Presentation Download

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USP-NF Up to Date Activities

Compendial Initiatives

Robert Femia, Ph.D.

Senior Vice President

Science, Chemical Medicines and General Chapters

Introduction

5

Works with more than

900 scientists,

practitioners, and

regulators to revise

standards that help

protect public health

Values-driven

organization focused

on empowering its

staff and volunteers

About USP

Internationally

recognized and

globally focused

More than 900

employees worldwide

Laboratory facilities in

U.S., India, China,

Brazil, and Ghana

Offices in Switzerland,

Ethiopia, Indonesia, the

Philippines, and

Nigeria

Founded in 1820,

nonprofit, private,

independent, and

self-funded

USP is cited in US

Law

US FDA (product

approval)

USP Documentary

Standard and

Reference Standards

(product compliance

in US)

Mission: USP’s mission is to improve global health through

public standards and related programs that help ensure the

quality, safety, and benefit of medicines and foods.

6

USP: The Organization

What We Do:

Establish and disseminate public written standards for the

quality, purity, identity, strength, and labeling of medicines

Provide physical Reference Standards to support tests and

assays in the USP–NF and FCC

Educate producers, practitioners, and others seeking

information on quality and USP standards

Verify products for manufacturers and award

the USP Verified Mark to those that meet

our standards

Work with international health agencies

to improve the quality of medicines

Worldwide

Work with FDA and Industry Stakeholders

FDA reviews proposed standards in Pharmacopeial

Forum and provides comments

Participates as delegates, provides resolutions,

provides members to the council of the Convention

and other Convention committees

Provides FDA liaisons to USP’s expert committees

Participates in workshops and stakeholder forums

Works with USP through cooperative research and

development agreements

Collaborates with USP through quarterly meetings,

pharmacopeial discussion group and special topics

such as OTC monograph modernization,

compounding, structured product labeling,

pharmacologic classes

7

FDA Engagement Goes Beyond Enforcing USP Standards

USP Standards-Setting Bodies

Expert Committees

Advisory

Bodies

Stakeholder

Forums &

Project

Teams

USP Staff

Expert Panels

Subcommittees

Joint Standards-setting

Subcommittees

USP

Convention

XXXX

XXXX

Council of

Experts

= Recommendation

= Recommendational body

= Decisional body

= Election of Experts

724 volunteers serving on 24 Expert Committees, 58 Expert Panels

‒ 415 Expert Committee members

‒ 309 Expert Panel members*

144 Government Liaisons from FDA

‒ CDER: 99 ‒ ORA: 4

‒ CFSAN: 8 ‒ OC/ONDQA: 3

‒ CBER: 9 ‒ CDRH: 1

‒ CVM: 20

8 other Government Liaisons (US and international)

Industry and consultants comprise almost 70% of volunteers

35% EC members are new, 25% are international

876 Participants in Standards-setting Activities

* Does not include Expert Committee members also serving on Expert Panels

USP CONVENTION MEMBERS Kazakhstan (1) Uzbekistan (1)

Russia (2) Belarus (1)

Ukraine (2) Canada (11)

Sweden (1)

Belgium (2)

U.K. (2) Switzerland (2)

France (1)

U.S. (388) Turkey (1) Japan (1)

South Korea (1)

Taiwan (1)

China (3)

Vietnam (1)

Philippines (1)

Morocco (1)

India (4)

Jordan (2)

Mexico (3) Colombia (1)

Thailand (1)

Sierra Leone (1)

Ghana (1) Peru (2)

Egypt (1) Indonesia

(1) Saudi Arabia (1)

Nigeria (1)

Ethiopia (1) Brazil (7) Chile (1)

Tanzania (1) Uganda (1) Australia (1) Argentina (3)

Total Categories* Countries Delegates at the 2015

INTERNATIONAL REPRESENTATION *COMPOSITION BY CATEGORY

15%

7%

4%

2%

72%

7 17 33 68

Nongovernmental Standards-Setting and Conformity Assessment Bodies

Consumer and Other Organizations

Representing the Public Interest

Manufacturer, Trade, and Affiliated

Associations

Governmental Bodies or Divisions or Associations Thereof

Health Practitioner Professional and Scientific Associations

Academic Institutions and

Associations Thereof

86% 1% EUROPE

1%

NORTH AMERICA

4% LATIN AMERIC SUB-SAHARAN

AFRICA AND CARIBBEAN

2% 2% 1% 137 196

NEWLY INDEPENDENT STATES

EAST ASIA MIDDLE EAST AND NORTH AFRICA

w w w.usp.org LEG101G_2015 -10

PR

AC

TITI

ON

ER

S

A

S

O

2% WORLD

SU

1% UTH ASIA

30%

42%

FAST FACTS 458 Members 6 (based on Bylaws) 39 Represented 262 Convention Meeting

11

Council of Experts

6 Collaborative Groups and 24 Expert Committees

USP Standard Setting

Process

13

Science is the Base of USP Standard Setting

General Notices, General Chapters,

and

Monographs

• General Notices – contain requirements applicable throughout

USP-NF unless superseded by a chapter or monograph

• General Chapters

– Contain requirements applicable to multiple monographs referencing

the specific general chapter(s)

– General Chapter requirements supersede General Notice

requirements

• Below <1000> - Enforceable Chapters (when referenced in

General Notices, General Chapters or individual monographs)

• Above <1000> - Information Chapters

• Monograph

– Requirements are specific to the article

– Monograph requirements supersede General Notices and General

Chapter requirements.

New monographs:

Proposed tests, limits, and validation (according to <1225>)

Packaging, storage, and labeling requirements

Reference Standard commitments

Revisions:

Reasonable justification

Adequate supporting data for methods and specifications showing

improvement

USP-initiated revisions:

Modernizations and other revisions can be based on other

pharmacopoeias’ standards, ICH specifications, etc.

