Extractables profiles for chromatography resins - adapted approach of upcoming USP <665>

The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Extractables Profiles
for Chromatography
Resins –
Adoption of Upcoming USP <665> Approach
Maren Apostel
May 28th 2020

The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

Agenda
1
2
3
Introduction
Risk Assessment for
Manufacturing Systems
Adoption of USP <665>
Approach for
Chromatography Resins
4
5
Extractables Profiles for
Chromatography Resins
Summary

Extractables Profiles for Chromatography Resins | May 28th 20205
Current status of industry
Introduction
Innovative manufacturing
 Flexible, customizable, easy-to-install
manufacturing solutions (single-use systems)
Global supply chain
 Risk management through increased
characterization of materials, process steps and
redundant measures
Safety concerns (biological and chemical)
 Traceability throughout entire supply chain for
raw materials and manufacturing systems

Typical manufacturing process for a monoclonal antibody (mAb)
Introduction
Typical monoclonal
antibody processes
can be multi-use
or single-use.

Chromatography is the key to attaining high-purity
products.
 Chromatography purification steps are widely used in the
manufacturing of biopharmaceuticals.
Chromatography steps are dependent on…
 process,
 molecule type,
 and chromatographic technique.
Often, chromatography is one of the challenges in
downstream processing.
Why are we talking about chromatography resins?
Introduction
The journey of a drug to
market begins with a molecule
that shows promise to treat,
cure or prevent disease. There
are many steps along this
journey; one of the most
important is the need to
separate and purify the
molecule from a complex
feedstream.

Benefits
 High binding capacities for target molecules
 Ease of operation and handling
 Broad pressure/flow operating window
 High caustic stability
Challenges
 Finding optimal packing procedure
 Evaluating extractables risk of polymeric resin
 Finding applicable and effective clean-in-place
procedures
Chromatography systems
Introduction

Risk Assessment
for
Manufacturing
Systems

Requirements for manufacturing systems according to
USP <665> (draft March 2019)
USP <665> provides guidance on the use of plastic materials, components and systems used in the
manufacturing of pharmaceutical drug products and biopharmaceutical drug substances and products.
In scope:
 Both single and multi-use processes
 Process steps involving liquid streams
 Plastic components such as
− bags, filters, tubes, valves etc.,
− packed chromatographic columns
Out of scope:
 auxiliary plastic items that are in contact with the process stream for a short period of time
 non-fluid path components
There is no industry standard referring to chromatography resins as bulk.

Requirements for manufacturing systems according to
USP <665>
The manufacturing system should be…
 composed of materials and components that are safe for use with the pharmaceutical or
biopharmaceutical product and all process intermediates and/or process streams,
 compatible with the pharmaceutical or biopharmaceutical product and all process intermediates and
process streams, and
 functional.
 To characterize manufacturing systems, a two-step evaluation is recommended:
1. Initial evaluation (in scope/out of scope)
2. Risk assessment (process-dependent)

Plastic
components
in process
USP <1665>
Risk dimensions for consideration
Temperature of
contact
Material of
construction
Chemical nature of
process stream
Duration of contact

Process stream
Risk dimensions per USP <1665>
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
If the process stream contains multiple solubilizers, e.g. protein and surfactant,
the risk increases.

Clearance and critical mitigating factors must be taken into account when establishing
the risk level.
Material of construction
Risk level
Additives
(by weight)
Treatment for
sterilization
Processing
Inert
Level 1
<0.1%
Intermediate
Level 2
0.1-1%
Chemical adhesives
/bonding of
component's
materials
Reactive
Level 3
>1%
Irradiation
/chemical
treatment
Chemical adhesives
/bonding of
component's
materials

Clearance and critical mitigating factors must be taken into account when establishing
the risk level.
Material of construction, temperature and duration
Risk level 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
Risk level
Additives
(by weight)
Treatment for
sterilization
Processing
Inert
Level 1
<0.1%
Intermediate
Level 2
0.1-1%
Chemical adhesives
/bonding of
component's
materials
Reactive
Level 3
>1%
Irradiation
/chemical
treatment
Chemical adhesives
/bonding of
component's
materials
Flushing/rinsing can be
used to reduce the
material reactivity by
one level

Components and systems
Testing requirements per USP <665> (draft)
Risk
level
Biological reactivity
tests
Chemical assessment Extraction solutions for
chemical testing
Chemical testing of
extracts
Low No testing Partial chemical assessment  Solution C3  Non-volatile residue
 UV absorbance
 Delta pH
Moderate 〈87〉
Cytotoxicity tests
Limited chemical assessment  Solution C3  Low-risk tests
 Organic extractables
profiling
High 〈87〉
Cytotoxicity tests
〈88〉
System injection test
Intracutaneous test
Full chemical assessment  Solution C1, C2 and C3  Low-risk tests
 Organic extractables
profiling
 Extractables elements
(as necessary and
appropriate)

Adoption of USP
<665> Approach
for
Chromatography
Resins

Typical manufacturing process for a monoclonal antibody (mAb)
Chromatography steps in manufacturing
Components
used late in the
process present
a higher risk, as
there are few or
no opportunities
for clearance of
any extractable
or other
impurities
Location of chromatography
steps in downstream may vary
from process to process
Extractables profiles support
the risk assessment process

Based on rules suggested by <USP> 1665
Example of risk evaluation
Product group Material Duration Temperature Process stream Risk level
Affinity resins 1 1 2 2-3
Low-
moderate
Ion exchange resins 1 1 2 2-3
Low-
moderate
This matrix is merely an example of an evaluation.
 Risk levels are highly dependent on the specific process and the evaluation criteria used.

