Process equipment characterization – how standardized extractables data support E&L risk assessment

Merck KGaA
Darmstadt, Germany
Simone Biel, Regulatory Expert Bioprocessing
Irene Cecchini, Principal Scientist
Webinar September 17th 2020
How standardized extractables data support E&L risk
assessment
Process
Equipment
Characterization

2
The life science business and healthcare
business of Merck KGaA, Darmstadt, Germany
operate as MilliporeSigma and EMD Serono,
respectively, in the U.S. and Canada.
Process Equipment Characterization with Standardized Extractables Data | 17 Sept 2020

1. Risk assessment: regulatory expectations and upcoming USP <665>
2. End-user’s process materials risk management
3. Case studies: extractables data evaluations
4. SUS supplier testing strategy
Agenda

4
“The parts of the
production equipment
that come into contact
with the product must
not be reactive,
additive or absorptive
to such an extent that it
will affect the quality of
the product and thus
present any hazard.”
European Commission, EUDRALEX
Volume 4, “Good Manufacturing
Practices, Medicinal Products for
Human and Veterinary Use”
Manufacturing system can affect patient outcome
Good Manufacturing Practices – GMP

James Oliver, 3D risk assessment model, JVT, Autumn 2008, page 70-76.
55
There are no purification steps in cell and gene
therapy manufacturing processes
Highest risk for patient safety is towards the end of the process
Risk Evaluation

Understand the nature and amount of potential leachables out of SUS
Regulatory Expectations
6
Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be
provided in the regulatory submission
EMA/CHMP/BWP/187338/2014
6.1.3. General issues related to single use equipment
When single use equipment is used in evaluation studies, consideration should be given to leachables
and extractables. Information should be provided on the nature and amount of potential leachables,
and the removal of such impurities. Besides data, this normally includes a risk assessment. Data do
not necessarily need to be generated under actual process conditions, for example supplier data or
data generated under representative model conditions may be suitable. During process evaluation,
small scale studies are acceptable to assess leachable profiles, leachable removal and the impact of
such impurities on cell culture performance. For verification studies, commercial scale equipment
should be used. Various batches of disposable components should be used, as appropriate, in the
manufacturing of verification batches in order to assess their impact on the product quality.

BioPhorum and USP <665> are driving the discussion
Representative Model Solvents
Potential Leachables or Process
specific Extractables
• Only RELEVANT worst-case scenario
Extractables
• Technology/polymer specific
• ALL worst case conditions according to BPOG/USP<665>
Leachables
• Real Drug & Process
1
2
3

8
Standardized Approach to Extractables Testing – USP <665> draft
“Ensure that the manufacturing system is suitable for its intended use”
“Plastic Components and Systems Used to Manufacture
Pharmaceutical Drug Products and Biopharmaceutical Drug
Substances and Products”
Pharmacopeial Forum PF 46(5), 1st September 2020
 Assessment process in two steps to establish the level of
characterization
 Initial Assessment
 Risk Assessment
 Standard extraction protocol
 New informational chapter USP <1665> provides additional
information
New General Chapter USP <665>
 ICH Q3E:
 Proposal of a new guideline
for E&L assessment
 Concept paper and business
plan published in June 2020
 To close a current lack of
alignment, consensus and
clarity among existing
guidelines

 All manufactured drug products (DP), including
pharmaceuticals (“small molecule” products) and
biopharmaceuticals (biologics)
 Drug substances (DS) for biologics
 Single-use (SU) and Multi-use (MU) systems
 Plastic components used in the manufacturing of
pharmaceutical and/or biopharmaceutical drugs
include, but are not necessarily limited to, bags, bioreactors,
cassettes, chromatographic columns, connectors, filling
needles, filters, sensors, stir bars, tubing, valves, and
vessels.
 Diaphragms, gaskets, and O-rings constructed of a polymer
USP <665>
Scope
9
processes that involve liquids

