Presentation on theme: "Raman Spectroscopy for Rapid Material Identification in the Pharmaceutical Industry April 12, 2013 Katherine Bakeev, PhD Director of Application Support."— Presentation transcript:
Raman Spectroscopy for Rapid Material Identification in the Pharmaceutical Industry April 12, 2013 Katherine Bakeev, PhD Director of Application Support Services B&W Tek Newark, DE USA
What is the need? Pharmaceutical companies must meet worldwide PIC/S initiatives, local Pharmacopeia and the US Food and Drug Administration’s regulations on Good Manufacturing Practice (GMP) There has been a trend of increasing product contamination incidents, product recalls and facility shutdowns Companies must develop and implement improved analytics to check the identity, integrity and quality of ingredients and products Implementation of 100% testing of raw materials is coming!
Taiwan New Zealand 2012: Japan and Korea applied for membership
Incremental Regulatory Control for Incoming Material Identification PIC/S recommendations on complete traceability of incoming materials GMP is expanding to new products Global Supply Chain Companies are moving toward a more delocalized supply chain Problems associated with supplier quality assurance and transportation Quality Assurance and Cost Reduction Increase analytical capabilities Reduce operational cost Optimize operational efficiencies Industry Trends and Requirements
100% Raw Material Inspection Why do we need to perform 100% container Identity Testing?
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 performed on each sample. This means: Europe requires 100% container testing
GMP for Raw Material Identification US FDA 21 CFR requires testing of raw materials: 21 CFR (d)- “At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.” Raw materials are quarantined until identity verified Raw materials must meet predetermined specifications US FDA Compliance Program Guidance Manual Program (Drug Manufacturing Inspections-FDA CP ) Material systems: at least one specific identity test is conducted on each lot of each component Dietary Supplement GMPs US 21 CFR 111 21 CFR (a)(1)(i) Conduct at least one appropriate test or examination to verify the identity of any component that is a dietary ingredient
US FDA Warning Letter Review- Identity Tests Xian Libang Pharmaceutical Co., Ltd., China. (Jan 28, 2010) 1. Failure of your quality unit to ensure that materials are appropriately tested and the results are reported. Your firm used the IR spectra for one lot to approve and release two subsequent incoming lots. This practice is unacceptable and raises serious concerns regarding the integrity and reliability of the laboratory analyses conducted by your firm. It is essential that at least one test be conducted to verify the identity of each lot of incoming material. In addition, the laboratory control records should include complete documentation of all raw data generated during each test, including graphs, charts and spectra from laboratory instrumentation. Requirement-development of methods/libraries with well-characterized materials
Regulatory Expectations for Spectroscopic-based Methods
Issues and Customer Concerns Can Raman help my project? What are the differences between Raman and NIR? Should I really perform 100% container ID test? What are my options? Do I need to validate the Raman method? If yes, what are the requirements for method validation? What is next after the Raman ID becomes a routine method? Do I need to know the filing expectations from regulatory agencies (JP/EMA/FDA..)? Can vendors provide GMP support & related documents? 10
Advantages of Raman Spectroscopy These materials cannot be identified by Raman, FTIR or NIR
Raman can measure through packaging: broad class BottlesManufacturerThickness Amber Glass VWR3 mm Clear Glass (A) I-Chem2 mm Clear Glass (B) VWR2 mm High Density Polyethylene (HDPE) VWR1 mm Teflon FEP Nalgene1 mm Polystyrene Uline1 mm Vials Amber Glass Kimball1 mm Clear Glass Kimball1 mm Bags Polypropylene (PP) Uline2 mil Low-Density Polyethylene (LDPE) VWR2 mil
Raman Applications in Pharma ID –Identification of raw materials (building up an extensive library of Raman spectra); This is the application for 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 (PAT) –Supporting chemical development process scale-up (as process steps are modified and refined to ascertain whether the desired chemical is being produced or not, and the rate at which it is formed).
