City of Newark Wastewater Treatment Plant City of Newark ...
Advantages of Handheld Raman in the Pharmaceutical Industry: Meeting PIC/S Requirements Dr....
-
Upload
dana-leonard -
Category
Documents
-
view
214 -
download
0
Transcript of Advantages of Handheld Raman in the Pharmaceutical Industry: Meeting PIC/S Requirements Dr....
Advantages of Handheld Raman in the Pharmaceutical
Industry: Meeting PIC/S Requirements
Dr. Katherine A. BakeevB&W Tek, IncNewark, DE
USASeptember 24, 2013
www.bwtek.com 1Copyright 2013 B&W Tek, Inc.
www.bwtek.com 2Copyright 2013 B&W Tek, Inc.
Industry Trends and Requirements
• Pharmaceutical companies must meet worldwide PIC/S initiatives and regulations on Good Manufacturing Practice (GMP) for local Pharmacopeia and the US Food and Drug Administration
• PIC/S is unifying the regulatory perspective globally
• There has been a trend of increasing product contamination incidents, counterfeits, product recalls and facility shutdowns
• Companies must develop and implement improved analytics to check the identity, integrity and quality of ingredients and products by incoming material inspection
• Implementation of 100% testing of raw materials is coming!
www.bwtek.com 3Copyright 2013 B&W Tek, Inc.
What is PIC/S?• The Pharmaceutical Inspection Convention and Pharmaceutical
Inspection Co-operation Scheme (jointly referred to as PIC/S) are two international instruments between countries and pharmaceutical inspection authorities, which provide together an active and constructive co-operation in the field of GMP.
• PIC/S' mission is "to lead the international development, implementation and maintenance of harmonised Good Manufacturing Practice (GMP) standards and quality systems of inspectorates in the field of medicinal products.“
• PIC/S currently has 4 partners and 43 member countries with applications for Brazil, Japan, Korea and the United Kingdom under review.
www.bwtek.com 4Copyright 2013 B&W Tek, Inc.
Copyright 2013 B&W Tek, Inc. www.bwtek.com 52012: Japan and Korea applied for membership
GMP for Raw Material Identification
EU GMP and PIC/S GMP Guide
Chapter 5. Production
5.30 There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material.
Annex 8 -Sampling of starting and packaging materials
2. Starting Materials
The identity of a complete batch of starting materials can normally only be ensured if individual samples are taken from all the containers and an identity test is performed on each sample. This means: 100% container testing
www.bwtek.com 6Copyright 2013 B&W Tek, Inc.
100% Raw Material Inspection
How can we rapidly perform 100% container identity testing?
www.bwtek.com 7Copyright 2013 B&W Tek, Inc.
Raman Spectral Information• Raman spectroscopy is a form
of molecular spectroscopy based on the scattering of light by molecules.
• A Raman spectrum is a molecular ‘fingerprint’ that provides structural information– Can identify materials based on
the spectrum
• Changes in intensity, frequency and peak bandwidth provide valuable information for quantitative and qualitative analysis
500 1000 1500 2000 2500 3000
Raman shift (cm-1)
(CH3)2C=O
CH3CH2OH
(CH3)2S=O
CH3CH2O2CCH3
C6H5CH3
C=O
C=O CH3
Ar-H
S=O
CH3CH2
C-O
CH3Aromatic
www.bwtek.com 8Copyright 2013 B&W Tek, Inc.
What Can Raman Do for You?Strong Raman Signal Active Pharmaceutical Ingredients Alcohols Antibiotics Antioxidants Buffers Coatings Diluents Emulsifiers Excipients Flavors Fragrances Lubricants Monomers and Polymers Polyatomic Inorganics Preservatives Solvents Vitamins
Weak Raman Signal Materials that are Dark in Color Highly Fluorescing Molecules Fillers/Binding Agents Glass Thin-walled Plastics Water
No Raman Signal• Black Materials• Metals• Mono-atomic ions
www.bwtek.com 9Copyright 2013 B&W Tek, Inc.
Raman Can Measure Through a Broad Class of Packaging
Bottles Thickness
Amber Glass < 2 mm
Clear Glass < 3 mm
High Density Polyethylene (HDPE) < 1 mm
Teflon FEP < 1 mm
Polystyrene < 1 mm
Vials
Amber and Clear Glass < 1 mm
Bags
Polypropylene (PP) < 0.1mm
Polyethylene (PE), Low-Density Polyethylene (LDPE)
< 0.1mm
www.bwtek.com 10Copyright 2013 B&W Tek, Inc.
Samples for Method Development
• The sample population for a qualitative or a quantitative procedure should cover all potential variation that may be encountered in routine production. (European Medicines Agency Draft Guidance on NIR; same approach applies for Raman spectroscopy)
• Variations in samples and sampling may include, for example:– Material Suppliers
– Process Variation (e.g. samples collected over an extended period)
– Sample Age and Positive Identification by Independent Means for Use in Library and Method Development
– Packaging and Sampling Accessories Used in Measurement
– Water and Residual Solvent Content
– Qualitative and / or Quantitative Variations in the Matrix (e.g. excipient grade, formulation)
20 Jan 2012 EMA draft “ Guideline on the use of Near Infrared Spectroscopy (NIRS) by the pharmaceutical industry and the data requirements for new submissions and variations”www.bwtek.com 12Copyright 2013 B&W Tek, Inc.