Active pharmaceutical ingredients (APIs) that are the
precursors to nonbiologic and non-biopharmaceutical DPs
 well-characterized, highly purified substances
Auxiliary items for dispensing / transferring of ingredients
Plastic spoons, funnels, pipettes, graduates cylinders,
beakers, …
 Relative short contact time
Diaphragms, gaskets, and O-rings constructed of elastomeric
materials (natural rubbers)
 no plastic materials
USP <665>
Out of Scope
10

First step: component or system testing needed?
Initial Assessment
Is the component isolated from the process
stream?
Component is in scope
Can a comparator component or system be
established?
Component is out of scope.
No component testing is required.
Proceed to risk assessment
Assessment is complete.
No component testing is required.
no
yes
yes
yes
no
11
Is the component in contact with a liquid
process stream?
Component is out of scope.
No component testing is required
no

12
Second step: the likelihood of leaching
Risk Assessment
Four Risk Dimensions per USP <1665>
1. The chemical composition of the process stream
2. The nature of the component's materials of construction
3. The temperature of contact
4. The duration of contact
And the likelihood to persist
- Accumulation or elimination of process-equipment related leachables (PERL)
- dosage form, daily dose volume, therapy duration

Organic
solvents (by
volume)
Surfactants
(by weight)
Blood/blood
-derived
substances
(by weight)
Lipids and
proteins (by
weight)
pH
Aqueous
Level 1
<5% <0.1% <1% <1% ≥ 3 and ≤ 9
Somewhat
organic
Level 2
5-40% 0.1-0.5% 1-25% 1-5%
Highly organic
Level 3
>40% >0.5% >25% >5% <3 or >9
Risk Dimensions per USP <1665>
Process Stream
If the process streams contain multiple solubilizers, e.g. protein and surfactant, the risk increases
Process
Stream
13

Risk Dimensions per USP <1665>
Material of Construction, Temperature and Duration
Additives
(by weight)
Treatment
for
sterilization
Processing
Inert
Level 1
<0.1%
Intermediate
Level 2
0.1-1%
chemical
adhesives/bo
nding of
component's
materials
Reactive
Level 3
>1%
Irradiation
/chemical
treatment
chemical
adhesives/bo
nding of
component's
materials
Temperature
(°C)
Duration
Level 1 Frozen (<-10) < 24 hrs
Level 2
refrigerated
(2-8)
Ambient (15-
25)
1-7 days
Level 3
Elevated
(>30)
> 7 days
DurationMaterial Tempera-
ture
14 Process Equipment Characterization with Standardized Extractables Data | 17 Sept 2020
 Clearance and clinical mitigating factors should be taken into account when establishing the
characterization level
 Flushing can be used to reduce the material reactivity terms by one level

15
Risk Evaluation Matrix
Risk Score to Risk Level
Dimension Scores of
Level 3
Score Risk Level Remark
Four 3333 C (high risk)
Three 3332 C
3331 C
Two 3322 C
3321
B (medium risk) or
C
if Level 2 is in temperature, solvent, or
duration dimesions, then C, otherwise B
3311
A (low risk)
or B
if one of the Level 1 scores is in the
component dimension, A, otherwise B
One 3222 B
3221 B
3211 B or A
if one of the Level 1 scores is in the
component dimension, A, otherwise B
3111 A
No 2222 B
XXXX A All other combinations
 Link the Risk Sequence
with a Level of risk
characterization
 Use mitigation factors to
adjust the result
(by -1 or -2)

Downstream Components Require Higher Level of Testing
Final Sterilization
Risk
Dimension
Material Tempe-
rature
Duration Process
Stream
Risk Score Risk
Level
Mitigating
Factor
Final Risk
Level
Final
Sterilization
Reactive
(3)
Ambient
(2)
1-7 days
(2)
Highly
Organic
(3)
3223 C 0 C
 A component used later
in the process presents a
higher risk to the patient
 Few or no opportunities
for clearance of any
leachables
 Mitigation factor depends
on the process

Risk
Level
Extraction Solution Component Testing
Low 50% Ethanol
 Non-volatile residue
 UV absorbance
Medium 50% Ethanol
 Organic extractables
profiling
High
1. 50% EtOH
2. 0.2M KCl, HCl, pH 3
3. 0.1M Phosphate buffer,
pH 10
 Organic extractables
profiling
 Extractable elements
(as necessary and
appropriate)
USP <665>
Testing Requirements
17
 Accelerated extraction at
40°C
 Extraction duration depends on
individual component and its
typical manufacturing
operations
 1, 7, or 21 days
 Dynamic extraction
 Surface-area-to-solution
volume ratio of 6 cm2/ml

