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