Advancing Quality Standards for Active

Pharmaceutical Ingredients (APIs)

Heather R. Joyce, Ph.D.Senior Scientific Liaison – Chemical MedicinesU.S. Pharmacopeial Convention (USP)HRJ@usp.org

• Developing Monograph Standards

• Modern Expectations (Up to Date)

• Chromatographic System Suitability Considerations

• Anticipating Future Needs

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Volunteers Make It Happen at USP

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2015-2020 Council of Experts

Expert Committees and Collaborative Groups

USP Standards

• Monographs

– Specifications for pharmaceutical articles in commerce (from release through end of shelf life)

– Tests, assays and acceptance criteria needed to demonstrate the article meets required quality standards

• General Chapters:

– Centralized methods and procedures to support monographs

– Test chapters (numbered <1000) contain validated methods

– Informational chapters (numbered >1000) contain best practices

• Physical Reference Materials

– Provide traceable standards to demonstrate broad-based acceptability of procedures contained in monographs and general chapters

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USP Reference Standards

• Drug substances

• Excipients

• Impurities

• Degradation products

• Biologics

• Food ingredients

• Dietary supplements

• Compendial reagents

• Performance test

tablets

Highly characterized

specimens of

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Science is the Base of USP Standard Setting

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Pharmacopeial Forum (PF)

The PF is a free bimonthly online journal through which USP develops and

revises standards for the USP–NF by a process of public review and comment.

www.usppf.com to access the PF (a one time registration is required)

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Types of Standards Development

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• New monographs:

– Substance/product must typically be legally marketed in the US

– Proposed tests, limits, packaging, storage, and labeling requirements

– Procedures with Validation data (<1225> Validation of Compendial Procedures)

– Shelf-life specifications

– Reference Standard commitments

• New General Chapters

• Revisions to existing monographs and general chapters:

– Reasonable justification (new specifications; new form has been approved)

– Improved analytical methodologies are available (Up to Date)

– Adequate supporting data for methods and demonstration of improvement

– Shelf-life specifications

– USP-initiated revisions

• Can be based on other pharmacopeial standards, ICH specifications, etc.

Details found at http://www.usp.org/get-involved/donate/submission-guidelines

• Developing Monograph Standards

• Modern Expectations (Up to Date)

• Chromatographic System Suitability Considerations

• Anticipating Future Needs

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USP-NF Up to Date Initiative

Add missing

procedures

Replace

non-specific

tests

Omit non-

relevant

monograph

s

Remove non-value-added procedures

Update or replace

hazardous tests

Update outdated

technologies

Develop standards that reflect

“state-of-the-industry” techniques

for monitoring drug quality, purity,

and strength.

Ensure that all monographs in the

USP–NF are current, relevant, and

suitable for their intended use.

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USP-NF Up to Date Drivers

Many monographs have been official for several years, decades in some

cases and may not have kept pace with scientific advancements

Content does not reflect current expectations for scientific procedures and

acceptance criteria

– Replace non-specific procedures with specific procedures

– Minimize & remove safety/environmental issues (chlorinated solvents)

– Ensure referenced equipment is readily available

– Remove unnecessary or outdated tests

– Address stakeholder concerns

Increase consistency across monographs & chapters

Modernization is a subset of ongoing development & revision activities

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USP-NF Up to Date Strategies

Traditional donor model (‘externally sourced’)

– Very difficult to engage sponsors, may need to reconcile more than one

USP laboratories (‘internally sourced’)

– Extensive testing facilities for procedure development

– Global effort: US, India, China, and Brazil

FDA (CRADA: ORA Labs)

Expert panels

– Gain industry expertise, early stakeholder input & buy-in

Adapt/Adopt (Other Pharmacopeias)

– Identify alternate source procedures (i.e., procedures that can be used

from other pharmacopeias; impurities which may be relevant)

– Prospective Harmonization12

Worldwide Scientific Capabilities

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USP-NF Up to Date Goals

High-quality public standards should include:

– Impurity tests such as Organic Impurities procedures

– 2 (or more) orthogonal Identification tests

– Objective procedures (exclude organoleptic tests such as those based on odor

and taste)

– Nonhazardous reagents (exclude the use of chlorinated solvents, mercuric

acetate, etc.) and procedures (exclude the use of open flames)

– Modern procedures (exclude outdated technology such as paper

chromatography, packed column GC, open column chromatography, etc.)

