A new plan for Teva api to contribute to the reduction of CO2 emissions by 15% by 2020, compared to our 2012 baseline in TEVA.
Teva api is planning to achieve energy efficiencies through investment in engineering improvements, energy management systems, adopting new technologies, and applying “Energy by Design” principles to seek energy savings in every project.
We continue to consider opportunities to source renewable energy and establish cogeneration or green energy production where possible. As part of these improvements, we are initiating a plan to minimize refrigerants gas leak and eliminate R-22 refrigerant in our equipment.
Reducing emissions:In our Opava factory in the Czech Republic, we made a change that saves more than 3,000 metric tons of greenhouse gas emissions per year. In 2014, we installed a condensing economizer to increase the efficiency and utilization of natural gas, the basic source of energy for the central steam boiler room at the site. Utilizing the condensing heat of water, which is produced during the combustion of natural gas, significantly increases the efficiency of the boilers and reduces our natural gas consumption.
Reducing waste:In our Villanterio site in Italy, we manufacture the active pharmaceutical ingredient allopurinol that is used to prevent the buildup of uric acid in the body to prevent liver or kidney diseases.
The allopurinol process yields different types of waste. Following detailed analysis of the waste streams, we improved the process by segregating process elements, increasing recovery of solvents and installing new equipment. As a result, we increased the yield of active ingredient by 2.4% and reduced the total unrecovered waste generated through this process.
For more information about Teva api’s EHS topics, please contact us.
Making the World’s Drug Supply Safer from Elemental Impurities
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.
We’ve created a series of 3 articles on the topic of elemental impurities and analytical capabilirites – read this intro to the topics to better understand the importance of elemental impurities and high standrds that effect your projects.
This is the first article in a series of 3 articles by Teva api’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.
Teva api takes an industry-leading, proactive approach to benefit customers
When ICH proposed its new guidelines in 2009, Teva apiwas 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, Teva apiR&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 Teva api 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 Teva api 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 Teva apiis 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.
Control of Genotoxic Impurities as a Critical Quality Attribute
For the past few years identification and control of genotoxic impurities in pharmaceutical products has become worldwide one of key issues within development and commercialization of the products. Since some of these impurities may cause mutations and potentially a cancer, there are efforts to avoid and/or keep them to minimal levels to limit the potential carcinogenic risks and so ensure the safety of the products.
Consequently, both drug developers and drug producers including API suppliers are investing vast resources in assessments of potential impurities in their products and in developing analytical methods to determine and control the toxic ones to assure compliance of their products with the relevant health regulations.
Genotoxic impurities in pharmaceutical products
Impurities in pharmaceutical products result from their synthesis and/or subsequent degradation and so their occurrence of the impurities cannot be completely avoided. They are defined as substances that yield no therapeutic benefit, but have the potential to cause adverse effects. Thus, impurity levels in the products must be controlled to ensure their safety. Some of the impurities are genotoxic and may cause deleterious changes in the genetic material of cells. The genotoxic compounds, which have a potential to directly damage DNA through chemical reactions with DNA, even if present at very low levels, leading to mutations and also subsequently potentially cause a cancer, are denominated as DNA-reactive or mutagenic. They may also act as mutagenic carcinogens. Thus, they should be controlled at levels expected to pose negligible carcinogenic risks. These levels are much lower than those for ordinary impurities. Other types of genotoxic compounds that are non-mutagenic (e.g. clastogens) typically have threshold mechanisms and usually do not pose any carcinogenic risks in humans at the level ordinarily present as impurities.
Tackling impurities through regulation
There are several regulatory guidelines focused on controlling impurities in pharmaceutical products. Since the guidelines for the ordinary impurities do not specify any acceptable levels for the genotoxic impurities, regulatory authorities have developed ones specifically addressing the genotoxic impurities: “A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity”, Muller et al., 2006; “Guideline on the limits of genotoxic impurities”, EMA, 2007; “Questions and answers on the Guideline on the limits of genotoxic impurities’”, EMA, 2010; “Guidance for Industry: Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches”, FDA, 2008 “Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic” ICH M7, 2014, and recently published addendum to ICH M7, 2015: “Application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes” (draft).