Define Measurement Parameters
• Choose operation settings that will be used for collecting the data
• Choose a sampling accessory appropriate to sample form
www.bwtek.com 13Copyright 2013 B&W Tek, Inc.
Tools for Identification and Verification
• Identification using a defined method with p-value (significance level) to verify material identification
• Investigation for unknown samples: HQI
• The HQI (Investigation mode) may be used for identifying unknowns and as an additional tool in method validation
www.bwtek.com 14Copyright 2013 B&W Tek, Inc.
Clear Results
www.bwtek.com 15Copyright 2013 B&W Tek, Inc.
Analytical Instrument Qualification
USP <1058> Analytical Instrument Qualification www.bwtek.com 16Copyright 2013 B&W Tek, Inc.
Self check: by performing calibration validation using ASTM 1840 ref material: Polystyrene
Calibration Validation: PQ
www.bwtek.com 17Copyright 2013 B&W Tek, Inc.
NANORAM EXAMPLE
www.bwtek.com 18Copyright 2013 B&W Tek, Inc.
NanoRam Method Development
Method Development
• The methods/libraries must be developed and can then be run on a routine basis after they have been validated
Developer/Administrator
Measure 20 representative spectra Build method based on PCA and establish threshold p-value (typically 0.05)
Test Method
500060007000800090001000011000
Wavenumber cm-1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Abs
orba
nce
Uni
ts
PC1
PC
2
PC1
PC
2
www.bwtek.com 19Copyright 2013 B&W Tek, Inc.
NanoRam Identification Method
Sample Analysis
1. Access Method 2. Scan Sample 3. Identify Material
Operator/Developer/Admin
www.bwtek.com 20Copyright 2013 B&W Tek, Inc.
Comparing Chemically Similar Materials
• Potassium Carbonate
• Potassium Carbonate Sesquihydrate
Raman spectra of potassium carbonate (red) and potassium carbonate sesquihydrate (blue).
www.bwtek.com 21Copyright 2013 B&W Tek, Inc.
HQI : Library Searching
Library Spectrum
SamplePotassium Carbonate
Potassium Carbonate Sesquihydrate
Potassium Carbonate HQI=99.5590 HQI=96.9013
Potassium Carbonate Sesquihydrate
HQI=97.5834 HQI=99.5908
Difficult to get unambiguous results as the HQI is >95 for both samples against library spectra
www.bwtek.com 22Copyright 2013 B&W Tek, Inc.
Identification Method Using p-value
Method
Sample
Potassium Carbonate
Potassium Carbonate
Sesquihydrate
Potassium Carbonate
p-value = 0.96390.97550.98250.99980.9262
p-value = 6.415 x 10-4
2.990 x 10-4
2.597 x 10-4
6.153 x 10-5
4.077 x 10-5
Potassium Carbonate
Sesquihydrate
p-value = 1.258 x 10-5
1.979 x 10-5
4.132 x 10-5
3.245 x 10-5
3.106 x 10-5
p-value = 0.99970.95340.99020.99190.9942
p-value > 0.05
0.001 <p-value≤ 0.05
10-6 <p-value≤ 10-3
0 <p-value≤ 10-6
www.bwtek.com 23Copyright 2013 B&W Tek, Inc.
Method Validation for Qualitative Analysis
• It is important to test methods to ensure the correct PASS of known good materials and the correct FAIL of materials that are known to be different from the material the method was developed for.
• Method Validation must include ensuring that there are not false positives or false negatives from the methods.
• Selectivity of qualitative methods should be challenged to ensure ongoing validity (EP 2.2.48)
• Validation requires risk assessment and should be done at a level commensurate with the risk that an incorrect result carries– Focus on minimizing possible harm to the patientwww.bwtek.com 24Copyright 2013 B&W Tek, Inc.
ICH Q7A GMP Guidance for Validation of Analytical Methods
(12.8)• Analytical methods should be validated • The suitability of all testing methods used should be verified under
actual conditions of use and documented. • Methods should be validated to include consideration of
characteristics included within the ICH guidances on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.
• Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods
• Complete records should be maintained of any modification of a validated analytical method and should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method.
www.bwtek.com 25Copyright 2013 B&W Tek, Inc.
ICH Q2(R1) Analytical Method Validation
www.bwtek.com 26Copyright 2013 B&W Tek, Inc.
Data Management and Reporting• Need to have a
system of secure data management
• Records Reporting• Audit Trail• Calibration Validation
Reports• Account Management• Library Management
and Transfer
www.bwtek.com 27Copyright 2013 B&W Tek, Inc.
Reports of Results
www.bwtek.com 28Copyright 2013 B&W Tek, Inc.
