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EXTRACTABLES & LEACHABLES
Standard Protocols in Single Uses
TechnologyUSP and BPOG Approaches; a discussion in brief
Dr. Andreas Nixdorf
SGS Life Sciences
2017 CPHI Frankfurt
2
RISK FACTORS ASSOCIATED WITH E&L
General quality consideration with leachables
Product stability
– Aggregation, increase in particulates, …
Interfere with analytical methods or diagnostic tests
Negatively impact on process performance
– cell growth, rate of drug release, drug solubility, pH,
product yield …
Product safety (toxicological risk)
The leachable may be toxic and poses a health risk to
the consumer
Efficacy consideration
The leachable interacts with the drug product
formulation or API so as to alter its stability and potency
3
THE CHALLENGES OF END USER
Functionality
by compatibility
Warning letters
from authorities
Regulatory
requirements
End User
Patient
Safety
Product
Impacts
Economic
Impacts
Regulatory
acceptance
Suppliers data
(complete?)
Supply
Chain
Risk Mitigation
Input
Su
sta
in a
Qu
alifie
d S
tatu
s
interpretation
Ke
ep
un
de
r yo
ur C
on
trols
4
LITERATURE SOURCES – STANDARD
PROTOCOL DISCUSSIONS
Some key publications
PDA, Application of Single-Use Systems in
Pharmaceutical Manufacturing, Technical Report No. 66
Parenteral Drug Association, Inc. 2014.
Biophorum operations Group (BPOG): Best Practices
guide for evaluating Leachables risk from polymeric
Single Use Sytems used in biopharmaceutical
manufacturing. (2017)
Ding W, Madsen G, Mahajan E, O’Connor S, Wong K,
Standardized Extractable Testing Protocol for Single-
Use Systems in Biomanufacturing, Pharmaceutical
Engineering, 2014; 34(6), 1–11.
Drafted USP <1665> and <665> USP forum (2017)
5
If extractables testing data provided by a supplier are not
sufficient, the end –user has to perform own studies;
these results in the same components being tested multiple
times and delay in application of SUS in biomanufacturing.
It would ensure, that a comprehensive and consistent set of
extractables testing data are readily available to the end-
users.
Assures comparability of chemical profiles from SUS
components from same functionality but delivered from
different vendors.
It would assist SUS suppliers in more efficiently selecting
materials in line with end-user needs.
“PROS” OF THE USE OF STANDAD
PROTOCOLS
BPOG „Standardized Extractables Testing Protocol for SUS in Biomanufacturing, Pharm. Eng. 2014.
6
Classify your disposables in different risk classes:
A: Baseline assessment
B: Expanded Baseline assessment
C: Full Testing assessment
Please compare with risk assessment procedure as
proposed by BPOG group:
Biophorum operations Group (BPOG): Best Practices guide
for evaluating Leachables risk from polymeric Single Use
Sytems used in biopharmaceutical manufacturing. (2017)
USP <1665/665> - RISK BASED APPROACH
7
ESTABLISH LEVEL A OF CHARACTIZATION
Level A (Baseline assessment):
The requirement is that all materials of construction must comply
with USP <661.1>:
• Identity;
• Physicochemical characteristics;
• Biological reactivity test, USP <87>;
• Additives (by proper reference to 21 CFR Indirect Food
Additives Used in Food Contact Substances);
• Levels of extractable metals.
8
ESTABLISH LEVEL B OF CHARACTERIZATION
Level B (Expanded Baseline assessment):
One requirement is that all materials of construction must comply
with USP <661.1> and,
• The materials of construction must meet the requirements for
Plastic Class VI designation, In Vivo <88>;
• Additives by “proper” testing (list of containing additives and
levels).
9
FOOD CERTIFICATE INFORMATION
Example (Polyurethane) of Food “Proper Testing List” (EU):
CAS Substance Restriction
822-06-0 Hexamethylene diisocyanate QM*(T) = 1 mg/kg
584-84-9 2,4-tolylene diisocyanate QM*(T) = 1 mg/kg
693-36-7 Octadecyl-3-(3,5-di-tert-butyl-4-
hydroxyphenyl) propionate
SML = 6 mg/kg
….. ….. ……
*QM max. conc. of residual in the plastic.
** SML restriction of specific migration limit.
Leaching Residue Potential Hazard
10
ESTABLISH LEVEL C OF CHARACTERIZATION
Level C (Full Testing assessment):
One requirement is that all materials of construction must comply
with USP <661.1> and specification for Level B met;
• Materials extractable profile has fully established relevant to
situation.
