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United State Pharmacopeia:
Compendial Plastic Standards: Beyond Packaging
Desmond G. Hunt, Ph.D. Principle Scientific Liaison
November 15, 2016Denver, CO
Scientific, independent, volunteer-driven, nonprofit
organization
– Established in 1820
– Headquartered in Rockville, MD
– Facilities in India, China, Brazil, Switzerland
– 800+ employees
Set public quality standards for prescription and over-the-
counter medicines, excipients (inactive ingredients), dietary
supplements, food ingredients, packaging and labeling
Worked closely with FDA and predecessors for >100 years,
developing and revising drug quality standards enforceable
by FDA
Legally recognized in 39+ and standards used in 140+
countries
USP
Identification
• Infrared Spectroscopy (IR)
• Differential Scanning Calorimetry (DSC)
Biological Tests
• USP <87>; Biological Reactivity Test, In Vitro
• USP <88>; Biological Reactivity Test, In Vivo (if a class designation is required).
Physicochemical Tests (water extract)
• Nonvolatile Residue (NVR); not required for PET/PETG
• Residue on Ignition (RoI, if NVR > 5 mg); not required for PET/PETG
• Heavy Metals (HM)
• Buffering Capacity (BC); not required for PET/PETG
Other Tests (for PET and PETG)
Test Methods Required in the Current USP <661>
USP <661> Containers—Plastics: 1965 - 2016
Plastics Standards
Situations in which a Medicine could
Contact a Plastic Material During manufacturing (plastics used in the
manufacturing suite)
During storage/distribution (plastics used in
packaging)
During clinical use (plastics used in medical
devices used to administer the medicine)
Thus, USP’s interested in plastics has expanded
beyond just packaging systems
5
A Starting Point for the USP Standards for Plastics
Building safety into a system by using well-characterized
and safe materials of construction (Quality by Design).
The testing required to select and qualify a system or a
system component is correlated to the risk that the system’s
finished output is adversely effected by its interaction with
the component or system (Risk-based Approach).
The USP standard serves as a baseline
• Should have value in every situation of use, but may not
necessarily address every individual situation of use
Scope and Objectives of USP Standards for Plastics
Scope Focus on:
• Safety
• Material and component-derived foreign impurities
Objectives To provide tests and specifications for the characterization of
plastic materials• So materials can be rationally selected for use and so that the selection
can be justified
To provide tests and specifications for the characterization of
plastic components• So plastic components/systems can be rationally selected for use and
that the selection can be justified
To provide tests and specifications for the safety qualification of
manufacturing, packaging and delivery systems (or their
components)
The Essence of the Current Strategy for Plastics
Standardize at the Materials
of Construction level
Customize at the Component
or System level
Characterization of
Materials of Construction
<661.1>
Component or System Testing for Packaging
<661.2>
Component or System Testing
for Manufacturing
Component or System Testing
for Devices
Extractable Guidance
<1663>
Leachable Guidance
<1664>
<661> Plastic Packaging Systems and their Materials of Construction
<661.1>Plastic Material of
Construction
<661.2>Plastic Packaging Systems for
Pharmaceutical Use
- Identification
- Biological Activity
- Physico-chemical Tests
- Extractable Metals
- Plastic Additives
- Biological Activity
- Physico-chemical Tests
- Safety Assessment
(Extractables/Leachables)
<661> Plastic Packaging Systems and their Materials of Construction
<661.1> Plastic Materials of Construction
Comparison of Testing Required for Various Dosage Forms
Test Parameter Oral and Topical Dosage Forms All Other Dosage Forms
Chemical Tests
Identification DSC/IR DSC/IR
Physicochemical Tests Water extraction: • UV absorbance,• Acidity/alkalinity • TOC
Water extraction: • UV absorbance,• Acidity/alkalinity • TOC
Extractable Metals Acid extraction:• ICP analysis for targeted and
relevant metals
Acid extraction:• ICP analysis for targeted and
relevant metals
Polymer Additives Proper Reference to Indirect Food Additive Regulations, CFR 174-186
Direct chemical testing
Biological Reactivity
In Vitro per USP <87> Required Required
In Vivo per USP <88> Not required Required as needed to obtain plastic classification
Comparison of Testing Required for Various Dosage Forms
Test Parameter Oral and Topical Dosage Forms All Other Dosage Forms
Chemical Tests
Physicochemical Tests Water extraction: • UV absorbance,• acidity/alkalinity • TOC
Water extraction: • UV absorbance,• acidity/alkalinity • TOC
Chemical Assessment—Extractables and Leachables(Reference to <1663> and <1664>)
