DEFINITIONS
Extractables are chemical substances that can be extracted from the product using aggressive solvent conditions including acidic, basic, organic and aqueous solvent and sohxlet or accelerated solvent extraction. Extractable studies are typically carried out to create a worst-case scenario and support the substances selection and early risk assessment.
Leachables are chemical substances that can be migrate into the normal pharmaceutical product during the storage conditions during product lifetime. It’s useful to carry out forced or accelerated leachable studies to assess leachables that migrate under simulated environmental conditions by analyzing the drug formulation after exposure to elevated temperatures. However, if the leachable interacts with the drug product or packaging material, new components can be present. These chemicals are called secondary leachables. Drug formulation often contains buffers, surfactants, fillers and other excipients; it results that secondary leachables can only be quantified after long stability studies over the typical drug shelf life.
Extractables and leachables, hence, are not exactly the same panel of substances that can migrate into a drug final formulation. Extractables are often a high number of substances generated by the aggressive extraction applied in the related studies; leachables are normally a lower number and more representative of the real situation. Leachables are normally considered part of the Exctractables (see Figure 1). This should be the ideal situation…. but secondary leachables do not fall under the extractables as generated by other reactions, as said. Secondary Leachables are, therefore, considered and studied as different substances.
In brief we can say that extractables evaluation lead to test the material (packaging for examples); with leachables evaluation one evaluates the product.
E&L REGULATIONS
USA FDA References (US Pharmacopeia)
Two main regulatory references are available:
USP 1663 which essentially describes the “who, what, when, where, why, and how”
of extractables testing including:
• Definitions for the language used when talking about extractables
• Who is responsible for extractables studies
• Functions of extractable studies
• Potential sources of extractables
• Discussion on:
– Choosing extraction media
– Extraction temperatures and times
– Extraction stoichiometry (sample preparation and surface area-to-volume extraction ratios)
Extraction techniques
• The process of characterizing extracts
• Preparing extracts for analysis
USP 1664 which essentially describes the “who, what, when, where, why, and how” of leachables testing including:
• Definitions for the language used when talking about leachables
• Background information on what leachables are and why they matter
• Who is responsible for leachable studies
• Functions of leachable studies
• Safety thresholds
• A lengthy discussion on leachables study design
• Analytical thresholds and their importance in method development
• Possible sample preparations
• Parameters for method validation
• Linking extractable studies to leachable studies
• Considerations for simulation studies
• Inorganic leachables (elemental impurities)
USP 1664.1 is a more recent chapter that addresses specific considerations for leachables in orally inhaled and nasal drug products (OINDP). Though these products contain both drug and device components, they are viewed as drugs from a regulatory perspective. They are considered high-risk dosage forms because of the increased likelihood that the drug product will interact with packaging components (often polymeric).
European Regulation
The requirement for extractables and leachables testing in the European Union was established in EudraLex Volume 4, Chapter 3, which states that pharmaceuticals must be manufactured in a way that “presents minimal risk of causing contamination of materials or products,” and that “…equipment should be constructed so that surfaces …….do not alter the quality of the intermediates and APIs beyond the official or other established specifications.”
The European Medicines Agency (EMEA) provided a more specific guidance document for submitting extractables & leachables data for final container & closure systems called the Guideline on Plastic Immediate Packaging Materials, which was last updated in 2005, and which is similar to the previously-mentioned FDA guidance document.
Other regulations
The International Conference on Harmonization (ICH) drafted guidelines for elemental impurities, which were adopted as law by the FDA and EMEA (along with Switzerland, Japan, and Canada) for all pharmaceuticals in 2017. ICH Q3D established a risk assessment framework for elemental impurities, and includes Permitted Daily Exposure (PDE) levels for each element. ICH Q3D includes a paragraph about analytical methods as well.
THE ANALYTICAL APPROACH
First step for a correct risk assessment is to carry out an analytical determination of extractables to get a wide picture.
A range of analytical techniques are used as follows:
- Volatile organic compounds: Headspace GC-MS
- Semi-volatile organic compounds: GC-MS or high-resolution accurate mass (HRAM) GC-MS
- Non-volatile organic compounds: HRAM LC-MS/MS
- Elemental impurities: ICP-MS
Quantification of E&L compounds is carried out using relative reference standards in which a qualified toxicologist calculates the analytical evaluation threshold (AET) above which and extractable or leachable needs to be reported for a detailed toxicological assessment. Analytical data of these substances is meant to provide information to help companies to determine further studies which are needed to understand and mitigate the risk associated with the final pharmaceutical product.
There is currently no single regulated method prescribed for evaluating extractables and leachables.