Types of Standards Development

Standards-setting Process: How to Develop a Monograph

Monograph development is initiated

Scientific Liaison performs technical review and drafts monograph

USP evaluates procedures requiring RS prior to publication and

RS collaborative testing (optional)

Proposal is published for 90-day public comment period

Scientific Liaison and Expert Committee reviews comments

Expert Committee ballots to adopt proposal

Monograph is published in USP-NF and becomes official six

months after publication unless otherwise indicated

Manufacturer submits proposal USP initiates development

Approved Not Approved Next

steps?

3-6

m*

15-1

8m

*

*Shorter if Accelerated Revision

General Chapters describe the basics of commonly used

analytical techniques or common requirements and how they

apply in compendial articles.

Originated by need (to avoid repetition of a test in

monographs); input from stakeholders; ECs or EPs; Staff, etc.

Early input is requested from stakeholders through USP

website announcement (“Prospectus”)

Stimuli articles and workshops maybe used to collect input and

asses impact of new or revised general chapters

EC’s workplans are accessible through www.usp.org

General Chapters Development Process

– Monograph Development

– Bulk Procurement – Donation from pharmaceutical industry

– Purchase

– In-house custom synthesis

– Protocol & Test Kit Preparation

– Bulk Sampling/Sample Shipping

– Collaborative Testing – USP Laboratories, Contract Laboratories, Agencies,

Industrial Laboratories

– Data Analysis/Value Assignment

– Internal Review/Approval

How Does USP Develop a Reference Standard?

19

Need for Ref

Std

Hand-off Meeting (RMA,

Science, RSE)

RSS Drafts PPD,

TP, TK

Testing Labs

Results received

from labs

Results analyzed

by RSS

RSS generates

RSCEP

RSCEP Peer

review (Stage 2)

OK Peer review

comment

Internal ballot QA

review (Stage 3)

Packaging

QA batch record review

(complete, accurate,

compliant)

QA/marketing Release

Testing issue

Additional testing if required

Comments to be addressed

Approved

Not approved

RSE Reference Standard Development Process

Collecting info (Documents)

Stage 1 Stage 2

Stage 3

RMA – Reference Material Acquisition

RSE – Reference Standard Evaluation

PPD – Product Planning Document

TP – Test Protocol

TK – Test Kit

RSS – Reference Standard Scientist

RSCEP – Reference Standard Candidate Evaluation Package

20

Uses of USP Reference Standards

There are two main types of USP Reference Standards:

Standards with Quantitative Applications

Assays (for drug substances and for formulations)

Limit tests (e.g., Impurity Reference Standards)

Standards with only Qualitative Applications

Identification tests

Elution markers

System Suitability tests

Up-to-Date Activities

22

Core Compendial Programs

The United States Pharmacopeia and

the National Formulary (USP–NF)

Food Chemicals Codex (FCC)

USP Dietary Supplements

Compendium (DSC)

Reference Standards

Other Resources

Pharmacopeial Forum (PF)

FCC Forum

USP Dictionary

Chromatographic Columns

23

United States Pharmacopeia – National Formulary

A compendia of internationally recognized standards for drug substances, dosage

forms, compound preparations, excipients, and dietary supplements.

It contains:

More than 4,900 monographs with specifications for identity, purity, quality, and

strength.

More than 320 General Chapters, with step-by-step tests and methods.

Standards that when deemed official by USP, are FDA-enforceable

for drugs manufactured or marketed in the U.S.

24

Expert Committees Therapeutic Category

Number of

Official

Monographs

Total

Number of

Volunteers

% new

volunteers

Chemical

Medicines 1

Antiviral, Antimicrobials

& Antibiotics 977 15 53

Chemical

Medicines 2

Cardiovascular, Cough,

Cold, & Analgesic 678 16 38

Chemical

Medicines 3

Gastrointestinal, Renal,

Endocrine and

Ophthalmology, Oncology,

Dermatology & Veterinary

959 17 41

Chemical

Medicines 4

Psychiatric, Psychoactive,

Neuromuscular, Aerosol, &

Imaging Drugs 799 18 39

Chemical

Medicines 5 Pulmonary & Steroids 570 16 38

Chemical

Medicines 6 Over the Counter (OTC) 475 18 27

Chemical Medicines – Demographics

2005: Initial evaluation of its documentary standards (in

USP-NF) identified ~700 outdated monographs.

2010: FDA established a Monograph Modernization Task

Group that interfaced with the USP Monograph

Modernization to address this need.

- The goal of the Task Group was to identify monographs

in need of modernization, especially regarding outdated

analytical methodologies.

2010-2015: Multiple approaches—apart from relying

solely on method submissions from industry

sponsors—have been used in developing modernized

monographs.

USP Monograph Modernization History

25

USP-NF Up to Date

USP Convention Resolution 2:

USP will meet the needs of U.S. Food and Drug Administration (FDA), industry, and other stakeholders for modern monographs within USP–NF. USP will work to: • eliminate the existing backlog of monographs in need of

modernization, and • proactively evaluate and update monographs to maintain their

relevance given scientific advances and evolving manufacturing and regulatory approaches.

USP will work with industry and FDA to explore new strategies for sharing analytical methods and specifications needed to modernize monographs.

26

27

New Strategy Aligned With Existing Mission

ASSAY Method

(Strength)

ORGANIC IMPURITIES

Method

(Purity)

Replace obsolete chromatographic

columns (GC packed

columns or non commercially

available HPLC columns)

• Add impurity method

• Combine multiple

impurity tests

Eliminate

Hazardous

Solvents and

reagents

Replace non-

specific tests

(wet chem., UV-Vis,

titration , etc.)

Add identification test(s) Replace

Thin Layer Chrom.