Risk-based testing* Risk-based testing*
Biological Reactivity
In Vitro per USP <87> Required Required
In Vivo per USP <88> Not required Required as needed to obtain plastic classification
<661.2> Plastic Packaging Systems for Pharmaceutical Use
*Alternative testing strategies for chemical safety assessment may be
appropriate in justified circumstances, subject to agreement by an appropriate
regulatory authority
Chapters became official May 1, 2016
Proposed revision to <661.1> and <661.2> in PF 42
(4) July 2016• Scope was revised to better clarify intent
− <661.1>
− <661.2>
• Proposed revision to remove of the Biological Reactivity
requirement for materials and packaging used for oral and
topical drug products
− <661.1>
− <661.2>
• Proposed addition of the Spectral Transmission Test in
<661.2>
− Test currently resides in <671> Container−Performance Testing
Chapter Status
Current Materials
• Polyvinyl Chloride, Plasticized
• Polyethylene
• Cyclic Olefin
• Polyethylene Terephthalate
• Polyethylene Terephthalate G
• Polyamide 6 (Nylon)
• Polycarbonate
• Polyethylene vinyl acetate
• Polyvinyl Chloride, Non
Plasticized
<661.1> PF 42 (4) July 2016
Future Materials
• Acrylonitrile butadiene styrene
• Polybutylene terephthalate
• Poly(methylmethacrylate)
• Polystyrene
• Polysulfone
• Polytetrafluoroethylen
• Polyurethane
United States Pharmacopeia:
USP GENERAL CHAPTER <661.3>: PLASTIC
COMPONENTS AND SYSTEMS USED TO
MANUFACTURE PHARMACEUTICAL DRUG
PRODUCTS
<661.3> Plastic Components and Systems
Used in Pharmaceutical Manufacturing
Scope: Parameters covered
Active pharmaceutical ingredients and drug products
Pharmaceuticals, Small Molecules,
Biopharmaceuticals products and Vaccines
Single-Use Systems and Multi-Use Systems
Introduction to <661.3>
<661.3> speaks to the characterization of materials of
construction
• Enabling the selection of proper materials used in
manufacturing components
<661.3> speaks to the characterization of components
• Enabling the proper selection of components used in
manufacturing operations
<661.3> does not speak to the qualification of materials,
components or systems
• Testing performed for the purpose of selection may be
relevant to qualification.
Introduction to <661.3>
Components are further characterized depending on the
level of risk associated with their application in a particular
manufacturing operation.
• USP <1661> contains a Risk Evaluation Matrix whose purpose
is to classify components and their associated conditions of
use into three risk categories.
High risk components must be profiled for extractables using
a Standard Extraction Protocol (SEP) as provided in
<661.3>.
• Standard extraction protocol, consisting of three solvents and
one time/temperature combination.
• <661.3> provides directions on how to perform extractions for
typical types of components
Component in
Contact with Liquid
Stream
No Actions
Conduct Initial
Assessment
Comparator
Component/System
Established
Proceed to Risk Assessment
No Actions
No
No
Yes
Yes
Figure 1. Initial Assessment
The Initial Assessment
Risk Assessment in <661.3>
18
Application of the Risk Evaluation Matrix The Risk Evaluation Matrix considers four dimensions which
address the risk that a plastic component will be leached by
a process stream to such an extent that process streams
could contain potentially impactful extractables. These
dimensions include:• The duration of contact,
• The temperature of contact,
• The chemical composition of the process stream, and
• The nature of the component’s materials of construction.
The matrix then considers each dimension separately and
assigns a level of risk associated with certain measures
relevant to each dimension. Three levels of risk are
established (A, B or C).
Using the Risk Matrix to Drive Testing
Table 2. Testing Requirements for Three Risk Levels (Revised)
Risk Assessment Testing RequirementsLevel Level Materials of Construction <661.1> Component or System < 661.3>
A
(lower
risk)
Baseline All individual materials of construction comply with <661.1>
for identity as follows:
Biocompatibility <87>
Physicochemical characteristics (TOC, UV, Acidity
/alkalinity
Extractable metals
(Additives (by proper reference to 21 CFR Indirect Food
Additive regulations)
Biocompatibility <87>
B Expanded
Baseline
All individual materials of construction comply with <661.1>
for identity as follows:
Biocompatibility <87> and Class VI <88>
Identification
Physicochemical characteristics (TOC, UV, Acidity
/alkalinity
Extractable metals
Additives determined by testing
Biocompatibility <87> and USP Class
VI <88>
Extractable Metals
C
(higher
risk)
Full Same as Expanded Baseline Biocompatibility <87> and Class VI
<88>
Full Extractables Profiling via
Standard Extraction Protocol
(Solutions C3, C4 and C5)
Bolded entries represent testing required in addition to the testing required in the lower risk levels.
