Tag Archives: elemental impurities

Forced Degradation Studies Can Reduce Stress(ors)

Forced Degradation is an important addendum to our previous post on Stability and Storage. Stressors are applied to new APIs and drug products to determine their degradation pathways and products under a variety of environmental conditions, including acid, base, light, heat, and oxidation. Forced degradation studies are also known as stress testing, stress studies, stress decomposition studies, and forced decomposition studies. These conditions “…are more severe than accelerated (stability) conditions and thus generate degradation products that can be studied to determine the stability of the molecule.”1  

Regulatory requirements for forced degradation were enacted by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in 1993.2   However, these guidelines are very general in (the) conduct of forced degradation and do not provide details about the practical approach towards stress testing. Although forced degradation studies are a regulatory requirement and scientific necessity during drug development, it is not considered as a requirement for (a) formal stability program.”1 However, stability studies have become a requisite for new drug moieties. In the absence of specific guidelines, the amount of stress needs to be representational: “Overstressing a molecule can lead to degradation profiles that are not representative of real storage conditions and perhaps not relevant to method development. Therefore, stress-testing conditions should be realistic and not excessive.”3 

AMPAC Analytical (AAL), an SK pharmteco company, can assist with forced degradation studies for products at all phases of development, in tandem with stability, storage, and method development, to ensure the viability of the drug products as they were designed. We introduce forced degradation studies early in method development to ensure your product quality throughout the development lifecycle. Contact AAL today to learn more.  


  1. https://www.sciencedirect.com/science/article/pii/S2095177913001007 
  2. http://www.columbiapharma.com/reg_updates/international/ich/q1a.pdf 
  3. https://www.researchgate.net/profile/Dan-Reynolds-3/publication/279607256_Available_Guidance_and_Best_Practices_for_Conducting_Forced_Degradation_Studies/links/5afd6a2ca6fdcc3a5a44c50f/Available-Guidance-and-Best-Practices-for-Conducting-Forced-Degradation-Studies.pdf 

Learn more: https://ampacanalytical.com/laboratory-services/stability-program/ 

Raw Materials Testing: Trust – and Verify – Your Sources

The CGMP guidance for APIs from the FDA states that raw material specifications should be established and documented. The guide’s key line states, “Quality measures should include a system for testing raw materials, packaging materials, intermediates, and APIs. (19.23)”1 

Medical products, pharmacology, dietary supplements

All raw materials used in producing APIs for clinical trials must be evaluated by testing or received from the supplier with accompanying analysis and subsequently subjected to identity testing. Raw materials and intermediates need to be designated by names and/or specific codes so that any special quality characteristics can be readily identified. Furthermore, written procedures should provide for the identification, documentation, appropriate review, and approval of any changes to raw materials. Additionally, changes to supply sources of critical raw materials should be treated according to the FDA’s established change control guidelines.  

A Range of Tests for Raw Materials Are Available
Some of the categories and tests that can be utilized for raw materials testing include: 

  • Determination of Physical Properties (appearance/description, density, refractive index, pH, water content by Karl Fischer titration (coulometric and volumetric), the color and clarity of the solution, conductivity, optical rotation, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), osmolality, particle counting, particle size distribution (wet and dry), total organic carbon (TOC), and various compendial tests) 
  • Identification (appearance/description, infrared spectroscopy – ATR, salt pellets, and salt plates (for liquids), nuclear magnetic resonance (NMR), liquid chromatography – HPLC and UHPLC, gas chromatography (GC), ion chromatography (IC), mass spectrometry (MS), ultraviolet spectroscopy (UV), X-ray powder diffraction (XRPD), residue on ignition/sulfated ash, ICP-MS and ICP-OES for elemental impurities, and various compendial tests) 
  • Assay and Impurity Testing (standard titration methods, liquid chromatography (both HPLC and UHPLC) detection systems including UV, MS, RI, and CAD (charged aerosol detection), residual solvents testing utilizing gas chromatography systems equipped with FID flame-ionization detection), ECD (electron capture detection), TCD (thermal conductivity detection) and MS, ICP-OES, ICP-MS, and a variety of pharmacopeia methods such as residue on ignition/sulfated ash, heavy metals, etc.) 
  • Pharmacopeia Testing (the ability to qualify and implement monographs and testing chapters from the various pharmacopeias and their standards, including USP (United States Pharmacopoeia), EP (European Pharmacopoeia), BP (British Pharmacopoeia), JP (Japanese Pharmacopoeia), FCC (Food Chemical Codex), and ACS (American Chemical Society, Reagent Standards)) 