Raman
Increase analysis
Cost reduction
Improve operations
Competitiveness
Raman has proven to be a promising tool to increase operational capabilities and reduce cost while providing rapid material identification.
Summary
www.bwtek.com 29Copyright 2013 B&W Tek, Inc.
THANK YOU !
www.bwtek.com 30Copyright 2013 B&W Tek, Inc.
Dr. Katherine A. BakeevB&W Tek Inc.19 Shea WayNewark, DE 19713, [email protected]
BACK UP SLIDES
www.bwtek.com 31Copyright 2013 B&W Tek, Inc.
How Does Raman Compare?In comparison to other vibrational spectroscopy methods, such as FTIR and NIR, Raman has several major advantages:
www.bwtek.com 32Copyright 2013 B&W Tek, Inc.
Raman Related Documents (1)Pharmacopeia•United States Pharmacopeia (USP34/NF29) General Chapter <1120> Raman Spectroscopy•European Pharmacopeia (Ph Eur 7.0) 2.2.48 Raman Spectroscopy•Pharmacopeia of the People‘s Republic of China (2010)- Raman Spectroscopy 拉曼光谱法指导原则
EMA Guidance – effective Oct 1, 2012•EMA/CHMP/QWP/811210/2009-Final Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) 2012- …may utilize process analytical technology (PAT) tools e.g. near infrared spectroscopy (NIR) and Raman spectroscopy
www.bwtek.com 33Copyright 2013 B&W Tek, Inc.
Raman Related Documents (2)• ASTM E1840 - 96(2007) Standard Guide for Raman Shift
Standards for Spectrometer Calibration• ASTM E1683 - 02(2007) Standard Practice for Testing the
Performance of Scanning Raman Spectrometers• ASTM E2529 - 06 Standard Guide for Testing the Resolution of
a Raman Spectrometer
• US FDA Advancing Regulatory Science at FDA: A Strategic Plan (August 2011): Section 2. Develop new analytical methods:a) Investigate feasibility and value of using emerging and improved analytical technologies like Nuclear Magnetic Resonance (NMR), mass spectrometry, or near infrared or Raman spectroscopy for evaluating product quality of pharmaceutical agents, and evaluate whether these technologies should replace existing methods;
www.bwtek.com 34Copyright 2013 B&W Tek, Inc.
Raman Applications in Pharma• ID
– Identification Verification of and Identification of unknown raw materials This is the application for the NanoRam
• Quantitative Analysis – Quantitative determination of active substances in different
formulations• Polymorphism
– Supporting polymorphic screenings (polymorphs have different solubility rates, thereby impacting the effective dosing)
• Process – Real time quantitative analysis for process analytical
technology (PAT) such as blending, titration, reaction monitoring and polymorphic transition monitoring
www.bwtek.com 35Copyright 2013 B&W Tek, Inc.
NanoRam User LevelsUser Type User Type
SymbolUser Privileges
Operator Select MethodPerform Material IdentificationSelect Operation PresetData Transfer
Developer All of the above, plus:Create /Edit MethodCreate/Modify Operation PresetCreate/Modify Data Library
Administrator All of the above, plus:Manage User Accounts Create calibration filesSet system clockSet password expirationCreate calibration file
www.bwtek.com 36Copyright 2013 B&W Tek, Inc.
Regulatory Standards Compliance
• 21 CFR Part 11 Electronic Records; Electronic Signatures
• 21 CFR Part 1040.10 Laser and Laser Systems
• US Pharmacopeia <1120> Raman Spectroscopy
• European Pharmacopeia Ch.2.2.48 guidelines for Raman Spectroscopy- includes information on spectral library validation
• ASTM 1840-96(2007) Standard Guide for Raman Shift Standards for Wavelength Calibration
www.bwtek.com 37Copyright 2013 B&W Tek, Inc.
Describe ID vs Investigation
www.bwtek.com 38Copyright 2013 B&W Tek, Inc.
Raman has Greater Specificity than NIR: L-Aspartic acid
www.bwtek.com 39Copyright 2013 B&W Tek, Inc.
Raman shift (cm-1)
175. 283. 393. 501. 606. 710. 811. 910. 1014 1121 1224 1326 1425 1521 1617 1710 1802 1890 1978 2063 2147 2229 2310 2388 2466 2540 2615 2687 2757 2828 2895 2963 3028 3093 3155 3217 3277
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50000
55000
60000
65000
70000Raman spectrum of L-aspartic acid
Wavelength (nm)
1000 1046 1094 1142 1190 1238 1286 1334 1382 1430 1476 1524 1572 1620 1668 1716 1764 1812 1860 1908 1955 2003 2051 2099 2147 2195 2243 2291 2339 2387 2435 2481 2529 2577 2625
0
0.1
0.2
0.3
0.4
0.5NIR spectrum of L-aspartic acid
39
Raleigh
Unchanged Elastic
Scattering
RamanInelastic Scattering
Laser785 nm Excitation
1,000,000 photons vs. 1
Raman Scattering
www.bwtek.com 40Copyright 2013 B&W Tek, Inc.