Raman vs non Raman FeatureFTIRRamanNIR Selectivity Very high; fundamental vibrations Very high; fundamental vibrations Low; broad, overlapping bands requiring chemometric models Interference Strong absorption of glass, plastics, water No issues with aqueous solutions; not sensitive to physical form of samples Influence from water; signal impacted by particle size, hardness, Sampling Sample prep may be needed; direct compressed sample contact for ATR No sample prep; measure through transparent or translucent containers; effective in the presence of solutions Can measure through glass, quartz; large sample area needed Method Development Can be by visual examination or library matching Sharp, distinctive spectral peaks can be used for accurate identification Analysis typically requires chemometrics; low selectivity Device Packaging Can be bulky and weigh > 2 kg; low battery life Handheld. Light weight (1 kg); > 4 hour battery life Bulky. Over 3 kg; low battery life 5/3/2015www.bwtek.com14
Benefits of Handheld Raman for ID Testing Reduced material movement – directly implement in warehouse, loading dock, fewer accidents/reduced manpower Easy and simple operations- simple training & improves manpower usage Reduce chemical exposure – scan through packaging materials & maximize personnel safety Fewer lab delays reduce cycle time – on-time production & higher throughput Free up laboratory instruments – increases lab capacity Reduced transcription – fewer errors; lower personnel and equipment overhead; control costs
Method Development- Special Considerations for Raman Technique Fluorescence interference/presence of impurities Baseline shifts and background signal Laser power Confirm that the sample is not being altered. Adjustable laser power from mW. Sample-position sensitivity Use of appropriate sampling accessory.
17 The Measurement Challenges- Measure Through Plastic Packaging Implementation advantages of spectroscopic methods No cross-contamination (the material inside the bag) Safe and easy to implement Can be implemented in warehouse, docking area or lab But…challenges exist if using NIR technique Spectral profiles include packaging absorptions Packaging interferences may reduce the specificity of the method when identify similar materials The library requires assessment or change if the bag changes, i.e., not suitable for multiple suppliers of same materials Packaging could have multiple layers, with different colors or materials
18 No PE bag (pure sample) Wavenumber (cm -1 ) Two layer PE bag One layer PE bag NIR Spectra of material –with plastic bag Required to evaluate the method specificity in the presence of bag! NIR Spectra of API (Plastic bag contribution)
19 Raman Spectra of API (Plastic bag effect) Raman shift [cm -1 ] Intensity No bag One layer bag Two layer bag No significant spectral absorption from PE bag
Raman has greater specificity than NIR 5/3/2015www.bwtek.com20
Regulatory Standards Compliance 21 CFR Part 11 Electronic Records; Electronic Signatures 21 CFR Part Laser and Laser Systems US Pharmacopeia Raman Spectroscopy European Pharmacopeia Ch guidelines for Raman Spectroscopy ASTM (2007) Standard Guide for Raman Shift Standards for Wavelength Calibration
Validation Process of providing documented evidence that something does what it is intended to do Process, system, method Qualification Inspection, testing and documentation review Is a part of the validation process which verifies module and system performance prior to being placed in routine use Equipment/instrument
Analytical Method Development Prerequisites for analytical method validation-Six “M”s Quality of the analytical method M an M achine qualified calibrated robust qualified M ethods suitable characterized documented M ilieu M aterial M anagement Quality Qualified Material Tempe- rature Analysts´ support skilled Humidity Vibrations Time Supplies Irradi- ation
Self check: by performing calibration validation using ASTM 1840 ref material: Polystyreneref Calibration Validation: part of the PQ 27
Near Infrared already established for ID Provides guidance on qualitative and quantitative analysis. Samples used in ID methods should be authenticated by appropriate means (certificate of analysis or relevant testing).