IDENTIFICATION Test

(Identity)

Monograph Modernization Prioritization Scheme

OTHER Test

• Update packaging

and storage conditions

• Update some test

methods Delete non value

added procedures

(odor test, flame test,

melting pt., Readily

Carbonizable Subst.,

Volatile Diazotizable

Subst.)

Add Identification Test

Add Organic Impurities

Replace TLC with HPLC or UHPLC

Replace outdated equipment (i.e., not commercially available)

Eliminate hazardous procedures and materials such as solvents, reagents,

and other chemicals

Replace non-specific tests with stability indicating procedures

Delete non value added procedures

Replace organoleptic tests

Provide alternative procedures (e.g. <197K. or <197A>)

Update on Reference Standards

Up-to-date

Omission

Reagents tagging

Additional monograph information (e.g., chemical structure, chemical

name. etc.)

Chapter dependencies and changes in General Notices

Update Description and Solubility

Monograph Modernization - Identification,

Assay, Organic Impurities, Other Sections

USP-NF Up to Date

30

What does “USP-NF Up to Date” mean?

Current: Add new monographs &

general chapters in timely

manner.

Omit monographs / general

chapters that are no longer

needed

Suitable for their

intended use: All components clear,

complete and correct.

Remove unnecessary tests.

Appropriate selection of

reference standards

Relevant: Modernize and/or revise

monographs & general

chapters to reflect “state of

the industry” practices.

Ensure availability of

Reference Standards

31

At least Assay, 103, 3%

At least impurities, 1265, 35%

ID Only, 238, 6%

Modernization to be balloted, 145, 4%

Omission Candidate, 805, 22%

Omission to be balloted, 25, 1%

Other test, 20, 0%

Up to date, 1052, 29%

Up-to-Date Totals

Distribution of Procedures Needing Update by EC

32

7 8 13 8 5 62

295

196

274

134 191

175

61

61

31

61 17

7

21

22

13

30 37

22

250

91

107

149 110 98

13

2 5

174

173

238

271

121 75

0

100

200

300

400

500

600

700

800

900

CHM12015 CHM22015 CHM32015 CHM42015 CHM52015 CHM62015

Up to date

Other test

Omission to be balloted

Omission Candidate

Modernization to be balloted

ID Only

At least impurities

At least Assay

• Traditional donor model (‘externally sourced’)

• Need to engage sponsors

• USP laboratories (‘internally sourced’)

• Extensive testing facilities for procedure development

• Laboratory sites in US, India, China and Brazil

• FDA (CRADA ORA Labs; OTC Working Group)

• Trade organizations (CHPA; Excipient Trade Association)

• Expert panels to leverage industry expertise, gain early stakeholder input and buy-in

• Other Pharmacopeias

• Identify alternate source procedures (i.e., procedures that can be used from other pharmacopeias)

USP-NF Up to Date Strategies

USP-NF Up to Date Opportunities and Challenges

• Opportunities:

• Stakeholder collaborations and global expert panels can stimulate additional avenues for both update and harmonization.

• Sourcing procedures from other compendia, literature, etc.

• Use of global USP laboratory facilities to develop and validate procedures.

• With FDA involvement, prioritizing and requesting submissions - the hope is that industry is much more likely to submit a proposal.

• Challenges:

• Prioritization of monographs and chapters in need of updating

• Obtaining procedures and acceptance criteria from sponsors

• Balancing the need to introduce modern methodology with the feasibility to implement by users globally

Global Health

Monographs

The Global Health Standards Program: Objectives

36

USP Mission: To improve global health through public standards and related programs

that help ensure the quality, safety and benefit of medicines and foods.

USP Vision: USP envisions a world in which all have access to high quality, safe, and

beneficial medicines and foods.

Global Health Standards Program Objectives: The global health standards

program’s objectives are to:

• Ensure availability of relevant, modern standards for the world’s most essential

medicines;

• Enable accessibility of these standards in non-US settings; and

• Engage stakeholders for development, adoption, and implementation of these

standards for improved public health outcomes

Prepared by Gaurvika Nayyar 37

GHS Program will focus on Medicines of global health

importance Marketed Outside the United States

The Global Health Monographs will have a New Section in

the USP-NF

38

New section of USP-NF

Starting USP 40-NF35

Section clearly distinguished

and designated to indicate non-

US status

Section Preface will explain the

regulatory status of GH monographs

Preface

“This section contains monographs for

articles which are not currently legally

marketed in the United States, but

which have been approved by a

stringent regulatory authority as defined

by the World Health Organization and

are used for essential purposes in other

parts of the world. Selection and

prioritization of new entries to this

section will be accomplished in close

collaboration with stakeholders

throughout the global health

community. These monographs are not

applicable to articles marketed for use

in the United States.”

Over the Counter

Monographs

40

Shared Goals … but difficult to balance

FDA

• Public Safety (maximize)

• Unambiguous enforceable specifications

• Referee method(s)

• U.S. scope, participate globally

Chemical Medicines 6 Expert Committee

Prescription Non-Prescription Drug Stakeholder Forum (OTC Team) – FDA/CHPA/USP

USP OTC Team – FDA OTC WG

Acetaminophen Expert Panel

CHPA

USP Industry Collaboration with HPLC Column Manufacturers

41

OTC Focused Teams

Three meetings conducted: April 6, July 1, and Sept. 7

Discussion topics include:

1. Update on Monograph Modernization list

2. GC <321> and GC <327>

Currently finalizing CDA to work collaboratively on OTC

projects

Case Study - To work on two diphenhydramine

monographs

42

USP OTC Team – FDA OTC WG

Collaboration

43

Prioritization Need Help from FDA,

Industry Stakeholders,

USP Expert Panels

Continuous Manufacturing

45

From Batch to Continuous Manufacturing

• Always work with 100,000 oranges.