Trust – and Verify – Your Raw Materials Testing Solution
The range of testing requirements, procedures, and record-keeping can be daunting. It is crucial to have an experienced, reputable, and thorough laboratory available to ensure that each raw material is released in accordance with regulations. It is also important that the partner you choose to perform these tasks does so in a timely manner, communicating every step of the way. AMPAC Analytical has decades of experience along with the resources to provide all the analytical solutions listed above, combined with a responsive customer service attitude, and a demonstrated history of regulatory audit compliance. We urge that you contact AMPAC Analytical today to learn more about you can trust and verify all your raw materials. 


  1. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-q7a-good-manufacturing-practice-guidance-active-pharmaceutical-ingredients#P309_13037 


Extractables and Leachables

Extractables and Leachables (E&L) are essential areas of concern for the pharmaceutical and food industries, specifically regarding their packaging, usage components (e.g., medical devices or syringes), and the manufacturing chain. We will examine testing of analysis of them within pharmaceutical applications. The two terms are related but distinct, each with its own analytical requirements.   

Definitions of Extractables and Leachables 

A handy article published in Pharmaceutical Engineering by the International Society for Pharmaceutical Engineering (ISPE) explains that “Extractables are chemical compounds that migrate from single-use systems (SUS) into model solvent solutions under controlled and exaggerated conditions depending on temperature, pH, polarity, and time.” In other words, this happens when using strong solvents. They note that “SUS are normally not exposed to such conditions in biopharmaceutical processes.”1  

ISPE’s article defines leachables as “chemical compounds that migrate from SUS into process solutions under normal biopharmaceutical process conditions. They further clarify that these compounds “may end up in the final drug product formulation. For the most part, leachables are a subset of extractables, although interaction with product components may produce leachables not seen as extractables.”1 

Guidance on Extractables and Leachables 

The FDA has released a series of guidelines for the pharmaceutical industry, including Container Closure Systems for Packaging Human Drugs and Biologics, that provide guidance for submission in support of an original application for any drug product. It also covers a wide range of forms and delivery systems of drugs:

  • Inhaled 
  • Injected 
  • Liquid-based  
  • Oral  
  • Solid oral dosage forms  
  • Ophthalmic 
  • Topical and topical delivery systems  
  • Powders for reconstitution   
  • And other dosage forms 

Additionally, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) also has issued the ICH Q3E: Guideline for Extractables and Leachables.2,3 These are both useful in providing direction for E&L concerns and control strategies. 

Plan Against Extractables and Leachables 

To guarantee adherence to all guidelines and regulations while ensuring patient safety, it is crucial to know and utilize materials compatible with your product. To accomplish this, solvent use, packaging, and delivery systems must all be tested and analyzed in cGMP and FDA-compliant laboratories.  This should include the following:

  • A thorough review of all materials used in packaging and production, production, and equipment to predict the compatibility of your packaging system with your product. AAL can provide reports for items from each step. 
  • Extraction studies on the materials used. 
  • Leachable studies to identify any impurity resulting from those materials found in the final product under normal usage conditions. 
  • If impurities are detected, AAL can provide toxicological evaluations, including profiles of the impurities and the risks they pose for the patients, establish safety limits, or adjust for different forms of medication application. 
  • We can assess risks created by various exposure levels due to the impurity in the finished product. 
  • Finally, AAL provides a detailed report of our findings in accordance with the applicable governing bodies (e.g., FDA, EMA, PQRI, PDA). 

