Magnesium stearate is a white powder that becomes solid at room temperature. In the pharmaceutical manufacturing process, magnesium stearate is the most commonly used lubricant for capsules and tablets, and is used to help prevent pharmaceutical ingredients from adhering to manufacturing equipment. Calcium stearate, and to a lesser extent, zinc stearate, are also used as pharmaceutical excipients in manufacturing, primarily for tablet and capsule lubrication. Magnesium stearate, calcium stearate and zinc stearate share a similar chemical compound structure and are more challenging to verify during the incoming raw material inspection process. While the Thermo Scientific™ TruScan™ RM handheld Raman analyzer has a built-in multivariate residual analysis decision engine to identify most materials, more complex materials analysis requires users to build custom, advanced methods. Thermo Scientific TruTools™ is an embedded chemometrics package for the TruScan RM analyzer. It enables users to create customized predictive applications, including classification, semi-quantitative and quantitative methods. TruTools leverages Solo, a chemometrics software package from Eigenvector Research Inc., which allows users to develop models that can be deployed onto the TruScan RM analyzer.
Ensuring Material Quality at the point of need: Stearates verification case study using handheld Raman analyzer
Introduction
Magnesium stearate is a white powder that becomes solid at room temperature. In the pharmaceutical manufacturing process, magnesium stearate is the most commonly used lubricant for capsules and tablets, and is used to help prevent pharmaceutical ingredients from adhering to manufacturing equipment. Calcium stearate, and to a lesser extent, zinc stearate, are also used as pharmaceutical excipients in manufacturing, primarily for tablet and capsule lubrication. Magnesium stearate, calcium stearate and zinc stearate share a similar chemical compound structure and are more challenging to verify during the incoming raw material inspection process. While the Thermo Scientific™ TruScan™ RM handheld Raman analyzer has a built-in multivariate residual analysis decision engine to identify most materials, more complex materials analysis requires users to build custom, advanced methods. Thermo Scientific TruTools™ is an embedded chemometrics package for the TruScan RM analyzer. It enables users to create customized predictive applications, including classification, semi-quantitative and quantitative methods. TruTools leverages Solo, a chemometrics software package from Eigenvector Research Inc., which allows users to develop models that can be deployed onto the TruScan RM analyzer.
In this application, a Principal Component Analysis (PCA) method was found to be successful in identifying the various stearates. A TruTools PCA method produces a Pass or Fail result screen, based on the logic selected in the TruScan RM analyzer’s WebAdmin functionality. PCA method setting in WebAdmin allows users to make a decision based on either normalized hoteling (T^2), normalized residual (Q), both or combined. Thus the user can control the PCA method’s selectivity. For example, if normalized Q value will be used for the Pass/Fail criteria to identify raw materials, then any Q values higher than 1 will be considered as Fail. Usually, normalized Q value is more common than normalized T^2 as the criteria for pass/fail indication, as Q value reflects the unusual variations outside the model.