Agenda

Healthcare’s pharma & biotech manufacturing network
CMO network
Rio
Mexico City
Montevideo
Atsugi
Mollet
Darmstadt
Nantong
Semoy
Aubonne
Vevey
Tres Cantos
Bari
Martillac
Guidonia
Ivrea
17 sites in 10
countries produce
our biotech and
pharmaceutical
medicines for the
more than 72 million
patients across the
globe
Calais
Meyzieu
Guidonia Site main
Activities
Analytical & Pharmaeutical Development
Biotech
Biotech Centralized QC & Stability Center
Global Analytical- Pharmaceutical Science &
Innovation
Chemical & Pharmaceutical Dev. NCEs

DSP product
contact
materials
DS/API
storage
container
F&F product
contact
materials
DP Container
Closure
System
Biotech Manufacturing Overview
20
1
2
3
“the Process is the Product”
E&L assessment covers
the entire process

ICH Q9: Higher risk requires
higher level of qualification
• The evaluation of the risk to quality should
be based on scientific knowledge and
ultimately link to the protection of the
patient
• The level of effort, formality and
documentation of the quality risk
management process should be
commensurate with the level of risk
21
Process materials risk management

22
Risk Mitigation/
Risk Control
Risk Assessment
Process
Mapping
and
process
conditions
Materials
list
FMECA risk
analysis
Critical
Material
Attributes
Preliminary
Process
Control
Strategy
Action List
Review of
risk and
Process
Control
strategy
E&L risk
analysis
Studies to
be planned
if necessary
Risk
Review
Risk
Review
Analysis
Strategy
plan
process
evaluation
Control
assessment

23
Extractables and Leachables assessment
Risk based approach
decision tree
Pre-work
Extraction
Leachables
Safety
assessment
output RISK
score
output RISK
Mitigation/
Risk Control
output Safety
assessment &
Risk acceptance
23

24
Risk based approach – risk assessment template
BPOG proposed RA template
The risk assessment is supported in the BioPhorum Operations Group (BPOG)
«Best pactice guide for evaluation leachables risk from polymeric
single-use systems used in biopharmaceutical manufacturing»
F&F operations
considered at
greater risk for
impurities vs
USP/DSP
operations.
This factor
therefore has a
higher weight in
the risk
assessment.
The conditions of use
make the difference for
the final score!

25
Risk based approach – risk assessment template
Adapted Risk Assessment template
Companies build up their own internal template to meet specific needs and procedures.
Medium
Risk
High
Risk
Low
Risk
Material meets compendial requirements
(e.g. USP, Class VI, EP…)
Low risk requirements plus appropriate Extractables
data evaluation that brackets the intended use available.
TOC/NVR data minimum test requirement to be used for
risk mitigation, should be complemented with FTIR info
for extractables identification to be submitted to
toxicological assessment.
Medium-risk requirements plus more complete
Extractables data involving different extraction
solvents/solutions and conditions and a variety of
techniques such as:
- GC-MS; LC-DAD; LC-MS; FTIR; NMR for organic
species identification and quantification.
- ICP/MS, ICP-OES, AAS for elemental analysis.
Leachables/Simulation studies may be needed.
Risk Classification & Requirements

26
Risk based approach – risk scoring example
Materials list and
dimensions:
Tube type 1
Tube type 2
Tube type 3
Tube type 4
Connector 1
Connector 2
Connector 3
Filter
SU mix Bag
Higher contact time
here during the DS
transferring and mixing
step (up to 72h) in the
bag.
Lower contact time from
this point on (<24h)
Very low surface-to
volume ratio for
connectors
Highest
risk score
here
Medium
risk
score
here

