Current Methods of Raman Spectroscopy in the Pharmaceutical Apps Dec 2011

Current Methods of Raman

Spectroscopy in the

Pharmaceutical Industry

Dr Caroline Rodger

Associate Principle Scientist

Pharmaceutical Development

AstraZeneca Macclesfield

December 2011

Agenda

1. A brief review of the Pharma Industry I. What is a Pharmaceutical?

II. Statistics

III. What is a tablet?

IV. Regulatory

2. What is Raman Spectroscopy? I. Simple Theory

II. Advantages and Disadvantages

3. Current Uses of Raman Spectroscopy

4. Opportunities!

5. Conclusions

6. Discussion

Author | 00 Month Year 2 Set area descriptor | Sub level 1

What is a Pharmaceutical Company?

• Pharma companies provide drugs Licensed for use as medicines:

I. Invent II. Develop III. Launch IV. Produce V. Market

• Highly regulated Industry

• Patent environment


What is a Pharmaceutical Company?

• On average ~10 years to get drug to market

• On average 1 in 10000 NCE is launched as a drug

• Cost of getting one drug to market is over $1 billion!

• 3 in 20 approved drugs bring sufficient revenue to cover development costs

• 1 in 3 generates enough revenue to cover costs of previous failures


What is a „Pharmaceutical‟?

“A chemical drug or medicine”

• Drug substance: - Solids, liquids, spray dried solids, etc

• Medicine: - Tablets, granules, solutions, capsules, emulsions, dispersions, depots,

injections, inhalers etc

• Packaging: - Syringes, polymers, plastics, adhesives, inks & resins


What is a tablet?

6 Author | 00 Month Year Set area descriptor | Sub level 1

Active Pharmaceutical

ingredient: API

Filler:

Lactose, CaHPO4

Binder:

Lactose, cellulose

Disintegrant:

Crosspovidone, Starch

Coating:

TiO2, sugars,

plasticizers

Lubricant:

Stearic acids, Mg

Stearate

Drug substance and formulated product

• Drug substance can exist as different polymorph, salts, hydrates, solvates etc.

• Drug substance and Tablet production is complex and involves many stages

- Blending - granulation - staged additions - drying - compression forces - Storage

• Commonly 5-6 ingredients in one formulation

• Tablets are “homogenous” mixtures of excipients and drug

• Pharmaceuticals are complicated!


Regulatory aspects

- Heavily regulated: to protect us...the patients - Each country has their own regulatory authority that requires a

separate dossier to gain approval to sell a medicine in their country

- Regulatory submissions are dominated by: - Well established analytical technique. i.e. Chromatography,

NMR, FTIR…

- Established and accepted methods of validation and calibration

- I am currently unaware of any primary method presented in a regulatory dossier by AZ using Raman spectroscopy

- Traditionally, regulatory authorities are conservative but things are changing...


„Guidance‟ Bodies and Documentation

- Regulatory authorities: FDA, EMEA, PMDA

- Pharmacopeia‟s: - Country/territory focussed - A „book‟ listing established and accepted methods of

validation and calibration - Generally for end product testing - Limited guidance on Raman Spectroscopy! Generally

around calibration of instrumentation

- ICH: International Conference of Harmonisation - Focuses on quality, safety and efficacy - A coalition of regulatory authorities and industry - Minimises differences between different regulatory

authorities - Provides generic guidelines


What is Raman Spectroscopy?

Raman scattering is associated with a change in the polarisability of a molecule


Some molecules gives rise to absorption, some to Raman

scattering and others to both absorption and Raman scattering

What is Raman Spectroscopy?


Rayleigh scattering

(filtered out)

Raman scattering

(Stokes shift)

LASER

200 400 600 800 1000 1200 1400 1600 1800 2000

Raman shift (cm-1)