 AMPAC Analytical can review your analysis and testing needs for extractables and leachables for any forms and delivery systems listed in the table above, complying with the strictest standards necessary. 


  1. https://ispe.org/pharmaceutical-engineering/may-june-2017/extractables-leachables-not-same 
  2. https://www.fda.gov/media/70788/download 
  3. https://database.ich.org/sites/default/files/ICH_Q3E_ConceptPaper_2020_0710.pdf 



Elemental Impurities

A special thanks to Matt Webberley, Associate Director Analytical Research and Development at our sister company, SK biotek Ireland Limited, for his assistance with the profiles of AAS, ICP-OES, ICP-MS, and XRD. 

A Definition of These Newsmakers
Elemental impurities in food have been in the news recently, with reports of everything from lead being found in baby food to arsenic, cadmium, and assorted heavy metals in dark chocolate and other foods.1-8 Of course, the FDA and Congress are taking notice.3 The US Pharmacopeia definition of elemental impurities states they “include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment and the container closure system).”9 As recent news reports show, the concern can be expanded beyond drugs and APIs (active pharmaceutical ingredients) to include food and beverages. 

Classifying Elemental Impurities
In addition to the recalls and resources, there are a variety of impurity classification levels, too. In the following table, the FDA and EMA sort them by elements.12,13 They are classified into three categories based on their toxicity and also based on occurrence in the drug product (note: this is usually assumed to be the same as for the drug substance but not always). 

Class 1: The elements, As, Cd, Hg, and Pb are human toxicants that have limited or no use in the manufacture of pharmaceuticals. Their presence in drug products typically comes from commonly used materials (e.g., mined excipients). Because of their unique nature, these four elements require evaluation during the risk assessment across all potential sources of elemental impurities and routes of administration. The outcome of the risk assessment will determine those components that may require additional controls, which may, in some cases, include testing for Class 1 elements. It is not expected that all components will require testing for Class 1 elemental impurities; testing should only be applied when the risk assessment identifies it as the appropriate control to ensure that the PDE will be met.  
Class 2: Elements in this class are generally considered as route-dependent human toxicants. Class 2 elements are further divided into sub-classes 2A and 2B based on their relative likelihood of occurrence in the drug product.  
Class 2A elements have [a] relatively high probability of occurrence in the drug product and thus require risk assessment across all potential sources of elemental impurities and routes of administration (as indicated). The class 2A elements are: Co, Ni, and V.  
Class 2B elements have a reduced probability of occurrence in the drug product related to their low abundance and low potential to be co-isolated with other materials. As a result, they may be excluded from the risk assessment unless they are intentionally added during the manufacture of drug substances, excipients, or other components of the drug product. The elemental impurities in class 2B include: Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, and Tl.  
Class 3: The elements in this class have relatively low toxicities by the oral route of administration (high PDEs, generally > 500 μg/day) but may require consideration in the risk assessment for inhalation and parenteral routes. For oral routes of administration, unless these elements are intentionally added, they do not need to be considered during the risk assessment. For parenteral and inhalation products, the potential for inclusion of these elemental impurities should be evaluated during the risk assessment unless the route-specific PDE is above 500 μg/day. The elements in this class include: Ba, Cr, Cu, Li, Mo, Sb, and Sn.  
Other elements: Some elemental impurities for which PDEs have not been established due to their low inherent toxicity and/or differences in regional regulations are not addressed in this guidance. If these elemental impurities are present or included in the drug product, they are addressed by other guidance and/or regional regulations and practices that may be applicable for particular elements (e.g., Al for compromised renal function; Mn and Zn for patients with compromised hepatic function), or quality considerations (e.g., presence of W impurities in therapeutic proteins) for the final drug product. Some of the elements considered include: Al, B, Ca, Fe, K, Mg, Mn, Na, W, and Zn. 
Ag, Silver; Al, Aluminum; As, Arsenic; Au, Gold;  B, Boron; Ba, Barium; Ca, Calcium;
Cd, Cadmium; Co, Cobalt; Cr, Chromium;
Cu, Copper; Hg, Mercury; Fe, Iron;  
Ir, Iridium; K, Potassium; Li, Lithium;
Mg, Magnesium; Mn, Manganese;
Mo, Molybdenum; Na, Sodium; Ni, Nickel;
Os, Osmium;  
Pb, Lead; Pd, Palladium; Pt, Platinum;
Rh, Rhodium; Ru, Ruthenium; Sb, Antimony; Se, Selenium; Sn Tin; Tl, Thallium; V, Vanadium;
W, Tungsten; Zn, Zinc 