• The juice is accumulated at evaporator, which is large

and does not work well with less than 100,000 oranges.

• Blender , freezers, and all other parts also require a

minimum of 100,000 oranges.

• Total amount of juice passed from one part to the other.

You will have orange juice as long as you

continuously feed oranges.

You decide how much orange juice you need.

46

Continuous Manufacturing---Why?

47

Control Challenges of Continuous Manufacturing

1. Material Control • Characterization of in-coming materials

• In-process measurements

• Selection of sampling frequency

• In-process parameters and material attributes

• Setting of appropriate acceptance criteria

2. System Control • System design

• Equipment integration

• Verification

3. Process Control • Analytical tools to the control system to support implementation of feed-back or feed-forward

control

• Sophisticated data management tools

• Defining representative sampling to consistently assure product quality over time

• Location of sampling probes

• Sample size and sampling frequency

• Need for enhanced process understanding

• Availability of mechanistic models for all processing steps

• Implementation of multivariate analysis for determination of product quality

4. Product release control

Potential USP roles in Pharmaceutical Continuous

Manufacturing development

• Control strategy standardization

• Ingredient characterization standardization (monograph and

reference standard)

• Product release standardization

• Equipment/system requirement standardization

• Sensing technology standardization

• System modeling standardization

• Other?

48

49

Interest in Continuous Manufacturing from FDA is Strong

50

Industry Early Adopters of CM Technology

Consigm

a lin

es

other

bra

nds

DS DP DC WG

RC HME

Capsu

les

Filed

Approve

d

Deployment Strategy

Janssen 2 1 X X X X FDA XFirst FDA approved CM DC product - first approvd Batch to CM conversion

First two lines for specific products - now full commitment to 70% of NPI portfolio

Vertex 2 X X X

FDA, EMA,

Canada, Aust. XFirst FDA approved CM Wet Granulation product - first approved NPI developed in CM

Develop and launch on same line - Hovione for all commercial production from 2018 onwards

Pfizer 1 1 X X X X Modular pod system rapid deployment, focus on emerging markets.

BMS 1 X X First Product selected, development on CDC50

Merck 1 2 X X Product identified for commercialization - CDC50 including twin coater

Roche 1 X X Equipment bought for product in 2012, was delisted

Bayer 1 X WG line including twin coater

AZ 2 X X X A lot of activity with CMAC on DS; Since one year started into DP effort.

GSK 2 X X X X

Partnership with Pfizer for PCMM deployment

Partnership with CMAC for API shaping (since 10y)

Lilly 3 X X X

Focus on DC: self built line - copy paste for development, clinical production, and commercial manuf.

Leaders in drug Substance CM; collaboration Pfizer, Limerick & Purdue

Novartis 1 X X X

Focus on process, not yet on deployment DS: continuous reaction, Crystallisation, drying

DP: Electrospinning, Thin Film, HME

Amgen X Less agressive timeline

Sanofi 2 X X X X Focus on process, not yet on deployment

Aesica 1 X X CMO, Vertex design, works with preblend, no inline feeding

Hovione 1 X X X X CMO, line based on Vertex design: DC, RC and WG

Patheon X X X CMO, Line design for Shire, 50% capacity will trigger next line

Chinoin 1 X X local X 3 approved products for Mexico

TEVA 2 X X X DC and WG line in Germany

generic in Bosnie

Herzegovina 1 X X Local X unkown amount of approved products on local market

Monograph Prioritization

1. Objective, readily available, and relevant measurement factors

2. Usable output – getting all factors down to one priority index

score

3. Customized to the program unit

4. Priority is set at the start of the process and carried through the

lifecycle

Requirements

52

Priority Index Score

53

WS * S

WS Sustainability Weighting

WI Public Health Impact DALY Weighting

WI-Exp Public Health Impact Exposure Risk Weighting

S Sustainability Factor- Normalized

I Public Health Impact DALY Factor- Normalized

I-Exp Public Health Impact Exposure Risk Factor- Normalized

PI Priority Index Score

*All inputs will be normalized to

one universal scale

WI * I PI WI-Exp * I-Exp

1. The inputs are value measures as determined by our current portfolio

i.e. – Use data on what drives the need for RS to as one decision point.

2. Mission- provide insight on monographs that are needed for mission that might not generate $ but will enable improvements in public health

3. Urgency- increase responsiveness to market by considering time to LOE (and time elapsed from LOE).

Chemical Medicines Objective: Increase Availability to Market

54

How does Monograph Volume Relate to API in the US?

How does Monograph Volume Relate to API Worldwide?

How does Monograph Volume Relate to API in the Rest of World (non-US)?

USP Donations

Many USP monographs need to be updated to modern analytical

methodologies

Replace organoleptic tests, TLC impurity tests, etc.

Addition of a dissolution test, specified impurities with different limits, etc.

FDA approved product not covered by current monograph

(USP won’t know unless you tell us)

Why submit a monograph revision?

59

Need to protect what is seen as trade secrets/intellectual property

Lack of resources within a company to devote to providing

monographs/materials

Product which may have long since been genericized

being seen as very low value to devote any resources

Can’t connect how USP fits into the overall

global public health interest

Too far in advance of patent expiry to donate

60

What We’ve Heard – Barriers to Donating

If a standard is based on another method, you will still need to comply

with the standard. Why shouldn’t that standard be based on your

company’s science?

As the foundation for a USP standard, your science will be viewed by

industry peers as the “science of choice” for establishing quality.