27
Risk based approach – risk mitigation
Use of the extractables data for potential exposure evaluation
Analytical
Data
Potential level
into the DP
Max daily
Dose
Potential
Patient
Exposure
Exposure
< TTC?
(e.g. 1,5
µg/day)
Yes
No further
action
No
Check
Specific
Compound
PDE
(if known)
Exposure
< PDE?
Yes
No further
action
No
Plan Adequate
Simulation/
Leachable
Study
𝐄𝐱𝐩𝐨𝐬𝐮𝐫𝐞 µ𝐠/𝒅𝒂𝒚 =
𝐄𝐱𝐭𝐫𝐚𝐜𝐭𝐚𝐛𝐥𝐞𝐬 𝐥𝐞𝐯𝐞𝐥 𝐩𝐞𝐫 𝐜𝐨𝐧𝐭𝐚𝐜𝐭 𝐬𝐮𝐫𝐟𝐚𝐜𝐞
𝒎𝒈
𝒄𝒎 𝟐 ∗ 𝐂𝐨𝐧𝐭𝐚𝐜𝐭 𝐒𝐮𝐫𝐟𝐚𝐜𝐞 𝒄𝒎 𝟐
𝐏𝐫𝐨𝐜𝐞𝐬𝐬 𝐒𝐭𝐫𝐞𝐚𝐦 𝐕𝐨𝐥𝐮𝐦𝐞 𝑳
∗ 𝑫𝑷 𝒎𝒂𝒙 𝒅𝒂𝒊𝒍𝒚 𝒅𝒐𝒔𝒆 (𝒎𝑳/𝒅𝒂𝒚)
Exposure
< PDE?
Yes
Exposure
< 30%
PDE?
Yes
No further
action
No
Plan adequate
Simulation/
Leachables study to
control EI in the DP
Evaluation for Elemental Impurities:
Evaluation for Organic Impurities:
TTC can be established based on posology and
relative toxicity.
30% PDE concept as threshold limit
established in the ICH Q3D for elemental
impurities can also be applied to organics

28
Extractables and Leachables Assessment
Process mapping
1
List of SU materials, available info and
conditions of use
Family Process step
Component
name/
Supplier
Material of
construction
Certifications
Surface –
to-volume
ratio
Max.
Product
Contact
Duration
Temper
ature
Compounding
bag
DS pooling and
mixing
SU mix Bag Pall
Film: Inner layer Ultra
Low Density
Polyethylene
Gas barrier layer EVOH
Outer layer Ultra Low
Density Polyethylene
Ports Polyethylene
USP Class VI
USP 87 (cytotoxicity)
ISO 10993 (biological
compatibility)
USP 661
Ph.Eur. (Section 3.1.5); JP
(Section 61 Part 1);
European directive
85/572/EEC
0,02 m^2/L 34h
Room
Temp
Connectors and
fittings
DS pooling and
mixing
MPC connectors
Sartorius
Polycarbonate; Silicone
USP class VI <0.001
m^2/L
2-10
Room
Temp
DP transfer
KPC Pall
connectors
Polycarbonate
USP class VI <0.001
m^2/L
18h
Room
Temp
Filters
DP and
excipients
filtration
Millipak 200 filter
Filter membrane PVDF
Structural components
Polycarbonate
USP <88>,
USP class VI
0,03 m^2/L 3h
Room
Temp
DP filtration
Opticap XL5
Filter
Filter membrane
PVDF
Structural
components
polypropylene
USP <88>,
USP class VI 0,01 m^2/L 3h
Room
Temp
Tubing
DP transfer tubes Raumedic
Platinum-cured silicone
(SIK8694)
USP class VI
ISO 10993-5
0,02 m^2/L 18h
Room
Temp
DS/DP transfer
PumpSil tube,
Watson Marlow
USP Class VI
ISO 10993-4, 5, 6, 10, 11
EP 3.1.9
0,01 m^2/L 2-10 h
Room
Temp
Final fill
Peristaltic pump
tube, B+S
FDA 21 CFR 177.2600, EP
3.1.9, USP Class VI, ISO
10993 (10&11), NSF-51
<0.001
m^2/L
18h
Room
Temp
Exemplified list
Process
Mapping
and
process
conditions
Materials
list
FMECA risk
analysis
Critical
Material
Attributes
Preliminary
Process
Control
Strategy
Action List
Review of
risk and
Process
Control
strategy
E&L risk
analysis
Studies to
be
planned if
necessary
2