Blo

ck

ing

Filte

r

0

Ex

cit

ati

on

fre

qu

en

cy

V = 0

Ra

yle

igh

sc

att

eri

ng

V = 1

Ram

an

sc

att

eri

ng

~~~~~~~~~~~~~~~ V = virtual

state

Advantages of Raman Spectroscopy

+ Sharp spectral features - Generally spectra have distinct peaks which can be readily

attributed to the API - Results in a high selectivity - Simplifies data modelling, easier to understand

+ Sensitive to solid state characteristics + Relatively insensitive to water

- Changes in humidity is not a problem - Can analysis solutions

+ Little or no sample prep required - No dissolving, grinding or pressure required hence integrety of

sample intact and solid state properties accessable - Small amount of sample required which saves valuable resource - Sample through packageing e.g blister pack, bottle, hot stage

microscopes etc


Limitations of Raman Spectroscopy

- Weak effect - 1 in 106 photons Raman scattered

- Small sampling volume - May lead to sub-sampling within single samples

- Transmission Raman offers a potential solution?

- Sample heating, absorption

- Solid phase transitions?

- Preferential orientation issue - Poor reproducibility?

- Sometimes obstructed by fluorescence - Makes data evaluation more interesting


Effect of fluorescence


532 nm laser

785 nm laser

FT-Raman, 1064 nm laser

500 1000 1500 2000 2500 3000 3500

What is Raman used for in Pharma industry?

• Identification of raw material, intermediate, final products, packaging…

• Assessing polymorphism of compounds • Solid state properties, hydration, solvates, salts etc • Monitoring stability studies • Salt screens • Kinetic measurements • Qualitative and quantitative assessment of API and excipients

(UOC) • Investigation of contaminates and production problems • Assessing domain sizes • Reaction monitoring • Troubleshooting • Product verification • …

Very limited use of Raman spectroscopy in regulatory field!


Solid state analysis Raman spectroscopy can be used to attain quantitative information about solid state forms of both the active and excipients


3600.0 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400 200.0

cm-1

INT

Alpha lactose monohydrate

Beta lactose anhydrous

Solid State Analysis Possible to perform qualitative and quantitative assessments of drug forms


Hydrate

Anhydrous

Solid State Analysis


Hydrate

Anhydrous

Hydrate

Anhydrous

Specificity


Anhydrous API

Hydrate API

Formulated Product

Placebo

High Throughput analysis

- Polymorph screening

- Non-destructive

- Automated data collection

- Automated data processing

- Automated data analysis

- Kinetic expt possible


Raman Sampling Geometries

• Conventional appraoch is backscatter geometry (diffuse reflectance)

• Transmission geometry, long interaction length Transmission Raman spectroscopy, P. Matousek and A. W. Parker, Appl. Spectrosc. 60, 1353 (2006)

Transmitted

light

s

a

Incident

light

v-vib

v-vib

Diffusely

reflected

1) More homogenous

sampling

2) Longer optical

pathlength means higher

Raman signal

Where are AZ using Transmission Raman:

Rapid Quantification of Drug Product

• Instrument purchased in 2009 and located in Mölndal

• The aim was:

- An automated tool for whole sample analysis of up to 30

tablets or capsules that allows determination of content

uniformity and solid state form completed within one hour,

including sample loading and sample logging,

measurements, evaluation and report generation

Technology

• Instrument delivered to Mölndal November 2009

• Used in pilot projects

• Aspiration to transfer to operations sites

200 400 600 800 1000 1200 1400 1600 1800 20000

500

1000

1500

2000

2500

3000

3500

4000

4500

Raman shift (cm-1)

Ram

an inte

nsity

Propranolol-Mannitol, API=20 %w/w, Horiba instrument, t=1 s

Uniformity of content

Current Status

• Analysis of content and content uniformity done by current methods

takes much resources (primarily), and can be slow (secondary).

• Alternative fast spectroscopic methods can be complicated, time

consuming and need substantial maintenance.

• Chromatography:

• Work horse in pharma: Universally accepted

• Accurate results

• Slow

• Requires sample preparation

• Real Time Realease???

Uniformity of content

SPECTROSCOPY

• Near Infrared:

• Accepted by authorities

• Provides fast results with no sample preparation

• Suitable for in-line approach: Real Time Realease?

