1. Director of Application Support Services
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

2. 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!
to the US (and has been adopted in Europe)
PIC/S Pharmaceutical Inspection Cooperation Scheme

3. 2012: Japan and Korea applied for membership
Taiwan
PIC/S is the abbreviation and logo used to describe both the Pharmaceutical Inspection Convention (PIC) and the Pharmaceutical Inspection Co-operation Scheme (PIC Scheme) operating together in parallel.
The PIC Scheme commenced operating on 2 November 1995 in conjunction with PIC which had already been operating since 1970 (see "Background on PIC"). Thus PIC/S became operational in November 1995.
The need to form the PIC Scheme became necessary when it was realised that an incompatibility between PIC and European law did not permit individual EU countries that were members of PIC to sign agreements with other countries seeking to join PIC. Only the European Commission was permitted to sign agreements with countries outside Europe, and the Commission itself was not a member of PIC.
Therefore, a less formal and more flexible cooperation scheme was developed to continue and enhance the work of PIC. Instead of being a legal treaty between countries (ie. like PIC), the PIC Scheme is a cooperative arrangement between Health authorities.
PIC and the PIC Scheme, operating together as PIC/S, provide an active and constructive co-operation in the field of GMP (Good Manufacturing Practice). The purpose of PIC/S is to facilitate the networking between participating authorities and the maintenance of mutual confidence, the exchange of information and experience in the field of GMP and related areas, and the mutual training of GMP inspectors.
New Zealand
2012: Japan and Korea applied for membership

4. Industry Trends and Requirements
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

5. 100% Raw Material Inspection
Why do we need to perform 100% container Identity Testing?

6. 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

7. 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

8. 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

9. Regulatory Expectations for Spectroscopic-based Methods
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.

10. 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?

11. Advantages of Raman Spectroscopy
These materials cannot be identified by Raman, FTIR or NIR

12. Raman can measure through packaging: broad class
Bottles
Manufacturer
Thickness
Amber Glass
VWR
3 mm
Clear Glass (A)
I-Chem
2 mm
Clear Glass (B)
High Density Polyethylene (HDPE)
1 mm
Teflon FEP
Nalgene
Polystyrene
Uline
Vials
Kimball
Clear Glass
Bags
Polypropylene (PP)
2 mil
Low-Density Polyethylene (LDPE)

13. Raman Applications in PharmaID
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).

14. Raman vs non Raman Feature FTIR Raman NIR Selectivity Interference
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
4/14/2017

15. 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

16. 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. NIR Spectra of API (Plastic bag contribution).4 .6 .8 1
1.2
1.4
1.6
1.8
8500
8000
7500
7000
6500
6000
5500
5000
4500
Wavenumber (cm-1)
NIR Spectra of material –with plastic bag
Two layer PE bag
One layer PE bag
Two Layers PE bag has higher NIR intensity as compared to One-Layer PE bag.
No PE bag (pure sample)
Required to evaluate the method specificity in the presence of bag!

19. Raman Spectra of API (Plastic bag effect)
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
900
2700
3600
4500
5400
6300
7200
8100
9000
9900
Raman shift [cm-1]
Intensity
No significant spectral absorption from PE bag
Two layer bag
One layer bag
No bag

20. Raman has greater specificity than NIR
Same finished tablet measured by NIR and Raman- note sharp, distinct peaks in Raman
4/14/2017

21. Regulatory Standards Compliance
21 CFR Part 11 Electronic Records; Electronic Signatures
21 CFR Part Laser and Laser Systems
US Pharmacopeia <1120> Raman Spectroscopy
European Pharmacopeia Ch guidelines for Raman Spectroscopy
ASTM (2007) Standard Guide for Raman Shift Standards for Wavelength Calibration

22. Validation Qualification
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

23. Analytical Method Development
Prerequisites for analytical method validation-Six “M”s
Man
Machine
Methods
qualified
calibrated
characterized
robust
documented
skilled
qualified
suitable
Quality of the analytical method
Qualified Material
Vibrations
Time
Irradi- ation
Analysts´ support
Tempe- rature
Quality
Humidity
Supplies
Material
Milieu
Management

24. Analytical Instrument Qualification
USP <1058> Analytical Instrument Qualification

26. DQ/IQ/OQ and PQ Documents for NanoRam

27. Calibration Validation: part of the PQ
Self check: by performing calibration validation using ASTM 1840 ref material: Polystyrene
Calibration Validation: part of the PQ
Standard spectra of the following materials
Reference spectra on :
1. naphthalene (Mallinckodt #94848) 2. 1,4 bis (2-methylstyryl) benzene (BMB) (Aldrich #25,740-0) 3. sulfur (Aldrich #41,498-0) /50 (v/v) toluene/acetonitrile (Mallinckrodt Analytical Reagents) acetamidophenol (active ingredients of Tylenol) (Aldrich A730-2) 6. benzonitrile (Baker B883-07) 7. cyclohexane (Mallinckrodt Analytical Reagents) 8. polystyrene (Aldrich #18,243-5)

28. 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).