If your company does not have the resources to devote to providing

monographs and materials, there are other ways to be involved:

– Providing comments to a developing standard through Pharmacopeial Forum

– Applying to serve on an Expert Committee or Panel

61

What We’ve Learned – The Benefits

Without quality standards, consequences include:

– Adverse public health events

– Inadequate treatment

– Therapeutic failure

– Breakdown in trust in the health system

By working with USP in advance of your loss of exclusivity, you can get

a jump-start in trying to establish a standard that can be harmonized

with other pharmacopeias.

– Harmonized standards can help eliminate/minimize redundant testing

Your company can mitigate risks associated with noncompliance.

If a USP standard is based on your company’s method, your company

can save time and resources.

62

What We’ve Learned – The Benefits

What would personally motivate you to partner with USP on this effort?

Your company?

What are the biggest barriers for you to participate? For your company?

How can we overcome these barriers?

How important is it to your company to be publicly recognized for its

commitment to quality?

What kind of information and outreach does your company need from

USP in order to make your ability to donate easier?

If you donate, what kind of input would your company want from USP

regarding the status of the standard in development?

63

Question & Answer

Presentation Download

http://bit.ly/USPatGPhA2016

USP Chapters <232> and <233>

Implementation Strategy

Kahkashan Zaidi, Ph.D.

Principal Scientific Liaison

Science, General Chapters

Delete <231> Heavy Metals

Over 1200 references in the USP-NF

Introduce Three New Chapters: 1. <232>Elemental Impurities—Limits (Official But Not Implemented)

2. <2232>Elemental Contaminants in Dietary Supplements (Official

But Not Implemented )

3. <233> Elemental Impurities—Procedures (Official)

USP’s Approach

68

<231> Heavy Metals <231> Deletion Date o Jan 1, 2018

Publish Omission of General

Chapter <231>

o Published in USP 38–NF 33 with an

official date of December 1, 2015

USP to publish/Post list of

monographs and Chapters with

cross reference to <231>

o Accomplished---July 2014 and Jan

14, 2015

Delete cross-references to General

Chapter <231> Heavy metals from all

individual monographs

o Accomplished---USP 38 and 39 and

following publications with delayed

implementation on Jan 1, 2018

69

<231> Heavy Metals

70

<232> Harmonization with Q3D---Today

USP 39

Q3D USP <232>

Scope Harmonized Harmonized

(Exception: TPNs)

List of Elements 24 15

Not Included: Tl, Au, Se,

Co, Ba, Sn, Li, Sb and Ag

PDEs Harmonized For 15

Elements

Harmonized For 15

Elements

Other Routes Harmonized

Harmonized

Options 4 options

3 options

Implementation Harmonized Harmonized

71

Table 1: Elemental Impurities for Drug Products USP 39--Official

Element Oral Daily

Dose PDE

(µg/day)

Parenteral

Daily Dose PDE

(µg/day)

Inhalational

Daily Dose

PDE (µg/day)

Inorganic Arsenic 15 15 2

Cadmium 5 2 2

Lead 5 5 5

Inorganic

Mercury

30 3 1

Chromium 11000 1100 3

Copper 3000 300 30

Molybdenum 3000 1500 10

Nickel 200 20 5

Palladium 100 10 1

Platinum 100 10 1

Vanadium 100 10 1

Osmium 100 10 1

Rhodium 100 10 1

Ruthenium 100 10 1

Iridium 100 10 1 72

Table 2. Example Concentration Limits for Components of

Drug Products with a 10-g Maximum Daily Dose

Elements

Concentration Limits (µg/g) for Components

Used in Oral Drug Products

Concentration Limits

(µg/g) for Components

Used in

Parenteral Drug Products

Concentration Limits

(µg/g) for Components

Used In

Inhalation Drug Products

Cadmium 0.5 0.2 0.2

Lead 0.5 0.5 0.5

Inorganic arsenica 1.5 1.5 0.2

Inorganic mercurya 3 0.3 0.1

Iridium 10 1 0.1

Osmium 10 1 0.1

Palladium 10 1 0.1

Platinum 10 1 0.1

Rhodium 10 1 0.1

Ruthenium 10 1 0.1

Chromium 1100 110 0.3

Molybdenum 300 150 1

Nickel 20 2 0.5

Vanadium 10 1 0.1

Copper 300 30 3

a See Speciation section.

73

Key changes Proposed in PF 42(2)

Requirements/language for Drug Substance

and excipients

Tables 1 & 3 (previously Table 2) revised to

add additional elements

Added a new section and new table (Table 2)

to clarify risk assessment

Analytical testing

Format changes

74

<232> Revision in PF 42(2)

Drug substances and Excipients

The limits presented in this chapter do not apply to excipients and drug substances, except where specified in an individual monograph. However, elemental impurity levels present in drug substances and excipients must be known, documented, and made

available upon request.▪However, manufacturers of pharmaceutical products need

certain information about the content of elemental impurities in drug substances or excipients in order to meet the criteria of this chapter. Drug product manufacturers can use elemental impurity test data on components from tests performed by drug substance or excipient manufacturers, who may provide test data, or if applicable, risk assessments. Elemental impurity data generated by a qualified supplier of drug product components are acceptable for use by a drug product manufacturer to demonstrate compliance with this chapter in the final drug product. Drug substance or excipient manufacturers who choose to perform a risk assessment must conduct that risk assessment using Table 2 in this chapter. Elements that are inherent in the nature of the material, as in the case of some naturally-sourced materials, must be considered in the risk assessment.▪1S (USP40)

75

Table 1: Permitted Daily Exposures for Elemental

Impurities

PF 42(2)

76

Table 3: Permitted Concentrations of Elemental Impurities

for Individual Component Option (PF 42(2))

77

Table 2: Elements to be Considered in

the Risk Assessment

Element Class

If Intentionally Added

(All Routes)