4
29
Extractables and Leachables Assessment
Process
Mapping
and
process
conditions
Materials
list
FMECA risk
analysis
Critical
Material
Attributes
Preliminary
Process
Control
Strategy
Action List
Review of
risk and
Process
Control
strategy
E&L risk
analysis
Studies to
be
planned if
necessary
DS thawing/
Transfer
Compounding
and Mixing
Step
Filtration Step Final Filling
PumpSil tube
(Watson
Marlow)
Pall mix bag
Raumedic
Tubes
Filters
Connectors
and
adaptors
Peristaltic
pump tubes
Consideration Scoring
Distance along
production
stream (DAS)
9 9 9 9 9 9
Exposure
Temperature (ET)
5 3 5 5 5 5
Exposure
duration (ED)
3 5 3 3 3 3
Process Fluid
Interaction (PFI)
3 3 3 3 3 3
Dilution ratio (DR) 3 5 3 3 1 1
Material
sterilization pre-
treatment (MS)
9 9 9 5 9 5
Total score
(LRR)
high high high medium medium medium
E&L Risk scoring
Product Contact Item
Material use in
manufacturing process
Risk Level Risk Mitigated
Pall Allegro Mixing Bag Compounding Step High Risk Yes
Raumedic platinum cured silicone
tubing
Solution Transferring High Risk Yes
Watson Marlow PUMPSIL tubing Solution Transferring High Risk Yes
PC Connectors Tubing Connectors Medium Risk Yes
Durapore® 0.22 μm
Hydrophilic Millipak® Filter Device
(MPGL20)
Filter for formulated solution Medium Risk Yes
Durapore® 0.22 μm
Hydrophilic Opticap® XL Capsule
Filter for formulated solution Medium Risk Yes
B+S peristaltic pump Pt cured silicone
tubes
Peristaltic pump tubes, used in
the filling step
Medium Risk Yes
E&L Risk mitigation
Extractables
data evaluation
with exposure
calculation &
safety
assessment
3
Control Strategy
Risk associated to each material is finally revised after
extractables data evaluation and toxicological assessment
Control strategy identifies actions to
do to mitigate and control the risk.

Agenda

31
Risk mitigation: Case Study 1
Extractables data from Supplier were clear and complete:
- Extraction conditions clear and well documented
- Complete analytical panel applied (GC/MS, LC/MS, ICP/MS, NVR) and comprehensive data format
- Comparison with the previous material was done
Case Study: Supplier Notification of material change in F&F process – impact evaluation
Supplier change of small polyethylene injection ports installed on polyethylene mixing bag used for the
pooling/compounding step.
Medium
Risk
Organic Extractables list (mg) from Supplier
material characterization report
Surface
submitted to
extraction
(cm^2)
Total
extractables
mg/cm^2
Total surface
normally in
contact with the
product Cm^2
Minimum DP
batch
volume (L)
Total
extractables
conc in DP
(worst case) -
mg/L
DP max
daily dose
(mL)
Max
Leachables
exposure
(µg/day)
Is exposure
<1,5
µg/day?
(yes/no)
Hexane 1.33 554 0.02 70 12 0.105 3.2 0.34 yes
2,4 di tert butylphenol 0.25
1,3 bis (1,1-dimethylethyl) benzene 1.12
Irgafos 168 Ox 0.1
Hexadecanoic acid 3.22
Octadecanoic acid 2.94
Erucamide 0.02
Other (NVR) 1
total 10.01
Elemental Impurities (µg)
Max Leachables
exposure
(µg/day)
Is exposure <
PDE? (yes/no)Element
ICH Q3D
Class
Parenteral PDE
(µg/day)
Detected level
(µg)
Copper Cu 3 300 3 0.000101 yes
Lithium Li 3 250 0.1 0.000003 yes
Outcome:
Potential exposure judged negligible: no relevant impact on the product safety.
Risk accepted  change implemented
Generic TTC
applied here
31

