Near-IR Solutions for Pharmaceutical Development and Manufacturing

near-IR solutions

for pharmaceutical development and manufacturing

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understand and control your critical processes

The current need for higher efficiency, lower cost of poor quality (COPQ) and faster time-to-market creates multiple pressures on pharmaceutical development and manufacturing organizations. It's becoming clear that better understanding and control of processes provides opportunities to develop better quality products and reduce operational costs in many areas. And that's exactly why many major pharmaceutical companies are using PerkinElmer's range of Near-Infrared (NIR) Spectroscopy products to help them achieve:

? Right-first-time formulation development ? Reduced scale-up delays and costs ? Faster time-to-market ? Faster troubleshooting ? Reduced raw material, work-in-progress and

final product inventories ? Reduced cost of poor quality ? Counterfeit detection ? Advance warning of out-of-specification

materials ? Faster product release

NIR Spectroscopy is the ideal technique to implement at multiple points across your organization. It's fast, non-destructive, requires no special skills or sample preparation and pays back the initial investment rapidly. Industry regulators are convinced that NIR Spectroscopy is important too. The U.S. Food and Drug Administration (FDA) is supporting NIR implementation and has put in place a series of initiatives to encourage wider adoption in pharmaceutical development and manufacturing organizations. NIR Spectroscopy is also seen as a key measurement technique for process analytical technology (PAT) development.

As a leading supplier of analytical instruments to the pharmaceutical industry, PerkinElmer offers a broad range of technologies for development and manufacturing.

Application

Analysis of metabolites in biological matrices Quantitation of trace impurities Degradation studies of active molecule Content uniformity Validation of process equipment cleaning procedures Dissolution tests

Pharmacopeia tests on raw materials Packaging testing

Contamination studies and production troubleshooting Color conformity testing for product and packaging Tablet dissolution studies Quantitation of residual solvents in raw materials Enantiomeric purity of drug compound Networked chromatography data management Complete laboratory information management

Technology

HPLC

HPLC

HPLC

HPLC HPLC

HPLC and UV/Vis Spectroscopy FT-IR and FT-NIR Spectroscopy FT-IR and FT-NIR Spectroscopy FT-IR and FT-NIR Imaging, FT-IR Microscopy UV/Vis Spectroscopy

UV/Vis Spectroscopy Headspace Gas Chromatography Polarimetry

Client/Server Chromatography Data Systems LABWORKSTM LIMS solutions

Whatever the application, we're committed to providing rigorous compliance with FDA's 21 CFR Part 11 regulations, GAMP 4 and IQ/OQ validation assistance, as well as offering the industry's largest global service and support network.

how it works

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NIR Spectroscopy

Each molecule's functional groups absorb Mid-IR radiation to generate a characteristic absorption or transmission spectrum that is typically rich in information and unique to that molecule. Spectra can be analyzed or searched against libraries of reference spectra to positively identify unknown materials. In the Mid-IR range, bands are often strong and samples may require dilution or thinning in order to measure usable spectra.

In the Near-IR range, however, absorptions are due to overtones and combination bands of fundamental vibrations and are much weaker and broader. While spectra are less easy to interpret, a major advantage is that sample preparation is not required. This means that samples like pharmaceutical tablets can be analyzed directly and non-destructively.

There are several types of NIR spectrometer, each suited to different applications. For highthroughput, in-process measurements, simple

filter instruments are often used successfully. Dispersive NIR spectrometers have also been used for QA/QC measurements. However, for materials quality and product development measurements in the lab or at-line, FourierTransform Near-IR (FT-NIR) Spectroscopy is now firmly established as the technology of choice. FT-NIR instruments have a wider operating range and work at higher spectral resolution, providing a wealth of important information not available to old-technology dispersive NIR systems.

FT-NIR vs. Dispersive NIR

6.0 nm 3.0 nm A 1.6 nm 0.8 nm 0.2 nm

1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 nm

Spectra of talc in a glass vial measured from 0.2 to 6.0 nm resolution using a SpectrumTM One NTS. The extra spectral information is shown in the shaded box.

