Throughout the production journey from starting materials to storage, and eventual administration to the patient, a drug product will contact manufacturing components including packaging systems, delivery devices and in-use components. These interactions may result in the migration of substances (leachables) from these materials into the drug product.

Assessment of extractable and leachable substances is important to ensure that the overall quality of a drug product (safety, identity, strength and purity) is not impacted. PharmSky have extensive knowledge in extractable and leachable assessments and can provide this service to support your product submission. We provide E&L services from early to late phase product development including:

• Risk assessments on manufacturing process, packaging materials or delivery systems and in-use components.
• E&L strategy and study design
• Extractables studies
• Method development and validation
• Leachables evaluation
• Compound identification

PharmSky is equipped with specialised instruments including UPLC-QToF MS, GC-MS and GC-MS/MS to accurately identify and quantify extractable and leachable substances. We offer customised protocol driven E&L testing services to help ensure that your product meets applicable regulatory requirements and is safe for patient use. Our experienced scientific team has performed E&L studies for various products, and is fully conversant with applicable standards and regulatory requirements. Our expertise includes, but is not limited to:

• Inhalation Products
• Ophthalmics
• Injectables (lyophilised products and parenteral solutions)
• Topicals
• Dermal Patches

Additionally, we have an extensive working knowledge of plasticisers, dyes, polymer species, phthalates, polycyclic aromatic hydrocarbons (PAHs), antioxidants, lubricants and curing agents typically used in the manufacturing of packaging and device components (rubber stoppers, glass vials, syringes, pre-filled syringes, inhalation devices, injectable bags, films, blister packs, large volume containers, plastic bags) as well as in process manufacturing components.

PharmSky can provide a custom extractables and leachables program specific to your product and appropriate to the phase of development. Contact PharmSky for your E&L testing needs.

International regulatory authorities have been investigating the presence of nitrosamine impurities in drug products since 2018. Several drug products including Valsartan, Losartan, Irbesartan, Ranitidine, Nizatidine, Varenicline, Rifampicin, Quinapril and Metformin were recalled from the market due to the presence of unacceptable levels of nitrosamine impurities. The term nitrosamine describes a class of compounds having a nitroso functional group bonded to an amine:

Regulatory guidance for industry has been published by the European Medicines Agency (EMA) in 2019 (Information on Nitrosamines for Marketing Authorization Holders, EMA/428592/2019) and the Food and Drug Administration (FDA) in 2021 (Control of Nitrosamine Impurities in Human Drugs, Revision 1). Recently, the Therapeutic Goods Administration (TGA) updated acceptable intake (AI) information for nitrosamines consistent with the EMA updates.

Therefore, pharmaceutical companies are required to assess the risk of nitrosamine contamination and develop appropriate control strategies to prevent or limit their presence in their drug product.

PharmSky offers nitrosamines assessments per regulatory requirements with services including: 

Risk Assessment – a comprehensive risk evaluation to identify API and/or drug product nitrosamine risk. This includes assessment of API synthesis, excipients, reagents, solvents, water, drug product manufacturing and packaging materials for nitrosamines and nitrosamine precursors (nitrosating agents and secondary/tertiary amines). A risk assessment is required for existing commercial drug products and for any new drug applications.

Confirmatory Testing – if a risk is identified, the presence or absence of the nitrosamine must be determined. PharmSky provides confirmatory testing on drug products to verify the presence or absence of nitrosamines and their amount (if applicable). If any nitrosamine is found above acceptable levels, regulatory authorities should be notified as soon as possible.

Risk Mitigation / Update Marketing Authorisations – If the presence of a nitrosamine is confirmed, corrective actions should be implemented to prevent or reduce risks through submission of a variation. PharmSky provides support on regulatory strategy and required documentation to update the Marketing Authorisation and Dossier and Drug Master File (DMF) information.

3-monochloropropane-1, 2-diol esters (3-MCPDE) and glycidyl esters (GE) are common impurities that form during the oil refinement process. During digestion, 3-MCPDE and GE break down to 3-monochloropropane-1, 2-diol (3-MCPD) and glycidol, respectively, both of which are potentially toxic. The highest concentrations typically occur in refined palm oil and palm olein oil however, 3-MCPDE and GE are also found in other refined vegetable oils (such as safflower, coconut, sunflower, and soybean oils) and refined marine oils (such as fish oils). The wide application of refined oils leads to high potential exposure to these impurities in common foods made from these oils (e.g., mayonnaise, spreads, infant food), and pharmaceuticals (e.g., lipid-based drug products), therefore posing a health risk.

International food safety and regulatory bodies have set tight limits for these impurities. The Food and Drug Administration (FDA) has established provisional tolerable daily intake (TDI) levels for 3-MCPD at 4 μg/kg body weight/day and for glycidol at 2 μg/kg body weight/day. The European Food Safety Authority (EFSA) has set a TDI for 3-MCPD at 2 μg/kg body weight/day and for glycidol at 0.6 μg/kg body weight/day. A higher risk has been identified in younger age groups, especially infants. Of particular concern is infant formula where refined vegetable oils are a major component (20-30% by weight) due to nutritional needs.

In the last decade, there has been a global effort to monitor these impurities. For instance, the FDA has monitored and tested 3-MCPDE and GE in various foods in 2013-2016, 2017-2019, and 2021-2023. Similar surveys were conducted in Europe, Australia and New Zealand on infant formula.

Analysis of MCPDE and GE in product matricescan be extremely complex, involving time-consuming sample extraction, purification, and derivatisation processes, coupled with low detection requirements (e.g. to 0.01 ppm level for infant formula). Given these challenges, method development and validation is typically customised to the product. In addition, calculating and interpreting free and bound 3-MCPD and glycidol is a multifaceted process. PharmSky can provide comprehensive analytical services for these compounds, utilising both internationally recognised methods and unique in-house analytical approaches. Our team offers guidance on method selection, sampling techniques, and assistance in interpreting test outcomes.

Our tailored method development services enable trace-level quantification (LOQ = 10 ppb) of MCPDs and glycidol compounds in various refined oils and complex matrices. At PharmSky, our expertise helps facilitate clients’ development of safe products whilst enabling them to meet regulatory expectations.