32
Risk mitigation: Case Study 2 – filter validation
Identified Extractables
compound
CAS n.
Extractables
level
(mg/Filter)
Potential Exposure
(µg/person/day)
PDE
(µg/person/day)
Is exposure
<PDE?
(yes/no)
Poly(acrylate) esters 25037-45-0 87.9 88.1 120 Yes
Irganox 3114 27676-62-6 87.9 88.1 20000 Yes
Tris (2,4-di-tert-
butylphenyl)
phosphate
95906-11-9 87.9 88.1 15000 Yes
Irgafos 168 31570-04-4 87.9 88.1 15000 Yes
Erucamide 112-84-5 87.9 88.1 100000 Yes
Propylene Glycol
Monostearate
1323-39-3 87.9 88.1 600000 Yes
Worst case data from
Extractables report 175 mg for
2 filters.
Based on filters conditions of use potential
leachables concentration in the final DP
and patient exposure has been calculated
 No safety risk!
Low dose Product

33
Worst case data correspond to about 183 mg of total
extractables.
Filter validation study  extraction study under worst case conditions as per
Customer’s process conditions. Extraction done in static mode by water and ethanol.
NVR and TOC data + RP-HPLC, GC/MS and FTIR for the extractables identification.
The results are used to generate a safety assessment on the filters.
Extractables identified as mainly polyacrylate esters by FTIR
and later confirmed by MS spec.

34
Potential exposure scenario calculation:
Exposure =
𝐸𝑥𝑡𝑟𝑎𝑐𝑡𝑎𝑏𝑙𝑒𝑠 𝑤𝑜𝑟𝑠𝑡 𝑐𝑎𝑠𝑒 𝑑𝑎𝑡𝑎
𝐹𝑖𝑙𝑡𝑒𝑟 𝑓𝑙𝑢𝑠ℎ𝑖𝑛𝑔 𝑣𝑜𝑙𝑢𝑚𝑒
x DP max daily dose
Calculated Exposure >TTC for
polyacrylates that is 120
µg/person/day.
Safety Assessment did not pass
 Problem: Extractables data showed a potential high level of polyacrylate esters in the product. Based on the filter
use and product dosage the expected level calculated might potentially exceed safety limits for these compounds.
Action Plan:
1) Require for more comprehensive extractables data obtained by LC/DAD/MS
providing extractables ID and semiquantification  Confirm the extractables
ID and levels  Emprove® Dossier!
2) Perform a Flushing study to determine the correct flush volume necessary
to reduce the potential leachables to acceptable levels.
3) Verify the leachables presence into the final DP
High dose Product
Don’t panic

35
Action 1:
LC/DAD/MS Emprove® Data (from Supplier) confirmed extractables ID.
The actual levels detected by LC/DAD/MS were much lower than the TOC or NVR data.
Nevertheless the potential exposure is still high  risk still not mitigated by theory.
Action 2:
Ad hoc flushing studies in collaboration with the supplier. Representative conditions applied.
Filter flushing with water under dynamic mode. Sampling at different timepoints.
TOC to evaluate the level of leachables.
12 Liters filter flushing guarantees the TOC to minimum level.
12 Liters
Risk Mitigated

36
Action 3:
Ad hoc leachables testing to verify the level of polyacrylates in the DP.
Dedicated liquid MS analysis was set up using calibration curve using Poly
hydroxypropyl acylate (PHPA) mixture as reference material.
The testing showed that the polyacrylates were below analytical threshold.
MS spectrum of Reference PHPA at 50 ppm:
Polyacrylates < 1 µg/mL (AET)
Safety guaranteed.
Risk Mitigated

Regulatory request
Question received from health authority :
“A list of single-use product contact materials used in
the manufacturing of [xxx omitted…] is presented […]
Provide a detailed summary of the results of the
extractables/leachables studies and the exposure
safety assessment used to support their use”.
We prepared a response with all the requested
additional data already previously collected.
The Response was well
received and accepted!