29. Spectroscopic-based Identity Method
The methods/libraries must be developed and can then be run on routine basis
2. Threshold p-value 0.05 based on PCA of 20 spectra
Method development
Measure 3-10 Batches;
NanoRam uses 20 spectra
3. Build & Test Method 
Trained analysts

30. Spectroscopic-based Identity Method
Sample analysis
1. Access method
2. Scan sample
3. Identify material
Operators

31. ID Method Development- Flowchart
Define intended purpose & scope
Choose sampling accessory that will be used
Authentic (or released) samples
For library one spectrum of each sample is scanned
Collect samples for methods
Powder in vial, in real package…
Any anomalies or outliers ?
The sources of variations (if any)
Scan barcode and samples; visual evaluation of scan
Tablet: Two faces scans/per tablet
Sample spectrum added to method being created; 20 spectra needed
Add sample to method
Capsule: better to remove capsule shell (if possible)
Method created after data collected
For library method development see NanoRam users manual section 6.4
The method on the NanoRam is automatically created after the 20 scans are collected. A user does not need to follow the steps of rigorous chemometric model building (as required with NIR). The data are normalized, and a second derivative applied. A PCA model of the 20 scans is developed, and model rank based on 90% explained variance of the data. In the Identification Mode samples are then projected onto the Method model, and if they fall within the 95% confidence of the PCA model (0.05 p value), they PASS the method ID.
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.
ID Method validation

32. 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

33. 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’sT2 limit determined (95% confidence; p = 0.05)
p-value used as Pass/Fail criterion

34. 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.

35. 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

36. 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.

37. Analytical Method Validation
Do we need to perform method validation of spectroscopic-based techniques ?

38. Japan Pharmacopoeia XVI (JP 16)

39. ICH Q2 Analytical Method Validation

40. Spectroscopic Method Validation
Method Building
Identification Method and operation preset settings
Notes should include ref to samples
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
Method Validation
specificity Internal
External (+, -)
Robustness*
One Positive Control per product, uses materials used for method development
One to three Positive Controls One Negative Control
* Robustness is not required from USP <1225> & ICH Q2(R1). In practice it is better to assess the variations of sampling techniques during early method development

41. Proximity Matrix www.bwtek.com
Proximity Matrix: Testing of all the materials in Identification Mode using specific methods generated by each of the reference materials
Method
Materials
Method A
Method B
Method C
Method D
Method E
Material A
PASS
Fail
Material B
Material C
Material D
Material E
Provides an overview to illustrate which chemicals may produce:
False Positive
False Negative
good signal
bad signal…
Green …no problem
Yellow… carefull, potential issue
red… detail studied is required
p-value
> 0.05
< 0.05
< 10-3
< 10-6
zero

42. 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.

43. 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

44. Spectroscopic Method:Iterative Nature
Intended use
Based on science
Configuration/Sampling
Spectral-pretreatment
Sample selection
Calibration/validation sets
Mainte-nance
Collection
Method
Validation
Develop-ment
Data storage
Continuous performance verification
Method update
Re-validation
Raman Spectroscopy
Method developed on NanoRam with defined settings
Chemometric/statistical methods/ algorithms
Protocol & report
Validation elements

45. Raman Method- Beyond Routine Analysis: Change Control & OOS
Out of Specifications- ID Failure
Periodic Performance Review
Method and Library Update

46. Raman Analytical Method Maintenance
VMP for Raman methods
Raman Method Maintenance
New Raman Method
Method Modifications
Method Review
Emergency Review (OOS etc)
Method Development
Critical Method Elements (Leading to Verification)
PC/Software
Instrumentation
Periodic Reviews (short/long term)
Materials change
Standards
Annual Review
Extensive Review
Acceptance limits
Operator

47. 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

48. 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

49. Regulatory Expectations for Spectroscopic-based Methods
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.

50. Raman Related Documents (1)
Pharmacopeia
United States Pharmacopeia (USP34/NF29) General Chapter <1120> 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

51. 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;

52. Raman Method–How do you make a regulatory filing?
Changes
US FDA
EU (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
Type 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
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).

53. 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

54. 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

55. Common Questions from Customers…….

56. 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!

57. 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

58. 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
Note: Different terminology:
Calibration in chemometrics- method/model calibration
Calibration in GMP environment - e.g., instrument calibration

59. 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”
Question: Can a Pharma Lab use commercial library for an ID test ?

60. 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.
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.

61. Summary Increase analysis
Raman
Increase analysis
Cost reduction
Improve operations
Competitiveness
Summary
Raman has proven to be a promising tool to increase operational capabilities and reduce cost while providing rapid material identification. 61

62. Thank you for your attention
Dr. Katherine Bakeev
Director Application Support Services
B&W Tek, Inc.
x1416 62

63. Back up slides

64. USP <1225>Validation of Compendial Procedures

65. 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

66. 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)

67. 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)

68. 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?