Calcium Stearate
Acquisition Parameters:
- Laser Power: 250 mW
- Exposure Time: 500msec
- Number of Coadds: 20
Number of Scans: 34
Eigenvector Solo Settings:
Wavelength: 302-2175.3cm-1
Pre-processing: SNV, 1st Derivative (order: 2, window: 13 pt, incl only, tails: polyinterp), Mean Center
Number of PCs: 2
Cross validation: venetian blinds w/ 8 splits and 1 sample per split
Cross Validated Calcium Stearate PCA method against Zinc Stearate and Magnesium Stearate
Magnesium Stearate
Acquisition Parameters:
- Laser Power: 250 mW
- Exposure Time: 500msec
- Number of Coadds: 20
Number of Scans: 23
Eigenvector Solo Settings:
Wavelength: 556.8-1980.3cm-1
Pre-processing: SNV, 1st Derivative (order: 2, window: 15 pt, incl only, tails: polyinterp), Mean Center
Number of PCs: 2
Cross validation: venetian blinds w/ 6 splits and 1 sample per split
Cross Validated Magnesium Stearate PCA method against Zinc Stearate and Calcium Stearate
Zinc Stearate
Acquisition Parameters:
- Laser Power: 250 mW
- Exposure Time: 500msec
- Number of Coadds: 20
Number of Scans: 21
Eigenvector Solo Settings:
Wavelength: 320.2-2060.9cm-1
Pre-processing: SNV, 1st Derivative (order: 2, window: 15 pt, incl only, tails: polyinterp), Mean Center
Number of PCs: 2
Cross validation: venetian blinds w/ 4 splits and 1 sample per split
Cross Validated Zinc Stearate PCA method against Magnesium Stearate and Calcium Stearate
Raman analyzer in GMP and Pharmacopeia-Compliant environment
Raman spectroscopy is a widely accepted alternative method of identifying raw materials to be used in the manufacture of drug products. Thermo Scientific TruScan portable spectrometers make the Raman method of identification fast and efficient. This article discusses the advantage of using TruScan portable technology when establishing good manufacturing practices (GMP) and when submitting changes to an approved drug file. Table 1 encapsulates rules and associated documentation pertaining to the use of Raman spectroscopy as an alternate method of GMP- and Pharmacopeia- compliant raw material identification (RMID). It also references associated U.S. and European filing requirements, highlighting the differences and similarities between the American and European systems. Pharmaceutical manufacturers who distribute their products in the United States and Europe must develop and adapt their processes to comply with regulations put forth by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, respectively. These regulatory agencies have differing standards for identifying and measuring raw materials used in the manufacture of drugs.
In the current American and European regulations, two sections are particularly relevant to the use of Raman handheld systems for RMID in the manufacture of prescription (Rx) versus over-the-counter (OTC) drug products:
Section on Good Manufacturing Practices
Section on the submission of changes to an approved drug file
Good Manufacturing Practices
GMP enables companies to comply with respective regulatory agencies’ drug safety requirements. A section in the GMP guidelines details the testing and approval process for the reception and subsequent release of raw materials by a manufacturer’s receiving and quality control departments.
Pharmacopeia
The U.S. and European Pharmacopeias set industry standards for qualitative and quantitative composition of medicines. Manufacturers are not required to meet pharmacopeia standards but doing so helps ensure that their products are appropriately identified and their strength, quality, purity and consistency meet regulatory standards, and are accurately measured against competitors’ products. The respective pharmacopoeias generate both monographs on approved compounds and general chapters pertaining to approved chemical testing protocols, such as spectroscopy techniques.
Tracking Changes to Approved Drugs
Pharmaceutical companies must get regulatory approval to produce and sell drugs to markets in which they wish to do business. Over time, advances in technology and/or processes prompt manufacturers to alter ways in which they produce approved Rx drugs. In the United States, companies must have a New Drug Application (NDA) accepted by the FDA. In Europe, approval comes in the form of a Marketing Authorization. In both cases, authorization is granted in part because applicants demonstrate evidence of approved manufacturing processes. When approved, such changes are documented in the drug’s file with the respective regulatory agencies. Manufacturers using TruScan technology to identify raw materials in the production of an approved Rx drug must meet two criteria. First, they must inform the regulatory body that they are using Raman spectroscopy as an alternate means of identifying raw materials. Second, they must demonstrate the TruScan handheld system used is, in fact, capable of properly identifying raw materials. When interacting with regulators, companies can expend considerable time, resources and money to ensure proposed changes meet regulations. However, filing the change or addition of an analytical method -- such as use of Raman spectroscopy as an alternative RMID method -- is well documented in the U.S. and Europe. The evidence required to ensure a change is up to par most likely will be discovered during the method development and validation phase of the TruScan deployment.
