REVIEW OF PROCESS ANALYTICAL TECHNOLOGY
TABLE OF CONTENTS
1.INTRODUCTION
2.PAT TOOLS
3.PAT TECHNIQUES & ITS APPLICATIONS
3.1. EXAMPLES OF PAT APPLICATION IN INDUSTRY
3.1.1 APPLICATION OF NEAR INFRA-RED
3.1.2 APPLICATION OF RAMAN SPECTROSCOPY
3.1.3 APPLICATION OF RAPID MICROBIOLOGY
3.1.4 APPLICATION OF IMAGE ANALYSIS
4. IMPLIMENTATION OF PAT
5. CONCLUSION
6. REFERENCES
INTRODUCTION:-
Process analytical technology is the scientific, risk based regulatory framework which design, analyse and control critical process steps and quality attributes of the raw material, in process material as well as process throughout manufacturing process in accordance to achieve higher quality final product.In this, analytical term describes that all chemical, physical, microbiological, mathematical and risk analysis conducted in an integrated manner.
“The important aspect of applying PAT to any process is to understand process properly. PAT says risk and process understanding are the reciprocal of each other. ”
Basically, PAT has 2 components
1)To support and enhance innovation it has scientific principles and tools.
2)To accommodate innovation it has strategy for regulatory implementation which includes creation of PAT team approach to chemistry manufacturing and control (CMC) review and CGMP (current good manufacturing practice) inspection. Not only has this but it also included inspection staff, PAT review certificate and joint training.
Process analytical technology will encourage manufacturer to develop and implement innovative ideas in routine pharmaceutical manufacturing as well as quality assurance. This innovative approach will leads to improvement in different technical aspects of pharmaceutical industry.
The most important objective of PAT is that, to design and develop well understood manufacturing process so that it will continuous produce required quality product at end of manufacturing process. To achieve this, process should have consistent quality by design as well as can increase efficiency with reducing risk to quality and regulatory concerns. Benefits, in quality, safety and efficiency may vary with product as well as with process however it might be gain from,
By using on-, in- and/or at-line controls & measurements, reduction in production cycle time.
Lead to Real Time Release.
Prevention of rejects, scrap and reprocess
Reduction in human error and enhancing operator safety by increasing automation
Improves use of materials and energy
Facilitates process by improving efficiency and managing variability.(A), (B)
PAT TOOLS:-
In PAT there are many techniques available for the process understanding. The tools are;
Multivariate tools for design, data acquisition and analysis
Process analysers
Process control tools
Continuous improvement and knowledge management tools
This tools when applied to system appropriately, it could provide effective & efficient information for process understanding and continual improvement. Furthermore, it develops various risk-mitigation strategies. This all tools may be applicable to single unit operation or to whole manufacturing process and its quality assurance. (A)
PAT TECHNIQUES AND ITS APPLICATIONS:-
TECHNIQUES / APPLICATIONS(B) , (1)
Near infrared(NIR) / Reaction monitoring
Moisture measurement
Polymorph determination
Testing of solid dosage form
Particle-size measurement in granulation
Powder blending
Solvent monitoring
Milling
Tablet compression
Crystallisation
Drying of powder
(B)
Particle size and shape (PS)/Particle analysis / Analysis of Raw material
Analysis of Drug powder
Analysis of particle in parenteral
Particles during granulation
In milling
In blending
(B)
Image analysis (IM) / Powder blending
Crystallization
Granulation
Milling
Compression of tablet
Particle size characterization
(B), (6)
Rapid microbiology (RM) / Process water testing
Sterility testing
Raw material testing
Fermentation and cell culture monitoring
Environmental monitoring
Microbial limit studies
Contamination assessment
In-process and Pre-sterilization bio-burden monitoring
Biological indicator survival studies
Antimicrobial effective testing
Bacterial endotoxin testing
(B), (3)
Raman spectroscopy (RS) / Polymorph screening
To determine amorphous content
Drying (fluidized bed drying)
Measure drug concentration
Raw material identification
Contents in coating material
Testing of final dosage form
Supporting chemical development process scale-up
Examples of PAT application in industry:-
Near Infrared (NIR):-
Nowadays, NIR is one of the most important tools of PAT. NIR is applicable to organic compounds for quantitative as well as qualitative analysis. Furthermore, in pharmaceutical is applies on several of processing steps. Its applications are useful in determining process end point, controlling limits of specification as well as in determining if a process performing in accordance with previous runs.
Application of NIR in measuring moisture in hard gelatine capsules:-
The presence of moisture in powder or solid pharmaceutical substances effects directly on the quality attributes such as crystal size, solubility, and decay rate. In current pharmaceutical manufacturing process moisture is determine by various methods such as LOD, Karl-Fischer test however for this test the process must be stoped for collecting samples for test which consumes more time to complete the drying. Not only this but also human collected sample faces changes in physical conditions such as humidity, temperature which may leads to inaccurate moisture measurement. Furthermore, manually handling of sample can create safety and hygienic issues as well as personal have to monitor other parameters such as air flow, air temperature which also could responsible for inaccurate result. In contras to this, NIR measure moisture online during drying process which give accurate result without any interference in process. (5)
Raman spectroscopy (RS):-
Raman spectroscopy is most promising PAT technique for on-line process monitoring and analysis in pharmaceutical industry. It is able to provide rapid and non-destructive measurements. Several pharmaceutical forms have been studied by RS. For, instance Amoxicillin, Atenolol, Cimetidine, Fluconazole, Lorazepam, Piroxicam, Sulfadiazine and on & on. The RS can do direct measurements on solids. During sample preparation there are various critical steps which influence the results. The most interesting benefit of this technique is that it does not require any sample preparation which is cost saving aspect for industry as well as less impact on measurements.
