —
| fi f $ $ Navh
pros Charges SPC Cholesterol PEG-lipid mRNA
Buschmann et al Vaccines 9, 65 (2021) Ty [A Fe)!

research
center
pharmaceutical T U
Micro-fluidic manufacturing of mRNA

Inlet Roaeons solution Inlet of lipid/ethanol solution vacci nes
v
® ®
V/4
"mm Mixer structure (0, 2, 6, 10, 20, 69 SHMs)
[1 Distance to Mixer (1, 6, 15 mm)
//
<
\
\\
zs Outlet https://www.precisionnanosystems.com/platform-
(( n I technologies/product-comparison/spark#videos
RE mm
Flow md 1 cycle ;
ARAARAY SENS
. ay | yi
b b
200 nll oo
a: 31 ym
b: 50 pm
Schematic illustration of microfluidic device with 69 cycle

numbers of staggered herringbone micromixers (SHM).
Time Step=3500 Time Step=499950
Maeki et al RSC Adv.,2015,5, 46181-46185 phy [A Ea)

research
center
pharmaceutical T U
Lipid nanoparticles and mRNA |
n of ase
containing: ;
= The stability of the mRNA lipid nanoparticles is ;

limited
= After manufacturing their are frozen to -60 to —80°C

(BionTech) and -20°C (Moderna) for 6 months (due
to limited data available at emergency authorization

date)
= 2x1024 b b
.. E a
= The nanoparticles are sensitive to temperature and $ | — Unstressed
mechanical stress in the liquid form = — Physically Stressed
Q.
= Stability in syringes (lubricated withmedical silicon 5 ios
oil, <0.25 mg/cm) confirmed for up to 8 h at < 25°C £
8
0 100 200 300
size (nm)
Brader et al Biophys J 120, 1-5 (2021) why | Lo a)

research
center
pharmaceutical
=E engineering
aflTy
= The particle size of the

nanoparticle matters for
the cellular up-take and
immune response
= The micro-fluidic settings

determine the particle
size of the nanoparticles
3wp1 = 3 weeks after 1st

2wp2 = 2 weeks after 2nd
Dosing schedule 3 weeks between

1st and 2nd dose
108,
1054
104
103
Anti-pentamer Titer (d21)
3wp1
Antibody Titer After Prime
100 150
LNP Diameter (nm)
10084
1054
104
Anti-pentamer Titer (d36)
100
2wp?2
Antibody Titer After Boost
4 ia #2 a
d i ! 4 R. $: A, po
28 SEE SE
£4 : ;
: 3
aA
a0 100 150 200
LNP Diameter (nm)
Balb/C mice IM administration 3 ug dose CMV mRNA
Moderna Science Day 2020
TREE)
=
pharmaceutical T U
Conclusion
= A decade of MRNA nanoparticle science enabled the Covid

19 vaccine development in record time
= The nanoparticle internal structure is still under investigation
= The mRNA and the ionic lipid forms a distinct amphiphilic

complex
= The complex is embedded or surounded by a lipophilic

membrane
= The excipients, composition and processing is subject of

intensive research
= Further progress can be expected
‘bleb - structures with distinctly

different electron density
wary [J coe)
Purification and fractionation in
up- and downstream processing
research
center
pharmaceutical T U
Up- and downstream Processing
Major need for downstream processing
= API synthesis and drug product (purification)

= Up-concentration
= Particle separation (fractionation)
= Buffer exchange
Upstream Primary Capture Viral removal #1 Polishing Viral removal #2 Filling

recovery
( a IEESENEEE)
—— » » » » » > pn» (EEE >»
eases iid) | To%e%e%e%e%e% |
Multi-stage : : : 2 : : 20-50 nm cut-off Ultrafiltration
LO aa Centrifugation Protein A pH adjustment Filtration CEX — AEX/HIC/MMC eal
itaton diafiltration
Hanke & Ottens Trends Biotechnol 32(4):210-20 (2014) fly [ 2)

Research
Impurity profiling
Development
Small scale
Clinical
Fractionation and
Fractionation and
4 Fractionation and iE SEE ie SITET [PECs purification process

= ee purification development and .
5 purification tests Quality by Design scaling u profiling
= Compound & y by g g up Economical and
Qo : program Process :
oO impurity A ecological
LL Process optimization a
characterization re. ya optimization
qualification Process validation
Process Clinical scale
Up-stream process Sele. SLIME tel: Commercial
~ design Process :
o review PON process review
© i. Equipment qualification Co
o Compound profiling : : Process validation
= Lo selection Product conformity NR
Q Heuristic or : Optimization
2 experimental Laboratory scale analysis strategy
desian process evaluation CMC
g Product & Process Documentation
specification
wiTy
EE)
research
center
pharmaceutical |
engineering G razm
Filtration metho ds Dead-end filtration Tangential flow filtration

surface filtration are defined by their pore size y n 0° 9 -
o 0-0. 4 °Q o E
depth filtration are defined by their pore size, depth filters are ° 060 YU
porous matrices purifying effectively throughout the entire depth of lo FREER
cross-filtration like Tangential flow filtration (TFF) leverages a LL bb Cheb ele
high velocity flow tangentially across the membrane surface to

purify proteins or nanoparticles.
Diafiltration (DF) is a cross-flow filtration technique in which

fresh solvent is added to replace the volume loss due to the
filtration process
Ultrafiltration (UF) or nano-filtration (NF) are pressure-driven

membrane transport technologies passing mixtures through
@
- — - [® Jo Yr 4
hollow fibers of membrane materialultra-filtration technologies. ; . Hour a |
Baseer Thesis Uni Saarbriicken (2019) phy [A EE)

armaceutical
— C
Sartoflow® Expert SU TFF System KrosFlo TEE

(Sartorius) (Repligen)
Chromatograpic methods
= Consist of a stationary phase (e.g. resin) and a liquid phase of the mixture
= Chromatography is a versatile purification technique based on compound specific

properties
= size, shape
Charge
isoelectric point
charge distribution
Hydrophobicity
Solubility
Density
ligand-binding affinity
metal binding
reversible association
= posttranslational modifications
= specific sequences or structures

=
pharmaceutical Il T U
Chromatographic methods
Chromatographic purification princip
Affinity (AFC) separation method based on a specific binding interaction between an

immobilized ligand and its binding partner
lon exchange (CEX, AEX) Separation based on ions and charged molecules by affinity
to the ion
exchanger
Hydrophobic interaction Separation of molecules according to differences in their

surface
(HIC) hydrophobicity
Size exclusion (SEC) Separation of molecules based on their size by filtration

through a gel
Reverse phase (RPC) Separation by a hydrophobic stationary phase and a polar mobile
phase
Multimodal (MMC) Separation by more than one form of interaction between the
stationary
phase and analytes
why | Ln as)
CPP
= Column capacity
1 2 3 4 5 6
= Pressure
= Solvent Loading of the feed | Ww W/P P | P/S io
[] pH |
= temperature
= Speed (velocity)
= feeds (desity)
= Mass transfer
= \/oltage
. ty ty te to te
= Time
Fig. 1. Schematic representation of a batch chromatogram.
= torque
Deluca et al Trends in Analytical Chemistry 132 (2020) 116051
Time
CQA
Peak retention time

Peak area
Amount
Peak height
Peak width at half height

Peak symmetry
Peak tailing
Capacity factor (k)
Plate numbers
Resolution between peaks
Selectivity
research
center
pharmaceutical T U
Hipersep® Flowdrive Pilot Hipersep® Flowdrive Process M Hipersep® Flowdrive XXL

System Flow rate
Hipersep® Flowdrive Pilot 6-90 L/h
Hipersep® Flowdrive Process M 60-500 L/h (20-200 L/h for the
low flow version)
why | Lo a)
research
center
pharmaceutical T U
Purification of a triterpene glycoside saponin and determination
triterpene glycoside
saponin analyzed by
LC/Q-TOFMS ~~ _
triterpene glycoside *'9, &
300- / saponin peak 24 2
=) 221
<< 20
s 200- '
Fn 18 o
— w
4 14 $
2 1.2 =)
“= 100 1.0
5 “lag 8 2
4] § 588 8% § 5 53 8
5 0 BY — SLE TR | :
T T T T T T T 1 1 0 TTR | PO n—. L Sh de, ICI...
0 5 10 15 20 25 30 35 40 45 200 400 B00 800 1000 1200 1400 1600 1800 2000 2200 2400
Time (min) Counts vs. Mass-to-Charge (m/z)
Qi & Fox J Chromatograph A 1635 (2021) 461705 phy [A 2)

Sustainability challenge
There is a huge push from regulatory agencies on

sustainable manufacturing
Actually for 1000 - 5000 Da peptides, the volume of

waste is estimated at 3000 - 15 000 kg/kg of API
including hazardous solvents and reagents
Significant efforts in making peptide chemistry greener

by green solvents, reaction conditions, auxiliary
reagents, purification technologies in peptide and
organic synthesis and continuous processing
Ferrazzano et al Green Chem., 2022, 24, 975
HPLC = High-Performance Liquid

Chromatography
IEC = ion-exchange chromatography
SEC = size-exclusion chromatography
Distribution (%)
HPLC IEC SEC All Others
Purification technology
Distribution of purification technology used

Parenteral dosage forms
aflTy
Manufacturing of aseptic and sterile products
= Aseptic and steril products consist of a tight packaging and or device component
= Aseptic products are always adminstered through a medical device component
= Prefilled syringe components
— >
Wa py =
ks “pa
aflTy
Regulatory framework of drug-device combination products
= In Europe, if the device and the medicinal product form a single integral product
which is
intended exclusively for
use in the given combination and which is not reusable is regulated as medicinal
products according to Directive 2001/83/EC. (including the essential requirements
for safety-
and performance-of the device features)
= In contrast, devices with exchangeable cartridges, for examples, reusable pumps

are
regulated in the EU as medical devices according to Directive 93/42/EEC
= In the USA, both device-drug combinations are regulated as combination products

according
to 21 CFR Part 3.
why
aflTy
Why do we need parenteral drug delivery?
— Acute drug interventions — immediate pharmacodynamic activity (e.g. stroke,

myocardial
infarction)
— Drug properties (e.g. poor solubility/permeability, first pass metabolism, inter

- intra subject
variability)
— Presystemic metabolism/degradation (e.g. proteins)
— Unconscious or ananesthetized patients
— Drugs with high therapeutic doses
— Patients with swallowing issues
— Drug titration or constant plasma concentrations (e.g. short half life drugs)
— Tissue or organ targeted drug delivery

= Buildings and facilities
a]
BUILDINGS AND FACILITIES
Critical Area — Class 100 (ISO 5)
Supporting Clean Areas
Clean Area Separation
Air Filtration
MEIMBEARE o.oo eee eee eee seen teen eee ens eae ens
High-Efficiency Particulate Air (HEPA) ...........cc.ccooooomiieeeeeeeeeee eee eee
eae ean eens eens aensnnnns
Design
PE
S CoCo G0 1 ~1 th &
l= =: seareh
sid rmaceutical TU
p=] Snaneering Grazm
= Personnel training, Qualification & Monitoring
= Components and container/closure

= Endotoxin control
V. PERSONNEL TRAINING, QUALIFICATION, & MONITORING.......ccereeennen. 12

