Hot Topic of The Season:

Spectroscopy USP

Paul Smith

Global Strategic Compliance

Program Manager

Agilent Technologies, Inc.

August 20, 2015

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August 21, 2015

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E-Seminar Structure

Contents

A. Pharmacopeia Structure

Context and Reference Information

B. Changes to USP

Spectroscopy Chapters

C. Spectroscopy Comparison

Across USP, Ph. Eur. & JP

Questions ?

Can’t answer detailed questions about

specific Analytical Methods, or

Instruments or Monographs…….

However, if you have a specific

compliance question related to

Pharmacopeia & you would like an

answer - use the on-line system to ask,

and we will provide reference information.

A key part of this e-Seminar is to provide

educational insight into Pharmacopeia

compliance.

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Pharmacopeia Structure

References and

USP Spectroscopy

Changes

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Detailed Comparison

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Presentations: • From 22 Pharmacopeia's

Links: • Meeting Report

• Meeting Summary

• Index of Pharmacopeia's

• Review of World Pharmacopeia's

2012

Pharmacopeia's Are Not Harmonised !

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2012

• Argentina

• Austria

• Belarus

• Belgium

• Brazil

• China

• Croatia

• Czech Republic

• Denmark

• Egypt

• Finland

• France

• Germany

• Greece

• Hungary

• Iceland

• India

• Indonesia

• Iran

• Ireland

• Italy

• Japan

• Kazakhstan

• Korea

• Lithuania

• Mexico

• Montenegro

• Norway

• Pakistan

• Philippines

• Poland

• Portugal

• Serbia

• Romania

• Russian Federation

• Slovakia

• Slovenia

• Spain

• Sweden

• Switzerland

• Thailand

• Turkey

• Ukraine

• United Kingdom

• USA

• Viet Nam

• Europe

• Africa

• WHO

Lists

Pharmacopeia

Requirements

For 46

Countries

Not Harmonised:

• Structure

• Contents

• Details (monograph / general)

WHO - Review of Pharmacopoeias

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WHO - Review of Pharmacopoeias

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Countries in Europe:

• Follow the Ph. Eur

• May have National Pharmacopeia

• e.g. BP and Ph. Eur….

Greater speed of

response / flexibility

Analysis of Content:

Care when Supplying with a country requirement !

Compliant Analysis of Samples – Is Influenced By:

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Laboratory compliance

requirements are influenced by:

• What samples you test

• What analysis you do

• What decisions the results are used for

• What samples you test

• What analysis you do

• What decisions the results are used for

Quality System

Laws & Regulations Supply [Products & Services]

How you perform the Test

Monograph requirements – of the Pharmacopeia

Compliance with USP-NF

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“An article of commerce that is recognized in the USP–NF complies

with USP–NF standards when it meets all”:

• The requirements stated in the articles monograph

• Applicable general chapters

• General notices.

See USP “FAQ”

What does this mean ?

Hierarchy of Requirements:

1. Pharmacopeia > GMP > Guidance

2. Monograph > General Chapter

Typically, Pharmacopeia's Contain:

• Monographs

• General Chapters

Pharmacopeia Structure…..

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USP • Good Practice – Familiarise With Structure

[different structure / content]

• Read the Explanation and General Information

General Chapters < 1000: Mandatory

General Chapters > 999: Informational

? What about USP <1058>

Extensive Cross-referencing between chapters

2 possible ways of interpreting:

- Don’t have to comply, <1058> is greater than 999

- A tool to Use - Simplify Instrument Qualification…….

Contribution….

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Pharmacopeia's provide a mechanism for providing feedback on draft chapters

and monographs……. Please Use !

• Draft documents are published in Pharmacopeial Forum

• 90 Days to Provide Feedback

• Example – USP Collation of Feedback USP 38 – NF 33

• Apply to be an observer (at USP meetings)

Polling Question 1

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USP Spectroscopy Changes

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References and

USP Spectroscopy

Changes

Changes to USP Spectroscopy General Chapters

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<231> Heavy Metals <232> Elemental Impurities - Limits

Mandatory Chapter Guidance Chapter

<233> Elemental Impurities - Procedures

<2232> Elemental Contaminants in

Dietary Supplements

ICP-OES

ICP-MS

Move to low level reliable analysis of regulated elements (interference free) • Implementation – January 2018 – ICH Alignment