11
HOW MANY STANDARDIZATION WOULD BE
USEFUL? STANDARDIZED EXTRACTABLES
TESTING USP <665>
Components Extraction
(solutions
C1, C2, C3)
Extraction at
40°C
Extraction Duration
1 day 7 days 21 days
Storage container X X – – X
Mixing bag X X X X –
Bioreactor bag X X – – X
Tubing connector and
disconnector
X X – – –
Aseptic/sterile connector and
disconnector
X X – – –
Sensor/valve X X X – –
Molded parts of mixers X X X – –
Polymer pump surfaces X X X – –
Tubing X X – – X
Gasket, O-ring X X X – –
Sterilizating filter X X X – –
Process filter X X – X –
Tangential flow filtration X X X – –
Chromatographic column X X X – –
Filling needle X X X – –
C1: acidic extraction at pH 3; C2: alkaline extraction at pH 10; organic extraction 1/1 ethanol/water (v/v)
Short term (Extraction?) Long term (Use Study?)
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BPOG
Extraction temperature 25°C (=< 30 min contact); 40°C
Extraction time depending on SUS component: 24h, 7d, 21d, 70d
Material to surface ratio 6 cm2/mL
USP
Extraction temperature: 40°C
Extraction time depending on SUS component: 24h, 7d, 21d
Material to surface ratio 6 cm2/mL
Solvents:
BPOG: 50% ethanol, 1%PS-80, 0.1M H3PO4, 0.5N NaOH,
5M NaCl, WFI
USP: 50% ethanol, HCl/NaCl at pH 3, Phosphate buffer pH 10
DIFFERENT PROTOCOLS – EXTRACTION
CONDITIONS
13
In general, standard extractable protocols do not take into
account the different chemical nature of polymers or coated
materials.
Not all polymeric materials will show chemical resistance
under certain conditions.
The chemical profiles may be overestimated, that could lead
to a disqualification of a beneficial material.
By protocol multiple orthogonal methods are used to
chemically profile materials extractables.
Particular critical substances may require target analysis,
thus they run out of analytical window by using screening
methods.
“CONS” OF THE USE OF STANDAD
PROTOCOLS
14
INADEQUATE CHEMICAL RESISTANCE –
SANITIZATION WITH 1M NaOH
600 cm2 / 150 cm Pt cured Silicone
Tubes
Simulated use study: 40°C&50°C
7d, 1M NaOH
TOC: 122 – 330 µg/cm2;
73 – 198 mg/150 cm
ICP-MS: Si element; saturated
detector after 1:1000 dilution.
Delamination of tube inner surface
(SEM: scanning electron microscope).
High risk of particle formation.
Oligomeric substances.
Degradation mechanism
SEM image of damaged area.
Delamination flakes
Mosammad Shamsun Nahar*, Jing Zhang „ Analysis of
Damaged Silicon Rubber Hose”, American Journal of
Analytical Chemistry, 2011, 2, 363-370
EXAMPLE
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INADEQUATE RESISTANCE - AQUEOUS
ALCOHOL SOLVENTS
Virus filter with PES membrane
Exaggerated Extraction: PBS
buffer pH 7.4 + 25% (v/v) iPrOH,
28d 40°C
Amount of embedded membrane
polymer found: > 350 mg/filter!
Under real use conditions only
minor
quantities are released below
toxicological relevant limit.
The filter membrane was
demonstrated incompatible to
aqueous alcohol solutions.
ESI + MS (QToF) Ion Trace
EXAMPLE
16
INADEQUATE RESISTANCE - PARTICLE
FILTER SYSTEM - 50% ETHANOL
Extraction conditions: 50% ethanol at 40°C for 48h:EXAMPLE
5 . 0 0 1 0 . 0 0 1 5 . 0 0 2 0 . 0 0 2 5 . 0 0 3 0 . 0 0 3 5 . 0 0 4 0 . 0 0 4 5 . 0 0 5 0 . 0 0
2 0 0 0 0
4 0 0 0 0
6 0 0 0 0
8 0 0 0 0
1 0 0 0 0 0
1 2 0 0 0 0
1 4 0 0 0 0
1 6 0 0 0 0
1 8 0 0 0 0
2 0 0 0 0 0
2 2 0 0 0 0
2 4 0 0 0 0
2 6 0 0 0 0
2 8 0 0 0 0
3 0 0 0 0 0
3 2 0 0 0 0
3 4 0 0 0 0
T i m e - - >
A b u n d a n c e
S i g n a l : S c r e e n i n g _ E x t r a c t a b l e s _ 4 0 7 6 4 4 0 _ 1 7 0 6 2 6 _ 2 4 . D \ F I D 1 A . c h
Advanced disintegration of polymeric material: high amounts of low mass oligomers.