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USP-NF Global Partnerships

How Stakeholders are helping

• Submitting their current analytical methods with validation data

• Providing samples of the article for USP internal laboratory

development

• Providing US FDA approved specifications

• Providing bulk quantities of materials needed to support revisions

Details found at http://www.usp.org/get-involved/donate/submission-guidelines

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Up to Date Includes USP Reference Standards

ENABLESMANUFACTURER

TESTING

ID Tests

Impurity Tests

Related Compounds

Limit Tests

Residual Solvents

Assay

Dissolution

Bringing Documentary Standards to Life

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• Developing Monograph Standards

• Modern Expectations (Up to Date)

• Chromatographic System Suitability Considerations

• Anticipating Future Needs

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Chromatographic System Suitability Considerations

System Suitability for USP Chromatographic Procedures –

Small Molecules

– Stimuli Article published in PF 39(5)[Sep – Oct 2013]

– Authors: Small Molecules Expert Committee Chairs and Vice Chairs

– General expectations for system suitability requirements for

chromatographic procedures submitted in new or revised monographs

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System Suitability Background

Parameters and acceptance criteria

– Described in <621> Chromatography

– May be similar to the European Pharmacopeia

– Monograph limits or definitions have priority over acceptance criteria or

definitions included in general chapters

Current Monographs may

– Reflect submissions received for products registered many years ago

with system suitability practices that do not reflect current expectations

– Reflect the standard practices of a single sponsor

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Expectations for Submitted Proposals

Test Typical System Suitability Parameters Case-by-Case Parameters

Assay Precision

Symmetry/Tailing Factor

Resolutiona

Theoretical Platesb

Retention/Capacity Factor

Resolution

Impurities Resolution

Precision

Sensitivity

Symmetry/Tailing Factor

Theoretical Platesb

Retention/Capacity Factor

Dissolutionc

and

Content Uniformityc

Precision

Symmetry/Tailing factor

Resolutiona

Theoretical Platesb

Retention/Capacity Factor

Sensitivity

a Often needed for combination products or if a significant impurity elutes near the main peak or there is

critical pair of impurities.b For isocratic or isothermal procedures only.c When test measurements are made using HPLC or GC.

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Relative Standard Deviation

Historically

NMT 2.0% for 5 replicate injections for the 98.0%-102.0% Assay acceptance range

– RSD results of 2.0% could mask problems with the procedure

– An injection system delivering no better than 2.0% RSD would result in a

significant number of out-of-specification results for a pure drug substance

because of the imprecision of the measurement

Currently

General Chapter <621> includes a table which acknowledges the relationship

between the specification range, the number of injections, and the required system

precision

– Modern HPLC systems have injection precision of 0.5% RSD or better

– Most USP modernization proposals include an RSD requirement of NMT

0.73% as indicated in <621> for an upper assay limit of 102.0% 21

Relative Standard Deviation

For the Assay in a drug substance monograph, unless otherwise

prescribed (such as in the monograph), <621> provides the following:

B = upper limit of the monograph definition minus 100%

• Tighter RSD values are needed for system repeatability the closer the

Assay range is to 100%

• Not intended to address tests for organic impurities

• Harmonized, to the extent possible, with European Pharmacopeia, 2.2.46,

Chromatographic Separation Techniques

Number of Individual Injections

3 4 5 6

B(%) Maximum Permitted RSD

2.0 0.41 0.59 0.73 0.85

2.5 0.52 0.74 0.92 1.06

3.0 0.62 0.89 1.10 1.27

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Tailing Factor (Symmetry Factor)

Excessive tailing is often a symptom of column aging or contamination and

can indicate that the column should be replaced.

Meeting the tailing factor requirement is usually a sufficient indication of

column efficiency and a check for theoretical plates is not routinely needed.

Because column brand names are not specified in USP monographs, tailing

factor may be important in showing that an acceptable column is being

used.

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System Suitability for Impurity Procedures

Selectivity to demonstrate that impurities are adequately resolved from each

other, from the drug substance and excipients

Signal-to-noise ratio (S/N) using a Sensitivity solution (analyte concentration

near the reporting threshold)

• <621> Chromatography is currently harmonized with the S/N calculation

in Ph. Eur. 2.2.46.

Precision of a Standard solution at a concentration comparable to the limit

For trace analysis procedures, spiked samples may be used to show

adequate detection of the analyte in the presence of the sample matrix.

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General Expectations

System suitability should be demonstrated throughout a

chromatographic run

• USP does not specify how this should be accomplished.