• Many Organisations Investing in Technology – Ahead of 2018 USP

Key Issues Page

Changes to USP <191> Identification Tests - General

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<191> Identification Tests - General “General chapter <191> is applied for

the identification of ions or counter

ions of drug salts”

Where the USP considers a significant change, or needs input “beyond” the

USP draft revision process – it will use a Stimuli to the Revision Process: [to Stimulate Discussion & Continual Review]

<191> Stimuli Article

Pharmacopeial Forum

• Access Free

• E-Mail Registration

• PF 41 (2)

Alternative Instrument Techniques

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Ion AA IR Raman IC ICP XRF

Chloride (MS)

Bromide (MS)

Iodide (MS)

Acetate

Bi/Carbonate

Citrate

Phosphate

Sulphate

Tartrate

Aluminium (OES/MS)

Calcium (OES/MS)

Magnesium (OES/MS)

Potassium (OES/MS)

Sodium (OES/MS)

Zinc (OES/MS)

Changes to USP Spectroscopy General Chapters

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<851> Spectroscopy and Light Scattering

[USP 38 – NF33]

Mandatory Chapter Informational Chapter

<852> Atomic Absorption..

<853> Fluorescence…

<854> Mid Infrared….

<857> UV-Visible….

<1852> Atomic Absorption..

<1853> Fluorescence…

<1854> Mid Infrared….

<1857> UV-Visible….

Theory & Practice Includes

Qualification

Split Up <851>

Linkage between General Chapters and USP <1058>

(Analytical Instrument Qualification)

- First Raised by Horacio Pappa at 2010 AAPS Round Table Discussion

What Does This Mean For HPLC Detectors ?

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Fluorescence

UV-Visible

Do these detectors have to comply with the USP

general chapters <853> and <857> ?

No Horacio Pappa:

“These chapters are referenced in

monographs when spectroscopic

measurements are performed” (e.g. not HPLC)

Unless you are using your HPLC detector as a stand

alone spectrophotometer !

USP <853> Fluorescence Spectroscopy

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Instrument Performance

Control of Wavelengths Six replicate Measurements • Standard Deviation < 1.0 nm

• Outside 240-650nm – Use other Rare earth Oxides or solutions

• Excitation & Emission Limits (Doped Polymer)

Hg or Xe Emission Lines

Rare Earth Oxide Solution (e.g. holmium oxide)

Doped Polymethylmethacrylate

Low Conductivity Water (18-Mohm) WATER Water is convenient to obtain in a pure state and allows

Inter-laboratory comparisons to be made with a high level

of confidence.

The Raman band is a low level signal that provides a good test

for both the optics and the electronics of an instrumental system.

• Excitation 350nm

• Emission 397nm

USP <854> Mid-Infrared Spectroscopy

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Instrument Performance

Wavenumber Accuracy 35μ Thick Matt Polystyrene • Peaks:

3060.0, 2849.5, 1942.9, 1601.2, 1583.0, 1154.5, and 1028.3 cm−1

• +/- 1.0 cm-1

USP <857> Ultraviolet-Visible Spectroscopy

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Acceptance criteria for critical instrument parameters that establish “fitness

for purpose” are verified during IQ and OQ.

Specifications for particular instruments and applications can vary depending

on the analytical procedure used and the desired accuracy of the final result.

Instrument vendors often have samples and test parameters available as part

of the IQ/OQ package. Wherever possible in the procedures detailed as follows,

certified reference materials (CRMs) are to be used in preference to

laboratory-prepared solutions. These CRMs should be obtained from a

recognized accredited source and include independently verified traceable value

assignments with associated calculated uncertainty. CRMs must be kept clean

and free from dust. Recertification should be performed periodically to maintain

the validity of the certification.

Contains IQ / OQ Information

Note: The Qualification Comments Across <853>, <854> and <857> are inconsistent !

USP <857> Ultraviolet-Visible Spectroscopy

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Instrument Performance

Control of Wavelengths Six replicate Measurements • Mean Measures & Certified Value

• +/- 1nm (200-400nm) +/-2nm (400-700nm)

• Standard Deviation < 0.5 nm

• Single Measurement – Diode Array

Hg or D2 Emission Lines

Rare Earth Oxide Solution (e.g. holmium oxide)

Rare Earth Glass

Control of Absorbance Acidic Potassium Dichromate / Neutral Density Filter • Option of other traceable solutions / optical filters

• Six replicate measurements (SD 0.5% A (> 1 A), 0.005 A (< 1 A))

• Absorbance Accuracy +/- 1 %A (> 1A), +/- 0.010% A (<1A))

• 2 or more absorbance levels

Resolution Toluene in Hexane (0.020% v/v)

• Measure ratio of Absorbance ~ 269 and 266nm

• Acceptance Criteria NLT 1.3 (2nm spectral bandwidth)

Limit of Stray Light Liquid or Solution • 190-205nm – Aqueous potassium chloride (12g/L)

• 210-259nm – Aqueous sodium or potassium iodide (10g/L)

• 250-320nm – Acetone

• 300-385nm – Aqueous sodium nitrite (50g/L)

Polling Question 2

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Pharmacopeia Spectroscopy Requirements

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USP

Ph. Eur.