Spectroscopic-based Identity Method The methods/libraries must be developed and can then be run on routine basis Threshold p-value 0.05 based on PCA of 20 spectra Method development 1.Measure 3-10 Batches; NanoRam uses 20 spectra 3. Build & Test Method Trained analysts
ID Method Development- Flowchart Define intended purpose & scope Collect samples for methods Authentic (or released) samples For library one spectrum of each sample is scanned Authentic (or released) samples For library one spectrum of each sample is scanned Scan barcode and samples; visual evaluation of scan Add sample to method Method created after data collected ID Method validation Any anomalies or outliers ? The sources of variations (if any) Any anomalies or outliers ? The sources of variations (if any) Sample spectrum added to method being created; 20 spectra needed For method the p value is used as pass/fail criteria. Default setting p>0.05 is defined under Settings Threshold can be modified during method development to decrease overlap of materials. For method the p value is used as pass/fail criteria. Default setting p>0.05 is defined under Settings Threshold can be modified during method development to decrease overlap of materials. Choose sampling accessory that will be used Tablet: Two faces scans/per tablet Capsule: better to remove capsule shell (if possible) Powder in vial, in real package…
Raman Method Development Raman bands are distinct and can be easily related to chemical structure -very good for fingerprinting. Conduct a feasibility test: –To ensure sufficient sensitivity for compounds to be included in the reference library (very weak scatterers) –Minimize fluorescence interference/impurities –Laser powers and exposure times confirm that the sample is not being altered –Sampling Appropriate sample accessory Collect valid representative samples –Understand the sources of variations Glass vial and packaging materials’ variability Material lot-to-lot variability Supplier variations –Need to evaluate the performance on testing numerous lots of material
Raman Method Development Raman bands are distinct and can be easily related to chemical structure -very good for fingerprinting. Raman spectral data collection –Measure through containers and plastic bags with appropriate accessory; contribution from the packaging components are usually very minor –System automatically determines scan time to give sufficient Raman signal for each sample –Collect 20 scans for each method – best to use different lots Identification Method –The method is based on the 20 scans of the material –A multivariate model of the spectra (PCA) with Hotelling’sT 2 limit determined (95% confidence; p = 0.05) –p-value used as Pass/Fail criterion
Tools for different verification modes of materials. Identification vs. defined method with p-value (significance level) Investigation for unknown samples: HQI In general, we recommend the use of p-value for ID (identification mode). The HQI (Investigation mode) may be considered an additional tool for validation.
Results from NanoRam Identification: Pass/Fail –sample identity verified by comparison to defined method; p-value used as pass criterion Investigation: Match/No Match –sample matched by correlation (HQI) to materials that are in the libraries available on the system
When running IDENTIFICATION and sample fails, there may show some potential hits. If an identification fails, the system will automatically run an investigation to suggest potential matches for reference purpose. 36
Analytical Method Validation Do we need to perform method validation of spectroscopic-based techniques ?
Japan Pharmacopoeia XVI (JP 16)
ICH Q2 Analytical Method Validation
Method Building Identification Method and operation preset settings Notes should include ref to samples Method Building Identification Method and operation preset settings Notes should include ref to samples Method Validation specificity Internal External (+, -) Robustness* Method Validation specificity Internal External (+, -) Robustness* Samples At least 3 lots (best to use more lots) Authentic (or released) samples If only 1 set is available is ok, method can be revisited at a later stage. Samples At least 3 lots (best to use more lots) Authentic (or released) samples If only 1 set is available is ok, method can be revisited at a later stage. (+) Positive Controls (one per product) – not being used in development (-) Negative Controls-similar materials (+) Positive Controls (one per product) – not being used in development (-) Negative Controls-similar materials One Positive Control per product, uses materials used for method development One to three Positive Controls One Negative Control Spectroscopic Method Validation * Robustness is not required from USP & ICH Q2(R1). In practice it is better to assess the variations of sampling techniques during early method development
Proximity Matrix Provides an overview to illustrate which chemicals may produce: False Positive False Negative good signal bad signal… Proximity Matrix: Testing of all the materials in Identification Mode using specific methods generated by each of the reference materials Method Materials Method AMethod BMethod CMethod DMethod E Material A PASS Fail Fail Fail Fail Material B Fail PASS Fail Fail Fail Material C Fail Fail PASS Fail Fail Material D Fail Fail Fail PASS Fail Material E Fail Fail Fail Fail PASS p-value > 0.05 p-value < 0.05 p-value < p-value < p-value zero
Method Validation for Qualitative analysis (ID) It is important to test methods to ensure correct PASS of known good materials and correct FAIL of materials known to not be what the method was developed for Our OQ and PQ procedures include tests for this – ensuring that there are not false positives or false negatives from the methods 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 patient.
