Understanding Process Analytical Technology

The company Kaiser Optical Systems, Inc., (Kaiser) provides global direction within scientific apparatus and applied holographic machinery. Kaiser released its first spectroscopic product in 1990, which was the holographic notch filter. From this point onwards, they have persisted to make ingenious ground-breaking goods which meet the spectroscopic community’s challenges.

FDA’s PAT Initiative

The U.S. Food and Drug Administration (FDA) declared a brand-new initiative in 2002, which was called Process Analytical Technology (PAT). PAT suggests that quality control should be combined or by design, leading to true comprehension of cGMP. This initiative has been interpreted as “systems for analysis and control of manufacturing processes based on timely measurements during processing of critical quality parameters and performance attributes of raw and in-process materials and processes to assure acceptable end product quality at the completion of the process.”

A draft guidance has been published by the FDA which defines both the philosophy and implementation of PAT. A primary aim of this framework is to modify existing processes, creating products of preestablished quality. This would lead to enhanced efficiency and quality, due to:

  • decreasing cycle times by utilizing on-, in-, or at-line analysis and commands
  • Avoiding reject waste and product
  • Increasing the ability for real-time product discharge
  • Expanding automation, thereby lowering operator errors and boosting operator safety
  • Aiding continuous processing by utilizing small-scale equipment, which results in increased capacity, and better energy and material utilization.

To combine quality into a process, assessment must be carried out, figuring out what the vital quality aspects are, overseeing the components which effect the key quality attributes, and regulating those aspects.

Collaborating with Experience

The Raman Rxn Systems™ suite of Kaiser’s Raman analyzers are especially well suited for measurement, monitoring, and regulation of chemical mechanisms; from development of API to DP creation. They also offer many PAT-capable Raman analyzers which have been evaluated in both the laboratory and within industry, and have been found to improve the process comprehension, safety, and production.

Raman Spectroscopy

A specimen is initially excited via illumination from a monochromatic beam of light. This beam originates from a laser, which scatters protons which can then be measured. A very minimal amount of these protons (around 1 in 107) are scattered inelastically in a process called Raman scatter, whereas those which are scattered elastically are termed Rayleigh scatter. Detection of vibrational energy, within Raman spectroscopy, creates an alteration within the polarizability of the molecule. This form of spectroscopy utilizes vibrations within the same region as mid-IR, which means that it also collects information of the majority of intrinsic vibrations. Therefore, as Raman and IR have very similar ranges, Raman can be utilized to identify chemicals and detect vibrations which are not present within a compound’s mid-IR spectrum.

The benefits of using near-IR are also present in Raman, and comparable data is collected to mid-IR. Raman also has the additional benefit that it does not require sample contact, therefore meaning that slip streams and grab samples are not required. Therefore, the overall measurement process is simplified, which results in real-time measurements and stops sample contamination. This method can also be used with fiber optic coupling and remote sampling, as it utilizes radiation within the visible and near IR region.

Table 1. Comparison of Near-IR, Mid-IR, and Raman Spectroscopies for In Situ PAT

Near-IR Mid-IR Raman
Spectral range (cm–1) 3800–13,300 400–4000 100–4325 (532-nm excitation)
Analysis of:
    Gases
    Liquids
    Solids
    Aqueous systems
    Macroscopic samples
    Microscopic samples

No
Yes
Yes
Yes
Yes
Yes

Yes
Yes
Yes

Difficult in transmission
Yes
Yes

Yes
Yes
Yes
Yes
Yes
Yes
Signal Origin Absorption Absorption Scattering
Sampling
Through glass windows
In situ
Easy
Yes
Yes
Difficult
No

Yes
Easy
Yes
Yes
Quantitative Yes Yes Yes
Noninvasive Yes Yes Yes
Fiber optic interface > 10 m Yes No (Light-pipe or reduced spectral range) Yes
Information content Low. Limited to O–H, N–H, and C–H High High
Process understanding, monitoring and modeling Requires chemometrics Yes, can use chemometrics Yes, can use chemometrics

Table 2. Demonstrated Raman Applications Opportunities

API / Drug Substance (DS) Manufacturing Opportunities Drug Product (DP) Manufacturing Opportunities
Structure elucidation / chemical ID Polymeric matrix in DP delivery
Polymorphic forms DS in polymeric DP delivery
Crystallization / recrystallization – hanging-drop crystallization Lyophilization
Grignard reactions Drug distribution in transdermal patch
Hydrogenation Blister pack analysis – shelf life
Purity of chiral materials Blister pack analysis – adulteration
Salt screening, salt form, solvate form, hydrate form (DS, excipients) DP counterfeiting
DS / excipient interactions Polymer packaging laminate ID
Aqueous solution measurements DP tablet pre-coating, during, and post-coating
Solvent measurements Transmission / whole tablet analysis
HTS wellplate analysis and combinatorial chemistry DP wet granulation
Polymerization Headspace analysis – shelf life
ID of TLC spots Raw materials ID of DS & excipients
Phase transformation Formulations
Slurry / suspension analysis Blending / blend uniformity
Reaction analysis, monitoring and control Content uniformity
Chemical imaging Release testing / QC
Chemical imaging

This information has been sourced, reviewed and adapted from materials provided by Kaiser Optical Systems.

For more information on this source, please visit Kaiser Optical Systems.

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