Raman Used as an Alternate ID Method
USA
Europe
GMP
Testing Requirements
One Test must be an ID test; number of containers to be tested based on Statistical Criteria √n+1
One test must be an ID test; number of containers to be tested; 100%
Implications on sampling
If suppliers are audited, CoA can be used in place of performing other tests (no purity, no assay testing are thus required)
If suppliers is not audited, assays testing is required
If suppliers are audited, CoA can be used in place of performing other tests (no purity, no assay testing are thus required)
If suppliers is not audited, assays testing is required
General Documents on Good Manufacturing Practices
21 CFR 210 and 211
Volume 4 EU Guidelines to GMP
Medicinal Products for Human and Veterinary Use Part I
Chap. 6 QC Annex 8 of same Chapter and Part II
Pharmacopoeia
Pharmacopoeia
United States Pharmacopoeia
European Pharmacopoeia
Presence of Raman spectrum in the monographs
No, but Raman can be used as an alternate ID Method as indicated in the general chapter
No, but Raman can be used as an alternate ID Method as indicated in the general method analysis chapter
Text governing the use of Raman spectroscopy
Raman can be used as an alternate ID methods to the one listed in the monographs as mentioned in
USP<1120> See our compliance statement
Use of Raman must be validated
Raman can be used as an alternate ID methods to the one listed in the monographs as mentioned in EP 2.2.48
See our compliance statement
Use of Raman must be validated
Validation of Raman spectroscopy as an alternate ID method
For product with a market authorization (NDA), notice to the regulatory body is required.
For a product with a market authorization, notice to the regulatory body is required (central or mutual recognition process=local applies)
Type of Change
Minor change
Addition of a new ID methods is considered a minor change/ see 21 CFR 314.70 (d) (vii)
The utilization of Raman spectroscopy shall be filled as an additional (i.e. alternate) to ID materials and not as the primary ID method. This technicality will avoid long filing process.
Minor change
Addition of a new ID methods is considered a type 1B change. See Commission Regulation (EC) No 1085/2003 of 3 June 2003 section 13.
The utilization of Raman spectroscopy shall be filled as an additional (i.e. alternate) to ID materials and not as the primary ID method. This technicality will avoid long filing process.
Filing Timeline
No waiting period. Annually as minor changes can be reported into the Annual Report.
Change 1B is filed before implementing the change. Response can be expected within 30 days.
Documents to be supplied
Documents developed for GMP are almost identical to the ones necessary for the filing
Section in the annual report with:
- A brief statement explaining the reason of the addition of the analytical methods
- Data demonstrating the suitability and validity of the new method (Data should at a minimum demonstrate equivalence with the method currently used):
Comparability protocol (optional)
Tests results (lab and live)
Comparison Matrix (Alternate method against Approved Method)
Change 1B is filed before implementing the change. Response can be expected within 30 days.
Data demonstrating the suitability and validity of the new method:
A summary of validation data
Amendment to relevant sections of Part IIG (old Part IIF) or equivalent in the CTD format (if applicable).
Comparative validation results showing that the current test and the proposed one are equivalent.
Application form for 1B variation change (see below)
Cover letter for Variation Applications
Guidance and useful documents for filing the amendment to the market authorization
Comparability protocol
Guidance on the Chemistry, Manufacturing and Control information change section of the Annual Report
Guidance on submitting analytical data
Application form for a 1B variation change
Variations, the Rules governing Medicinal Products in the European Community, Notice to Applicants (timing, responsibilities of the different parties)
“MRFG Best Practice Guides for the Submission and processing of Variations in the Mutual Recognition procedure, Chapter 1: MRFG Best Practice Guide for the allocation of the Mutual Recognition Variation Number for Type I Notifications and Type II variations
EMA/CMDh Explanatory notes on variation form application
Common grounds seen for invalidation and delay for variations applications
Guideline on Dossier requirements for Type IA and Type IB Notifications
Post-Authorization Guidance Type I Variations
Notice to Applicants, Volume 2B - Electronic Common Technical Document
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Magnesium stearate is a white powder that becomes solid at room temperature. In the pharmaceutical manufacturing process, magnesium stearate is the most commonly used lubricant for capsules and tablets, and is used to help prevent pharmaceutical ingredients from adhering to manufacturing equipment. Calcium stearate, and to a lesser extent, zinc stearate, are also used as pharmaceutical excipients in manufacturing, primarily for tablet and capsule lubrication. Magnesium stearate, calcium stearate and zinc stearate share a similar chemical compound structure and are more challenging to verify during the incoming raw material inspection process. While the Thermo Scientific™ TruScan™ RM handheld Raman analyzer has a built-in multivariate residual analysis decision engine to identify most materials, more complex materials analysis requires users to build custom, advanced methods. Thermo Scientific TruTools™ is an embedded chemometrics package for the TruScan RM analyzer. It enables users to create customized predictive applications, including classification, semi-quantitative and quantitative methods. TruTools leverages Solo, a chemometrics software package from Eigenvector Research Inc., which allows users to develop models that can be deployed onto the TruScan RM analyzer.