A. Personnel..... 13
B. Laboratory Personnel 15
C. Monitoring Program 15
VI. COMPONENTS AND CONTAINER/CLOSURES......erersresssssnsssssssncsssasssssnees 15

A. Components.. 16
B. Containers/Closures 17
I. Preparation.............. ee
teeeeeteeeeeesaseeeessssneesesennseseeensnsaeeeeannneseennnnnnseannnnnsaeannnns 4 1
2. Inspection of Container Closure System... eee eee eesae eee a nannaee anaes ae
aannannas en nnnnneeannneeaeeainneaees AO
VIL ENDOTOXIN CONTROL...
eieeieceaecsssiesssnsssssssssnssssassssssssssnssssassssssssssnsssssssssassssansss
19
TREE)
l= =: seareh
sid rmaceutical TU
= Validation of aseptic processing and sterilization
IX. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION......cccceeneee. 20

A. Process Simulations 20
Study Design ... ce eee

seteeeeteseseeseesessstesesssssessesssseessseseesnsensesassseeesssesssssnseasessnnn
es 21
Frequency and Number er of urs .
feteesesssstessssessessessessesssssssssstesssssesesssssesssssmssesessseeesassssesas
nne D2
Duration of Runs...
teiereseersesssessesssssesesssessesssessesessssiesssssesstesssesssessesseeesesesean
sessesseraransnssnrereere 22
Size of Runs... eet
esteeseeestesteseeseeseeeseessesssesseesssesseessesssessesesesstesssesssessessessss
sssessessessessssssasesns
Line Speed... a
eeeeeesseeseeeseeeeesssssessesseseesssseesesssessesessessessssetsssssssssssssssesss
ssessessssesessssseessssseessaans 23
Environmental Conditions... eet ete eaten aes eteeeeae estes eene tessa eeenne BF
Media .. .. etter eaaees DF
Incubation and Examination of Media Filled Units... eee eens aetna enn ae een
eeeeenaaeeenennes BF
Interpretation of Test Results... ee
eeeetteeeeeseteeeesseseeeesssesessesesesessnsessasssasesnneeeessseseeannnseeassaaea
as DO
Filtration Efficacy 27
Wo Nk wo ~
C. Sterilization of Equipment, Containers, and Closures 28
1. Qualification and Validation .. ce ene ee eeeeeeeaeeeeenne ee nte eens ae ennnt

enn te ens aeennsaeennnes DT
2. Equipment Controls and Instrument Calibration . ete een ee eneee eens ae nne een
anneeeennneeennnaneenneanannnaees JU)
TREE)
l= =: seareh
sid rmaceutical TU
p=] Snaneering Grazm
= Laboratory controls & sterility testing
X. LABORATORY CONTROLS 31
A. Environmental Monitoring 32
1. General Written Program.............. eee eeeaeteeeebeaeeeeateeeesateeabeae ee

esanteeansaeaeesaneeenanteeeennnaees 3D
2. Establishing Levels and a a Trending Program

eeeeeeseeesebeeeeeaeeeeeeseeeeetaeeenaneeeenaeeeesaneeesanneeessaeaes 3D
3. Disinfection Efficacy... Ce
eteeesteeeeeieseesseessessseesstesseesssesssesseesssessssssssssssessessssesssesssse
sssesssesasesaes 39
4. Monitoring Methods... OPTUS RTRRUPRPRPRRRR £
B. Microbiological Media and Identification . 35

C. Prefiltration Bioburden 36
D. Alternate Microbiological Test Methods 36
E. Particle Monitoring. 36
XI. STERILITY
TESTING ..iiiiiiisieninnnnsssssasssssssssssssssssssssssssssssssssssssssssssssssssss
sssssssssssss 37
A. Microbiological Laboratory Controls 38
B. Sampling and Incubation 38
C. Investigation of Sterility Positives 39
TREE)
aflTy
Administration of aseptic
product
Infusion (large volumes) —

injection (small volumes)
Administration (intraveneous,
intramascular, subcutaneous,
intra-occular (intravitreal,
subretinal), intrethecal,...
Ampoules
Vials
Pre-filled syringes
Injection-Pen
Major requirements for
injectables
Safety/toxicity
Immunogeneity
pH
Impurities
Leachables
Particles
Sterility
Absence of mirco-organisms
Free of pyrogens
Free from bacterial
endotoxins
Isotonicity
Biocompatibility
Formulation and drug

delivery approaches
Aqueous solutions
Emulsions
Active compound conjugates

Biodegradable particles
Liposomes
(Lipid) nanoparticles
Thermo-hydrogeling
systems
yy [) Ea)
research
center
pharmaceutical T U
= Packaging
Leaching Permeation
Adsorption (Selective)
Extenta Potential Leachables Extent? Potential Agents Extenta

Borosilicate 1 Alkaline earth and heavy N/A
metal oxides
Soda-lime 5 Alkaline earth and heavy N/A
metal oxides
Plastic polymers
Low density 2 Plasticizers, antioxidants Gases, water vapor, other
molecules
High density 1 Antioxidants Gases, water vapor, other
molecules
PVC 4 HCI, especially plasticizers, Gases, especially water
antioxidants, other stabilizers vapor and other molecules
Polyolefins 2 Antioxidants Gases, water vapor
Polypropylene fe Antioxidants, lubricants Gases, water vapor
Rubber polymers
Natural and 5 Heavy metal salts, lubricants, Gases, water vapor
related synthetic reducing agents
The USP provides a classification of glass: Butyl 3 Heavy metal salts, lubricants,
Gases, water vapor
reducing agents
Type I, a borosilicate lass; Silicone 2 Minimal Gases, water vapor
Type 11, a soda-lime treated glass;
Consider extractable volume® for ampoules and vials

(excess volume)
Type III, a soda-lime glass; and

NP, a soda-lime glass not suitable for containers for
parenterals.
Glass delamination
= |s the pH lower than 7 (acidic), an H30+ exchange will occur with

the most mobile cations, i.e., typically with Na+ or other network-
modifying ions
= OH- ions in alkaline solutions (pH > 7) are able to split the structural wo,
units of silicate glasses directly (i.e, the siloxane bridges). Duringa ==
basic attack, the backbone of a silicate glass is destroyed = edi
= At neutral pH values (around pH = 7), a combined mechanism will be *
observed due to the auto-dissociation of water. At first, ion-exchange 1 -

reactions occur similar like in acids. By that, the concentration of OH-
in the water raises leading to a start of a base attack
Regulatory guidance Most critical
= Pharmacopoeial monographs give detailed recommendations for the areas for
setup of respective studies (see, e.g., EP 3.2.1 and USP <1660>) delamination
Roehl et al Challenges in protein product development (2018) Ed. Mahler &Warne wiTy
5i=
research
center
engineering
pharmaceutical mp T U
Grazm
= Ingredients and potential leachables found in closure systems
Elastomer
Vulcanizing (curing agent)
Accelerator
Activator
Antioxidant
Plasticizer/lubricant
Fillers
Pigments
Ingredient Examples
Natural rubber (latex)

Butyl rubber
Neoprene
Sulfur
Peroxides
Zinc dibutyldithiocarbamate
Zinc oxide
Stearic acid
Dilauryl thiodipropionate
Paraffinic oil
Silicone oil
Carbon black
Clay
Barium sulfate
Inorganic oxides
Carbon black
research
center
pharmaceutical T U
Stopper elastomer performance requirements
Parameter Reason
Glass transition temperature <—55 °C Maintains rubber characteristic at all

temperatures of
lvophilization
Hardness (Shore A) = 45-55 Enables casy stopper insertion, good seal integrity over
time,
Low compression set good spike /needle penetration and reseal while minimizing
Good sealing against glass /polymer formation of fragments
Low level of coring and fragmentation
Low level of water absorption Maintains shelf life of drug product

Low level of water permeability
Low level of oxygen permeability
Low level of potential extractables Minimizes risk of interaction of drug product

with a chemical
Low level of volatiles compound from stopper
Low level of surface tackiness Eases handling prior to insertion in vial
Ease of processing Minimizes production costs
McAndrew et al Lyophilization of pharmaceuticals and biologics Ed Ward &

Matechtschuk (2019) fly [ EE)
research
center
pharmaceutical T U
, Two-leg stopper” for lyophilization products
<> Schematic of lyophilization stopper displaying

Stopper/vial system. Stopper positions of fluoropolymer film and silicone polymer
is partly inserted—this is the coating.
configuration during (A) neither film nor coating
lyophilization process (B) fluoropolymer film only
a TE
(C) fluoropolymer film and silicone polymer coating

(D) silicone polymer coating only

Matechtschuk (2019) fly [A EE)
research
center
pharmaceutical T U
= CCl is a container system’s ability to prevent bacterial or chemical

ingress from exceeding the maximum allowable leak limit (MALL)
The stopper seal the vial
in 3 ways
= USP <1207> Package Integrity Evaluation—Sterile Products
1. land seal
» = Deterministic. Leakage event detected/measured is based on a
2. transition seal predictable chain of events based on technologies that are
readily
3. valve seal controlled/monitored, and yield quantitative data
= Probabilistic: Leakage event measurement relies on a series of

nnn sequential and/or simultaneous events, random outcomes
ne a described by probability distributions. associated with uncertainties
and require large sample sizes and rigorous test controls
* laser-based headspace analysis (typically oxygen)
high-voltage leak detection
tracer gas leak detection (typically helium)
mass extraction
vacuum decay
= tracer liquids (probabilistic)

Matechtschuk (2019) fly [A EE)
USP <1207> methods

research
center
pharmaceutical
=E engineering
aflTy
= Comparision of different
Container Closure Integrety
(CCI) test methods
Roehl et al Challenges in protein product development (2018) Ed. Mahler & Warne
Method Pro Con

Microbial = Extremely small * Media-filled sample (non-product
immersion microorganism filled)
* Probabilistic
+ Long test time
Vacuum decay
» Sensitive
* Repeatable, non-destructive
* FDA consensus standard
* Defect clogged by large molecules in

product
Dye ingress * Convenient but long test + Hazardous waste/water consumption

duration * Limited sensitivity
* Repeatable + Destructive
* Detects clogs
HLVD system * Clogs are detected = Suitable positive control research
* Potential for 100% online

inspection
« Potentially destructive
+ Wet leak path required
Helium leak test
» Extremely sensitive
* Cryogenic temperature
+ Helium-filled sample
* Complex setup
testing «+ Test interfered by degassing

= Reliable
Headspace « Potential for 100% online * 05, HO, and CO, detection only
analyzer inspection « Sufficient headspace clearance
* Non-destructive
TREE)
=
pharmaceutical T U
Color codes and specifications for hypodermic needle
= Needles are available

in different sizes . :
(length and diameter) Sr Sl — - _
and tips (31G nx EE
smallest diameter,
14G largest diameter) Saget _— | E——