• Extensive calibration efforts, susceptible to changes in process parameters (good

or bad)

• Sensitivity issues?

• Raman

• Standard technique for solid state characterisation but, due to sampling issues,

hasn‟t been applied to UOC until now….

Uniformity of Content

Batch ID Content-TR

(% nom)

RSD-TR

(%)

AV-TR Content-LC

(% nom)

RSD-LC

(% nom)

AV-LC

#1-LD 99.7 2.0 4.8 99.7 1.0 2.3

#2-LD 99.1 1.9 4.6 100.1 1.3 3.1

#3-LD 98.6 2.1 5.1 98.8 0.7 1.7

#4-LD 99.6 2.2 5.4 98.4 0.7 2.0

#5-HD 100.6 1.2 2.8 99.6 1.0 2.4

#6-HD 99.8 1.0 2.3 97.9 0.7 2.0

#7-LD-C 100.3 1.6 3.8 98.8 1.6 3.7

#8-HD-C 97.3 0.90 3.4 97.3 1.1 3.7

Predictions were made with local calibrations, using MCR.

AV= acceptance value, calculated as 2.4*SD if mean is between 98.5-101.5% and n=10, otherwise a penalty is added; [98.5-mean] or [mean-101.5]

• LC and TR correlate • AV comparable to LC

UOC: possible in a regulatory environment

• Proof of principle has been carried out on several projects

• Key conclusions:

• API >1 % detection limit

• MCC < 75 % or issues with fluorescence

• Preferably uncoated tablets (coated possible but may

effect sensitivity

• Possible to assess 60 tablets in one hour

• Comparable to LC in most cases but will not completely

replace LC!

Raman imaging in the pharmaceutical

industry • Raman imaging has traditionally been limited by:

- Time required to sample a statistically representative area

- Complexity of data processing

- Subjectivity of comparing images

• This may be overcome by:

- Fast Raman imaging – Allows large areas to be sampled but data

processing may still be problematic

- Reduced data collection – „lean‟ Raman imaging

• Principles of „lean‟ Raman imaging:

- 1 dimensional data collection – line scans

- Simple, automated data processing – univariate where possible

- Statistical analysis to extract numerical descriptors of the sample

Raman Imaging


sample

laser

mapping

Obtained Raman

spectrum

Chemical Image

Raman Imaging


200 400 600 800 1000 1200 1400 1600 18000

500

1000

1500

2000

2500

3000

3500

Wavenumber (cm-1)

MCC

200 400 600 800 1000 1200 1400 1600 18000

1000

2000

3000

4000

5000

6000

Wavenumber (cm-1)

Lactose

200 400 600 800 1000 1200 1400 1600 18000

500

1000

1500

2000

2500

3000

Wavenumber (cm-1)

Salicylic acid

Raman: Lean Imaging for assessing sedimentation

Problem:

- A semi solid dispersion of a drug and

polymer displays different dissolution

profiles:

Author | 00 Month Year 31

Raman spectra of Drug

and polymer can clearly be

differentiated

0

500

1000

1500

2000

2500

3000

3500

200300400500600700800900

Raman Shift (cm-1)

Inte

nsity

API

Polymer

277 cm-1

713 cm-1

0

500

1000

1500

2000

2500

3000

3500

200300400500600700800900

Raman Shift (cm-1)

Inte

nsity

API

Polymer

277 cm-1

713 cm-1

Peak Ratio: Peak height @ 713cm-1

Peak height @ 277cm-1

Raman: Lean Imaging for assessing sedimentation

To quantify sedimentation of drug: • Calculate the average ratio of the peaks at 713cm-1 and 277cm-1 for each

line scan • Calculate the standard deviation of the six peak ratios


Mean = 0.97

%RSD = 75.41

As sedimentation

increases the

standard deviation

increases

1. Rapid Screening Method for Sedimentation –

Method Validation

• Method validated by HPLC - each capsule was cut into 4 and assayed

• Good agreement was obtained between the Raman and HPLC data

• RMSEP of 5% for Raman method

1. Rapid Screening Method for Sedimentation -

Results

•Two batches showing „good‟

dissolution profiles (batches A

and B) and two batches

showing poor dissolution

profiles (batches C and D)

were mapped to assess

sedimentation.

0

20

40

60

80

100

0 10 20 30 40 50 60

Time (mins)

Dis

so

luti

on

(%

)

Batch A

Batch B

Batch C

Batch D

•Analysis of the 95%

confidence intervals

for all good batches

tested shows: Peak

ratio RSD < 10%

indicates the

sample that has not

undergone

significant

sedimentation.

1. Rapid Screening Method for Sedimentation -

Conclusions

• Rapid Raman screening method provides: • Efficiency gains over HPLC (approx 15 mins per sample)

• Minimal sample preparation and handling

• Improved spatial information over wet chemistry techniques

• New approach to vibrational imaging: • Rapid, fit for purpose method

• Data collection minimised – only collect the critical information

about the sample

• Simple statistical analysis: • Simple, rapid data analysis