• It is up to analytical laboratories to establish appropriate requirements.

• Common practices:

Standard injections throughout the run to check precision

System suitability injections throughout the run to check selectivity

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• Developing Monograph Standards

• Modern Expectations (Up to Date)

• Chromatographic System Suitability Considerations

• Anticipating Future Needs

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Flexible Monograph Approach

Address differences in drug substance, ingredient, or product

attributes

• Polymorphic forms

• Impurity profiles

• Product-specific dissolution tests

• Labeling

Different tests or acceptance criteria as approved by the US FDA

Flexible approach is not generally used for Assays

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Different Polymorphic Forms

Azithromycin

• WATER DETERMINATION, Method I < 921 >

Where it is labeled as anhydrous: NMT 2.0%

Where it is labeled as the dihydrate: 4.0%–5.0%

Where it is labeled as the monohydrate: 1.8%–4.0%, except that it may

be 4.0%–6.5% when the requirements of the Loss on Drying test are met

• LABELING: Label it to indicate whether it is anhydrous, or the monohydrate, or

the dihydrate. …

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Different Manufacturing Processes

Trazodone Hydrochloride

• LIMIT OF TRAZODONE RELATED COMPOUND F AND CYCLOPHOSPHAMIDE

RELATED COMPOUND A [Note—Perform this test only if trazodone related

compound F and cyclophosphamide related compound A are known process

impurities. ]

Rocuronium Bromide

• LIMIT OF 2-PROPANOL [Note—Perform this test only if 2-propanol is a known

organic manufacturing process impurity. ]

• LIMIT OF ACETIC ACID [Note—Perform this test only if acetic acid is a known

organic manufacturing process impurity. ]

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Different Impurity Profiles

Tacrolimus

• ORGANIC IMPURITIES, PROCEDURE 1 Use Organic Impurities, Procedure 1

when the impurity profile includes tacrolimus methylacrylaldehyde and

tacrolimus diene.

• ORGANIC IMPURITIES, PROCEDURE 2 Use Organic Impurities, Procedure 2

when the impurity profile includes ascomycin, desmethyl tacrolimus, tacrolimus

8-epimer, and tacrolimus 8-propyl analog.

• LABELING: If a test for Organic Impurities other than Procedure 1 is used,

then the labeling states with which Organic Impurities test the article

complies.

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Drug Products: Formulation-Specific Dissolution Tests

Tacrolimus Capsules, Revision Bulletin, 01-Feb-2013

• DISSOLUTION <711>

Test 1

Test 2: If the product complies with this test, the labeling indicates that it

meets USP Dissolution Test 2.

Test 3: If the product complies with this test, the labeling indicates that it

meets USP Dissolution Test 3.

Test 4: If the product complies with this test, the labeling indicates that it

meets USP Dissolution Test 4.

• LABELING: When more than one Dissolution test is given, the labeling states

the Dissolution test used only if Test 1 is not used.

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Accelerated Revisions

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• Revision Bulletins: narrow revision scope; no public comment period;

posted to the USP website with short notice of official status

• Interim Revision Announcements (IRAs): proposed in PF with a 90-

day notice and public comment period; if approved, posted to the USP

website with about a two month notice of official status

• Errata: text erroneously published in USP-NF or its Supplements that

does not accurately reflect the intended requirements as approved by

the Expert Committee; updates are posted on the USP website with

short notice of official status

USP-NF General Notices, Section 3.10

Early adoption of revised standards in

advance of the official date is allowed by

USP unless specified otherwise at the

time of publication

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…General chapter citations in NF monographs

refer to USP general chapters.

Early adoption of revised standards in advance of

the official date is allowed by USP unless

specified otherwise at the time of publication.

Where revised standards for an existing article

have been published as final approved “official

text” (as approved in section 2.10 Official Text) but

have not yet reached the official date (six months

after publication, unless otherwise specified; see

“official date”, section 2.20 Official Articles),

compliance with the revised standard shall not

preclude a finding or indication of conformance

with compendial standards, unless USP specifies

otherwise by prohibiting early adoption in a

particular standard.

USP-NF General Notices, Section 5.80

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Where USP or NF tests for assays

call for use of a USP Reference

Standard, only those results

obtained using the specified USP

References Standard are

conclusive.

Advancing Quality Standards

QUALITY PRODUCTSimprove the health

of patients

STRENGTHENthe quality chain with

USP Reference Standards

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