0c a
= Colors are used to

avoid errors
: Erm— Com—
5 green = = “Ee
yellow | =
|=—a] =
cream
white
pale green hE]

research
center
pharmaceutical T U
= Drug formulation need to be tested | i ae] err

on compatibility with the packaging 2 if £
component which is much more 5, oor 8 8 1yao 8
critical then for oral forms § Ei i £
Particle size (um) * Particle size (um)
2x10° 2x10" 2x 10° yom 2x 10°
. . TE
-_ = ary Hl Glass-S0F -
: EF 5 — Pehle g
£ 1x10" L1x10° : 2 1% 10° L 1x10 5
Protein ol 0 ol : él : Lo
particle Particle size (um) elke oo Gas) “
Concentration of protein particles for (a) abatacept PBS (b) abatacept acetate
buffer (c) adalimumab PBS and adalimumab acetate buffer formulation
Krayukhina et al J Pharm Sci 2015 wiTy
[ 2)
research
center
pharmaceutical
=E engineering
aflTy
Key attributes to build quality into the biologic drug product from manufacturing
to patient
Sterility
* Aseptic manufacturing
process (environment,
personnel, practices)
* Design/selection of
container closure system
(CCS) (dimensional fits,
container closure integrity
[CCI], manufacturability)
* Design of process
(operations critical to CCl
e.g. sealing, capping, raised
stopper detection, etc.)
* Contact materials
assessment (sterility, of
manufacturing equipment)
* Sterility testing
* Functionality testing
for devices
Design/Selection
of CCS
* Design of Process
¢ CCI testing on stability
¢ Sterility testing on
stability
Simulated shipping
studies (impact on CCl
and functionality)
Shipping qualification
* Microbiological hold
time after opening
(growth promotion
characteristics)
* Stopper/Closure
resealing (multidose
products only)
* Pharmacy Manual
(dose preparation
instructions)
* User training
Mahler HC et al AAPS Newsmagazine 7:12-17 (2018)
TREE)
5i=
research
center
pharmaceutical
engineering G razm
py
to patient
Particulate
Matter
Aseptic manufacturing
process (environment,
personnel, practices)
Design/selection of CCS
(efficiency of preparation
process, particle load)
Design of process (particle
shedding, materials contact)
Contact materials
assessment (particle
shedding from preparation
and during use)
100% Inspection
after fill/finish
AQL testing
Particulate monitoring
on stability (subvisible
and visible particles)
Simulated shipping
studies (subvisible and
visible particles)
Shipping qualification
* Simulated adminis-
tration studies
(subvisible and visible
particles)
* |n-use filtration
Mahler HC et al AAPS Newsmagazine 7:12-17 (2018)
why
)))
research
center
pharmaceutical T U
to patient
Biologic * Formulation Development | * Stability studies ¢ Simulated shipping ¢

Simulated
Stability (representative or final CCS) (product quality) studies (product quality)
administration
* Design/selection of * Leachable study ¢ Shipping qualification studies (product
CCS (extractables and quality)
leachables)
* Design of process (prepara-

tion, materials contact)
* Contact materials
assessment (compatibility)
Mahler HC et al AAPS Newsmagazine 7:12-17 (2018) Lo CREE)

research
center
pharmaceutical T U
= Clean air in the manufacturing is key for sterilized products or aseptic

preparations
= Clean rooms are defined e.g. in WHO guidelines by airborne particles
WHO Technical Report Series, No. 961, 2011
Maximum permitted airborne particle concentrat

pe Annex 6
Maximum permitted number of particles per m* greater WHO good manufacturing

practices for sterile
than or equal to the tabulated size 0
pharmaceutical products
At rest® In operation®
Grade 0.5 pm 5.0 ym 0.5 pm 5.0 ym . . .
Clean rooms grades required in operations
A 3 520 20 3520 20
Examples of ati to be ried out in the i grades
e 3520 29 352 000 2900 pes ol perEtons oe eA ne Tres
Grade Examples of operations for terminally sterilized products
C 352 000 2900 3 520 000 29 000 (see sections 4.12-4.15)
D 3 520 000 29 000 Not defined Not defined . Fling of products when unusualy at
risk
Cc Preparation of solutions when unusually at nisk. Filling of products
* The “at rest” state is the condition where the installation is complete with
equipment installed and D Preparation of solutions and components for subsequent
filling
operating in a manner agreed upon by the customer and supplier, but with no
personnel present
® The “in operation” state is the condition where the installation is functioning
in the defined operating Grade Examples of operations for aseptic preparations
mode and the specified number of personnel is present. The areas and their
associated environmental (see sections 4.16—4.20)
control systems should be designed to achieve both the “at rest” and “in operation”
states A Aseplic preparation and filling
[] Preparation of solutions to be filtered
D Handling of components after washing
TREE)
=E
research
center
pharmaceutical
engineering G razm
= Clean rooms and clean-air devices should be routinely monitored while in

operation and
the monitoring locations based on a formal risk analysis study and the results
obtained
during the classification of rooms and/or clean-air devices.
Recommended limits for microbial contamination®
Grade Air sample Settle plates Contact plates Glove print

(CFU/m3) (diameter 90 mm) | (diameter 55 mm) (5 fingers)
(CFU/4 hours)® (CFU/plate) (CFU/glove)
A <1 <1 <3 <1
B 10 5 5 5
Cc 100 50 25 -
D 200 100 50 —~
CFU, colony-forming units.

* These are average values.
® Individual settle plates may be exposed for less than 4 hours.
WHO Technical Report Series,

No. 961, 2011
Annex 6
WHO good manufacturing

practices for sterile
pharmaceutical products
TREE)
= Air treatment systems are composed of multiple different filter systems
= |n duct UVC at outlet is the C band of UV light (UVC), the most effective
germicidal light
wavelengths INSIDE AN AIR HANDLING UNIT

RUN-ARCUND
COIL 8 PP SYN AM PLUG
DAMPER FILTER ELECTRIC HEAT ~~ CCOUNG COIL HEATING COIL FAN DRIVE
Outside ar
contains mould
sperms, bacteria,
vinuses and VOCs
Spores ap DRAINPAN ~~ ULTRAVIOLET HUMIDIFICATION

n DISINFECTION
Ar supplied 10
building
Return ar fom buiding camans mold UVC photonisers destroy mould, bactina,
spores, bactena, viruses and YOCs viruses and VOCs preventing them from
re-gntering tha air Vy umes Esjanring Greg LM 1216
research
center
pharmaceutical T U
Production decontamination 35
= The industry standard for containment 3.0 Y*-00077x+ 29919
decontamination is the treatment with . # protein1+10 ng/ml
vapor phase hydrogen peroxide (VPHP) z a
EF 5 A protein1+250 ng/mL
= Critical factor to be considered in QbD: £ protein1+1000 ng/ml
. . lo} y=-0. x+2. mAb1+ m
residuals of the VPHP in the 1s a Job - oe
containment atmosphere or absorbed to E 1.0 * oT y=-0.1841x+1.7702 ® mAb1+1000
ng/mL
the surfaces interacts with the product i
C 0.5 y =-0.1435x + 1.0959 PRN.
= Assessment of the product sensitivity to
hydrogen peroxide by a spiking study 00 z = g z = r 7
(Methionine + H,0, => Methionine- Months at 5C
oxidized) Pseudo-first-order kinetic reactions of H202 consumption by
oo Met oxidation observed for various concentrations of H202
= The Spiking depends on the molecule spiked-in mAb1 formulation (10 mg/mL protein
concentration)
and its methionine residues represented by solid lines; and in small protein
formulation (5
mg/mL) by dashed lines
Grauschopf et al Challenges in protein product development (2018) Ed. Mahler &Warne

Ty [A Ea)
research
center
pharmaceutical T U
120000
= Early tests of materials of

construction (MOC) to be performed 100000
= several materials used within the

containment show different patterns 80000
of hydrogen peroxide uptake E

= probability of slow decrease of VPHP 3 600001
levels inside the containment =
40000
= Potential risk for interaction with the
product during production p—
0
Aluminum Red Clear Poly PVCClear P.ET Hypalon Delrin
Silicone Silicone Carbonate (Glove)
VPHP uptake rate (ng/cm?3) in various materials of

construction

Ty [A Ea)
research
center
pharmaceutical T U
= Consideration of high hydrogen peroxide uptake by aqueous phases
180
160
—
No
o
0 Meniscus Reverse
0 Droplet
DO Reverse
80
H202 (ng/ml)
40 Meniscus
; [= =
15 min 1.6 30min 1.6 15min 2.4 30min 2.4
Droplet
Hydrogen peroxide uptake into the drug product solution at differently

shaped menisci of drug product solution at the tip of the filling nozzle

Ty
[E)
pharmaceutical
engineering Graz
Bosch prefilled syringe line
ye
pharmaceutical
engineering Graz
Lyophilized dosage forms
research
center
pharmaceutical T U
Lyophilization (freeze drying) Ty = Glas transition temperature

= the lyophilization process comprises three fem freezmapomt Freezing point curve
rocess steps ©] water Vapor pressure
: i urve water
g g 10° 4 3 || solution liquid
i 1
— Freezing (1)
— primary drying which is characterized

by the removal of crystallized water 10! 4
by sublimation under vacuum with
gentle heating (2a and 2 b)
— secondary drying in which unfrozen

water is desorbed under vacuum by
controlled heating to more elevated
temperatures (3)
Vapor pressure
Curve solution
solid 2a
: Triple point water

Triple point solution
gas
Vapor pressure (hPa)
T T
0 20 40 60 80 100 120
Temperatur (°C)
TREE)
research
pos
pharmaceutical T U
= Formulations for lyophilization

requires some functional
excipients
= Inclusion of additional excipients

that reduce the overall glass
transition temperature of the matrix
(e.g. Sodium choride)
= additional tonicity by disaccharides

or bulking agents to enable more
efficient lyophilization
Herceptin [31] | Enbrel [32] BeneFIX [33] Remicade [34]

Protein 420 mg/fvial 25 mg/mL 50-600 IU/mL 100 mg/vial
Buffer 9.5 mg/vial 10 mM 8 mM L-histidine | 6.1 mg/vial dibasic
L-histidine tromethamine sodium phosphate,
HCL (Tris) dihydrate
6.1 mg/vial 2.2 mg/vial monobasic
L-histidine sodium phosphate,
monohydrate
Stabilizer | 381 mg/vial 10 mg/mL 0.8% sucrose 500 mg/vial sucrose
trehalose sucrose
Bulking n/a 40 mg/mL 208 mM glycine n/a
agent mannitol
Surfactant | 1.7 mg/vial n/a 0.004% 0.5 mg/vial
polysorbate-20 polysorbate-80 polysorbate-80
Other n/a n/a 0.234% sodium n/a
chloride®
“Sodium chloride is added in the reconstitution solution
Composition of marketed products
Dixon et al Challenges in protein product development (2018) Ed. Mahler &Warne
TREE)
research
center
pharmaceutical T U
Successive stages in lyophilization: the evolution of the process parameters and

the
corresponding state of the product to be lyophilized
FREEZING : PRIMARY DRYING : SECONDARY DRYING
Unfrozen
Water
i aye
: concentrated
Nanocapsules od HB |
+ of; nanocapsules |
—5f: ~N
Ice crystals 1 : ills :
Nanocapsules Formation of: Sublimation of Desorption of : Desorption of Lyophilized
suspension ice crystals : ice crystals unfrozen water : unfrozen water nanocapsules
: i 1000
: Chamber pressure Product temperature : re
Temperature (°C)
(leq) ainssaid
—— a ———— = ——- —i L 0.01
Time (minutes)
= 2)
Degobert et al Pharmaceutics 2021, 13, 1112 wiTy

research
center
pharmaceutical T U
= Examples of freeze-dried nanocapsules and process conditions
Conditions of Lyophilization Process
Encapsulated >
Drug Freezi Primary Secondary References
Polymer Drying Drying
Olmesartan 4 z : : g
PCL Mads] —40 °C overnight Different drying phases for about 48h [81]
PCL Vitamin E ~45°Cfor120min ~20°Cfor480min “20 107 2% [52]
Gradually
Chitosan + dextran IutA protein from _80°C —40to 20°C increase 83]
sulphate Escherichia coli for35h temperatures
up to +20 °C
’ Quickly frozen in igen 24 hin high
Chitosan Docetaxel liquid ni 35°Cfor60h a" [84]
Hyaluronic acid Docetaxel —20°C 3 Chih gecfor2h [55]
mTorr
Ee gr Apmis! Ovalbumin ~50°Cfor30min ~~ —40°Cfor6h 20°C for4h [86]
Isobutylcyanoacrylate lodized oil Liquid nitrogen —90 °C for 48 h under 10 mPa *
[57
PCL Fish oil = -cmy —50 °C under 0.05 mbar * 157]
* No further information on the drying stages.
Degobert et al Pharmaceutics 2021, 13, 1112

research
center
pharmaceutical T U
= |shikawa diagram of a risk assessment for a lyophilization process
| Primary drying |
Shelf temperature
Collapse temperature Capacity ice condenser
Resublimation ice condenser