Ensuring Material Quality at the point of need: Stearates verification case study using handheld Raman analyzer
Introduction
Magnesium stearate is a white powder that becomes solid at room temperature. In the pharmaceutical manufacturing process, magnesium stearate is the most commonly used lubricant for capsules and tablets, and is used to help prevent pharmaceutical ingredients from adhering to manufacturing equipment. Calcium stearate, and to a lesser extent, zinc stearate, are also used as pharmaceutical excipients in manufacturing, primarily for tablet and capsule lubrication. Magnesium stearate, calcium stearate and zinc stearate share a similar chemical compound structure and are more challenging to verify during the incoming raw material inspection process. While the Thermo Scientific™ TruScan™ RM handheld Raman analyzer has a built-in multivariate residual analysis decision engine to identify most materials, more complex materials analysis requires users to build custom, advanced methods. Thermo Scientific TruTools™ is an embedded chemometrics package for the TruScan RM analyzer. It enables users to create customized predictive applications, including classification, semi-quantitative and quantitative methods. TruTools leverages Solo, a chemometrics software package from Eigenvector Research Inc., which allows users to develop models that can be deployed onto the TruScan RM analyzer.
In this application, a Principal Component Analysis (PCA) method was found to be successful in identifying the various stearates. A TruTools PCA method produces a Pass or Fail result screen, based on the logic selected in the TruScan RM analyzer’s WebAdmin functionality. PCA method setting in WebAdmin allows users to make a decision based on either normalized hoteling (T^2), normalized residual (Q), both or combined. Thus the user can control the PCA method’s selectivity. For example, if normalized Q value will be used for the Pass/Fail criteria to identify raw materials, then any Q values higher than 1 will be considered as Fail. Usually, normalized Q value is more common than normalized T^2 as the criteria for pass/fail indication, as Q value reflects the unusual variations outside the model.
Calcium Stearate
- Exposure Time: 500msec
- Number of Coadds: 20
Cross Validated Calcium Stearate PCA method against Zinc Stearate and Magnesium Stearate
Magnesium Stearate
- Exposure Time: 500msec
- Number of Coadds: 20
Cross Validated Magnesium Stearate PCA method against Zinc Stearate and Calcium Stearate
Zinc Stearate
- Exposure Time: 500msec
- Number of Coadds: 20
Cross Validated Zinc Stearate PCA method against Magnesium Stearate and Calcium Stearate
Raman analyzer in GMP and Pharmacopeia-Compliant environment
Raman spectroscopy is a widely accepted alternative method of identifying raw materials to be used in the manufacture of drug products. Thermo Scientific TruScan portable spectrometers make the Raman method of identification fast and efficient. This article discusses the advantage of using TruScan portable technology when establishing good manufacturing practices (GMP) and when submitting changes to an approved drug file. Table 1 encapsulates rules and associated documentation pertaining to the use of Raman spectroscopy as an alternate method of GMP- and Pharmacopeia- compliant raw material identification (RMID). It also references associated U.S. and European filing requirements, highlighting the differences and similarities between the American and European systems. Pharmaceutical manufacturers who distribute their products in the United States and Europe must develop and adapt their processes to comply with regulations put forth by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, respectively. These regulatory agencies have differing standards for identifying and measuring raw materials used in the manufacture of drugs.