The purpose of these guidelines is to provide a practical framework that can be applied to the identification, categorization, qualification, and control of genotoxic impurities to limit potential carcinogenic risks.
Toxicological assessments
All actual and potential impurities with known structures that are likely to arise during synthesis and storage of a drug substance and a drug product should be assessed for their genotoxicity by literature searches for carcinogenicity and mutagenicity data. If no data are available, an assessment of Structure-Activity Relationship (SAR) should be performed by a computational toxicology assessment (QSAR -quantitative SAR software using one rule-based system (e.g. DEREK) and one statistical-based system (e.g. Sarah) to identify presence of alterting structures in molecules predicting mutagenicity in bacteria. The impurities are then categorized to Classes 1 – 5 (Müller’s approach). Based on the literature data, known mutagenic carcinogens are classified as Class 1, known mutagens with unknown carcinogenic potential as Class 2 and compounds with sufficient effidence of no mutagenic and carcinogenic effects as Class 5. Compounds with the structural alerts, which are not related to the structure of the drug substance, are classified as Class 3 and those with the structural alerts related to the structure of the drug substance which has been proved to be non-mutagenic, as Class 4. Compounds with no structural alerts are Class 5. The outcomes of the computer programs should be always reviewed by experts to provide additional supportive evidence of the results. Since the bacterial mutagenicity assay is able to detect mutagenic carcinogens in rodents and humans, the positive structural alerts may be overruled by negative results of this assay. Optionally, if there are positive results from the in vitro test in bacteria, their relevance can be further investigated using appropriate in vivo tests.
Risk characterization
Appropriate acceptable intakes must be set for the impurities of Class 1 – 3 while the impurities of Class 4 and 5 are treated as non-mutagenic impurities. In case of Class 1 compound-specific limits can be derived either from their rodent carcinogenic potency, if there are positive carcinogenicity data. or their no-observed effect levels if there is evidence of a practical threshold. The compound-specific acceptable intakes can be also based on recommended values published by internationally recognized bodies (e.g. WHO, US EPA).
To control the genotoxic impurities withoutsufficient toxicological data, i.e. Class 2 and 3 compounds,, a concept of Threshold of Toxicological Concern (TTC) has been proposed. The TTC concept defines an acceptable intake of any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects. This concept takes into account the fact that duration of exposure is a key factor impacting on the probability of a carcinogenic response. A daily intake of a genotoxic impurity at a level of 1.5 μg/day over life-time is considered to be associated with a negligible carcinogenic risk (<10-5). Accordingly, the acceptable cumulative lifetime dose is 38.3 mg (1.5 μg/day x 25,550 days). Then, if there are less-than-lifetime exposures this cumulative lifetime dose is distributed over total number of days during the exposure. The recommended limits for daily intakes of an individual genotoxic impurities are: 1.5, 10, 20 and 120 μg/day for more than 10 years to lifetime, 1-10 years, 1-12 months and less than 1 month, respectively. . However, higher intakes may be justified in some cases, e.g. human exposure is much greater from other sources, indications for severe disease, reduced life expectancy, late onset but chronic disease, or with limited therapeutic alternatives etc.
Options to control genotoxic impurities in APIs
The strategy for monitoring genotoxic impurities is based on product and manufacturing process understanding, and utilizes risk management principles, aimed at ensuring process performance and product quality. The impurity may be then tested in the drug substance or raw or intermediate material at or below the acceptable limit, at an intermediate stage with a higher limit if its fate and purge lead to the levels in the drug substance at or below 30 % of the acceptable limit. If the impurity is effectively purged due to its physico-chemical properties and used manufacturing process, no testing of the impurity is required.
Conclusion
Extensive efforts are being made to control impurities, particularly the DNA-reative ones identified based on the toxicity assessments, to assure the safety of the pharmaceutical products. It means extensive investment in resources which may include the redesigning of the synthetic process to avoid introducing of unsafe impurities and/ormodification of relevant process parameters to remove or reduce such impurities to acceptable carcinogenic risk level, and to take additional considerable measures for controling the impurities at very low concentrations.