Method Validation Depending on the criticality of the Raman method, steps for checking the method validity should be done on a periodic basis A method performance test can include running a check sample by the Raman method and testing the results versus the compendial method used as reference for the method development PQ is done to test instrument performance at regular intervals
Mainte- nance Collection Method Validation Develop -ment Data storage Continuous performance verification Method update Re-validation 44 Spectroscopic Method:Iterative Nature Raman Spectroscopy Intended use Based on science Configuration/Sampling Spectral-pretreatment Sample selection Calibration/validation sets Method developed on NanoRam with defined settings Chemometric/statistical methods/ algorithms Protocol & report Validation elements
Raman Method- Beyond Routine Analysis: Change Control & OOS Out of Specifications- ID Failure Periodic Performance Review Method and Library Update Out of Specifications- ID Failure Periodic Performance Review Method and Library Update
Raman Analytical Method Maintenance VMP for Raman methods Raman Method Maintenance Method Review Periodic Reviews (short/long term) Extensive Review Annual Review Emergency Review (OOS etc) Method Modifications Critical Method Elements (Leading to Verification) Instrumentation PC/Software Standards Materials change Acceptance limitsOperator New Raman Method Method Development
Raman Routine Analysis- More Details Similar to QC methods, but… ID results - Out of Specification –Follow internal SOPs, investigate root causes Instrument or operating errors? Variations of material sources or grades? Change Control –Risk assessment of incidents (e.g. laser, accessory, change of packaging material) Periodic Performance Verification (PQ) –Should be run at regular intervals (or N batches) –Event trigger: changes of hardware/software, change of material supplier or results trends 47
Standard Operating Procedures (SOPs) Guidance for Raman ID Method Development: B&W Tek doc available SOPs for Raman General Operation: NanoRam User Manual Procedures that describe how to use the system: NanoRam User Manual SOPs for Raman Calibration and Maintenance, including relocation performance check : annual system recertification SOPs for Raman System Disaster Recovery User’s internal SOPs for Change control plan- –Hardware/software upgrade –Change of sampling module (e.g., point and shoot to vial holder). –SOPs for Raman Method Performance Verification –Periodic performance verification PQ –SOPs for Method and Library update Conditions and decision to launch a method update Requirements for electronic data archival
Regulatory Expectations for Spectroscopic-based Methods
Raman Related Documents (1) Pharmacopeia United States Pharmacopeia (USP34/NF29) General Chapter Raman Spectroscopy European Pharmacopeia (Ph Eur 7.0) 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) … may utilize process analytical technology (PAT) tools e.g. near infrared spectroscopy (NIR) and Raman spectroscopy
Raman Related Documents (2) ASTM E (2007) Standard Guide for Raman Shift Standards for Spectrometer Calibration ASTM E (2007) Standard Practice for Testing the Performance of Scanning Raman Spectrometers ASTM E 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;
Raman Method–How do you make a regulatory filing? ChangesUS FDAEU (new) NIR/Raman based analytical method (new or alternative method) API: starting material, intermediate FP: excipient, product Annual Report PAS (if high risk to quality)* Type IB as “other changes to a test procedure (including replacement or addition). Changes requiring prior approval Change in test procedure for the immediate packaging or reagents (low quality risk) of the API & FP Annual ReportType IA Minor variation- Not requiring immediate notification 1.Real-Time Release Test 2.Introduction of new or extension of existing Design Space PAS (Post Approval Supplement) Type II Major var. Significant impact on Q/S/E Changes requiring prior approval Reference only- Need to consult with specific Regulatory Affairs contact Ref: US FDA 21CFR314.70Rev. 2012, and EMA "Guidelines on the details of the various categories of variations for medical products for human use and veterinary medicinal products" (2010/C 17/01).
Challenges for using Raman Methods Within Pharma organization –Introducing new technology can be a challenge –QA or regulatory staff adverse to change –Confusion about the validation elements & procedures: B&W Tek can help Local regulatory agencies –Lack of existing USP, EP or EMA guidance specific to Raman ID –Different outcomes and comments from reviewers Instrument vendors/sales representative –Limited knowledge of the regulatory process –Not always staffed for applications support
Strategy and Approach for Raman Implementation Define objectives- intended use Project Team: Requires complete preparation and coordination –Identify project members and leader (coordinator) –Treat Raman technique as a general GMP method –Understand advantages and limitations of technique –Review GMP regulation (EU, US FDA, PIC/S) and pharmacopeia (USP, EP, EMA) requirements –Contact instrument supplier/vendor and evaluate their technical/GMP/supporting capability; partner with supplier –Full participation of internal departments (QC, QA, Regulatory affairs, Manufacturing, R&D) with open discussions to reduce communication/technical barriers
Common Questions from Customers……. 55
Q1: What is the difference between ID and purity tests “Identity” and “Purity” are two separate specifications. “Purity” implies some type of quantitative method; typically HPLC “Purity” is a test for specific impurities such as low level contaminants/adulterants. An identity test says nothing about purity, strength, or composition. Usually gives “binary result”: Positive/Negative; Pass/Fail; Yes/No Identity verifies it is similar to what has been used in the past Every proposed method should be validated if it is used for quality decision!