The Standard Extraction Protocol for High Risk Situations
Standard Extraction Protocol for Components or
Systems Designated as Risk Level C
Extraction Solvents• Solution C3, Acidic Extraction, pH 3
• Solution C4, Basic Extraction, pH 10
• Solution C5, Organic Extraction, 1/1 (v/v)
Ethanol/water
General principles and recommended best
practices for preforming the extractables
assessment of can be found in <1663>.
21
Is/Is Not: Standard Extraction Protocol
Aspect Is Is NotApplication Components (systems) Materials of Construction
High Risk Low or Moderate Risk
Purpose Component Selection1 Component Qualification1
Focus “Aim for the Middle”(most commonly encountered)
“Aim for the Extreme”(most extreme conditions possible)
Objective Generate Useful Information
Generate Worst Case Information
Note: (1) Under certain circumstances, information for selection may be appropriate as
information for qualification.
The <661.3> Standard Extraction ProtocolSolvents
22
Considering Additional Extraction Solvents
1. Any additional extraction solvent should provide
information in addition to information provided by
the adopted solvents.
2. Any additional extraction solvent should be
analytically expedient.
The <661.3> Standard Extraction ProtocolSolvents
23
What about Water?
Water provides no additional information that is not already
provided by the pH extreme solvents.
What about 5 M NaCl?
5 M NaCl is the weakest extraction solvent (for organics) and
provides no additional information that is not already provided by
the pH extreme solvents.
5 M NaCl is an analytically challenging solution.
What about 1% Polysorbate 80?
50% Ethanol may be an appropriate simulant for 1% PS80.
1% PS80 is an extremely challenging solution to analyze.
Thus, there is no compelling reason to include these
solvents in the Standard Extraction Protocol.
The <661.3> Standard Extraction ProtocolSolvents
24
What about low pH?
Data suggests that pH 3 salt solution and 0.1M phosphoric acid
produce similar extractables profiles.
Phosphate matrix produces minor analytical challenges.
USP would consider a statement that made 0.1M phosphoric
acid and pH 3 salt solution “interchangeable”.
What about high pH?
In certain situations, 0.5 N NaOH may be a more aggressive
extraction solvent than pH 10 buffer.
0.5N NaOH can be an analytically challenging matrix, especially
related to instrument “wear and tear”.
0.5N NaOH may not fit the intent of the SEP to “aim for the
middle”
USP considers the “issue” of the high pH extraction solvent
to be open for discussion.
The <661.3> Standard Extraction ProtocolSolvents: Score card
25
50% Ethanol; Alignment
Water, 5 M NaCl, 1% Polysorbate 80; Alignment
• USP allows for the use of additional solvents at
the discretion of the sponsor
Low pH; Alignment (interchangeable solvents)
High pH; To be resolved
The Standard Extraction Protocol for High Risk Situations
26
Standard Extraction Protocol for Components or Systems
Designated as Risk Level C
Extraction Conditions
Component Extraction
Solutions
C3 through C5
Extraction
Temperature
Extraction Duration
40° 1 day 7 days 21 days
Storage Container X X X
Mixing Bag X X X
Bioreactor Bag X X X
Connector X X X
Disconnector X 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
Sterilizing Filter X X X
Process Filter X X X
Tangential flow Filtration X X X
Chromatography Column X X X
Filling Needle X X X
Expert Panel taking feedback from workshop
and PF proposal in May 2016 and revising draft
accordingly
Revised <661.3> (<665>) to be republished
• Target PF: 43 (3) May 2017
• Comment Deadline: July 31, 2017
• Target Official Publication: USP 41 Second Supplement
Target Official Date: August 1, 2018
Status
Upcoming Revisions/Development
<381> Elastomeric Closure for Injection
• The Expert Panel began working on the revision of <381> in May 2014
• Workshop June 19-20, 2017
<87> Biological Reactivity, In vitro, <88> Biological Reactivity, In
Vivo3200-
• The Expert Panel began working on the revision of <87> and <88> in March
2015
<660> Container−Glass
• The USP Glass Expert Panel began work on revising <660> and <1660> in
September 2016
• Workshop June 19-20, 2017
Metal Packaging Systems and Their Materials of Construction
• Stakeholder Webinar April 2015
• To form Expert Pane early 2017