A comparison between Mid-IR and NIR Spectroscopy

Features and Benefits

Mid-IR Spectroscopy Near-IR Spectroscopy

Functional group interpretation Commercial libraries available Qualitative analysis Quantitative analysis Sampling directly in containers Remote-sampling of bulk samples Sample preparation required Non-destructive

Easy Many Easy Liquids and thin films only No No For many samples Sometimes

Difficult Few Easy Liquids, thin films and solids Yes Yes No Always

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multiple applications to improve process and product quality throughout your organization

Pharmaceutical Development

Pre-Clinical R&D Phase

Clinical R&D Phase

Manufacturing Phase

IND

Bio-Statistics

NDA

Approval

API Discovery

PK/PD Correlation

Clinical Trials Phase 1 Phase 2 Phase 3 Phase 4

Toxicology/ Carcinogenicity

Metabolism Studies

Drug Characterization

Rapid API functional group identification. Spectrum One FT-IR

Clinical Trial Design

Analytical Development

Development of accurate, precise and robust FT-IR and FT-NIR methods for raw materials qualification and in-process testing. Spectrum One NTS, AssureID, Tablet Autosampler

Analytical Transfer

QA/QC Methods

Synthesis Scale-Up

Qualify raw materials and monitor reactions during API scale-up. Spectrum One FT-IR, Spectrum One NTS

API Process Development

Manufacturing Process Transfer

Formulation Development

Fast, informative troubleshooting aids understanding of formulations. Spectrum Spotlight, Spectrum One NTS, Tablet Autosampler

Product Development

Clinical Trials, Validation and Pilot Production Batch Manufacture

Verification of identity and quality of raw materials, intermediates, final products and packaging. Spectrum One NTS, Tablet Autosampler

Pharmaceutical Manufacturing Raw Materials

API Supplier

In Process

In Manufacture

Goods In

Loading Bay, Raw Materials Lab, QA/QC Lab Verification of identity and quality of production materials or packaging. Spectrum One NTS, AssureID

Excipient Suppliers

Dispense

Preblend, Granulate, Dry, Screening, Mill,

Final Blend

In Process Monitor process variations such as water content and active concentration in blends. Spectrum One NTS, AssureID, Tablet Autosampler

QA/QC Lab Test tablet for uniformity and active concentration. Tablet Autosampler

Press and Coat

Process Lab Measure tablet active content and trend batch uniformity. Tablet Autosampler

Pack

Release

QA/QC Lab Test tablet for uniformity and active concentration. Tablet Autosampler

Analytical Service Laboratories

Failure analysis of blends, tablets and coatings leading to better understanding of materials and processes. Spectrum Spotlight and FT-IR Microscopy

Example: wet granulation tablet manufacture

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improving process and product quality

Key Specifications ? 30-position autosampler

FT-NIR tablet analysis at scale-up delivers significant savings during full production

Near-IR Tablet Autosampler

Utilizing the latest advances in FT-NIR technology, the tablet autosampler offers a new approach to improving process and product quality in pharmaceutical tablet manufacturing. Rapid, non-destructive, whole-tablet analyses deliver vital information about active content and batch uniformity, meeting the demands of the industry and its regulators.

The tablet autosampler can be deployed at many points throughout the development and manufacturing cycle, from formulation development to final product release. Incorporation of NIR measurements into a method during development or scale-up enables tighter control of quality, less waste and reduced rework costs during full-scale manufacture.

A comparison between FT-NIR and HPLC

Features

FT-NIR Tablet Analysis

HPLC

Sample preparation Time per pablet Solvent required Chemical information

Physical information

Surface analysis Moisture content Low concentration impurities

Non-destructive Typically 30?60 seconds No Active concentration and content uniformity Yes (e.g., hardness, dissolution properties) Yes, using reflectance mode Yes No

Crush and dissolve Typically 20?30 minutes Yes Active concentration and content uniformity No

No No Yes

? Transmission and reflectance modes for full-tablet characterization

? Custom sample molds accommodate different-sized tablets and minimize stray light

? Controlled by AssureIDTM software -- workflow design decreases operator error and reduces training costs

? Full technical compliance with 21 CFR Part 11

Custom Tablet Holders

For reproducible and accurate results, it is essential to minimize stray light in tablet transmission measurements, preventing light from passing around the side of the tablet and onto the detector. Special custom tablet holders easily accommodate various tablet sizes and shapes, ensuring a light-tight fit between tablet and holder.

A major pharmaceutical company implemented FT-NIR tablet analysis in their production facility in order to better understand and control a tablet scale-up

manufacturing process.

After pressing and coating, samples were

analyzed to measure active concentration

and uniformity of composition across a

production run. Using an AssureID PLS

(Principal Least Squares) model, which had been built

using 20 calibration samples and 60 validation samples

of varying concentrations, batches of 10 tablets were

analyzed. For each batch, statistics including individual

Results Browser

File Edit View Tools Help

Sample View: My Views - MyView1

Database Results

Identifier/ Sample ID Analyst Name Analysis Date Quality Check Component1 Comp1 Resul Comp1 Calcu Comp1 Mean Comp1 SD Comp1 Mean Comp1 Quant Con