Vial type
Vial heat transfer coefficient
Load configuration
Sample volume
API type + concentration
Product temperature
Dry layer resistance
Excipient type + concentration
Product quality attributes

Process duration
Shelf temperature Shelf temperature
Annealing temperature
Annealing duration
Secondary drying Managment
Junckers et al Processes 2021, 9, 1600 aiTy

research
center a . -
= The results of the risk assessment revealed the potentially most critical factors
Risk Impact Occurrence Comment

Shelf temperature affects drying rate in both phases, too high
Shelf temperature variation 8 2 value could cause collapse but a low value leads to
long drying
times, once freeze drying recipe is set, temperature easy to control
High pressure could lead to melt back, during MTM pressure is
increased in an interval that is safe for the product
Freezing step sets the foundation for drying phases, once freezing
Freezing step variation 7 RK recipe is set the temperature can be controlled easily
but stochastic
nature of nucleation still leads to small deviations in ice crystal size
Chamber pressure rise 3 10
Uncalibrated measurement units lead deviation from recipe,
Equipment not up to date 9 1 prevention through mai 1

2x 5.3 Formulation has high impact because it sets the failure mode,
Eicipient vilatic 7 . once formulation is set, composition can be good controlled
Fill level 3 1 Increased height can lead to collapse if the process is rigorously
optimized, but fill level can be controlled easily
Junckers et al Processes 2021, 9, 1600 ay B Fe)!

research
center
pharmaceutical T U
= The potentially most critical factors

displayed in Occurrence Impact diagram
Chamber pressure rise
= Design of experiments to evaluate the most critical
v
il
=
9 factors (temperature and pressure
=
< -
a #
> [J Shelf Temperature (°C) Chamber Pressure (mbar)
= Shelf temperature
- variation 1 +— -15 0.133
or - 2 ++ —15 057
Excipient ® 3 —— —25 0.133
variation | (3) Equipment not 4 1 _15 0.133
up to date 5 ++ -15 057
6 _ _25 0.133
Relative Impact 7 —+ —25 0.57
8 —+ -25 057
9 CP —20 0.352
10 CP —20 0.352
11 CP —20 0.352
Junckers et al Processes 2021, 9, 1600 phy [A Fe)!

=E
research
center
pharmaceutical
engineering
aflTy
Process consideration for the development of lyophilization
Freezing ramp rate

Freezing temperature
Annealing ramp rate
Annealing temperature
Annealing time
Refreezing rate
Refreezing temperature
Primary drying ramp
Primary drying temperature
Primary drying duration
Chamber pressure
Secondary drying ramp
Secondary drying time
Secondary drying pressure
Step Process parameters Step time Cumulative

Shelf temperature Pressure (min) time (h)
(ramp/hold) (mT)
Freezing Load at 5 °C n/a —

Hold at 5 °C 30 0.5
Ramp to =50 °C 110 2.33
Hold at =50 °C 120 433
Chamber Hold at =50 °C 100 60 5.33
evacuation
Primary drying Ramp to +20 °C 100 140 7.66

Hold at +20 °C 100 1440 31.66
Secondary Ramp to +50 °C 100 150 34.16
drying Hold at +50 °C 100 360 40.16
Post lyo Ramp to 5 °C 100 120 42.16

Hold at 5 °C 100 n/a
Typical lyophilization cycle
Dixon et al Challenges in protein product development (2018) Ed. Mahler &Warne

Radhakrishnan et al Challenges in protein product development (2018) Ed. Mahler
&Warne
wr T
center TT) . or i .
= Process parameter to be considered for nanoparticle formulation
Process Parameters Formulation before FD Ge ga

= Characterization of
rmal Lyophilized NCPs
" Temperature Pressure aie a yop
Cooling temp. e Particle size and size
Freezing Cooling rate Tp < Tew, Tg’ distribution
Duration * . eo Moisture content and
Heating rate p> prerie sorption isotherms
poo Annealing temperature To>T.’ e Reconstitution time
Annealing Duration * P> Ts e Zeta potential and
Cooling rate polydispersity index
. . Duration * e Drug content
Primary drying Heating rate Reduced Tp<2-5°Cof TcorTy Thermal analysis
(sublimation) ue pressure 2 g :
Sublimation temp. e Microscopic electronic
Secondary Desoption temp. Reduced observations (SEM, TEM)
drying Heating rate Tp< Tg? e Activity of active substances
(desorption) Duration * P and functionalized ligands
* Duration: The duration is important to ensure the completion of each stage for
all the vials. * Considering the drug encapsulated (proteins,
enzyme, etc.) and the functionalized ligands (cf. Figure 1).
Degobert et al Pharmaceutics 2021, 13, 1112 nfl B Fe)!

research
center
pharmaceutical T U
Amorphous formulation Partially crystalline formulation

- Ad d iti on al Cooling/heating Temperature/pressure | Time Coolingheating
Temperature/pressure | Time
P rocess Low-fast conditions/cycle Low-fast conditions/cycle
Freezing
pa ra m ete r to be Small pores (or lower SSA—for amorphous Fast Low shelf Longer
Fast Low shelf Longer
: d d formulations) or low crystallinity (for partially temperature duration of
temperature duration of
considere crystalline formulations) annealing annealing
Primary drying
High product temperature Fast High shelf NA® Fast High shelf NA*®
temperature + high temperature + high
chamber pressure chamber pressure
Secondary drying
High water content Fast (risk of Low shelf Shorter Fast Low shelf Shorter
exceeding Tg'/Tc) | temperature duration temperature duration
High-slow conditions/cycle High-slow conditions/cycle
Freezing
Large pores (or lower SSA—for Slow | High shelf temperature Longer duration of |
Slow | High shelf temperature Longer duration of
amorphous formulations) annealing annealing
or high crystallinity (for partially
crystalline formulations)
Primary drying
Low product temperature Slow | Low shelf temperature + low | NA* Slow | Low shelf
temperature + low | NA®
chamber pressure chamber pressure
Secondary drving
Low water content Slow High shelf temperature Longer duration Slow High shelf
temperature Longer duration
“The duration of primary drying should be sufficient to ensure sublimation has

completed in all vials and should not be a variable independently examined during
design
space construction
Dixon et al Challenges in protein product development (2018) Ed. Mahler &Warne Ty =

Fe)!
research
center
pharmaceutical
=E engineering
aflTy
= The model
concept was
build on the
determined
parameter
= MTM is able
to determine
the dry
layerstance
of the
lyophilized
cake
dQ
Heat transfer rr Ay Ky (Toners — Tp)

Heat transfer to 1 frm)
LC — + ———) (Toners = T;) = Ky - (Toners = T,
sublimation interface (x Kfrozen ( shelf i) v ( shelf »)
dm _ Pi — Pc
Mass transfer de ~ PF R,
Coupled heat and dQ dm
mass transfer ar Msn gr
Product Temperature constraint
product < T
Collapse
Equipment constraint
Jot = Jhtax
Equipment characterization
# 1.1 Shelf temperature distribution (Tz.
* Determination of crifical vials + DSC, LT-FDM, Literature
# 1.2 Maximum allowed sublimation flux Jy,
= 2.2 Dry layer resistance
Formulation characterization
* 2.1 Collapse temperature Teogapse
2.1 Dry layer

resistance (R.)
+ log slab testing
#* 1.3 Vial heat transfer coefficient K,
Arm AR gy pr fAE
Agiar(Tspo=Tproduct)
* Gravimetric determination
* Toroduce determination with WTM
- K,=
MTM: Manometric temperature measurement
* Experiment with product solution

_ A(Pjce=pPc)
* R,= =
* Determination with MTM measurement and fitting
to pressure rise data
Junckers et al Processes 2021, 9, 1600
ry ——
ATTEiE
¥
TREE)
Defining the CQA of lyophilised parenterals
= Appearance of cake and reconstituted solution
= pH
= Reconstitution time
= Residual moisture
= Potency
= Concentration or protein content for biotherapeutics

= Particulate matter
= Content uniformity
= Product purity- and impurity-related quality attributes

= Sterility
= Endotoxin
=E
pharmaceutical
engineering
research
center
vials
TY,
= The lyophilization is performed on trays with e.g. 580

Other factors to be considered
Lvophilization chamber position
which theoretically should provide the same
= The trays are introduced into the lyophilization chamber,

temperature and pressure conditions to all vials
Wall
LEONG)
(m)
MN bf bf — —
whist — r— — b. , ), Sv — S— cy — bf ry
mr -— -— -— -— 4 4 -— -— 4 -— -— -— bed
> L
El=
I i CRORCROROROR
research
center
pharmaceutical T U
= 580 vials were arranged in hexagonal (A) Chote ie hoods cide
clusters in a bottomless tray
= Vials were filled with 0.4 + 0.02 mL with a

mAbs formulation
= The freezing step was performed by

decreasing the shelf temperature from 4 to
50 C atabout0.5C min; 3.75 0r7 C min
= The vials were then held at constant

temperature for 1 h
= Chamber pressure was decreased (3, 5,

and 9 Pa) and shelf inlet temperature was
raised (29, 32 or 35 C) to the target primary
drying temperature in 30 min.
= A total of 124 edge vials and 100 central

vials were individually assessed
Freezing 0.5C/min
Freezing Precooled shelves

hy
The bottom product temperature T, differs within the
lyophilization chamber
TREE)
Cell- und Gene Therapy (CGT)
research
center
pharmaceutical T U
Cell- and Gene Therapy
The number of cell and gene therapies launched globally has steadily increased.
: CGT IS he fastest growing Cumulative global CGT" launches by type of therapy

(including launches in individual markets, eg,
research area for Japan, Russia, South Korea)?
therapeutic innovation
100
96 Total
Drug Manufacturer EMA approval
Holoclar CHIESI Farmaceutici Feb 17, 2015 75
Strimvelis Orchard Therapuetics May 26, 2016 70 Cell
Spherox CO.DON July 10, 2017
50
Kymriah Movartis Aug 22, 2018
17 RNA
Yescarta Gilead Sciences Aug 23, 2018
2b
Alofisel Takeda Pharmaceutical Aug 23, 2018
Luxturna Spark Therapuetics Mov 22, 2018 9 Gene replacement
0
Zynteglo bluebird bio May 28, 2019 1997 2000 2005 2010 2015 2020
estimated
Zolgensma Movartis May 18, 2020
"Cell and gene therapy.

