All PublicationsLCGC InternationalLCGC North AmericaLCGC EuropeLCGC Asia PacificLCGC SupplementsThe ColumnE-BooksThe Application Notebook
Columns
All NewsInterviews
All App NotesBiological, Medical, and ClinicalBiopharmaceuticalsCannabisChiralEnvironmentalFood and BeverageGCGC-MSGeneralIndustrialLCLC-MSMedical/BiologicalMisc TechniquesPharmaceuticalsPolymersSample PrepSize-Exclusion Chromatography (SEC)Supercritical Fluid Chromatography (SFC)
Conference CoverageConference Listing
All WebcastsChromAcademy
ProductsE-BooksChromTubeEventsAnalytically Speaking PodcastPodcastsPodcast SeriesSponsored VideosQ&AsSponsored ContentContent Engagement HubsTips & TricksIndustry InsightsCareer OpportunitiesPeer Exchange
DirectorySubscribe
Analytical Instrumentation
Analytical Theory
Biological, Medical, and Clinical Analysis
Biopharmaceutical Perspectives
Biopharmaceuticals and Protein Analysis
Cannabis Analysis
Capillary Electrophoresis
Chiral Chromatography
ChromAcademy
Corporate Profiles
Data Acquisition, Handling, and Archiving
Data Analysis, Statistics, and Chemometrics
Dietary Supplements Analysis
Environmental Analysis
Field-Flow Fractionation (FFF)
Food and Beverage Analysis
Forensics, Narcotics
From the Editor
GC–MS
Gas Chromatography (GC)
HILIC
HPLC
Ion Chromatography
LCGC Interviews
LCGC TV: Gas Chromatography
LCGC TV: Hyphenated Techniques
LCGC TV: Liquid Chromatography
LCGC TV: Sample Preparation
LC–MS
Liquid Chromatography (LC/HPLC)
Market Profiles
Mass Spectrometry
Medical/Biological
Multidimensional GC
Multidimensional LC
Peer-Reviewed Articles
Pharmaceutical Analysis
Preparative-Scale Chromatography
Process Analytical Technology (PAT)
Quality Control/Quality Assurance (QA/QC)
Quality by Design (QbD)
Regulatory Standards, GLP and GMP Compliance
Sample Preparation
Size-Exclusion Chromatography (SEC)
Solid-Phase Extraction (SPE)
Supercritical Fluid Chromatography (SFC)
Supercritical Fluid Extraction (SFC)
The Next Generation
Thin Layer Chromatography
Trends
UHPLC
Web of Science
Spotlight -
  • Agilent Technologies Battery Summit
  • Advances in Gas Chromatography
  • The 2025 LCGC International PFAS Summit
IS1
  • Applied Clinical Trials

  • BioPharm International

  • Cannabis Science and Technology

  • Chromatography Online

  • Nutritional Outlook

  • Pharmaceutical Commerce

  • Pharmaceutical Executive

  • Pharm Tech

  • Spectroscopy Online

  • Turbo Machinery Magazine

Analytical Instrumentation
Analytical Theory
Biological, Medical, and Clinical Analysis
Biopharmaceutical Perspectives
Biopharmaceuticals and Protein Analysis
Cannabis Analysis
Capillary Electrophoresis
Chiral Chromatography
ChromAcademy
Corporate Profiles
Data Acquisition, Handling, and Archiving
Data Analysis, Statistics, and Chemometrics
Dietary Supplements Analysis
Environmental Analysis
Field-Flow Fractionation (FFF)
Food and Beverage Analysis
Forensics, Narcotics
From the Editor
GC–MS
Gas Chromatography (GC)
HILIC
HPLC
Ion Chromatography
LCGC Interviews
LCGC TV: Gas Chromatography
LCGC TV: Hyphenated Techniques
LCGC TV: Liquid Chromatography
LCGC TV: Sample Preparation
LC–MS
Liquid Chromatography (LC/HPLC)
Market Profiles
Mass Spectrometry
Medical/Biological
Multidimensional GC
Multidimensional LC
Peer-Reviewed Articles
Pharmaceutical Analysis
Preparative-Scale Chromatography
Process Analytical Technology (PAT)
Quality Control/Quality Assurance (QA/QC)
Quality by Design (QbD)
Regulatory Standards, GLP and GMP Compliance
Sample Preparation
Size-Exclusion Chromatography (SEC)
Solid-Phase Extraction (SPE)
Supercritical Fluid Chromatography (SFC)
Supercritical Fluid Extraction (SFC)
The Next Generation
Thin Layer Chromatography
Trends
UHPLC
Web of Science
IS1
  • Applied Clinical Trials