Study design – supporting worst-case approach
Adoption of procedures of USP <665>
For the high-risk level, USP <665> suggests:
 3 extraction solvents: pH 3, pH 10 and 50% ethanol
 Use same systems or components as for extraction
Chromatography resins:
 Material is shipped and stored in 20% ethanol / 150 mMol NaCL and never used in dry stage
 Storage solution needs to be removed for use in process (pretreatment necessary)
 Material is used in the process in packed bed (compression depends on process)
Approach:
Follow USP <665> as closely as possible
Apply standard pretreatment conditions (as in use in industry)
 Wash with water to replace the storage solvent (20% EtOH/water)

Study design – supporting worst-case approach
Adoption of procedures of USP <665>
Applied extraction conditions as suggested by USP <665>:
Solvent Duration Temperature
Organic, 1/1 (v/v)
ethanol/water
24 h 40°C
KCl solution at pH 3.0 24 h 40°C
PBS buffer at pH 10.0 24 h 40°C
For the risk levels in the example, only extraction in 50 % ethanol would be mandatory.

Extractables
Profiles for
Chromatography
Resins

Extractables profiles for chromatography resins
Analytical methods used for extractables profiling
Method Extractables
HS GC/MS
headspace gas chromatography-mass spectrometer
Volatile substances
GC-FID/MS
gas chromatography-flame ionization detector-mass spectrometer
Semi-volatile substances
HPLC-DAD/MS
high-performance liquid chromatography coupled with diode-array
detection and electrospray ionization mass spectrometry
Non-volatile substances
 For quantification of extractables, external and authentic standards were used.
 Characterization of peak identification data: tentative, confident, confirmed and
unknown.

Few components with very low amounts detected.
Example profile for Eshmuno® Q
Extraction solvent
(procedure condition)
Substance CAS ID level
Standard used for
quantification
Method and
detection mode
pH = 3 Acetaldehyde 75-07-0 confirmed external HS-GC-MS
pH = 3 Dichloromethane 75-09-2 confirmed external HS-GC-MS
pH = 10 Ethanol 64-17-5 confirmed external HS-GC-MS
50 % aqueous ethanol
(v/v)
2-Hydroxytetrahydrofuran 5371-52-8 tentative external GC-FID/MS
(v/v)
1,4-Butandiol 110-63-4 confirmed external GC-FID/MS
(v/v)
Unknown - unknown external HPLC-DAD/MS

Most of the resins tested so far show a similar profile:
 Few components were detected in extracts
 Component amounts detected were low
 Most components can be traced back to base matrix or packaging material
The probability of chromatography resins adding significant risk to the safety of the
drug product is low.
Summary

Factors to be considered by customer:
 Adaptation of data to packed resin
 Buffers used in manufacturing process
 Time of contact
 Volume of continuous phase used for purification
steps
Preconditions for extractables profiles
provided:
 Bulk resin
 Pretreament with 10 BV (bed volume) of water
 Extractions under worst-case conditions (as
described in USP <665>)
How to adapt data for customers’ risk assessments
Chromatography resins are just one part of the manufacturing process.
The customer needs to assess their entire process.

Emprove® Suite
Convenience, ease and relevance
Emprove® Suite – making it easier to
find the information you need:
 Online access to all dossiers in the
entire Emprove® portfolio in their
most current version
 One-time registration (incl. CDA) per
company
 24/7 access for 1, 2 or 5 years

Emprove® Chromatography
29
Dossier library
Operational Excellence Dossier
 Manufacturing process (detailed
information)
 Elemental impurity information
 Residual solvents statement
 Extractables profile
 Product quality report
 Analytical procedure
Material Qualification Dossier
 General information
 Manufacture
 Quality information
 Specification, release criteria
 Packaging material
 Regulatory statements (BSE/TSE,
allergens…)
 Storage and shelf life
 Environmental statement
Quality Management Dossier
 Supply chain information
 Product quality self-assessment
 Supplier and process evaluation
statement
 Stability data

Testing strategies applied for Emprove® Portfolio
Emprove® Program approach for
consumables
Emprove® Program approach for
chromatography
Scope
Fluid path Single-use and multi-use components and
devices
Bulk chromatography resins
Solvents = BPOG + USP <665> USP <665>
Analytical methods
= BPOG
Additionally: IC and conductivity
Described in USP <1665>

Assess the risk to
patient safety
 Patient safety
evaluation
Identify and
quantify the
extractables
 Extractables data
Regulatory
submission
Assess the risk
 Define the process: feed
formulation, filtration,
chromatographic and
process conditions
Re-assess the risk
to patient safety
 Update patient
safety evaluation
Identify and
individually quantify
the leachables
 Leachables tests
 Flushing/risk
mitigation
Risk-based approach continues beyond
chromatography resins and extractables

Summary
The risk of chromatography resins
introducing additional impurities into
the final drug product is low.

Maren.apostel@milliporesigma.com
Maren Apostel
Millipore, the vibrant M, Emprove, Eshmuno and Fractogel 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.

Extractables profiles for chromatography resins - adapted approach of upcoming USP <665>

Extractables profiles for chromatography resins - adapted approach of upcoming USP <665>

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Extractables profiles for chromatography resins - adapted approach of upcoming USP <665>