In the current American and European regulations, two sections are particularly relevant to the use of Raman handheld systems for RMID in the manufacture of prescription (Rx) versus over-the-counter (OTC) drug products:
Good Manufacturing Practices
GMP enables companies to comply with respective regulatory agencies’ drug safety requirements. A section in the GMP guidelines details the testing and approval process for the reception and subsequent release of raw materials by a manufacturer’s receiving and quality control departments.
Pharmacopeia
The U.S. and European Pharmacopeias set industry standards for qualitative and quantitative composition of medicines. Manufacturers are not required to meet pharmacopeia standards but doing so helps ensure that their products are appropriately identified and their strength, quality, purity and consistency meet regulatory standards, and are accurately measured against competitors’ products. The respective pharmacopoeias generate both monographs on approved compounds and general chapters pertaining to approved chemical testing protocols, such as spectroscopy techniques.
Tracking Changes to Approved Drugs
Pharmaceutical companies must get regulatory approval to produce and sell drugs to markets in which they wish to do business. Over time, advances in technology and/or processes prompt manufacturers to alter ways in which they produce approved Rx drugs. In the United States, companies must have a New Drug Application (NDA) accepted by the FDA. In Europe, approval comes in the form of a Marketing Authorization. In both cases, authorization is granted in part because applicants demonstrate evidence of approved manufacturing processes. When approved, such changes are documented in the drug’s file with the respective regulatory agencies. Manufacturers using TruScan technology to identify raw materials in the production of an approved Rx drug must meet two criteria. First, they must inform the regulatory body that they are using Raman spectroscopy as an alternate means of identifying raw materials. Second, they must demonstrate the TruScan handheld system used is, in fact, capable of properly identifying raw materials. When interacting with regulators, companies can expend considerable time, resources and money to ensure proposed changes meet regulations. However, filing the change or addition of an analytical method -- such as use of Raman spectroscopy as an alternative RMID method -- is well documented in the U.S. and Europe. The evidence required to ensure a change is up to par most likely will be discovered during the method development and validation phase of the TruScan deployment.
If suppliers is not audited, assays testing is required
If suppliers is not audited, assays testing is required
Medicinal Products for Human and Veterinary Use Part I
Chap. 6 QC Annex 8 of same Chapter and Part II
USP<1120> See our compliance statement
Use of Raman must be validated
See our compliance statement
Use of Raman must be validated
No general chapter in the pharmacopoeia
Addition of a new ID methods is considered a minor change/ see 21 CFR 314.70 (d) (vii)
The utilization of Raman spectroscopy shall be filled as an additional (i.e. alternate) to ID materials and not as the primary ID method. This technicality will avoid long filing process.
Addition of a new ID methods is considered a type 1B change. See Commission Regulation (EC) No 1085/2003 of 3 June 2003 section 13.
The utilization of Raman spectroscopy shall be filled as an additional (i.e. alternate) to ID materials and not as the primary ID method. This technicality will avoid long filing process.
Guidance on the Chemistry, Manufacturing and Control information change section of the Annual Report
Guidance on submitting analytical data
Variations, the Rules governing Medicinal Products in the European Community, Notice to Applicants (timing, responsibilities of the different parties)
“MRFG Best Practice Guides for the Submission and processing of Variations in the Mutual Recognition procedure, Chapter 1: MRFG Best Practice Guide for the allocation of the Mutual Recognition Variation Number for Type I Notifications and Type II variations
EMA/CMDh Explanatory notes on variation form application
Common grounds seen for invalidation and delay for variations applications
Guideline on Dossier requirements for Type IA and Type IB Notifications
Post-Authorization Guidance Type I Variations
Notice to Applicants, Volume 2B - Electronic Common Technical DocumentContact Us