  • BioPharm International

  • Cannabis Science and Technology

  • Chromatography Online

  • Nutritional Outlook

  • Pharmaceutical Commerce

  • Pharmaceutical Executive

  • Pharm Tech

  • Spectroscopy Online

  • Turbo Machinery Magazine

    • Columns
    • Directory
    • Subscribe
Advertisement

Indentifying Packaging-Related Drug Product Impurities

August 1, 2007
By John D. Lennon III
Alan D. Hendricker
  • Thomas N. Feinberg

Article

LCGC North America

LCGC North AmericaLCGC North America-08-01-2007
Volume 25
Issue 8
Pages: 710–717

This month's installment of "MS - The Practical Art" provides a slightly different view of how practitioners employ the skills of interpretation that have been the focus in recent columns.

One recent column (1) examined a structured, methodical approach to characterizing suspected counterfeit active pharmaceutical ingredients (API). A logical conclusion this month provided by guest contributors from Cardinal Health (Research Triangle Park, North Carolina) takes the methodology a step further. Once a properly manufactured and tested drug has been packaged, there can be anomalies found on reanalysis after storage. The practitioners in these cases need to employ a variety of tools as well as their experience to come up with a confirmed identity for the anomaly as well as a possible source for its presence. Once again, mass spectrometers play a central role in the effort. Identifying drug-product-related impurities is a challenge that all pharmaceutical companies face. Compared with drug-substance-related impurities, which most commonly originate with the synthetic process or subsequent degradation, drug-product-related impurities can originate from several additional sources. Those sources include excipients and interaction with the packaging or container–closure devices. Although we can identify drug-product-related impurities solely via a sound analytical approach (2,3), considering and understanding all potential sources of those impurities can facilitate the process and expedite a solution.

Identifying impurities originating from the drug substance or excipients is not necessarily trivial, but at least those things lend a starting point for the investigation. But identifying impurities originating from the packaging or container–closure devices can sometimes prove more challenging for several reasons:

  • The plastic and rubber materials used in the packaging and container–closure devices are often proprietary.

  • The additives, potential leachables, are not always known.

  • The manufacture of plastic and rubber materials does not usually proceed according to current good manufacturing (cGMP) conditions, and minor changes in process or technique can affect potential leachables significantly.

  • Impurities often can appear as drug substance degradants that form on stability, which can lead the investigation astray.

  • Some leachables can migrate through several layers of seemingly impermeable packaging, which can prove surprising, warranting the consideration of all components of the packaging or container–closure devices as potential sources of leachables.

Several researchers have published studies on impurities related specifically to the packaging of drug products (4–6).

After an initial assessment evaluating both ultraviolet and mass spectral data, if an impurity is categorized as unrelated to the drug substance or excipients, you should evaluate the packaging and container–closure devices. Review the literature as we have indicated in the references, or product information sheets (if available) from the manufacturer of the plastic or rubber materials used in the packaging or container–closure devices. Analyzing the components of the packaging or container–closure devices is also a viable option that can narrow the investigation, provide a source with a relatively greater amount of the impurity compared to the drug product, or provide a source not hindered by drug product excipients that can interfere with mass spectrometry (MS) analysis.

Here, we present several case studies illustrating how we identified leachables in drug-product formulations.

A typical scenario for these situations occurs during stability testing of a drug product when an unknown peak crosses the 0.1% threshold (or other defined threshold) at which impurities must be identified.

Example 1

Figure 1 shows a high performance liquid chromatography (HPLC)-UV chromatogram of an active pharmaceutical ingredient (API) stability assay for an injectable drug. In the chromatogram, an unknown peak is eluted at about 38 min, a peak we had not observed during the drug product analyses performed before the drug was stored in its final packaging (amber glass vial with gray, rubber stopper). In this relatively simple packaging scenario, the likely origin of any impurity that is container closure-related is the elastomeric stopper. But an assay solely by HPLC-UV makes it almost impossible to identify the impurity.

Figure 1

Even with diode-array spectra of the unknown versus the API (which requires minimal effort other than detector substitution), it is nonetheless difficult to discern the identification (Figure 2). Hence, an ideal scenario for a mass spectrometry solution to the problem.

Figure 2

The particular method involves no involatile buffers (for example, phosphate buffers) and, thus, requires minimal modifying to convert to an LC–MS method. When analyzed using negative-ion atmospheric pressure chemical ionization (APCI), a [M–H]- appears at m/z 339, suggesting a molecular weight of 340 Da. LC–MS-MS analysis showed a primary fragment appearing at m/z 163, an impurity that corresponds to a well-known antioxidant 2,29-methylenebis (4-methyl-6-tert-butyl phenol), CAS# 119-47-1.

Figure 3

You can confirm this species using LC–MS by spiking an authentic reference standard and analyzing according to the method shown in Figure 4. The mass spectral fragmentation behavior, along with the retention time match, provides positive confirmation: the source of the impurity is indeed the rubber closure. The product, therefore, should be monitored to ensure the level of impurity does not pose a toxicological risk to patients.

Figure 4

Example 2

Figure 5 shows an HPLC-UV chromatogram drug product analysis and expanded scale showing an impurity eluted late in the assay. This impurity, unobservable on the full scale, could go undetected. In this case, the drug product is an oral steroid tablet packaged in a high-density polyethylene (HDPE) bottle — at first blush not a likely scenario for migration of container closure species. We converted the method to LC–MS and analyzed using ion APCI MS. It showed a [M+H]+ 183, suggesting a molecular weight of 182 Da (Figure 6).

Figure 5

When attempting to identify unknown species, high-resolution MS can be a quick-screening tool for confirming an empirical formula. In this case, we analyzed the species using a high resolution QTOF LC–MS system (Waters, Milford, Massachusetts) to determine the unknown by exact mass: 183.0801 for the [M+H]+ ion. We proposed the formula C13H11O, with a mass accuracy delta of 4.9 ppm. This species is benzophenone, a common UV inhibitor in label–ink–adhesive systems. The source of benzophenone in the tablets proved to be the secondary label on the HDPE bottle that contained the tablets. The benzophenone was migrating from the labels, through the bottles, and into the solid tablets. Obviously, the manufacturer failed to foresee this migration during the drug product's development, underscoring the need to understand the entire drug development system and implement appropriate levels of control.

Figure 6

Example 3

The final case study involves an inhalation-solution drug product. Figure 7 shows an LC-UV chromatogram of the API assay. The unknown is eluted at approximately 25 min. In this case, sourcing the impurity was the primary focus. With limited availability of the drug product, we used saline to extract the container closure system in an attempt to source the unknown. Interestingly, however, we observed the unknown in the saline diluent before any interaction with the product's container closure system. Indeed, it was present in the diluent in larger quantities than in the drug product (Figure 8 shows an overlay chromatogram of each). LC–MS analysis demonstrated no ionization in positive ion APCI mode. Negative ion formation appeared to be suppressed by the formic acid buffer used as a substitute for the nonvolatile phosphate buffer.

Figure 7

We used the LC method on a system that collects fractions. The saline diluent was liquid–liquid extracted with methylene chloride, evaporated to dryness, and diluted in a solvent appropriate for reversed-phase LC. We injected the concentrated sample on a preparative LC system and collected multiple fractions of the unknown. The fraction pool was again extracted with methylene chloride and then injected onto a gas chromatography (GC)–MS system.

Figure 8

Unlike APCI analyses, electron ionization (EI) is a well-characterized technique that easily lends itself to library searching. Figure 9 shows a GC–MS total ion chromatogram for the results of this analysis and an EI spectrum for the unknown, along with the reference library match of benzoic acid. Finally, Figure 10 shows a diode array spectrum of a benzoic acid reference standard along with the drug product, showing identical spectra.