Teva api is more than an API provider, we’re your API partner. We are committed to putting our market know-how to work for you.
With more than 400 active pharmaceutical ingredients (APIs) in our portfolio, Teva api is the world’s leading supplier of APIs and we’re proud of our 84-year track record of excellence. Through the years we’ve learned a lot – from the industry, from the global marketplace and from the customers we serve. Today, our accumulated knowledge helps nearly 1,000 customers in more than 100 countries achieve success.
As part of Teva Pharmaceutical Industries, one of the top 10 pharmaceutical companies in the world, Teva api brings tremendous expertise, global experience and resources to support our customers, and our commitment to quality is uncompromising. We adhere to the highest standards in everything we do — from new product sourcing to development and manufacturing to regulatory compliance and product delivery. We take a holistic approach to the customer experience and strive to anticipate customer needs at every touch point. Members of our global sales team know every aspect of their markets, which they share with our customers to help position them for success. The account manager heads up a personalized team of Teva api professionals who provide individualized support to each customer along every step of the customer journey. And, our partnership continues in the commercial phase where we support customers in the ever-changing pharmaceutical industry.
Teva api is always innovating to help our customers stay a step ahead in the marketplace. We make a substantial ongoing investment in R&D to provide a steady flow of new APIs. In 2015 alone, our R&D experts introduced 25 new APIs to the market and our global supply chain supported the launch of 33 new products. Our extensive knowledge of rigorous industry standards and regulatory agencies’ expectations enables us to streamline development time and time to market for our customers.
Teva api has more than 5,000 professionals around the world who are committed to helping our customers succeed. Customers benefit from the experts on Teva api’s IP team, who help them identify and take advantage of market opportunities and are available to assist with patent issues. Likewise, the marketing team shares business and product insights with its attentive understanding of the fast-changing market landscape. Our operations expertise provides the newest thinking and best practices from numerous areas, including Environmental, Health and Safety (EHS), Operational Excellence (OPEX), and more.
Our deep market know-how is unique in the industry and gives customers the confidence and support to launch new products and capitalize on new market opportunities.
For more than 80 years quality has been the cornerstone upon which Teva api is built, ensuring that you consistently receive best-in-class products and services.
Our commitment to quality is uncompromising and we demonstrate it by:
Complying with current Good Manufacturing Practice (GMP) standards
Conducting regular internal and external audits of our manufacturing sites
Undergoing regular inspections by the FDA, other health authorities and Teva api customers. These inspections keep us at high GMP compliance standards at all times.
Implementing continual quality improvement initiatives according to emerging industry trends
Enforcing rigorous end-to-end control. We ensure our suppliers comply with quality regulations and standards through periodic audits of their facilities.
Our high standards mean you get products you can trust.
Teva api downstream processing (DSP) capabilities cover a broad range of products: from antibiotics, statins and immunosuppressant’s to high-potency compounds and enzymes. Our cutting-edge technologies, deep process understanding, and exceptional R&D services meet the most demanding industry standards.
Teva api owns large and modern downstream processing plants harmonized with our fermentation plants. They are highly automated and operated by skilled and experienced professionals who specialize in performing recovery processes required after fermentation.
Our R&D experts are involved in all stages of the product lifecycle to continually improve productivity and product quality for both new compounds and existing products.
Downstream Processing Activities
Our downstream processing activities cover diverse operations including whole broth extraction, vacuum-drum filtration, membrane filtration, evaporation, thin film evaporation, silica gel chromatography, ion-exchange chromatography, adsorption resin chromatography, crystallization, filtration, and drying. A DSP pilot plant and a DSP mini plant advance technology by delivering and implementing new processes across the facility.
Over the years, the Teva api downstream processing (DSP) team has conducted several technology transfer projects that have strengthened our QA, regulatory and other industry-leading competencies. Our R&D, engineering and production teams collaborate closely to ensure we consistently operate efficiently and effectively.
Teva api products, which involve the use of downstream processing expertise, are varied and include API products such as: Mitomycin, Tacrolimus, Caspofungin and more.
Our commitment to quality is uncompromising and we demonstrate it by:
