Making the World’s Drug Supply Safer from Elemental Impurities
By Mislav Runje, Associate Director, R&D, TAPI Analytics
This is the first article in a series of 3 articles by TAPI's Analytical capabilities experts, make sure to follow up on the other 2 articles to have a full reveiw of this topic
When consumers reach for a prescription drug, over-the-counter medicine or dietary supplement, the ingredients in the final dosage form may have been sourced from more than one country. In the United States alone, the FDA estimates that 80 percent of active pharmaceutical ingredients (APIs) used by US drug manufacturers came from other countries. Of all drug products that Americans take, an estimated 40 percent were manufactured internationally1. Because pharmaceutical production is a global industry and growing, regulators will soon be requiring API suppliers and drug manufacturers to meet new universal standards in general, including specific standards for elemental impurities to help ensure drug products are safe, regardless of where they are made.
What are elemental impurities?
Controlling elemental impurities has recently become one of the fastest growing areas in pharmaceutical R&D. Elemental impurities are certain chemical elements that yield no therapeutic benefits and have the potential to harm patients, so they must be tightly controlled to ensure safety. There are several ways elemental impurities can end up in the final drug product:
- from elements that are naturally occurring in the drug substance (APIs)
- from excipients (binders, preservatives, flavors)
- by being inadvertently introduced during the manufacturing process (byproducts from production equipment or impurities in the water used for wet granulation)
- during the product’s synthesis (residual catalysts added intentionally in chemical reactions)
- from container/closure systems (packaging)
If pharmaceutical companies’ manufacturing processes and packaging remain the same, then APIs and excipients would be the most likely sources of elemental impurities.
New standards tighten controls
To protect public health and the world’s drug supply, API suppliers and drug manufacturers are required to follow standards that cover the chemical and physical properties of drug substances, excipients and final drug products, and regulations that control elemental impurities. Two of the most authoritative industry standards have recently been updated: the Guideline for Elemental Impurities Q3D issued by the International Council for Harmonisation (ICH) and two General Chapters in the United States Pharmacopeia (USP) that govern limits and testing procedures for elemental impurities. In Europe, ICH guidelines for products already on the market take effect in December 2017; new guidelines are already in effect for companies applying for new marketing authorizations. In the US, the new USP standards are in effect now for new product authorizations; implementation for existing products with monographs will take effect January 1, 2018.
The revisions were set in motion in 2008, when the United States Pharmacopeial Convention decided its limits on elemental impurities should be updated based on the most current scientific data. It also concluded that testing by colorimetric analysis should be replaced by more sophisticated analytical procedures that can better detect trace impurities: inductively coupled plasma – atomic (optical) emission spectroscopy (ICP-AES or -OES) or mass spectroscopy (ICP-MS).
The following year, the ICH proposed new guidelines for finished drug products and set Permitted Daily Exposure (PDE) standards for each element of toxicological concern. In order to establish safe PDEs, the ICH factored in:
- the likely oxidation state of the element in the drug product
- human exposure and safety data, when it provided applicable information
- the most relevant animal studies
- routes of administration: oral, parenteral or inhalation
- the relevant endpoint(s)
The ICH also concluded that levels of elemental impurities could exceed an established PDE under certain circumstances including: intermittent or short term dosing, and for specific indications such as life-threatening or unmet medical needs, or for the treatment for rare diseases. In 2014, the USP aligned its directives and timetable with the Q3D step 4 requirements to streamline compliance for drug manufacturers.
Risk assessment safeguards quality and safety
ICH Q3D recommends using a risk-based approach to assess the potential presence of elemental impurities in drug products. Although the guidelines are intended for manufacturers of finished products, the risk assessment will impact all phases of the product lifecycle.
Q3D categorizes elemental impurities in three primary classifications based on their toxicity in terms of PDEs and the likelihood of their occurrence in the finished drug product:
- Class 1 (As, Cd, Hg and Pb): significantly toxic across all administration routes and have limited or no use in pharmaceutical manufacturing.
- Class 2: toxicity based on administration route
- Class 2A: Relatively high probability of toxicity based on administration route
- Class 2B: Relatively low probability of toxicity based on administration route
- Class 3: Relatively low toxicity (high PDEs) by the oral route of administration, but may require consideration in the risk assessment for the inhalation and parenteral routes
To simplify calculations and prevent mistakes, the ICH provided a table within Q3D listing allowable concentrations of elemental impurities for drug products with daily doses of 10 grams per day or less.
TAPI takes an industry-leading, proactive approach to benefit customers
When ICH proposed its new guidelines in 2009, TAPI was among the first to develop what we consider to be an industry-leading strategy and implementation plan so the products we supply to our customers would fully comply with the future regulations. As soon as the new requirements were announced, we took action in an effort to ensure our customers would be able meet the ICH and USP’s new standards on time. Eight years ago, TAPI R&D and Quality experts began enhancing our analytical services by reviewing our current processes for testing and controlling elemental impurities. We installed what could be considered the best analytical instruments on the market and ensured our top experts had the latest information so they could help guide our customers. Over time, we have implemented several significant changes in the ways we identify, control and document elemental impurities in all of our products:
- In 2009 we began using our first ICP-OES in Zagreb to detect the presence of metals in cases where traditional USP analytical methods were insufficient. The following year we developed the methodology for screening elemental impurities, using ICP-OES and ICP-MS to resolve issues as might be identified by regulatory authorities.
- Between 2011 and 2014, we established a risk assessment protocol for elemental impurities and tested all TAPI products using the new USP standards and ICH Q3D guidelines.
- In 2015 and 2016, we validated and finalized our analytical methods according to the new ICH Q3D directives.
- We have invested in state-of-the-art instrumentation – ICP-MS, ICP-OES and X-Ray Fluorescence (XRF) – in three TAPI labs, providing support by region. In the years since our first ICP-OES came on line in Zagreb, we have built a network of three major ICP centers, capable of performing analyses requested by regulatory authorities.
- Our R&D researchers and QC analysts have received extensive training on the standards, technology and methodology, and share their industry-leading expertise with customers.
- In 2017, our research team will start to develop well-defined process to test and evaluate new speciation.
For more than 80 years, quality has been the foundation upon which TAPI is built. We use the most technologically advanced equipment available and have some of the industry’s most knowledgeable experts across multiple analytical fields to support our customers. We are committed to continuous improvement to meet changing industry standards and will always strive to deliver products our customers can trust. In the months ahead, we will work closely with our customers in an effort to ensure that their drug products meet the new guidelines and continue to safely treat patients around the world.
Mislav Runje is Associate Director of R&D for TAPI Analytics, with more than 10 years of experience in analytical development, especially in trace analysis.