“Cumulative launches, not considering if therapies have been taken off market at
some point post launch.
Source: EvaluatePharma, October 2020, Evaluate Ltd.
— gm s))
research
center
pharmaceutical T U
= CGT therapeutics manufacturing is

an emerging field of science and
technology
= Quality and GMP standards as well

as guidelines are limited and not
harmonized
= The use of cell and genes derived

from patients or donors cause new
challenges for clinical (commercial)
manufacturing and quality control
= The demand and investments will

drive the CGT manufacturing
infrastructure
Growth forecast of next-gen therapeutics far exceeding the

overall pharma market — Rapid growth driven by CGT
Cell and gene, Regenerative and Nucleic Acid Therapy sales [2020-2026E; USD bn]
—_— 10.8
27
2020 2021 2022E 2023E 2024E 2025E 2026E
Gene-modified cell therapy [1 Gene therapy [Bl DNA and RNA therapeutics Cell
therapy
Source: Evaluate Pharma; Roland Berger
TREE)
Gene Therapy Medicinal Products (GTMPs)
= in this context DNA is directly used pharmacological substance, as recombinant

genes are
inserted into cells. GTMP is defined as “an active substance which contains or
consists of a
recombinant nucleic acid used in or administered to human beings with a view to
regulating,
repairing, replacing, adding, or deleting a genetic sequence; its therapeutic,
prophylactic or
diagnostic effect relates directly to the recombinant nucleic acid sequence it
contains, or to the
product of genetic expression of this sequence” (cited from Regulation EC No
1394/2007 of the
European Parliament).
Stem cell production: Processes, practices and regulations Ed. F.A. Khan (2022):
https://doi.org/10.1007/978-981-16-7589-8 nflTy
Somatic Cell Therapy Medicinal Products (CTMPs)
= |tis defined as “biological medicinal product which contains or consists of cells

or tissues that
have been subject to substantial manipulation so that biological characteristics,
physiological
functions or structural properties relevant for the intended clinical use have been
altered, or of
cells or tissues that are not intended to be used for the same essential
function(s) in the recipient
and the donor” (cited from Regulation EC No 1394/2007 of the European Parliament).
Cell
selection, ex vivo expansion of cells, generation of clones with both anti-
neoplastic and anti-
infectious activity can be considered for example substantial manipulations. Cells
most often
used in the development of CTMPs are adult stem cells, unspecialized cells that can
be selected
from various tissues of the body and have high differentiation capacity. These
cells are
autologous when obtained from a donor and reinfused in the same person, or
allogeneic, when
donor and recipient are two different people.
Tissue Engineering Products (TEPs)
= It is defined as “a product that contain or consist of cells or tissue engineered

by different
methods, including viral or bacterial plasmid vectors” (cited from Regulation EC No
1394/2007 of
the European Parliament). They can be used to repair, regenerate, or replace
tissues. The first
products developed include artificial skin, bone, and cartilage.
Combined: Advanced Therapy Medicinal Products (ATMP)
= |tis defined as “a product that contain one or more medical devices as an

integral part of the cell
or tissue based medicinal product” (cited from Regulation EC No 1394/2007 of the
European
Parliament).
research
center
pharmaceutical T U
Research Laboratories GMP Facility Clinic
= CGT is a new and exciting field
for pharmaceutical sciences in
the coming decade

n = The advantages of in-house GMP
| facility in a hospital is the proximity
of a manufacturing facility to the
— | | hospital operating rooms and the

Process Development GMP Manufacturing pr Tumor Leukapheresis
material material cl n ical u Nn its .
Era — CONC Enable on demand manufacturing

Release " at lower cost, rapid quality control,
> product supply and optimal

organization and transport of
te cellular material.
Immune-monitoring
Cument Opinion in Biotechnology
Good Laboratory
Good Manufacturing Practice

(GMP)
Practice
(GLP)
bench
ov
Bench to bedside process flow.
lancu et al Curr Opin Biotechnol 2020, 65:233—241 phy [ Fe)!

aflTy
= Advanced Therapeutic Medicinal Products (ATMP) are emerging from

academic research focusing on life-threatening diseases, rare and orphan
disease
= They represent a new type of drug products, which are based on either on
— a gene therapy medicinal product
— a somatic cell therapy medicinal product
— a tissue engineered product
= They are handled / approved by the Paul-Ehrlich-Institute (PEI)

= They often include a medical device component
nihTy,
aflTy
a.
‘Advanced therapy medicinal product’ means any of the following medicinal

products for human use:
a gene therapy medicinal product as defined in Part IV of Annex | to Directive

2001/83/EC,
— a somatic cell therapy medicinal product as defined in Part IV of Annex | to

Directive 2001/83/EC,
— a tissue engineered product as defined in point (b)
‘Tissue engineered product’ means a product that:
— contains or consists of engineered cells or tissues, and
— is presented as having properties for, or is used in or administered to

human beings with a view to regenerating, repairing or replacing a human
tissue.
REGULATION (EC) No 1394/2007 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL ny

aflTy
c. Cells or tissues shall be considered ‘engineered’ if they fulfil at least one of

the
following conditions:
— the cells or tissues have been subject to substantial manipulation, so that
biological characteristics, physiological functions or structural properties
relevant
for the intended regeneration, repair or replacement are achieved. The
manipulations listed in Annex |, in particular, shall not be considered as
substantial manipulations,
— the cells or tissues are not intended to be used for the same essential function
or functions in the recipient as in the donor.

aflTy
d. ‘Combined advanced therapy medicinal product’ means an advanced therapy

medicinal product that fulfils the following conditions:
— it must incorporate, as an integral part of the product, one or more medical
devices within the meaning of Article 1(2)(a) of Directive 93/42/EEC or one or
more active implantable medical devices within the meaning of Article 1(2)(c) of
Directive 90/385/EEC, and
— its cellular or tissue part must contain viable cells or tissues, or
— its cellular or tissue part containing non-viable cells or tissues must be liable
to
act upon the human body with action that can be considered as primary to that of
the devices referred to.

aflTy
= Tissue Engineered Products (TEP) are individualized therapies manufactured

manually or by automated systems
A
The manufacturing process is a complex
sequence of different process steps
QUALITY CONTROL
CELL ISOLATION MATRIX —_—
NASAL CARTILAGE
cell preparation, eg thawing & washing Ea = = so cutrune ) roves =m)
1.
2. selection,
3. activation, = a
4. transduction, ‘| — — )
5. expansion, i
6. harvest and a ix Us i
7. final formulation of the cells BP ea =
Haeusner et al Product. Front. Med. 8:712917 hu

= Manufacturing of viral
vectors for cell
transfection
Upstream process § Therapsutic gene FAecombrant AAV

Introduction of [7 § Vieus genet
3 genes by regent § Veus gene?
- Analyss and
ry
a-.- - ~- ~~ ~ on
Recombinant AAV
Ultrafiltration (UF) Affinity lon Exchange UF/DF

Lysis Depth Filtration /DiafitrationiDF) Chromatography Chromatography Formulation
Vialed Product
https:/Aww. nature.com/articles/d42473-021-00020-x URE)

wr T
center TT) . or i .
= Viral vectors used
Retroviruses Lentiviruses Adenoviruses AAV HSV

Example(s) Oncoretroviruses, VSV-pseudotyped, HFV Human adenoviral Human
parvovirus, HSV-1
spumaviruses, VSV serotypes 2 and 5 AAVs 1-6
Genome RNA RNA dsDNA ssDNA dsDNA
Exogenous Up to 8 kb 8-10 kb >8 kb 5kb >30 kb
DNA insertion
Advantages Effective integration Efficiently transduce Clinical phase, No known
disease Efficient infectivity
into target cell nondividing cells (e.g., demonstrable efficacy associated with AAV
for multiple cell
chromatin, in clinical CNSa), long-term transgene infection, low toxicity, types
testing expression, application in long-term expression, in
adoptive T-cell platforms, in clinical testing
clinical testing
Disadvantages Limited ex vivo Insertional mutagenesis, Preexisting immunity T-cell
response, antibody Lack of long term
application, insertional preclinical phase, limited and inflammatory
neutralization, low DNA expression and
mutagenesis cassette size response, complexity packaging capacity patient
experience,
for manipulation in preclinical phase
Manufacturing Amenable to RCR-free Amenable to large-scale 10-L to 50-L clinical-
DSP complexity Low titers
considerations scale-up and banking clinical production grade production
achievable
AAV = adeno-associated virus; HSV = herpes simplex virus; RCR = replication-

competent retrovirus; CNS = central nervous system (including neurons and glial
cells);
VSV = vesicular stomatitis virus; HFV = human foamy virus; DSP = downstream
processing
https://bioprocessintl.com/2016/emerging-platform-bioprocesses-for-viral-vectors-
and-gene-therapies/ nfl B dln
research
pos
pharmaceutical T U
Full
capsids
Correct genome
Causes packaging
Ratio of Harvest: < 30%
all capsids Purified: > 70%
Therapeutic intended in vivo
Effect gene transfer
© of
Partially-filled Empt
y P y Aggregates
capsids capsids
Ros cli No genome Low stability and
EEE EER 2 packaging solubility in matrix
host cell DNA
Small: < 2%
Large: <1 ppm
Harvest: > 70%

Purified: < 30%
Harvest: < 10%

Purified: < 1%
increases risk of immunotoxicity, reduces transduction
Overview of the main types of capsids generated during rAAV production
Gimpel et al Mol Ther Meth Clin Dev 20, 740-54 (2021)

https://doi.org/10.1016/j.omtm.2021.02.010.
hy
fe hy
[A Ea)
research
pos
pharmaceutical T U
Relevance Characteristic Description Importance

accuracy closeness of result to true value medium® The importance of each
characteristic during
repeatability Pron UOT fa High selection of analytical methods during process
CO ons, Intra-assay precision - - - -
mrmediae precon vin a boston, gu development is based on guidance for validation of
precision inter-assay precision analytical methods and qualification plans during
reproducibity Fro een medium’ early-stage process development.
Quilificsion PEI a ones ED a. Accuracy can be inferred from precision, linearity,
and
and validation toccon po thelowest amount of analyte | specificity. It may be
difficult to establish due to a lack of
that can be detected adequate standards.
quantification the lowest amount of analyte low
Hmit that can be quantified b. Reproducibility only gains importance for lab-to-lab
transfer
linearity rests direct aon High and method standardization.
erie) ofsoalyte condone 4 c. The detection and quantification limits are relevant
mainly
* accurate, and precise to assays quantifying low levels of impurities.
volume of sample required for . . . .
sample volume a i High d. Range strongly overlaps with linearity, precision, and
erance of mel 0 matrix accuracy.
Needs in robustness Loe {method ¢ tr medium® y
evelopment Wrmaround time required from sampling eh e. Robustness is considered in
later stages of assay
time to result development.
throughput number of samples being high
processed in parallel
Gimpel et al Mol Ther Meth Clin Dev 20, 740-54 (2021)