Figure 9

For this case study, we obtained quantitative information about the level of benzoic acid present in the drug product. By using an authentic reference standard and API, we obtained a response factor: the amount of benzophenone was approximately 1/15,000 of the API level — about 33 ng in a 2.5-mL inhalation solution ampoule.

Benzoic acid is a common antimicrobial used in many cosmetic applications. Its apparent source was from raw materials used in the production of the drug product.

These studies demonstrate the need to understand materials beyond those in direct contact with the drug product during stability, including those used in conjunction with raw materials, manufacture, and other production.

Figure 10

Conclusions

In its various forms, MS is central technology employed when solving impurity-related problems in the pharmaceutical industry. The examples presented here involve LC–MS-MS, high resolution MS, and GC–EI MS. They show that a systematic approach that adopts the various MS techniques (and used in conjunction with other analytic techniques) can solve challenging issues related to drug product impurities.

References

(1) M.P. Balogh, LCGC 25(6), 554–570 (2007).

(2) D.L. Norwood and F. Qiu, Pharm. Rev. 7 92–99 (2004).

(3) S. Ahuja and K.M. Alsante, Handbook of Isolation and Characterization of Impurities in Pharmaceuticals (Academic Press, San Diego, California, 2003).

(4) K.W. Scott and J. Thompson, Medical Polymers 15–16, 89–110 (2004).

(5) D.R. Jenke, J. Story, and R. Lalani, Int. J. Pharmaceutics 315, 75–92 (2006).

(6) J.S. Kauffman, Pharm. Technol. Anal.Methods S14–S22 (2006).

Michael P. Balogh "MS — The Practical Art" Editor Michael P. Balogh is principal scientist, LC–MS technology development, at Waters Corp. (Milford, Massachusetts); an adjunct professor and visiting scientist at Roger Williams University (Bristol, Rhode Island); and a member of LCGC's editorial advisory board.

Michæl P. Balogh

Articles in this issue

i8_t-447627-1416913670225.jpg
Isolation and Recovery of Triclosan from Liquid Hand Soap Using Reversed-Phase Solid-Phase Disk Extraction and a Capillary GC-AED Determinative Technique
Peaks of Interest
i1-447622-1408672268358.jpg
Worldwide Ion Chromatography Demand
i8_t-447625-1408672258135.jpg
Indentifying Packaging-Related Drug Product Impurities
i8_t-447623-1408672265249.jpg
HPLC Column Expert Predictions - Revisited
i4-447626-1417780249233.jpg
Glossary of Terms Related to Chromatographic Method Validation
i4-447628-1408672248718.jpg
Different Approaches to Synthesizing Molecularly Imprinted Polymers for Solid-Phase Extraction
i8_t-447624-1408672262501.jpg
The Perfect Method, Part III: Adjusting Retention
Recent Videos
Related Content

Border Patrol Agents With Confiscated Drugs. Generated with AI. | Image Credit: © Gayan - stock.adobe.com.

New Contactless Compact Mass Spectrometry System Set to Improve Narcotics Detection

Will Wetzel
July 8th 2025
Article

Composition with variety of drug pills and dietary supplements | Image Credit: © monticellllo - stock.adobe.com

Quantifying Prodrug Metabolites Using HILIC

Aaron Acevedo
July 2nd 2025
Article

To better conduct the analysis of nucleoside analogues, hydrophilic interaction liquid chromatography–tandem mass spectrometry (HILIC-MS/MS) was used to quantify antitumor prodrugs and their metabolites.


Silver Spring, MD, USA - June 25, 2022: The FDA White Oak Campus, headquarters of the U.S. Food and Drug Administration (FDA), a federal agency of the Department of Health and Human Services (HHS). | Image Credit: © Tada Images - stock.adobe.com

FDA Grants Breakthrough Status to AI-Enhanced GC-MS Device for Bladder Cancer Detection

Aaron Acevedo
July 1st 2025
Article

A new cancer detection test to analyze volatile organic compounds through urine analysis, was granted the Breakthrough Device Designation status by the U.S. FDA. The system, which is built on gas chromatography–mass spectrometry (GC–MS) and proprietary AI, generates real-time cancer risk scores.