Tools for Testing Elemental Impurities 

Beyond the FDA, EMA, and the USP, other assets are available to industries, including testing for and mitigating these elemental impurities.  Detection by testing plays a crucial role in ensuring the quality and safety of food, beverages, and medical products. In a very relevant article in Pharmaceutical Technology, published two years ago, Felicity Thomas states, “The most commonly used techniques to analyze elemental impurities are inductively coupled plasma–mass spectrometry (ICP–MS) or inductively coupled plasma–optical emission spectroscopy (ICP–OES).” Both systems utilize high-energy plasma charges that ionize any elements present in the sample preparation and detect them using elemental masses or emission bands. The authors quote Paul Kippax, Pharmaceutical Sector director at Malvern Panalytical, who says, “The advantage of using ICP is that it can detect a wide range of elemental impurities at very low concentrations. This [capability] enables the product safety requirements for the main product types (oral solid dose, inhaled, and injectable products) to be assessed.”14 However, elemental impurity testing is not limited to ICP-MS or ICP-OES. Other techniques available include material characterization (including particle size and thermal analysis), chromatography, x‐ray diffraction and foreign matter identification, and NMR (nuclear magnetic resonance) spectroscopy, each with specific advantages or limitations depending on factors such as time, budget, material or impurities and levels being tested. Here is each profile:  

Atomic Absorption Spectroscopy (AAS)
Atomic absorption spectrometry (AAS) detects elements in either liquid or solid samples through the application of characteristic wavelengths of electromagnetic radiation from a light source. Individual elements will absorb wavelengths differently, and these absorbances are measured against standards. In effect, AAS takes advantage of the different radiation wavelengths that are absorbed by different atoms. In AAS, analytes are atomized by an Air/Acetylene or Nitrous oxide/Acetylene flame so that their characteristic wavelengths are emitted and recorded. When a hollow cathode lamp is passed into the cloud of atoms, the selected metals to monitor absorb the light from the lamp, and the concentration is measured by a detector. Most of the elements reach excitation temperature using this source, which has a maximum temperature of 2,600 °C. For a few elements, such as V, Zr, Mo, and B, the source temperature is not sufficient to atomize the molecules, and as a result, sensitivity is reduced. Moderate detection limits and not all elements can be determined by AAS are some of the limitations of atomic absorption spectroscopy. 

Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES or ICP-AES)
The source in ICP-OES is plasma at temperatures as high as 10,000 °C, where all elements, including refractory elements, atomize with higher efficiencies than in AAS. As a result, elements can be determined more precisely, and lower limits of detection levels are possible. There are two variants in ICP-OES, radial and axial. Axial viewing increases the path length and reduces the plasma background signal [over radial viewing], resulting in lower detection limits. ICP-OES is a multi-element technique. Under the source of plasma, the sample dissociates into its atoms and ions. At their excitation level, they emit light at characteristic wavelengths. The concentration of a particular element in the sample can be measured from the intensity of the emitted light with a detector. However, the detection limits in ICP-OES are moderate to low. 