If Not Intentionally Added

Oral Parenteral Inhalation

Cd 1 yes yes yes yes

Pb 1 yes yes yes yes

As 1 yes yes yes yes

Hg 1 yes yes yes yes

Co 2A yes yes yes yes

V 2A yes yes yes yes

Ni 2A yes yes yes yes

Tl 2B yes no no no

Au 2B yes no no no

Pd 2B yes no no no

Ir 2B yes no no no

Os 2B yes no no no

Rh 2B yes no no no

Ru 2B yes no no no

Se 2B yes no no no

Ag 2B yes no no no

Pt 2B yes no no no

Li 3 yes no yes yes

Sb 3 yes no yes yes

Ba 3 yes no no yes

Mo 3 yes no no yes

Cu 3 yes no yes yes

Sn 3 yes no no yes

Cr 3 yes no no yes

78

<232> Elemental Impurities

• ANALYTICAL TESTING

– If, by process monitoring and supply-chain

control, manufacturers can demonstrate

compliance, then further testing may not be

needed. When testing is done to

demonstrate compliance, proceed as

directed in Elemental Impurities—Procedures

⟨233⟩. and minimally include arsenic,

cadmium, lead, and mercury in the Target

Elements evaluation.▪▪1S (USP40)

79

Harmonization with Q3D---Future

Q3D USP <232>

Scope Harmonized Harmonized

(Exception: TPNs)

List of Elements Harmonized (24) Harmonized (24)

PDEs Harmonized Harmonized

Other Routes Harmonized

Harmonized

Options 4 options

3 options

Implementation Harmonized Harmonized

80

<231> and Veterinary Product Monographs

• Veterinary Products are out of scope

• Should we remove heavy metals testing from these

monographs?

– 197 official monographs

• 76 are drug substance monographs.

• Not all of these have labeling to indicate for vet use

only.

– Many vet drug products contain drug substances

that are also used in human formulations

– Human drug product may also have an

approved vet product.

81

New Chapters

• <730> Plasma Spectrochemistry

• <1730> Plasma Spectrochemistry—

Theory and Practice

• <735> X-Ray Fluorescence

• <1735> X-Ray Fluorescence Spectrometry

82

Chapters Impacted by <231> Deletion

1. <381> ELASTOMERIC CLOSURES FOR INJECTIONS

2. <661> PLASTIC PACKAGING SYSTEMS AND THEIR MATERIALS OF CONSTRUCTION

3. <661.1> PLASTIC MATERIALS OF CONSTRUCTION

4. <661.2> PLASTIC PACKAGING SYSTEMS FOR PHARMACEUTICAL USE

5. <661.3> PLASTIC COMPONENTS AND SYSTEMS USED IN PHARMACEUTICAL MANUFACTURING [NEW--- In PF 42(3)]

83

Arsenic ⟨211⟩

Lead ⟨251⟩

Selenium ⟨291⟩

Mercury ⟨261⟩

84

Other Element Specific Chapters

Limit tests and references to element specific chapters are included in about 1000 monographs?

What is the future of element specific chapters?

Are these specific element chapters and limit tests in monographs unnecessary unless there is a known quality- or safety-related reason to maintain the specific elemental impurity limit(s) in place for selected components (drug substances or excipients)?

With ⟨233⟩ in place, analytical procedures specific to individual elements are no longer

necessary? Removing references and (special) limits from drug product monographs would

align those monographs with ⟨232⟩, providing industry with only one set of elements and limits, as well as one analytical procedure.

Other Chapters

85

Other Element Specific chapters

86

87

ALUMINUM 2.0% TALC 04-Excipients

ALUMNIUM 0.2 ppm SODIUM CHLORIDE 04-Excipients

ANTIMONY NMT 2 µg/g TITANIUM DIOXIDE 04-Excipients

ARSENIC 3 µg/g MONOBASIC POTASSIUM PHOSPHATE04-Excipients

ARSENIC 3 ppm PROPYLENE GLYCOL ALGINATE 04-Excipients

ARSENIC NMT 1.5 ppm POTASSIUM ALGINATE 04-Excipients

CADMIUM NMT 0.2 ppm CHITOSAN 04-Excipients

CADMIUM NMT 1 ppm FERROSOFERRIC OXIDE 04-Excipients

CADMIUM 3 ppm MAGNESIUM STEARATE 04-Excipients

CALCIUM 0.9% TALC 04-Excipients

LEAD NMT 0.5 µg/g CORN SYRUP SOLIDS 04-Excipients

LEAD NMT 0.5 ppm CHITOSAN 04-Excipients

LEAD NMT 0.5 mg/kg INOSITOL 04-Excipients

LEAD 25 µg/g HYDROPHOBIC COLLOIDAL SILICA 04-Excipients

LEAD NMT 10 ppm FERROSOFERRIC OXIDE 04-Excipients

LEAD NMT 5 ppm GALAGEENAN 04-Excipients

LEAD NMT 10 µg/g GUAR GUM 04-Excipients

LEAD NMT 10 ppm HYDROXYPROPYL CELLULOSE 04-Excipients

LEAD NMT 15 µg/g MAGNESIUM ALUMINUM SILICATE04-Excipients

LEAD 10 ppm MAGNESIUM STEARATE 04-Excipients

LEAD NMT 10 ppm MONOSODIUM GLUTAMATE 04-Excipients

LEAD NMT 10 ppm PROPYLENE GLYCOL ALGINATE 04-Excipients

LEAD NMT 0.5 µg/g GALACTOSE 04-Excipients

LEAD NMT 10 µg/g PURIFIED SILICEOUS EARTH 04-Excipients

LEAD NMT 10 ppm SODIUM ALGINATE 04-Excipients

LEAD 40 µg/g BENTONITE 04-Excipients

LEAD 15 µg/g PURIFIED BENTONITE 04-Excipients

MERCURY NMT 0.2 ppm CHITOSAN 04-Excipients

MERCURY NMT 1 ppm FERROSOFERRIC OXIDE 04-Excipients

MERCURY NMT 3 µg/g FERRIC OXIDE 04-Excipients

MERCURY NMT 1 µg/g TITANIUM DIOXIDE 04-Excipients

NICKEL NMT 200 ppm FERROSOFERRIC OXIDE 04-Excipients

NICKEL NMT 1 µg/g GLYCERYL DISTEARATE 04-Excipients

NICKEL 5 ppm MAGNESIUM STEARATE 04-Excipients

NICKEL NMT 1 µg/g MALTITOL 04-Excipients

PHOSPHOROUS 700 µg/g ALPHA-LACTALBUMIN 04-Excipients

SELENIUM NMT 10 ppm SODIUM SULFITE 04-Excipients

SELENIUM 30 µg/g MONOTHIOGLYCEROL 04-Excipients

TIN NMT 0.1 µg/g MEDIUM-CHAIN TRIGLYCERIDES 04-Excipients

Excipient Monographs with Specific Limits

Stim Article in PF 42(4)

88

Other Element Specific chapters in the USP-NF

STIMULI TO THE REVISION PROCESS Stimuli articles do not necessarily reflect the policies

of the USPC or the USP Council of Experts

Future of Element-Specific Chapters in the USP–NF

USP’s Chemical Analysis Expert Committee and Kahkashan Zaidia ABSTRACT

The Chemical Analysis Expert Committee (CAEC) is evaluating the idea of removing element-specific chapters and limit tests in monographs from the USP–NF. The CAEC is considering the effect of this proposal, as well as the effect of retaining these chapters and limit tests. The CAEC strongly encourages comments and discussions regarding this proposal.

89

Element Specific Chapters

Questions:

a. Are these element specific limit tests in monographs

necessary?

b. Are there known quality- or safety-related reasons to keep

specific elemental impurity limit(s) in the monographs (drug

substances, excipients and Drug Products)?

USP needs stakeholder’s

Feedback

90

Element Specific Chapters

It will not be an Easy Task

BUT IF IT CAN BE DONE THEN,

a. Removing references and (special) limits from drug product monographs would:

a. Align those monographs with ⟨232⟩, providing industry with only one set of elements and limits, as well as one analytical procedure.

a. Will simplify compliance and establishment of consistent, safety-based elemental impurity limits with the focus on the drug product rather than component-specific limits.

b. With ⟨233⟩ in place, analytical procedures specific to individual elements

are no longer necessary

General Notices (GN)

– Overarching – Apply to all chapters and monographs

General Test Chapters

– Tests and assays applying to multiple monographs

– Supersede GN if conflicting

Monographs: API, Excipients, Drug Products

– Supersede both GN and Chapters if conflicting

General Information Chapters

– Guidance

– Do not contain specifications

Structural Hierarchy

91

Implementation

• Implementation through General

Notices

• No reference to <232> will be in

monographs

92

<232> Implementation USP General Notices:

5.60.30. Elemental Impurities in USP Drug Products and Dietary Supplements Effective January 1, 2018 • Elemental impurities will be controlled in official drug products

according to the principles defined and requirements specified in Elemental Impurities—Limits ⟨232⟩. Effective January 1, 2018, elemental contaminants are controlled in official dietary supplements according to the principles defined and requirements specified in Elemental Contaminants in Dietary Supplements ⟨2232⟩. Also effective January 1, 2018, Heavy Metals ⟨231⟩ will be omitted and all references to it in general chapters and monographs will be deleted. Early adoption of the requirements in ⟨232⟩ and ⟨2232⟩ are permitted by USP, and if ⟨232⟩ or ⟨2232⟩, as applicable, is fully implemented with respect to a particular drug product or dietary supplement in advance of the January 1, 2018 date, that product and its ingredients will no longer need to comply with applicable ⟨231⟩ requirements to be considered by USP to be in conformance with USP–NF requirements.(RB 1-Apr-2015)

93

USP General Notices

3. CONFORMANCE TO STANDARDS

– 3.10. Applicability of Standards

• Early adoption of revised standards in advance

of the official date is allowed by USP unless

specified otherwise at the time of publication.

94

Analytical Procedures Harmonized analytical procedures should be

established by the pharmacopoeias for determining

levels of metal impurities, with allowance for use of any appropriate

validated procedure for a particular application.

USP Chapter <233> Elemental Impurities—Procedures

Proposed in PF 36(1) (2010)

Sample Preparation

Procedures

Validation requirements

Harmonization through PDG 95

USP Website

• March 27, 2015 • General Chapters and Related Information

• To be Published in Second Supplement to USP 38-NF 33: (official

on December 1, 2015)

– <232> Elemental Impurities—Limits

– <233> Elemental Impurities—Procedures

• Revision Plan (updated March 27, 2015)

• Frequently Asked Questions

• FAQs on the Implementation of USP General Chapters <232>

Elemental Impurities—Limits <233> Elemental Impurities—

Procedures, and <2232> Elemental Contaminants in Dietary

Supplements (updated 27–Mar–2015)

96

Implementation – USP

ICH Q3D step 4 published Dec 16, 2014

Implementation of <232> and <2232> o Jan 1, 2018

Via USP General Notices

Omission of Chapter <231> o Jan 1, 2018

Delete cross-references to General

Chapter <231> Heavy metals from all

individual monographs

o Jan 1, 2018

o Deletion Marked up---USP 38 and

following publications with delayed

implementation on Jan 1, 2018

97

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United State Pharmacopeia:

Plastic Packaging Standards: <661> Chapters

Desmond G. Hunt, M.S., Ph.D. Principle Scientific Liaison Science, General Chapters

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: “The Old”

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 (Aim for the

Middle).

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>

The Foundation

United States Pharmacopeia:

USP GENERAL CHAPTER <1663> Assessment of

Extractables Associated with Pharmaceutical

Packaging/Delivery Systems

1. PURPOSE

2. KEY TERMS

3. SCOPE

4. BACKGROUND INFORMATION

5. GENERATING THE EXTRACT 1. General Concepts and Critical Experimental Design Parameters

2. Chemical Nature of the Extracting Medium

3. Extraction Time and Temperature

4. Extraction Stoichiometry

5. Mechanism of Extraction—Extraction Technique

6. Extractions That are Not Solvent Mediated

6. CHARACTERIZING THE EXTRACT 1. Objectives and Challenges

2. Processes Involved in Extract Characterization

3. Preparation of Extracts for Analysis

7. SUMMARY 1. Assessing the Completeness of an Extractables Assessment

2. Example Extractables Profiles—Materials Characterization

10

8

<1663> Extractables Associated with

Packaging/Delivery Systems

United States Pharmacopeia:

USP GENERAL CHAPTER <1664> Assessment of

Leachables Associated with Pharmaceutical

Packaging and Delivery Systems

<1664.1>

Orally Inhaled

Nasal Drug

Products

<1664.2>

Parenteral and

Ophthalmic Drug

Products

(To Come)

<1664> Assessment of Leachables Associated with

Pharmaceutical Packaging and Delivery Systems

<1664> Leachables Associated with

Packaging/Delivery Systems

1. PURPOSE

2. KEY TERMS

3. SCOPE

4. BACKGROUND INFORMATION

5. CONCEPTS 1. General Concepts for Leachables Assessment

2. Safety Thresholds

3. Information Sharing

6. LEACHABLES STUDY DESIGN

7. LEACHABLES CHARACTERIZATION 1. Analytical Thresholds

2. Analytical Method Requirements

3. Preparing the Drug Product for Analysis—Sample Preparation

4. Analytical Techniques

5. Quantitative Methods—Validation Considerations

8. ESTABLISHING A LEACHABLES–EXTRACTABLES CORRELATION

9. CONSIDERATIONS IN DEVELOPING LEACHABLES SPECIFICATIONS AND

ACCEPTANCE CRITERIA

10.ADDITIONAL CONSIDERATIONS 1. Simulation Studies

2. Inorganic (Elemental) Leachables

<1664> Leachables Associated with

Packaging/Delivery Systems

Overview: <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

Objective: To gain as much information about a

material of construction to determine potential

suitably

• Development

• Packaging System Change

Requirement of <661.1> can be met by :

• The materials of construction meeting requirement of

<661.1>

• The component or system meeting the requirement of

<661.2>

<661.1> Material Characterization Chapters

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

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

Revision Impact

50 year standard being revised

Added new polymers

Added new testing procedures and specifications

New testing paradigm

• Materials of Construction

• Packaging System

Currently approved drug products that uses a

plastic component in it’s packaging system could

be impacted.

Qualification: Packaging Material/System (High-

Risk Dosage Form)

1 month: selection of alternative material/component

8 months: develop extractable profile with toxicological

assessment

24+months: leachable migration study

• If sponsor wants to submit actual shelf-life data

− 2 year self-life

− Control room temperature product

~3Years: qualify a new packaging systems for one drug

product

A company can have many products that use the same

packaging component, which increase the issue

exponentially.

Currently Approved Products

Rationale

Goal of <661> revision

• “To aid in the selection and qualification of packaging

materials and components that are deemed suitable

and safe”

Suitability and safety of a packaging system, with it’s

drug product, is determined by regulatory authorities

• A packaging system, with a specific drug product,

would meet the requirements of <661.1> and <661.2>,

if it had gained regulatory approval.

New Products

Existing Products

– Material/Component Change

• New raw material/component supplier

• Process changes

–Reaction conditions, cycle times, equipment, etc.

• Stock outs or product withdrawal

Incoming material and component quality control

Situation Required Testing

General Situation Specific Circumstance <661.1> <661.2>

Changes to a packaging system used with a currently marketed pharmaceutical product

A new material is introduced into the packaging system

Yes (for the new material)

Yes

A material of construction in the packaging system is changed in either composition or process

Yes (for the changed material)

Yes

The packaging system is changed, in either composition or process, in a manner that does not involve a change in its materials or to its materials (for example, changing the thicknesses of individual layers in a multi-layered film)

No Yes

Packaging System Change

Situation Required Testing

General Situation Specific Circumstance <661.1> <661.2>

Packaging system used with a currently marketed pharmaceutical product is to be applied to a different pharmaceutical product

Dosage form and conditions of use are similar for the current and different pharmaceutical products

No No

Dosage form and/or conditions of use are different from the current pharmaceutical products (moving from “high risk” to “low risk”)

No No

Dosage form and/or conditions of use are different from the current pharmaceutical products (moving from “low risk” to “high risk”)

Yes Yes

Packaging System Applied to New Product

Application and Applicability

Current Materials

• Polyvinyl Chloride, Plasticized

• Polyethylene

• Cyclic Olefin

• Polyethylene Terephthalate

• Polyethylene Terephthalate G

• Polyamide 6 (Nylon)

• Polycarbonate

• Polyethylene vinyl acetate

• Polyvinyl Chloride, Non

Plasticized

Future Revision: <661.1> PF 42 (4) July 2016

Future Materials

• Acrylonitrile butadiene styrene

• Polybutylene terephthalate

• Poly(methylmethacrylate)

• Polystyrene

• Polysulfone

• Polytetrafluoroethylen

• Polyurethane

Proposed revision of chapter’s Scope 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

Topic of Discussion

• Should specific date be proposed when the grandfathering clause should be

removed from the chapter

Future Revision: <661.1> and <661.2> PF 42 (4) July

2016

Upcoming Packaging 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

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