Cambridge Massachusetts USA cityscape. | Image Credit: © SeanPavonePhoto - stock.adobe.com

Characterizing Oligomers Using a 2D-LC–MS Workflow

Aaron Acevedo
July 1st 2025
Article

Using two-dimensional liquid chromatography–mass spectrometry, a new workflow was developed to characterize phosphorodiamidate morpholino oligomers, which can help treat infectious diseases.


Aerial View of CBD Overpass in Zhengdong New District, Zhengzhou, Henan Province, China | Image Credit: © Govan - stock.adobe.com

Detecting Polycyclic Aromatic Hydrocarbons with UHPLC–MS/MS

Aaron Acevedo
June 30th 2025
Article

To better detect polycyclic aromatic hydrocarbons in the human body, a UHPLC–MS/MS method was developed and tested on urine samples from workers exposed to diesel exhaust.


Mass detector coupled with GC-MS - Gas Chromatography. Analytical laboratory. | Image Credit: © khaw - stock.adobe.com

Quality Control in GC–MS Analysis of Amino Acids

Aaron Acevedo
June 28th 2025
Article

Gas chromatography–mass spectrometry was used alongside quality control systems to analyze amino acids present in urine samples.

Related Content

Border Patrol Agents With Confiscated Drugs. Generated with AI. | Image Credit: © Gayan - stock.adobe.com.

New Contactless Compact Mass Spectrometry System Set to Improve Narcotics Detection

Will Wetzel
July 8th 2025
Article

Composition with variety of drug pills and dietary supplements | Image Credit: © monticellllo - stock.adobe.com

Quantifying Prodrug Metabolites Using HILIC

Aaron Acevedo
July 2nd 2025
Article

To better conduct the analysis of nucleoside analogues, hydrophilic interaction liquid chromatography–tandem mass spectrometry (HILIC-MS/MS) was used to quantify antitumor prodrugs and their metabolites.


Silver Spring, MD, USA - June 25, 2022: The FDA White Oak Campus, headquarters of the U.S. Food and Drug Administration (FDA), a federal agency of the Department of Health and Human Services (HHS). | Image Credit: © Tada Images - stock.adobe.com

FDA Grants Breakthrough Status to AI-Enhanced GC-MS Device for Bladder Cancer Detection

Aaron Acevedo
July 1st 2025
Article

A new cancer detection test to analyze volatile organic compounds through urine analysis, was granted the Breakthrough Device Designation status by the U.S. FDA. The system, which is built on gas chromatography–mass spectrometry (GC–MS) and proprietary AI, generates real-time cancer risk scores.


Cambridge Massachusetts USA cityscape. | Image Credit: © SeanPavonePhoto - stock.adobe.com

Characterizing Oligomers Using a 2D-LC–MS Workflow

Aaron Acevedo
July 1st 2025
Article

Using two-dimensional liquid chromatography–mass spectrometry, a new workflow was developed to characterize phosphorodiamidate morpholino oligomers, which can help treat infectious diseases.


Aerial View of CBD Overpass in Zhengdong New District, Zhengzhou, Henan Province, China | Image Credit: © Govan - stock.adobe.com

Detecting Polycyclic Aromatic Hydrocarbons with UHPLC–MS/MS

Aaron Acevedo
June 30th 2025
Article

To better detect polycyclic aromatic hydrocarbons in the human body, a UHPLC–MS/MS method was developed and tested on urine samples from workers exposed to diesel exhaust.


Mass detector coupled with GC-MS - Gas Chromatography. Analytical laboratory. | Image Credit: © khaw - stock.adobe.com

Quality Control in GC–MS Analysis of Amino Acids

Aaron Acevedo
June 28th 2025
Article

Gas chromatography–mass spectrometry was used alongside quality control systems to analyze amino acids present in urine samples.

About
Advertise
Author Guidelines
Contact Us
Editorial Advisory Board
Ethics Policy
Do Not Sell My Personal Information
Privacy Policy
Permissions
Subscriptions
Terms and Conditions
Contact Info

2 Commerce Drive
Cranbury, NJ 08512

609-716-7777

© 2025 MJH Life Sciences

All rights reserved.
Home
About Us
News