TREE)
r Cc research
center
=E engineering
pharmaceutical
aflTy
Analytical methods
used, their
application and
suitability
The methods must
be selected
specifically for each
program and
qualified & validated
accordingly
Method Target Repeatability’ Turnaround” Purification Preparation steps Sample

volume Range” Key references
AEC content ratio <1%—4% 30 min no none 5-20 pL >10"! vg/mL nas
AUC content ratio 2% B i L 2% 10"= I
: 6 yes titration into linear range 400 pw 12 SEs
aggregation +1% SD” 5% 107 cp/mL
BLI capsid titer ~~ 10% 30min-1h no none unavailable 10°10" vg/mL es
CDMS content ratio <2% 2h yes buffer exchange unavailable nanomolar =
. removal of non-encapsidated 7 21.3557.58
ddPCR genome titer ~~ 2%-10% 1-2 h no DNA, protein denaturation 2-5pul 107-10 vg/mL
. i removal of non-encapsidated i6 nis 59,60
DyeBA genome titer ~~ 4%—16% 30 min-3 h yes DNA, capsid lysis 1-10 pL. 1077-10"
vg/mL
ELISA capsid titer ~~ 10%-20%" 25h no serial dilution 100 pL 10°-10" ¢p/mL Hrnares
FV capsid titer ~~ 5%-31.5%" 30 min no dyeing 195 pL 10°-10° cp/mL see
MassP content ratio not available ~~ 2-5 min no none 0.5-1 pL 10-10" cp/mL ores
capsid titer 2%-22% nN
oD 15 min yes protein denaturation 2 pL-1 mL 5x 10"-10" vg/mL 7°
content ratio 2%-15%
: e removal of non-encapsidated 5_1pl0 212435,37-39,57,7172
qPCR genome titer ~~ 5%-30% 1-2h no DNA, protein denaturation 1-10 pul. 107-10"
vg/mL A
SEC-FS aggregation 59%" 30 min yes none Jul >10"? cp/mL 3%
capsid titer not available
SEC-MALS content ratio not available ~~ 30 min yes none 30 pL >4 x 10" cp/mL Th
aggregation not available
capsid titer 5%—45% — ran
SLS-DLS 2-5 min yes centrifugation 1-30 ul. 6% 10-10" cp/mL oe
aggregation up to =50%
TEM content ratio 15% SD 36h yes staining 3-20 ul not available FRASSETLIETE
aflTy
CTLO19 is designed to hunt and destroy
= CAR-T cell therapy is an CD19-positive B-cell cancers in patients
individualized drug therapy
= Patient leukocytes are harvested @ ovormenss (© wate Tents

and equipped” with a Chimeric de =i
Antigen Receptor (CAR) - i
= They are reinfused into the same 2 \1 4) SS © remit
patient under strict clinical survey or T— Sa
conditions and procedures a J = 73
al © root sctaton <7 Modified T-col »
I fa - nee
Ee YS 5
Se > NOVARTIS
https://www.ema.europa.eu/en/documents/presentation/presentation-chimeric-antigen-
receptor-car-t-cells-david-lebwohl_en.pdf
TREE)
research
center a . -
Cleanroom classification for cell therapy facility based on ISO 14644-1 and EU GMP,
PIC/S
EU GMP, PIC/S Grade | ISO 14644-1 classification numbers (N)

At rest In operation
A ISO 5 ISO 5
B ISO 7
C ISO 7 ISO 8
D ISO 8 Not defined
EU GMP, PIC/S Grade | Maximum allowed particles 1000 L (1 m”) of air sample volumes
At rest In process
0.5 pm 5.0 pm 0.5 pm 5.0 pm
A 3520 20 3520 20
B 29 352,000 2900
C 352.000 2900 3520,000 29,000
D 3520,000 29,000 Not defined Not defined

research
center
pharmaceutical T U
= Major equipment for cell laboratorium
Table 1. Equipment needed to start a cell processing lab
Required equipment:
Biosafety cabinet
(or equivalent)
Water bath
Plasma extractor
Cryo-transporter
(=80°C) or liquid
nitrogen dry
shipper
Pipette aid
Desired equipment:
Sterile
connecting
device
Label printer
Microscope
Shared equipment:
Flow cytometer
Hematology
analyzer
Refrigerator
Centrifuge (with
carriers to hold
600 mL blood bags)

Tubing sealer
Micropipettes
(100 pL and 1000 pL)
Hemostats
Controlled rate
freezer
CO; incubator
Personal computer
Automated
instrument for cell
processing
Balance (Scale)
Freezer (£-70°C)
Tubing stripper
Reference
thermometer
LN, storage freezer
Hemocytometer
Microbiology lab
for bacterial and
fungal culture
Abbreviation: LN, = liquid nitrogen.
Leemhuis et al Bone Marrow Transplant (2014), 49, 1098 — 1105

Airlift Bioreactors
= Airlift bioreactors are used where the injection of a gas is made in the culture
medium which can cause
the broth to circulate between the riser and an interconnected down comer
compartment of the
bioreactor.
Fluidized Bed Bioreactors
= |n a fluidized bed bioreactor, mixture of culture medium is moved in upward

direction through a packed
bed of immobilized cells suspends them inducing a fluid-like behavior.
Packed Bed Bioreactors
= Packed bed bioreactors are used in cell and tissue engineering applications.
These bioreactors
support the growth and expansion of different types of cell lines for long period
of time under various
culture conditions.
Photo-Bioreactors
= |n photo-bioreactor, light source is used to cultivate phototrophic

microorganisms. These phototrophic
microorganisms apply photosynthesis process to generate biomass by converting light
energy into
biomass using light and CO2.
research
center
pharmaceutical T U
Different technologies used to
J :
I | \ Le expand CTMPs. Production
eT YE A 1 processes development begins
EE | | sx) using flasks or multilayer
T— ie systems at preclinical level
Disposable bioreactor Hallow-fiber bioreactor
(standard culture systems), then

the scale-up of the processes
occur mainly using bioreactors,
to obtain adequate cells number
for patients treatment. The blue
table indicates the best system
concerning the expansion
capacity, the timing of
expansion, the scalability, the
S— safety of the final product, and
the costs.
[E)
research
center
pharmaceutical |
engineering G razm
Conceptualized automation of ATMP

manufacturing
» The central six axis dual arm robot

can reach the circumference.
= Necessary equipment, disposables

and liquids are safely channeled in
through an air lock linked glove box
without the need of personnel
entering the isolator directly from an
unclassified maintenance back side.
* Pre-packed, sanitized disposables,

materials or biologicals can be
unpacked easily and set in place for
robot-driven procession. Devices for
cell culture (green) and quality control
(blue) are included in the design.
research
center
pharmaceutical
=E engineering
aflTy
01 Ventilation system
02 Freezer (-20-C)
03 Fridge (4-C)
04 Disposables storage
05 Packaging material
06 Incubator (37°C)
07 Storage for plates

and membranes
08 Gate
09 Barcode reader
10 Washing station
11 Sampling station
12 Shaker
13 Air-lock
14 Cell counting device
15 Storage for Cell culture

tubes
16 Six axis dual arm robot
17 Centrifuge
18 Plate handling positions
19 Decapper (centrifuge
flask)
20 Decapper (Cell culture

tubes)
21 Tissue grinder
22 Pipettes
23 Liquid waste
24 Sealing machine
25 Solid waste
26 Microscope
01
01
© T= 2 |
06
__/ les oo 05 |||
HY fF Hon
/ a 3
09 10
1
15 12
0 NX
(2 x ) EE 13 |
17 -
9) pel [1] [C1] (1 it
~ [OOF mg
10 )
- PE) i 3 2
oN < 13 | ) Sr
01
TREE)
research
center
pharmaceutical T U
Manufacturing of an allogeneic T-cell product genetically modified to express a

chimeric
antigen receptor T cell.
e2ssl
12
Stage 0: Stage 1: Stage 2: Stage 3: Stage 4: Stage 5: Stage 6: Stage 7: Stage 8:

Donor-Derived Thaw of CD24+ Rocovery Transduction Expansion & Expansion & Volume
Wash & Final Fill &
Starting Material ~~ Working Cell Bank Differentiation Differentiation Reduction
Formulation Cryopreservation
Collection {Small-scale) (Large-scale)
M. Scott et al. Cytotherapy 22 (2020) 669676 phy = 2)
ClinMACS Prodigy platform
(for cell manufactring)
MACSQuant Tyto
(for cell sorting)
=)
wr T
center AA + - aro - 1
pharmaceutical I U We make tomorrow's drugs possible.
= MACSQuant is a flow cytometry

tool for mining and harvestig rare
cells, analyzing the efficiency of
cell manufacturing processes or
investigating signaling pathways
Miltenyi Biotech MACSQuant Tyto Cartridge (cell sorting)
AUWNEL LW
nflaTy B Fe)!
Ambr 250 high throughput perfusion (Sartorius) - fully-automated bioreactor system

for
intensified cell culture process development
High Throughout Perfusion is a

parallel bioreactor system for rapid
development of scalable perfusion
processes using 100 — 250 mL
single-use bioreactors and a fully
automated liquid handling platform.
Ambr 250 high throughput perfusion (Sartorius) - fully-automated bioreactor system

for
intensified cell culture process SEVERE
Single-use pressure sensors to

9 p Cell retention filter standards are
continuously monitor pressure at the

culture fluid inlet and permeate outlet Hl 0,2 ym or 30kDa
Single-use pump chambers to exchange

x i SE culture fluid between the bioreactor
© BR = and the hollow fibre filter.
Single use perfusion

reactor
The single-use pinch valve cassette at the
4 alll base of the perfusion tower to guide the fluids

through the perfusion tubing for automated
collection.
TREE)
research
center
pharmaceutical T U
System monitor
Media and =
nutrient feeding >
pipe
Air
« Sensors
Reactor tank >
Thermal jacket
NS
~N
Submerged aerator
= Effluent
Diagrammatic representation of the bioreactor for cell culture
Rate of mixing in the bioreactor
Organism types Rate of mixing

Bacteria, yeast, fungi S500-1500/min
Mammalian or plant cells 30-300/min
Temperature range in different organisms
Type of organisms Temperature range

Bacteria, yeast, fungi +20 *C to +60 °C
Mammalian or plant cells +25 °C to +37 °C
pH range for different organisms
Type of organisms pH range

Bacteria, yeast, fungi 4.5-7.0
Mammalian cells 6.7-74
Stem cell production: Processes, practices and regulations Ed. F.A. Khan (2022) en
https://doi.org/10.1007/978-981-16-7589-8 ny, - 2)
Biostat STR® 500 Biostat STR® 1000 Biostat STR® 2000
Qbd for Medical devices and combination
products
QbD for Medical Devices and combination products
A ‘medical device’ means any instrument, apparatus, appliance, software, implant,

reagent, material or
other article intended by the manufacturer to be used, alone or in combination, for

human beings for one
or more of the following specific medical purposes:
— diagnosis, prevention, monitoring, prediction, prognosis, treatment or

alleviation of disease,
— diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury

or disability,
— investigation, replacement or modification of the anatomy or of a physiological

or pathological process
or state,
— providing information by means of in vitro examination of specimens derived from

the human body,
including organ, blood and tissue donations,
— and which does not achieve its principal intended action by pharmacological,
immunological or
metabolic means, in or on the human body, but which may be assisted in its function
by such means.
— The following products shall also be deemed to be medical devices:
— devices for the control or support of conception;
— products specifically intended for the cleaning, disinfection or sterilisation of

devices as referred to in
Article 1(4) and of those referred to in the first paragraph of this point.
Regulation EU 2017/745 Ty
aflTy
Usability studies in the targeted

patient population and their
environment is required
= If the device has not been used in the Oo

proposed patient population before EUROPEAN MEDICINES AGENCY
or if the setting of use is new and a i
different from the intended use as
confirmed by the certificate of 29 May 2019
conformity or NBOp (e.g. a prefilled Committee for Medicinal Products for Human Use
(CHMP)
syringe used for the first time in an
outpatient setting or used for the first
time in patients with conditions which
could impair use), a usability study —
to evaluate whether the DDC can be
used safely to deliver the medicinal
product to the target population - is
expected
Guideline on the quality requirements for drug-device

combinations
Draft
aflTy
FDA regulation
This guidance recommends that

manufacturers follow human factors or
usability engineering processes during
the development of new medical
devices, focusing specifically on the
user interface, where the user interface
includes all points of interaction
between the product and the user(s)
including elements such as displays,
controls, packaging, product labels,
instructions for use, etc
Applying Human Factors and

Usability Engineering to Medical
Devices
Guidance for Industry and Food

and Drug Administration Staff
Document issued on: February 3, 2016

As of April 3, 2016, this document supersedes “Medical Device Use-Safety:
Incorporating Human Factors Engineering into Risk Management” issued

July 18, 2000.
nihTy,
research
center
pharmaceutical T U
Hazards traditionally considered in risk Define intended users, use | ———— | Device
Users, Use Environments and
. . environments and user interface User Interface (Section 5)
analysis include: : 2
= Physical hazards (e.g., sharp corners or Identify use-related hazards Preliminary
Anolyses and
Evaluations (Section 6)
edges), = 3
. . . Identify and categorize critical

= Mechanical hazards (e.g., kinetic or tasks
EZ
Develop and implement risk

mitigation/control measures
Validate use safety and
potential energy from a moving object),
= Thermal hazards (e.g., high-temperature

components),
Elimination or Reduction of Use-

Related Hazards (Section 7)
Human Factors Validation Testing
effectiveness (Section 8)
= Electrical hazards (e.g., electrical current,
electromagnetic interference (EMI)), Use related
= Chemical hazards (e.g., toxic chemicals), co
= Radiation hazards (e.g., ionizing and non-
ionizing), and soot rl VES
introduced?
= Biological hazards (e.g., allergens, bio-
incompatible agents and infectious agents). ed
Document HFE/UE process Documentation (Section 9)
The ability of a user to operate a medical device depends on his or her personal
characteristics, including:
= Physical size, strength, and stamina,

= Physical dexterity, flexibility, and coordination,
= Sensory abilities (i.e., vision, hearing, tactile

sensitivity),
= Cognitive abilities, including memory,
= Medical condition for which the device is being

used,
= Comorbidities (i.e., multiple conditions or

diseases),
= Literacy and language skills,

= General health status,
Mental and emotional state,
Level of education and health literacy

relative to the medical condition involved,
General knowledge of similar types of

devices,
= Knowledge of and experience with the
particular device,
Ability to learn and adapt to a new device,
Willingness and motivation to learn to use a

new device
aflTy
Similar to the Risk Assessment for the drug development, HFD includes a task
analysis to answer the following questions:
= What use errors might users make on each task?
= What circumstances might cause users to make use errors on each task?
= What harm might result from each use error?
= How might the occurrence of each use error be prevented or made less frequent?
= How might the severity of the potential harm associated with each use error be
reduced?
aflTy
Medical device user interface framework
Cognitive
Information Processing Control
Perception Actions
Device
Processing
& Reaction
research
pe » a
engineering G razm
Medical device regulations
REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
. 7 https://eur-lex.europa.eu/legal-
CE content/EN/TXT/PDF/?uri=CELEX:020
on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and
17R0745-20170505&from=EN
Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and

93/42/EEC
(Text with EEA relevance)
(OJ L 117, 552017, p. 1)
Medicines Agency Guidance Medical devices [z5=-
Table of contents
» Medical devices legislation
https //www.ema.europa.eu/en/hum » Medicinal products that include a medical device

(‘combination products’)
an-regulatory/overview/medical-
devices
Medical devices with an ancillary medicinal substance
Companion diagnostics ("in-vitro diagnostics’)
Medical devices made of substances that are systemically absorbed

Borderline products
yy B fa)
= Medical Device classification is based on potential risk of the device (I = low;

[Il = high)
= Conformity assessment is the method by which a manufacturer demonstrates that

their
devices comply with the requirements of Directive 93/42/EEC
CONFORMITY CLASSES
ASSESSMENT
PROCEDURES
ANNEXES [ I I lla Ib mn
Sterile measure
Il (+ section 4) N
II (- section 4) \ V v V
In N V
Iv v \ N V \
V v \ N N N
Vi N N N N
Vil N N N N
Technical documentation relating to products in class lla and class IIb must be
reviewed by a notified body of the basis of a programme of representative sampling
in the context of Annexes Il, VV and VI of Directive 93/42/EEC.
aflTy
There are two types of combination:
— integral: the medicinal product and device form a

single integrated product e.g. pre-filled syringes
and pens, patches for transdermal drug delivery
and pre-filled inhalers; [|
camiage selecion
Dosage
Residual
re indie adr
ale
AY Retidual cone
Pan Cap
Rubber
stopoer
— co-packaged: the medicinal product and the device
are separate items contained in the same pack e.g.
reusable pen for insulin cartridges, tablet delivery

system with controller for pain management.
Insulin Pen
— Needle —
attachmat
point
Insulin
reservoir
Mex
U a
£l
Tl) es Ml iD §
—> 3
Dose adjustment dial

«a BD - Injection button
TREE)
r Cc research
center
harmaceutical
Pb =k
engineering
aflTy
= Combination products in the USA are drug-device products (fixed dose combinations
are
drug-drug products)
= The regulations emerged early this century with the increasing number of targeted
and
personalized threatments
1970's First
combination
products fall
under FDA
regulatory
authority
1997 Regulation of
combination
products falls
under the FDA
Modernization Act
(FDAMA)
2004 Published
the draft cGMP for
Combination
Products
1990 Safe Medical 2002 Medical 2013 Final Rule

Devices Act Device User Fee
21 CFR Partd
(SMDA) includes and Current Good
provision for the Modernization Act Manufacturing
regulation of (MDUFMA) of Practice
combination 2002 - Requirements for
products Office of Combination
1991 Product Combination Products
Jurisdiction Produc.
Regulations 21 establishe
CFR Part 3
ED)
aflTy
FDA Guidance treats the device part and the

drug part as separate constituents
= The cGMP requirements for constituent parts .

of cross-labeled combination products that are Guidance for Industry and
entirely manufactured at separate facilities are FDA Staff:
the same as those that would apply if these
constituent parts were not part of a
combination product (e.g., for a drug/device
Current Good Manufacturing Practice

Requirements for Combination Products
combination product, only parts 210 and 211 FINAL GUIDANCE

(21 CFR parts 210 and 211) would apply to the
manufacture of the drug constituent part(s) of The draft of this document was
issued in January 2015.
the cross-labeled combination product, and

only part 820 (21 CFR part 820) would apply to
the device constituent part(s)).
nihTy,
research
center
pharmaceutical T U
Typical combination products are Inhalers
= three different types exist

— pMDI (pressurized metered dose inhaler)
+ Propellant driven
+ Mechanical pressure driven
— Nebulizer solutions
— Dry Powder Inhaler
« Capsule based metered

- Blister based metered
« Reservoir based metering chambers
Propellant with
drug suspension
Mouthpiece
5 |
pMDI
Mouthpiece with 1g"

spiral shaped PRA
<I Extra air inlets
channels e
-
Inhalation channel
One metered dose
Rotating dosing disk

Drug reservoir
Air inlet —t28
Turning grip —
Reservoir based
metering chamber
ADVAIR uy
Smimel
Blister based metered

nihTy,
[E)
The DPI product consist of four elements of equal importance for the performance
1. Interactive powder mixture (API, powder blend, porous particles)

2. Powder container/primary packaging (capsule, blister, reservoir)
3. Device
4. Processing 7a
(1) (2)
aflTy
The critical factors for dry powder manufacturing
Input materials
= Material propertise (particle size, size distribution, surface propertise,

triboelectrics, physical
state, carrier coarse-fine particle ratio, storage history, moisture content, etc)
Room conditions
= Room temperature, relative humidity
Particle size reduction/mixing
= Type and geometry of miller/mixer, load, order of entry, time & intensity of
milling/mixing, etc)
Filling
= Type of filling equipment, nozzle size, diameter, length, machine

speed/vibration, powder
transport, powder flow, powder bed height, nozzle diving depth, etc
research
center
B pharmaceutical
engineering Grazm
Harro Hofliger microdosator filling
Courtesy of K-H Seyfang from Harro Hofliger Ty

research
center
pharmaceutical T U
= B engineering G razm
Harro Hé6fliger drum filling
Stirrer
Filling Position Powder bed
Dosing bore
Filter Scraper
membrane blade
Drum
Vacuum/air § = sleeve
channel
Exhaust Drum
core
Blister
Caonsule
Courtesy of K-H Seyfang from Harro Héfliger wiTy = ))

research
center
pharmaceutical T U
Propellant free liquid inhaler systems
= Mechanical pressure driven inhalation device, manufactured and assembled in one

operation
spring
= Respimat, the first propellant free liquid inhaler system
~~
nozzle
piston=capillary cartridge
Cross-section of Respimat®
H. Wachtel, Patient-centric inhalation product design AAPS Workshop Oct. 2012 nflTy
B Fe)!
= The main element of the
Respimat is the Uniblock
whereby two fine jets of
liquid converge at a preset
angle
= The collision of the jet

liquids form 65-80 % of fine
mist particles of < 5.8 um,
delivering a dose of 2.5 ug
tiotropium
Mouthpiece
Uniblock tess...
%
0)
Dose-release button
Capillary tube
Upper housing
—
Transparent base
Spring
Cartridge
LT
ou
LIN
SLT
“e
LIT
“e.
**e00esnss.
TON
.
SLT
SLT
SALT
vee,
LT
SLT
LITT
Nozzle outlet
Filter structure
Silicon wafer
ee eeeeee®
A Glass
enna,
Ri TIVO
=E
research
center
pharmaceutical
engineering G razm
= Excellent delivery performance across 120

actuations...
0 10 20 30 40 50 BO FO BO 80 100 110 120 130
130 130
125 om mmm mm mm ee me L125
120 4 ——— mmm E120
115 + F118
110 4 L110
Delivered volume [% of target value] + SD

2 8 8
I
I
|
I
I
i
T T T T
88 &
[i] 0 20 30 40 S50 80 TO BO 80 100 MO 120 130

Number of actuations
= ...but very expensive and complex and

prone to errors for patients
Spiriva*
Respimat*®
inhaler
How 10 use
SPIRIA Fi SOUAT imboler
Thi tafe ax plane aw 1 ca 3d cam tar

pot SRA FE PMAT rear Pass ead
306 otal toh hee Aurea Tx
aha section 3. Haw EA
The TINA WLANs comes

0 2M (M0 medicinal toasy THe Som
fil Pr TY ee re ey
mascasee = WL Wher Be oir cours
& Mot Oe TPTRMA RESPIMAT irae

Be re ares of the scale, hero in,
medcatos
Song hey Ooze.

Be ding ded
1 Femi 190 SPRNA RESPIMAT nares

wre
¥ senate = Oe 167 BT of 6 een
Each dhmcy ous we & 13ks TWO
iby POL 0 SI CINK 20 Tred
. urna ~
AL 9 lgtat, Stews TONLE Bel 36 te
SPR RESFMAT Fhaber h0sE 28
3 Open ve green cap (A weed saa uly

ogee, Saree and
trea | or
rer sa
‘omg at corse
=
mm
Rope viaps | nd 1 50 Aa you ge Be

Nt eon
lies id a 6 Polo me SARMA SESFIMAT maar

or Tas vas he Wet wares ne ~~ ste
Cmtegmacmit Come the pm cp wb ves so your

Page saps. S20 6 well ond -— ——
FRA RITUAL her tn on em
430 Nor ros han 7 oye mba ne
Thom apex maps 5 ane 6 frie moss Arete a rar
res 5 ara ees pg remy pert
21 aps rep ps 4106 ar 2 cond is
Your SPO RESHMA] Pha br 8 Sow let "het noe sen b © § thes men
aD = ——
hero ups wi ct Soci renter of
005 ¥FH0R AR DEFIANT Ou
SPIRIVA SESPINAT infor will De ate
Performance testing of DPI products
= Three different DPI product concepts
» Targeted performance is verified in e.g. Next Generation Impactors
Blister-based system Multidose reservoir Capsule — based

system system
WS
Wi
Recovery (%)
2 8 5 8
Tw 3 ll
aflTy
Engineered particles for pulmonary delivery
= An emerging field in pulmonary drug delivery is the manufacturing of engineered

particles in the size range < 5 ym using of Spray Drying
= Engineered particles are typically used for biologics, drugs with poor
crystalline
geometry and high dosed drugs
= They contain excipients that provide specific functionality to achieve a desired

aerodynamic particle size/shape
= The suitable excipients are limited due to safety and toxicity issues/concerns
for
pulmonary applications
= Engineered particles are used for e.g. tobramycin (TOBI™ Podhaler™) or have been
used for e.g. insulin (Exubera™ — withdrawn from the market),
nihTy,
Key process parameter y
Spray Solution
= Stability versus process time
= Shear, pH, concentration, interactions

Atomization
= Define target particle size
= f (geometry, pressure) mn
EE
L |
Drying Conditions (i o
= Product morphology Separator
= Water content Te
= Physical state
- f (Tin Tout Moin Mgas) O Solution

Collection Efficiency Tank
= High Value Product \ /
= f (geometry, product properties) |
oO Powder
Handling
research
center
pharmaceutical
=E engineering
aflTy
Excipients selection for
spray drying DPI
formulation
= should be kept at a
minimum
= should provide a
required functionality
Chemical classes of excipients used for particle engineering of DPI
Amino acids Sugars/polyols Polymers Lipids

Alanine lactose Chitosan Cholesterol
arginine Mannitol Dextran/dextran-10 Phospholipon
cysteine Raffinose Hypromellose Phospholipids
Glycine Sucrose Polyethylenglycole Phosphatidylcholine
Leucine/isoleucine Trehalose Polyvenylalcohol
Lysine Polyvenylpyrrolidone
Methionine
Phenylalanine
Serine
Threonine
Trileucine
Tryptophan
tyrosine
valine
Possible functionalities provided
Stabilization of API
Stability of API
Stability of API
Aerodynamic Properties
Surface properties Particle Morphology | Morphology Dispersibility
Particle and surface | Solubility Particle density
Morphology Dispersability Drug release
Flowability Dispersibility
dispersability
aTy [) Ea)
research
center
pharmaceutical T U
= Increasing drug load in carrier based powder mixtures

can be targeted release higher doses and emitted FPF
= Jet milled (IMSS) and Spray dried salbutamol (SDSS)

mixtures with lactose (Lactohale 100) at 1 % and 10 %
drug load were filled at 5 and 10 mm powder bed height
= The FPF, was 29 % (152 ug) for 1 % drug load and 62 %

(3633 ug) for 10 % drug load
Sample ED (pg) FPD (ug) FPFgp (%)

LL-JMSS_5 mm 408.4 + 44.9 88.2 + 7.2 21.7 + 2.1
LL-JMSS_10 mm 512.5 + 23.0 152.2 + 17.6 20.7 + 3.6
LL-SDSS_5 mm 535.8 + 25.5 51.9 + 13.7 9.7 + 2.4
LL-SDSS_10 mm 552.2 + 16.6 48.8 + 6.2 8.8 + 1.1
HL-JMSS_5 mm 5074.1 + 1536.9 2828.0 + 1530.8 53.5 + 12.8
HL- JMSS_10 mm 3633.2 + 526.6 3633.21 + 526.6 62.8 + 3.8
HL-SDSS_5 mm 5004.9 + 306.0 1094.5 + 63.0 21.6 + 2.6
HL-SDSS_10 mm 7051.7 + 943.7 1450.0 = 107.9 20.0 + 4.3
Pinto et al J Drug Del Sci Technol 48: 466—477 (2018)

= Complex design, with > 22 high precision pieces
= Requires an integrated manufacturing line
= Single use - waste

>a 1
Re | —
sy
[=] pharmacevtical | U We make tomorrow's drugs possible.
Blister manufacturing (1)

Blister strip buffer (2)
Blister coiling and Inhaler assembly (3)
The manufacturing line are product specific and are not easily scalable
research
center
pharmaceutical
engineering
Conclusion
Cc research
center
pharmaceutical T U
ply U.S. FOOD & DRUG
ADMINISTRATION
+—Home / Mews & Events / Congressional Testimony / Safeguarding Pharmaceutical

Supply Chains in a Global Economy - 10/30/2019
TESTIMONY
Safeguarding Pharmaceutical Supply

Chains in a Global Economy
OCTOBER 30, 2019
Ff Share | 9 Tweet jn Linkedin | 3% Email =k Print
© More Congressional Testimony of Before the

Testimonies Janet Woodcock, M.D. House Committee on Energy and Commerce,
Director - Center for Drug Evaluation and Research Subcommittee on Health
why | Lo a)
aflTy
“Using traditional pharmaceutical manufacturing technology, a U.S.-based company

could never offset the labor and other cost advantages that China enjoys simply by
achieving higher productivity. However, FDA believes that advanced manufacturing
technologies could enable U.S.-based pharmaceutical manufacturing to regain its
competitiveness with China and other foreign countries, and potentially ensure a
stable supply of drugs critical to the health of U.S. patients. Advanced
manufacturing is
a collective term for new medical product manufacturing technologies that can
improve
drug quality, address shortages medicines, and speed time-to-market. Every field
has
a different set of production techniques that are considered advanced. Examples of
some cross-cutting advanced manufacturing technologies include continuous
manufacturing and 3D printing. Advanced manufacturing technology, which FDA
supports through its Emerging Technology Program (ETP), has a smaller facility
footprint, lower environmental impact, and more efficient use of human resources
than
traditional technology, as will be explained later in this testimony.”
Janet Woodcock Oct 30, 2019
TREE)
research
center
pharmaceutical
engineering
Univ.-Prof. Dr. Sven Stegemann

Graz University of Technology
Inffeldgasse 13
8010 Graz
Austria
e-mail:
Phone: +43 316 873 0422

Mobile: +49 172 6054869
Fax: +43 (316) 873 - 1030422

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research

K1 Competence Center - Initiated by the Federal Ministry of Transport, Innovation

Promotion Agency (SFG).

= Introduction = Lipid nanoparticles & mRNA

= Future of manufacturing = Purification and franctionation in up-

= Quality-by-design and economy and downstream processing

= Quality-by-Design (QbD) in = Parenteral dosage forms

= Statistical tools used in QbD = Cell and Gene Therapy (CGT)

= Design of Experiments (DoE) = Medical devices and combination

= Process Analytical Technology (PAT)

= QbD for special dosage forms = Conclusion

INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL

ICH HARMONISED TRIPARTITE GUIDELINE

Product development cycle

| Stage 1 | Stage 2 | Stage 3 | | Staged

Source: Pharmacedtical Ressanch and Manufasiurars of amar.

& optimization Preformulation

Formulation and process

development Manufacturing transfer

Screening (10,000 molecules)

EERE EEE EEE RRR]

LE EY FEE EEE EEE EEE]

FEEF FTA EERE

IEE EEE EEE

yor 1 medicinal product

0 5 years 10 years 15 years 20 years 25 years

HB NME Biologic == Percent biologics FDA approvals 1998 - 2022

Number of FDA approvals

2022 figures of FDA approvals

= The traditional drug development and product portfolio continues to change

Fast Track Breakthrough Therapy Priority Review Accelerated Approval

CDER identified 21 of the CDER identified 6 of the

CDER identified 13 of the

20 (54%) of CDER's 37 CDER designated 12 of

hitps://www.fda.gov/imedia/164429/download?attachment wht | Bo as)

= Newly approved drugs by the FDA 2015-2019

Drug approved from year 2015 — June 2020

Number of drugs approved

Cancer caer cores os tend Infections a C Re . re mong Miscellaneous

Changing drug research and approval portefolio

59 % der Neuzulassungen 2022 sind Biopharmazeutika? Other 28%]

FDA approvals 2022 by

Biopharmazeutika: Senior et al Nature 41:174-82 (2023)

I Originale [I Biosimilars Chemische und sonstige Medikamente

BCG & VFA: Medizinische Biotechnologie in Deutschland 2023

Changing drug research and approval portefolio

Gesamtzahl der zugelassenen und im Markt verfugbaren Produkte nach Wirkstoffart?

binante stoffe? nungs- tums- Hormone thera- tums- ferone schlechts-

BCG & VFA: Medizinische Biotechnologie in Deutschland 2023

ALLOCATION OF R&tD INVESTMENTS BY FUNCTION (%)

R&D spendings Pre-clinical

million ($2 ) 558 (Phase IV) Source: PARMA, Annual Membership

. 2021 data; total values may be affected by

DiMasi et al, Journal of Health Economics, January 2016 mflaTy [A Fe)!

= General excellence of standard or level.

= A plan or drawing produced to show the look of function or workings of a

= The art or action of conceiving of and producing a plan or drawing of something

What is Quality by Design (QbD)?

= A concept introduced to the pharmaceutical

& EUROPEAN MEDICINES AGENCY

“Quality by design is an approach that aims to

ensure the quality of medicines by employing

vg. . . Risk Reduction

methodology in the design, development and