New USP Chapter on oral Dosage Forms

The USP has published the new informative chapter <1664.5> Oral Dosage Forms for comment in the Pharmaceutical Form PF 51(5). The new chapter provides guidance on the assessment of leachables that may migrate from manufacturing or packaging components into oral dosage forms. The new chapter applies to:

• Liquid oral dosage forms (LODFs) such as solutions, suspensions, emulsions and elixirs. These are usually packaged in glass or plastic bottles (multiple doses) with suitable barrier properties. Mixing containers, filtration systems and filling lines, possibly with polymer-containing contact materials (e.g. silicone), are used in the manufacturing process.
• Semi-solid oral dosage forms (SSODFs) such as pastes or gels. These are packaged in plastic laminate tubes or bags with gas and moisture barriers; metal tubes may also be required for volatile components. The manufacturing equipment is comparable to that used for LODFs.
• Solid oral dosage forms (SODFs) such as tablets, capsules, granules and powders. These are typically packaged in HDPE bottles or blister packs with suitable barrier properties and protection from light. Metallic equipment (especially stainless steel) is commonly used in manufacturing, as the majority of the substance being processed is dry. Classic processes include direct compression, granulation and coating.

Regulatory assessment

The regulatory requirements for Extractables and Leachables (E&L) testing for oral dosage forms (ODFs) are based on the risk potential of the respective dosage form and the materials that come into contact with the product.

• For liquid oral dosage forms (LODFs) without surfactants, cosolvents or other extraction-promoting excipients, no separate E&L testing is necessary, provided that the packaging material is covered by regulations - i.e. has already been toxicologically evaluated by the aforementioned regulations. 
• However, if an LODF contains surfactants, co-solvents or solubilising aids, it must be checked whether the resulting extraction power is still covered by the existing regulatory assessment. If not, additional data on extractables - and, if necessary, leachables - are required.
• The following applies to LODFs and SSODFs: If sufficient regulatory coverage cannot be demonstrated, a risk-based assessment must be carried out, including toxicological evaluation and, if necessary, analytical testing.
• For solid oral dosage forms (SODFs) such as tablets and capsules, the risk of interactions with packaging or manufacturing materials is considered to be very low. If the materials comply with applicable regulations such as the FDA Food Contact Regulations (21 CFR Parts 174-186) and the relevant USP chapters (e.g. <661.1>, <661.2>, <665>), they are considered safe. In this case, E&L testing is not required.

Chemical evaluation & limit values

The need for E&L testing depends on the dosage form and intended use of the material (packaging or manufacturing). The USP makes a clear distinction here:

Packaging materials

• No E&L testing is required for SODFs, provided that the packaging material complies with the relevant compendial requirements and FDA regulations for food contact materials.
• For LODFs without leaching-promoting additives, regulatory compliance of the packaging materials is also sufficient; additional testing is not required.
• For LODFs with surfactants, cosolvents or solubilisers, it must be assessed whether the material behaviour is sufficiently taken into account within the framework of the Food Contact Regulations (e.g. with regard to extraction capacity). If this is not the case, extractables tests must be carried out; leachables studies may also be necessary.
• Special feature of nitrosamines: Packaging materials (e.g. blisters with nitrocellulose) can be a source of nitrosamines. A risk-based assessment is therefore necessary. If there is a justified risk, it is recommended that targeted nitrosamine analyses be carried out.

Manufacturing

• E&L testing is also not required for LODFs with metallic parts that come into contact with the product, unless there is reasonable suspicion of elemental contamination (e.g. heavy metals). In this case, an extractables test is sufficient; leachables only need to be tested if threshold values (e.g. >30% of the PDE) are exceeded.
• For LODFs with plastic components in their manufacture (e.g. hoses, seals), an assessment of the leachables risk is required. Only if these components are fully characterised and covered by regulations additional testing can be waived. If not, extractables testing must also be carried out here first, and leachables studies if necessary.
• For SODFs, no E&L testing of the manufacturing systems is required, as the product streams are fixed and metallic contact materials do not usually pose a risk for organic leachables.

Auxiliary devices and dosing aids

Auxiliary devices such as dosing syringes or applicators must be made of known, evaluated materials. If these materials are covered by both compendial and food law requirements, no E&L testing is necessary. Targeted testing is only required in the case of non-standard materials or potential safety risks. The USP emphasises that the contact time between the auxiliary device and the product is crucial.

The new chapter <1664.5> supplements the existing USP chapters on E&L with specific requirements for oral dosage forms. SODFs are classified as particularly low risk, while LODFs with certain excipients may require further evaluation. Chapters <661>, <661.2>, <665>, <1663>, <1664> and <1665> should be used as a reference and methodological basis.

Comments can be submitted until the end of November. The draft of the new chapter is available free of charge on the USP Pharmacopeial Forum website; only a free registration is required.