Q2: How long does it take to get a Raman Method in place Bottleneck: –Document preparation & internal review –Assembling samples Example: Develop an ID method for 10 materials: –Training < 1 week –Method development 1-2 weeks –Specificity & robustness tests < 1 week –Documentation (prepare, review & approve) 2-4 weeks The first ID method validation takes weeks The next ID validation project takes only 1-2 weeks B&W Tek can provide Support Services
Q3: How do traditional vs. spectroscopic-based methods compare? In traditional methods often have a univariate calibration model Spectroscopic method based on chemometric modeling or statistical calculations –Identification/Qualitative Calculate spectral similarity between method and unknown samples Specificity test- interval validation evaluation focus on the model correctness of spectral library 58 Note: Different terminology: Calibration in chemometrics- method/model calibration Calibration in GMP environment - e.g., instrument calibration Note: Different terminology: Calibration in chemometrics- method/model calibration Calibration in GMP environment - e.g., instrument calibration
Q4: Can I use a commercial spectral library Motivation: reduce development time & manpower if the spectral library or database can be supplied by Vendor or Third Party. Challenges: under Pharma GMP: qualified raw material library should be evaluated: –Authentic materials?- identify sources, lot number, expiration date etc. and assess the authenticity (with test record) –Qualified instrument? – assess instrumentation/configurations (resolution, range, probe etc),experimental and GMP qualification documents. Suitability: Commercial library/database could be used for general screening purpose (e.g., contract lab, food/chemical industry), –Understand intended use- e.g., “…This library is designed for those laboratories studying pharmaceutical formulations using Raman spectroscopy” 59 Question: Can a Pharma Lab use commercial library for an ID test ?
Issues on using Commercial Spectral Library or Database US FDA Warning Letters Jilin Shulan Synthetic Pharmaceutical Co 5/13/2010 #5. You routinely failed to utilize a suitable standard for the spectral comparison during the FTIR testing of XXX. Instead, you compared sample spectra with the spectrum of XXX in the Chinese Pharmacopeia. The USP requires that you compare the spectrum of your test sample with that of your reference standard. Yunnan Hande Bio-Tech. Co. Ltd. 10/15/10 #4. a. Your firm does not concurrently analyze the FTIR samples with a XXX reference standard. Instead, you analyze the sample against a spectrum stored in the memory of the FTIR. During our inspection, you were unable to provide data to show when and how you prepared and qualified the FTIR spectrum standard. 60 EP Raman Spectroscopy …This database is then valid for use only with the originating instrument, or with a similar instrument, provided the transferred database has been demonstrated to remain valid. EP Raman Spectroscopy …This database is then valid for use only with the originating instrument, or with a similar instrument, provided the transferred database has been demonstrated to remain valid.
Raman has proven to be a promising tool to increase operational capabilities and reduce cost while providing rapid material identification. 61 Summary
THANK YOU FOR YOUR ATTENTION Dr. Katherine Bakeev Director Application Support Services B&W Tek, Inc x
BACK UP SLIDES 63
USP Validation of Compendial Procedures
Why do Raman ID methods fail? (1) Failure to include lot-to-lot variability use numerous non-consecutive lots realize material potential variability (particle size, moisture, mechanics etc.) Failure to understand the limitation of Raman fluorescence interference low Raman scattering signal (e.g., cellulose, salts, metals) low concentration (e.g., tablet API) Potentially close materials give ambiguous results (pass more than one method) Adjust p-value to narrow acceptance range for material, and limit overlap of methods
Why do Raman ID methods fail? (2) Occasional operational errors Sampling/scanning problem Quality of sample vials (sealed, glass etc.), plastic bags or containers Method specific to particular sampling accessory and/or packaging Limited knowledge or misuse of identity algorithms Performance/sensitivity of identification method (p-value is based on a PCA model on the 20 scans in the method)
Deficiencies of Filed Spectroscopic Methods (1) Absence of instrument description –Light source, design, detector, sampling module, software package Minimal description of chemometric techniques –Algorithms for pass/fail results –Method validation Limited results for method validation –Without acceptance criteria (ID thresholds) –Detailed results (with predicted values, not just pass or fail) –Inappropriate selection of negative control samples (material structurally similar or closely related to the analyte)
Deficiencies of Filed Spectroscopic Methods (2) Inadequate SOPs and plan for change control –Spectroscopic method performance verification? –Spectroscopic method maintenance plan? Lack of information for library/method update plan –SOPs for method/library update?