Application of RS to monitor solid dispersion:-
The drug in amorphus state is suspended in polymer carrier in solid dispersion. The therapeutic performance of carrier may be affected under stress condition by recrystallization. The solid dispersion of anti-inflammatory agent ibuprofen is monitored under stress conditions (from -90○ to 90○), together with the content and the homogeneity of the drug distribution in formulation matrix to investigate physiochemical stability of dispersion. By using this method it can be easily detect changes such as recrystallization as well as also monitored spatial distribution of drug in dispersion. (10)
Rapid microbiology (RM):-
Rapid microbiology is the technique widely used in biopharmaceutical industries. RM is the technique which elements long time waiting for microbiological test results. Not only it reduces time but also it enhances sensitivity, accuracy, precision, reproducibility and can be detect single cell without the need of microbial growth. Further, by offering more understanding of process RM could increases microbial control strategies and risk based analysis. (6)
Application of RM to identify micro-organism on membrane filter:-
Specific micro-organism can be identifyingdirectly on the membrane filters by chemiluminescent in situ hybridization (CISH).To perform this short culture step is used in which soybean peroxidase (SBP) –labelled PNA (Peptide nucleic acid) probes targeted to a species-specific rRNA sequence. The microcolonies present on filter membrane are hybridized with SBP-labelled PNA probe for 30 minutes. The excess probe is removed by washing filter with stringent wash buffer for three to four times. In each colony, reaction between peroxidase and chemiluminescent substrate generates light which is captured by X-ray film or high speed Polaroids. The results appear as a spot whose location and numbers are same as on membrane filter. In this process no further manipulation required as compare to colonies grown on agar plates.
This technique used in identification of gram-negative bacteria, gram-positive bacteria as well as yeasts. (9)
Image analysis (IM):-
Automated image analysis techniques are used to generate data of particle size and shape. This technique complements microscopy and laser diffraction for particle characteristics. In addition to this, it generates statistical data of particles like that someone can study systematically on particle shape and its effect on product which provides merits as compare to manual microscopy.
Application of IM on crystallization:-
Crystallization of drug compound from the solution is the very important and critical step in pharmaceutical process as shape and size of crystal of compound has significant effect on product quality as well as product purity. To view the how crystal are formed image analysis plays very important role in it.
By using transmitted light, a CCD and a lens system image analyser captures images of crystals at various stages of crystal formation. Further, due to development in modern technology all image are recorded & stored so that it can be visualize as well as analyse. The image analysisimproves product quality as well as process efficiency by defining process end point. (4), (7)
Implementation of PAT:-
To implement PAT effectively the flexibility, coordination and communication of FDA with manufacture is critical. Further, ideal way of use of PAT principles and tools is to introduce them in development phase. This gives benefit to create opportunities to improve mechanistic based regulatory specifications for products. Manufacturer should evaluate suitability of PAT tool on experimental and production equipment and process by doing risk analysis of the impact of it on product quality before implementing PAT tools.The risk analysis could be done within facility’s quality system without notification to FDA. (A)
CONCLUSION:-
All in all PAT provides lots of merits to pharmaceutical industry. To implement PAT it is necessary to have experience and expertise in pharmaceutical environment as well as better understanding & control of chemical & pharmaceutical process. PAT provides wide knowledge of raw materials, manufacturing parameters and their impact on quality to finished dosage form. This technology need higher cost for implementation however once after implementation of PAT, it reduces cost of testing at various processing step. Not only has this but it also improves product quality continuously and shorten time to market.(2), (8)
REFERENCES:-
- GENERAL REFERENCES:-
A) FDA, Guidance for Industry – PAT A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance, Government Printing Office, Rockville, MD, 2004
B) Student Manual, HES 6402 GMPS for Manufacturing Operation Year 2009,Module 1
- SPECIFIC REFERENCES:-
- Bakeev, K, Near Infrared Spectroscopy as a Process Analytical Tool, ‘Molecular Spectroscopy Workbench’, January 2004, page no 39-41, view date17 May 2009.
- Banerjee, S, Bhatwadekar, N, Mahajan, P, Karode, P & Mishra, A, Process Analytical Technology : Boon to Pharmaceutical Industry, vol. 6, issue June 2008, view date 21 May 2009
- cdipharma.com, view date18 May 2009, from the website of CDI PHARMA
- Crystallization Imaging Offers Sneak Peak Inside Reactor, A new tool for “right first time” and PAT, view date 20 May 2009
- Das, P, Herrold, R, Kinney, T, Gortat, J, Real Time On-Line Monitoring of Fluid Bed Dryers Using NIR Spectroscopy, view date 23 May 2009
- Miller, M, ‘Rapid Microbiological Methods for a New Generation’, these are exciting times, as 19th-century microbiological methods make way for rapid detection, qualification and characterization technologies, view date 18 May 2009
- Pharmaceutical international, ‘Particle Shape-An Important Parameter In Pharmaceutical Manufacturing ’, view date18 May 2009
- Scott, P, Process Analytical Technology: Application to the Pharmaceutical Industry, view date 21 May 2009
- Stender, H, Fiandaca, M, Hyldig-Nielsen, J & Coull, J, PNA for Rapid Microbiology, 19 October 2001, DOI 10.1016/S0167-7012(01)00340-2, view date 20 May 2009
- Vankeirsbilck, T, Vercauteren, A, Baeyens, W, Van der Waken, G, Verpoort, F, Vergote, G & Remon, J, Application of Raman Spectroscopy in Pharmaceutical analysis, 12 December 2002, DOI 10.1016/S0165-9936(02)01208-6, view date 20 May 2009
1