17
CUSTOMIZE REALISTIC EXTRACTION
CONDITIONS -5M NaCl
5M NaCl, high salt
concentrations
are not appropriate!
Salt effect will lower solubility of Leachables. There will be no chemical interaction
between lipophilic polymer (surface) and 5M NaCl.
So, why this extraction?
EXAMPLE
18
CUSTOMIZE REALISTIC EXTRACTION
CONDITIONS - POLYSORBATE
PS-80 generates high analytical background noise. It also suppress detectability of
Extractables.
PS-80 can be simulated by ethanol
or IPA/water mixtures!*
Tween could contain carry over
leachables that are sourced by
storage conditions and chemical
decomposition of PS-80.
*Dennis Jenke, Ph.D. A Means of Establishing and Justifying Binary Ethanol/Water Mixtures as Simulating Solvents in Extractables Studies,
Smithers/Rapra E&L USA 2015: Bethesda, MD; May 13, 2015.
EXAMPLE
19
CUSTOMIZE REALISTIC EXTRACTION
CONDITIONS – POLYSORBATE RELATED
IMPURITIES
PS-80 is a polymeric mixture consisting from lipophilic monoesters condensed with
ethylene oxide.
EXAMPLE
Class Examples Source
Alcohols C4-8 PS-80 Breakdown
Aldehydes C6-10 PS-80 Breakdown
Ketones C5-C8 PS-80 Breakdown
Carbonic
acids
C4-8, C18, C16 PS-80 Breakdown
others Glycols-ethers PS-80 Breakdown
Leachables Antioxidant, fatty acids, fatty
alcohols,….
Interaction with
storage container
20
RADIATION RESISTANCE
Validation of radiation regarding impact on extractable conc. level was
missed!
Dose: approx. 32 kGy
Extraction of Pt cured silicone tube at 50 °C for 24 h with WFI
Analyte Blank µg/mL µg/cm2 Compared to Blank
(LOQ) an increase
by factor of
Formaldehyde < LOQ1 21 7 233
Formiate < LOQ2 106 34 25
Acetate < LOQ2 18 14 9
1 0.03 µg/cm2 2 1.6 µg/cm2
EXAMPLE
21
STANDARD EXTRACTION PROTOCOLS
- SELECTION OF EXTRACTION CONDITIONS
Misapplied use of plastic could cause chemical attack; it may
occur in several ways:
Disintegration or degradation of physical nature due to absorption,
permeation, solvent action, swelling…
Oxidation, where chemical bonds are attacked,
Hydrolysis, were e.g. ester bonds are attacked,
Radiation, were chemical reaction are triggered,
Thermal degradation,
Delamination, due to chemical attack.
In E&L studies those substances must be assessed that could
migrate into DP or process steam.
22
STANDARD EXTRACTION PROTOCOLS
- RISK ASSOCIATED WITH SEP
Misconceptions increases the risk of faulty decisions.
Extraction conditions are too harsh:
Decomposition of the polymeric network, high levels of
oligomers are expected,
• Generation of high conc. levels of breakdown products.
Extraction conditions are too harsh:
• Screening methods do not discover all relevant
substances – combine with target analysis.
Material qualification can become not longer valid:
Under real use condition there is probably no risk on
leaching into the drug product.
23
IMPROVEMENTS TO DISCUSS
– SOME CUSTOMIZATION NEEDED
Simulated migration studies with conditions that are selected
close to real process conditions would be the best practice to
asses risk from SUS such as bags, tubes, connectors and
filters ….
Extractables studies conditions should be selected to avoid
materials damage!
Extraction conditions selection must based on damage mode
studies and/or chemical resistance studies.
SGS is offering:
Chemical characterization (Extractables studies),
Simulated Use Studies (Leachables studies),
and Damage Mode Studies to support end-user materials
qualification process.
24
LIFE INSPIRED
THANK YOU FOR YOUR ATTENTION
Visit us at our booth Hall 4.2 B30
Dr. Andreas NixdorfLife Sciences
Senior Scientist / Business Development Manager
SGS INSTITUT FRESENIUS GmbH
Extractables & Leachables – Impurity Profiling
H578
Kasteler Str. 45
D-65203 Wiesbaden
Phone: + 49 611 962 5903
E-mail : [email protected]
Web : www.sgs.com/lifescience