In general, the PRODUCT QUALITY RESEARCH INSTITUTE (PQRI, Washington, USA) recommendation document is accepted by authorities and widely used by Industry as primary source to follow. The document was drafted with the involvement of USA FDA. The Product Quality Research Institute Leachables and Extractables Working Group includes pharmaceutical development scientists representing industry, government, and academia. The Working Group was created and constituted to address scientific and regulatory questions concerning the pharmaceutical development process for Orally Inhaled and Nasal Drug Products (OINDP) related to organic extractables and leachables. This effort has resulted in the creation of a detailed “Recommendation Document”, which was submitted to the U.S. FDA for consideration in September 2006. The recommendations include proposed safety and analytical thresholds for leachables and extractables, as well as detailed “best practice” recommendations for various aspects of the OINDP pharmaceutical development process, including materials selection for OINDP container closure system components, Controlled Extraction Studies, Leachables Studies, and Routine Extractables Testing. The Working Group’s processes and the detailed and comprehensive recommendations that resulted from those processes, demonstrate that the Product Quality Research Institute collaborative process can result in consensus science-based and data driven recommendations that could have a positive effect on patient care.
Despite the fact that the PQRI document is the main reference in the E&L world, there are several additional methods (drafts) that can be considered as guidance documents released from industry bodies such as BPOG (BioPhorum Operation Groups) and BPSA (BioProcess Systems Alliance).
THE TOXICOLOGICAL AND RISK ASSESSMENT
The toxicological and risk assessment is carried out on substances (Extractables and/or leachables) which resulted above their analytical evaluation threshold (AET); as said these chemical must be reported for a detailed toxicological and risk assessment. The evaluation is substance based (substance by substance); in few cases it is possible to apply a family group assessment but the similarity within the family must be clearly and scientifically supported.
The assessment consists of the following phases:
- Extensive and robust data search on relevant toxicological effects. In particular the data search is addressed to find data on CMR properties (Carcinogenesis, Mutagenesis and toxicity for reproduction), repeated toxicity with NOAEL, NOEL determination, sensitization end-point. Other relevant information may include: ADME (Adsorption, Distribution, Metabolism and Excretion) data, acute toxicity effects and general human adverse effects including human intake;
- Determination of the critical effects. This means the identification of the most adverse toxicological effect/s;
- Verification of any safe value (e.g. ADI by JECFA: Joint FAO/WHO Expert Committee on Food Additives) already reported in literature;
- Application of predictive approaches such as Q-SAR by two different methods (statistical and rule-based + consensus) when literature data are lacking. The prediction evaluation needs a careful approach to avoid unreliable results;
- Determination of the Safety Threshold for the given substance by application of uncertainty factors and calculation of a PDE (Permissible Daily Exposure) or similar value. The safety threshold is calculated by the following formula:Where:
NOAEL = the value from the selected reference toxicological study
Weight adjustment = a standard body weight of 50 kg should be used for human medicinal products.
α1 = α2 = to be conservative dermal absorption in humans is assumed equal to the absorption after oral intake in the target species.
Safety factors which consider uncertainties in the data:
- F1 = to account for extrapolation between species:
- F2 = to account for variability between individuals
- F3 = to account for the selected toxicological study
- F4 = to account for adverse effects
- F5 = is applied in case the no-effect level could not be established
- Overall Safety Factors calculation
SPECIAL APPROACHES
The application of the TTC approach is adopted in some cases.
The threshold of toxicological concern (TTC) defines a generic exposure threshold value for groups of chemicals below which no appreciable risk to human health exists. The TTC approach is based on the analysis of the toxicological or structural data of a broad range of chemicals and was developed as a substitute for substance-specific information. The concept proposes that such a value can be identified for many chemicals, including those of unknown toxicity, when considering their chemical structures.
The application of the TTC principle provides a method to assess the potential risk to human health based on the following:
- already available data (including chemical structure plus any in vitro, in vivo and/or in silico information),
- information on potential exposure and intake,
- the predicted in vivo toxicity based on chronic toxicity data for compounds that have similar chemical structures.
The TTC principle is used by the European Medicines Evaluation Agency (EMEA) to assess genotoxic impurities in pharmaceutical preparations (EMEA, 2004). The TTC principle has also been endorsed by the WHO International Program on Chemical Safety for the risk assessment of chemicals (IPCS, 1998) and by the EU Scientific Committee on Toxicology, Ecotoxicology and the Environment (Bridges, 2003).
Application of the TTC principle is now commonly extended to other categories of chemical use, such as constituents of cosmetics and consumer products, as well as trace impurities present in regulated compounds/substances, such as food additives, pesticides, and pharmaceuticals E&L. To extend the TTC method to non-oral exposures, appropriate methodologies should be developed to allow for route-to-route extrapolation and to assess combined multi-route exposure. Application of the TTC approach could be used to indicate analytical data needs, based on the levels of an impurity in a product that would result in an intake that was not a health concern (as for example for indirect food additives, as it is used in the United States).
In addition, since the principle is based on safety evaluations relating to daily intake throughout life, the approach could be used to define exposure levels that would be of concern for contaminants and naturally occurring plant constituents, or as a science-based alternative to define concentrations of chemicals in nature as part of the application of the precautionary principle.
Figure 1. E/L world.