JP

USP

Comparison of Identification by Infrared

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Ph. Eur

Pharmacopeia

<854>

2.2.24

2.25

1.7

Chapter Instrument Performance

• Reference Substance

• Reference Substance

• Reference Substance

• Reference Substance

• Reference Spectrum

• Reference Spectrum

• Reference Spectrum

JP

WHO International

Example Properties – Infrared Spectrum

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Infrared

Spectrum

Signal to Noise

Resolution Wavenumber

So, these need to be controlled !

Polystyrene - From Ph. Eur

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This pattern shows an

“interference fringe”,

therefore, this is not a “matt”

Polystyrene ! (which is specified)

The length of x and y is dependent on the

resolution used to record the spectrum……….

But Pharmacopeia's are inconsistent over:

• Polystyrene thickness

• How large X and Y should be

• If limits are in Absorbance or % T

• Limits on wavenumber positions.

x

y

Identification – by Reference Substance

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The appearance of an Infrared Spectrum is dependent upon:

• Sample Preparation – how the sample was prepared

• Skill of the Analyst – when grinding the sample (e.g. mull or disk)

• Instrument conditions - (e.g. resolution)

Therefore, spectra should only be compared with spectra recorded under the

same sample preparation and equivalent conditions………

Historically, where identification was performed using a reference substance,

any potential differences in the instrument performance would effectively be

cancelled out, if the spectrum was recorded at the same time (concordantly).

This is why the USP did not specify instrument performance – until now !

However, for infrared, the only instrument performance criteria currently

specified is wavenumber accuracy – resolution is not included !

How this is managed

has data integrity /

LIR / OOS implications

USP

Comparison of Identification by Infrared

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Ph. Eur

Pharmacopeia

USP 38-NF33

Ph. Eur 8

JP 16 2nd Supplement

Forth Edition 4th Supplement

Version

<854>

2.2.24

2.25

1.7

Chapter Identification By

• Reference Substance

• Reference Substance

• Reference Substance

• Reference Substance

• Reference Spectrum

• Reference Spectrum

• Reference Spectrum

JP

WHO International

USP

Comparison of Identification by Infrared

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Ph. Eur

Pharmacopeia

35μ

35μ

0.04mm

Manufacturer

Guidance

- Polystyrene

Film

Polystyrene

JP

WHO

Wavenumber

3060.0, 2849.5, 1942.9,

1601.2, 1583.0, 1154.5

1028.3cm-1

+/-1cm-1 (FT-IR)

3060.0, 2849.5, 1942.9,

1601.2, 1583.0, 1154.5

1028.3cm-1

+/-1cm-1

3060.0, 2849.5, 1942.9,

1601.2, 1583.0, 1154.5

1028.3cm-1

+/-1cm-1, +/-1.5 (FT-IR)

Manufacturer

Guidance

- Polystyrene

Film

Resolution

X = 18 %

Y = 12 %

N/A

Manufacturer

Guidance

- Polystyrene

Film

X = 0.33 A

Y = 0.08 A

Reproducibility

N/A

N/A

N/A

0.5 % T 3000-1000

5cm-1 3000

1cm-1 1000

Polystyrene x 2

Example – Matt Polystyrene Spectrum

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FDA Warning Letters……

Note: From

December 2014,

FDA now remove

Warning Letters

older than 10 years

from their

web site. This

change is reflected

in the numbers.

• HPLC – 64

• GC – 28

• KF – 2

• FTIR – 7

• FT-IR – 12

• Infrared – 50

• Chromatography – 39

• Dissolution – 31

• UV – 42

• Qualification 299

• Stability – 299

• Calibration – 322

• Training > 500*

July 2015

HPLC: More Warning Letters – Than Any Other Technique

Data Integrity problems are being identified

For more than chromatography……..

Polling Question 3

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Questions

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