• Numerical measure of sedimentation – allows ranking of samples

and setting of specifications

Raman imaging in the pharmaceutical

industry

New

Image

Descriptor

s

Objective – Use fast and/or „lean‟ Raman mapping approaches to generate rapid, fit for purpose methods

Process Analytics

Part of an army of technologies…

37

UV-Vis Lasentec Raman NIR

38

• Formation of the amide intermediate is rapid (<5 mins)

• In earlier campaigns, a 90h Dean and Stark distillation was used to

remove water formed during the conversion to cyclised product. - This was replaced with 3 solvent replacement cycles to remove wet solvent and

replace with fresh, dry solvent.

• Rate of conversion was very sensitive to temperature/pressure.

• Had never run this new process on scale before. - During the 3 solvent replacement cycles, the current extent of conversion

would be unknown. Sampling would be time consuming.

NH2

NH2

R'''n

O

R'O R"O

NH NH2

R'''

R"n

N

NH

R'''

R"

n

3 x "Put & Take" with Solvent

110 - 130C~800 mbar

1.0 eq.

Solvent

'Amide'

Example 1: Monitoring a cyclisation

reaction

Example 1: Monitoring a cyclisation

reaction

• Raman spectroscopy exhibited good selectivity for both the amide intermediate and the cyclised product.

• Only simple baseline correction and spectral normalisation required to pre-process spectra.

• Linear regression applied to correlate Raman peak ratio to GC peak ratio using samples taken after each solvent replacement step.

Raman spectra collected during

laboratory development.

Intermediate amide

Product

A B

C

D

Ra

tio

Pro

du

ct

: A

mid

e

Maintaining a constant ~800 mbar proved very difficult in the pilot

plant.

Higher vacuum caused solvent to distil at a lower temperature,

leading to poor rate of conversion – in-situ Raman prediction

provided early warning(A)

Based on in-situ Raman results, distillation was performed at

atmospheric pressure (C and D).

Example 1: Monitoring a cyclisation reaction

Plot of predicted

conversion was

provided in real-time.

When sampled for final

off-line analysis, the

end-of-reaction criterion

was met (>99% product).

Example 2: Rapid Product Development Tool


Raman and NIR sampling workflow

Store

Move

Measure

•Powders, solutions, tablets and

capsules

•Chemical and Physical stability

•Flexible temperature, humidity &

photostability

•Suite of analytical tools –

•Raman

•NIR

•UPLC-UV-ELSD-MS

•sample prep

•optical images

•weight

•oxygen level

Product Verification:

Development of a portable Raman device for remote

identification of Drug Product

Business Benefits: • Rapid, Non destructive remote/mobile testing • Valuable tool to AZ product security Current success: • Deployed international within AZ Product security

Areas of AZ this impacts on: • Raw material testing: CS, Supply Chain, AS, FS,

Operations • Clinical material testing: Supply Chain • Product security: Operations Effort/costs to achieve the benefits: • ~6 devices within product security and one master

within AS


Product Verification: The device….


(a) (b) (c)

Vial slides in/out

http://www.google.com/imgres?imgurl=http://www.ahurascientific.com/img/content/tru-scan.png&imgrefurl=http://www.ahurascientific.com/material-verification/products/truscan/index.php&usg=__h-TFLzdah5pTPBJIkgrKH-rVTi8=&h=279&w=171&sz=70&hl=en&start=6&zoom=1&itbs=1&tbnid=Ho-qNugHkDPNjM:&tbnh=114&tbnw=70&prev=/search?q=truscan+Thermo&hl=en&sa=G&biw=1259&bih=631&tbm=isch&ei=irDoTauGFMyp8AOj4pCRAQ

Product Verification: work flow


suspect

sample

Sensor

device

0

10000

20000

30000

40000

1600 1400 1200 1000 800 600 400

Intensity / Raman Shift (cm-1)

638

516

395

spectrum for suspect

sample

interrogate

database

database

Contains

spectra for

reference

samples

output

List of best „hits‟

based on a

correlation

function. Not

always

unequivocal

A unique and valuable addition to the toolbox

technology for product verification

Opportunities: ICH 8, 9 and 10….


ICH Q8/Q8(R) -Pharmaceutical Development: Product and Process understanding (Design space and flexible regulatory approaches)

ICH Q10 – Pharmaceutical Quality Systems

Track, trend and respond to product quality

ICH Q9 –Quality Risk Management:

Couples sound science with risk management tools: risk –v- quality

FDA PAT Guidance

What is Quality by Design?

Key aspects: Quality CAN NOT be tested into products rather it

should be designed or planned