38
Main points for
improvement:
• Collaboration and data sharing
• Not easy to find comprehensive
Extractables data for all the
materials  especially complicated
for Tubing or small parts. Format
sometimes not easy for further data
interpretation.
• Standard data are mostly based on
basic analyses as TOC and NVR;
characterization data needed for tox
evaluation; at least FTIR
identification of extractables
• Standardized protocols and
quantitative data are more than
welcomed
Positive aspects:
• Risk assessment approach
efficiently manages the risk associated
to SU material
• RA template is a powerful tool for
manufacturing sites to collect and
elaborate the information received
from suppliers and to prepare
adequate data package to justify the
use of SU materials
• Use in dossier drafting and responses
to Health Authorities
• Good interaction with Suppliers for
getting comprehensive data and for
support in case specific studies are
necessary
Overall Summary and
Considerations

Agenda

Revised BioPhorum protocol published in April 2020
Extractables Best Practices Guide
• Updated Extractables Protocol
• New reference guide for Quality expectations
from a testing laboratory
• New guide for reporting extractables test data
• Website has a new dedicated extractables portal
linking to suppliers websites
https://www.biophorum.com/resource/extractables-
and-leachables/extractables-portal/

Emprove® Extractables Test Strategy
BPOG Requirements USP <665> draft Emprove® Program Approach
Scope Single-use components in contact with
fluid path (for biopharmaceutical
manufacturing)
Single-use and multi-use components
and devices with fluid path contact (for
pharmaceutical and biopharmaceutical
manufacturing)
Single-use and multi-use components
and devices with fluid path contact, all
relevant existing and new products
Solvents
1) 50% Ethanol
2) 1% Polysorbate 80
3) 5M NaCl
4) 0.5N NaOH
5) 0.1M Phosphoric Acid
6) WFI
1) 50% Ethanol
2) 0.2M KCl, pH 3
3) 0.1M Phosphate buffer, pH 10
= BPOG + USP <665>
Analytical methods
HPLC-DAD/MS (APCI,ESI, +/-)
ICP/MS DI-GC/MS, HS-GC/MS
TOC pH
NVR
Described in USP <1663>. Broader
scope in methods selection.
= BPOG
Additionally: IC and Conductivity
Time points 1-3, dependent on component 1, dependent on component = BPOG + USP <665>
Pre-treatment
…‘should be pre-treated the same way
before … extractables testing…‘
“…tested when they have been
conditioned or processed in a manner
consistent with their intended use and
as specified in the manufacturer's
instructions for use.”
• Separate tests and reports for gamma
irradiation or autoclave pre-treatment
• No pre-flush unless required (worst
case)
Timing Published 2014, updated 2020 3rd draft published September 2020
• Reports released since August 2017 for
many key Filtration and Single Use
Products.

Components to Validate

43
…and it becomes even fuzzier when looking closer
Our components
3rd Party components
E.g. Tubing, connectors, fittings

Process Equipment Characterization with
Standardized Extractables Data | 17 Sept 202044
Report for Mobius® SU
library components:
 Extractables Data as per
BPOG and USP <665>
 Are available off-the-
shelf
 presents full extractables
profile for the list of
library components from
specific component family
Emprove® Extractables report for Mobius® Single Use Library Components

45
There is more to do than collecting the data
Prerequisite to Patient Safety Evaluation
Maximise efforts towards
assuring patient safety

Adoption of SUS in manufacturing processes
Regulatory expectations to understand the nature and
amount of potential leachables.
Risk evaluation by the drug manufacturer
USP <665> provides guidance of risk assessment and
testing approach for SUS.
USP <1665> helps to establish the level of component
chemical characterization.
Standardized extractables data package
SUS suppliers provide comprehensive packages to
enable initial qualification and to assure material safety.
All about patient safety!

Lead Scientist
Impurities Analytics - Analytical Development Biotech Dept.
Rome, Italy
irene.cecchini@emdgroup.com
Regulatory Expert – Bioprocessing
Life Science
Darmstadt, Germany
simone.biel@emdgroup.com
Irene Cecchini
Dr. Simone Biel
The vibrant M, BioReliance, Millipore, Emprove, Durapore, Opticap, Mobius are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks
are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources.
© 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

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