Inductively Coupled Plasma-Mass Spectrometry ICP-MS (ICP-MS)
The same source as in ICP-OES is used to dissociate a sample into atoms and ions. It is also a multi-element technique. The basic difference between ICP-OES and ICP-MS is that ions are directly detected by an MS detector rather than by emission of light, as in the case of ICP-OES. The ions are separated by a Quadrupole based on the mass-to-charge ratio. The best detection limits are available for most of the elements in ICP-MS as the number of ions produced is high, and although some spectral interference is seen, these are defined and limited. 

X-ray fluorescence (XRF)
X-ray fluorescence (XRF) is a non-destructive analytical technique used to determine the elemental composition of materials. Analyzers determine the chemistry of a sample by measuring the fluorescent (or secondary) X-rays emitted from a sample when it is excited by a primary X-ray source. Each element in a sample produces a set of characteristic fluorescent X-rays (“a fingerprint”) unique for that specific element, which is why XRF spectroscopy is an excellent technology for qualitative and quantitative analysis of material composition. The ICP-OES technique has better sensitivity and lower detection limits compared to XRF. Therefore, using XRF for determining lower levels has higher errors, and the correlation with ICP-OES is weaker. 

Recalls and Resources
The FDA’s actions on contamination from elemental impurities range from issuing guidance to product recalls. There are three class recall levels (I-III) and two related activities: a market withdrawal and a medical device safety alert.10 The former of these are voluntary, while the latter can be considered, in some cases, a recall.

Additionally, the FDA has a range of resources available for both consumers and manufacturers.  For consumers, these include:  

For industry resources, the offerings consist of the following: 

The European Medicines Agency also provides numerous guides and requirements on their site, including the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use’s ICH Q3D Elemental impurities – Scientific Guideline.11 

 Final Thoughts on Elemental Impurities 

Whether it is in food and beverages or drug products, there is increased scrutiny by regulatory agencies and consumers on the presence of elemental impurities. Industries hoping to avoid costly product withdrawals, recalls, and possible litigation is advised to safeguard the quality and safety of food, beverages, and medical products by testing for elemental impurities. AMPAC Analytical has decades of experience and the full array of equipment and methods to ensure our products avoid these worst-case scenarios. Furthermore, these analytical services are accompanied by a devoted customer focus, with communication and guidance at each step to assist with all regulatory and filling requirements. 


  1. https://cen.acs.org/safety/consumer-safety/FDA-seeks-limit-lead-baby 
  2. https://www.nytimes.com/2023/01/26/health/baby-food-metals-lead.html 
  3. https://oversightdemocrats.house.gov/sites/democrats.oversight.house.gov/files/ECP%20Second%20Baby%20Food%20Report%209.29.21%20FINAL.pdf 
  4. https://www.nytimes.com/2023/02/09/well/eat/dark-chocolate-metal-lead.html 
  5. https://www.reuters.com/business/retail-consumer/consumer-reports-urges-dark-chocolate-makers-reduce-lead-cadmium-levels-2023-01-23/ 
  6. https://www.npr.org/2022/12/30/1146254933/hersheys-lawsuit-dark-chocolate-heavy-metals-lead 
  7. https://www.usnews.com/news/health-news/articles/2023-02-08/how-are-toxins-like-lead-arsenic-getting-into-baby-foods 
  8. https://www.consumerreports.org/health/food-safety/lead-and-cadmium-in-dark-chocolate-a8480295550/ 
  9. https://www.usp.org/sites/default/files/usp/document/our-work/chemical-medicines/key-issues/c232-usp-39.pdf 
  10. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/recall-resources 
  11. https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-16.pdf 
  12. https://www.fda.gov/media/148474/download 
  13. https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-32.pdf 
  14. https://www.pharmtech.com/view/approaching-elemental-impurity-analysis 

Resources, Related Topics, and Further Reading