51

Developer 18 March, 2003 Fail

Active_Prop

17.913313 9.9909176 Pass

52

rha_cs.sp Developer 18 March 2003 Pass

Active_Prope Pass

17.865123

NNPZXMD

53

rhb_cs.sp Developer 18 March 2003 Pass

Active_Prope Pass

17.851469

NNPZXMD

54

rhc_cs.sp Developer 18 March 2003 Pass

Active_Prope Pass

17.704782

NNPZXMD

55

rhd_cs.sp Developer 18 March 2003 Pass

Active_Prope Pass

17.825428

NNPZXMD

56

rhe_cs.sp Developer 18 March 2003 Pass

Active_Prope Pass

17.872060

NNPZXMD

57

rhf_cs.sp Developer 18 March 2003 Pass

Active_Prope Pass

18.010157

NNPZXMD

58

rhg_cs.sp Developer 18 March 2003 Pass

Active_Prope Pass

17.963381

NNPZXMD

59

rhh_cs.sp Developer 18 March 2003 Pass

Active_Prope Pass

17.992427

60

rhi_cs.sp Developer 18 March 2003 Pass

Active_Prope Pass

17.623473

NNPZXMD NNPZXMD

61

rhj_cs.sp Developer 18 March 2003 Pass

Active_Prope Pass

17.773665

NNPZXMD

Comp1 Calculated Value

Calculated Value

Active Content / mg 18.4

3 x Std Dev 18.2

2 x Std Dev

18.0

Mean: 17.848196 17.8

2 x Std Dev 17.6

3 x Std Dev

17.4

1

2

3

4

5

6

7

8

9

10

Sample Index-Date Order

and mean assay values, standard deviation, and maximum and minimum assay values were calculated and output to reports and the secure AssureID database. The

standard deviation gives a measure of the uniformity of

the blend. Further studies enabled the measurement

and control of tablet potency and blend uniformity:

? During the run of a tablet press

? Between runs of a tablet press

? Between tablet presses

? With differing blend conditions

Transmission tablet holders, mold kit and 30-position tablet wheel.

Overall, significant savings in scrap and rework cost were made when the tablet was transferred to full production. Further studies using FT-NIR include the measurement of moisture content, coating thickness and tablet hardness, promising further process improvements and cost savings.

8 understanding solid dosage forms

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SpectrumTM Spotlight 350 FT-NIR Imaging System

In tablet production, the microscopic distribution of ingredients is known to impact important quality parameters such as dissolution, stability, bio-availability and hardness. However, to date there have been no convenient techniques that can provide this information, which means that the blending and tabletting processes are often poorly understood, adversely affecting product quality.

In both formulation development areas and the process analytical support functions, it is essential to be able to identify anomalous distribution of ingredients. FT-NIR imaging is rapidly being implemented by major pharmaceutical companies to help solve these and many other manufacturing problems.

Key Benefits

? Seamless automation simplifies setup and measurement, increasing productivity and reducing errors.

? Two-in-one detector enables single-point microscopy as well as IR imaging, allowing microcontaminants in products and packaging to be identified in seconds.

? Powerful built-in data processing routines automate data analysis and provide quick answers.

? Superb visible image quality ensures accurate and easy sample inspection.

? User-defined sampling area and aspect ratio allows you to match the image size to the sample size.

? Full-range imaging from 7800?2200 cm-1 covers the most information-rich areas of the spectrum, maximizing applications flexibility.

? Image pixel sizes of either 6.25 x 6.25 m or 25 x 25 m are available.

Further Applications There are many other application areas where FT-IR and FT-NIR imaging can troubleshoot problems and lead to significant cost savings.

? Tablet stability studies

? Dry powder electrostatic coating analysis

? Counterfeit detection

? Contamination identification

? Packaging development

? Transdermal patches and related delivery systems

Chemical images of active distribution (red). Upper row: good blend uniformity. Lower row: poor blend uniformity.

Spectrum Spotlight offers blending process insight to improve quality and address regulatory concerns

A major pharmaceutical company employed FT-NIR Imaging to gain insight into the blending process in tablet production. HPLC measurements on the active concentration showed that some batches exhibited poor content uniformity without any obvious reason.

The Spectrum Spotlight 350 system was used to investigate blends from good batches and problem batches. Samples were taken from the top, middle and bottom of the blender for each batch and images generated and compared for each.

The images showing the distribution of the active component were particularly significant, showing clear differences between good and problem batches. In addition it was noted that the original active particle size was 11 m before blending, whereas aggregates 10?40 times larger were observed after blending.

This was thought to be an example of "overmixing," in which particles attract each other to form large aggregates, having a detrimental effect on final product quality because the active ingredient cannot be uniformly distributed between tablets in the batch.

In this example the new information provided by FT-NIR Imaging allowed process optimization and significant quality improvement, reducing costs and addressing regulatory concerns.

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