1. By design of effective and efficient manufacturing processes

product quality and performance are guarenteed

2. Product and process specifications are based on a mechanistic

understanding of how formulation and process factors affect

product performance

3. Quality assurance is continuous and real time

4. Relevant regulatory policies and procedures are tailored to

accommodate the most current level of scientific knowledge

5. Risk-based regulatory approaches recognize both the level of

scientific understanding and the capability of process control related

to product quality and performance

Raman Spectroscopy has a role to play!


Critical Quality Attributes The attributes that have been determined to be necessary to ensure the safety and efficacy of product tablets.

CQA Analyte/test Target value Confirmed on spec

Physical state Description A white to off-white powder Yes

Identification FTIR (DRIFT) or NIR Consistent with the reference standard Yes

Assay HPLC 98%-102% w/w Yes

Organic purity Impurity C 0.20% w/w maximum Yes

Impurity D 0.15% w/w maximum Yes

Des Methyl 0.10% w/w maximum No

Genotoxic impurities 5 ppm maximum each (TTC level) No

Any individual unspecified impurity 0.10% w/w maximum Yes

Total organic impurities 0.5% w/w maximum Yes

Residual solvents Solvent 5000 ppm maximum No

Solvent 5000 ppm maximum No

Solvent 720 ppm maximum Yes


Formaldehyde 9 mg/day TDI No

Formic acid 5000 ppm maximum No



Water content Karl Fischer 0.2% w/w maximum No

Metal content Heavy metal 100 ppm maximum No

Heavy metal 50 ppm maximum No

Inorganic purity Residue on ignition/sulphated ash 0.1% w/w maximum No

Particle size distribution D (v, 0.1) 5 microns maximum Yes

D (v, 0.5) 14 microns maximum Yes

D (v, 0.9) 52 microns maximum Yes

Polymorphic form X-ray powder diffraction Form 1 No

Microbial purity Bioburden <10 cfu per gram No

TTC Threshold of toxicological concern. TDI Tolerable daily intake.

48

Raw Materials

Reaction

Quench

Dist/SolvSwap

Crystallisation

Filter

Dry

Clean

Raw Materials

Reaction

Quench

Dist/SolvSwap

Crystallisation

Filter

Dry

Clean

Raw Materials

Reaction

Quench

Dist/SolvSwap

Crystallisation

Filter

Wet Mill

Dry API

Clean

Inte

rme

dia

te A

Inte

rme

dia

te B

Crude/API

Excipients

Blend

Granulate

FBD

Granules Excipients

Blend

Compression

Coating

Product

Characterisation

Dru

g P

rod

uc

t

Characterisation

•Particle Size

•Moisture Content

•Purity

•Flow Properties

Blend Homogeneity

Moisture Distribution

Moisture Analysis

Drug Assay in Granulation

Granule Hardness

Drug Assay in Granulation

Post Blending Segregation

Drug Assay in tablet cores

Coating Thickness

Drug Assay in coated tablets

Content uniformity

Disintegration time

Dissolution

Hardness

Packaging

Process NCRM ID

EOR/Steady State

Conversion

Solution Assay

Titrate

Hydrogenation

Kinetics

Endpoint

Continuous Addition

Solution Assay

Loss to liquors

Supersaturation

Particle Size

Steady State

Polymorph

Kinetics

Particle Size

Solvent saturation

Cleaning Endpoint Drying end-point

Where can Raman Spectroscopy add value for

QDB • Limited/no sample prep:

• A place for Raman on/at line to monitor & control quality • Automation?

• Process Analytics • Deliver robust processes, quality and control

• Selectivity: Raman has the potential to rapidly probe: • Qualitative and Quantitative assessments (UOC) • Solid state properties • Real Time Release?

• Imaging • Monitoring quality of output? • Real Time release?

• Rapid Analysis: Method are quick and robust: • fast response to deviation from design space • Maintain quality • Minimise risk


Conclusions

• There is a growing and important role for Raman Spectroscopy within the Pharmaceutical Industry

• Specialist must understand opportunities and work together within the industry, academics, vendors and regulatory authorities to maxmise benefit and utilisation

Key to success • Requirement to increase skills and uptake of Raman

spectroscopy in operation areas. Is cost still a barrier?

• Engage, partner and educate regulatory authorities


Acknowledgements….

AZ: Steph Brookes Andy Brookes Kevin Sutcliffe Nick Pedge Rich Hart Jonas Johansson Olof Svensson Anders Sparen Horiba: Mike Claybourn Thermo: David James



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Current Methods of Raman Spectroscopy in the Pharmaceutical Apps Dec 2011

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