USP published Pharmacopeial Forum (PF) 52(5) on 1 September 2026, with the commenting period running from 2 September through 30 November 2026. Among the proposals in this issue are three developments with potential relevance for pharmaceutical manufacturers, quality units and analytical laboratories, all carrying a proposed official date of 1 December 2027.
The most substantial change is the proposed new general chapter ⟨1664.5⟩ Assessment of Leachables in Oral Drug Products, which introduces a risk-based framework for evaluating leachables from packaging and manufacturing systems used for oral dosage forms. PF 52(5) also proposes a revision to ⟨469⟩ Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances, including a new gas chromatographic Procedure 1B, together with revisions to General Notices sections 2.20 and 5.40 addressing official article terminology and Identification testing.
Importantly, the texts published in Pharmacopeial Forum remain proposals rather than official compendial requirements. They cannot currently be used to demonstrate compliance and may be modified before becoming official.
PF 52(5) at a Glance
| Proposal | Key change | Practical relevance |
|---|---|---|
| ⟨1664.5⟩ Assessment of Leachables in Oral Drug Products | New framework for assessing leachables from packaging and manufacturing systems used for oral dosage forms | Introduces documented food-contact justification as a qualification route and defines when extractables or leachables testing may be required |
| ⟨469⟩ Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances | Adds Procedure 1B using a G16 column and revises the applicability of the existing procedure | May require laboratories to assess method applicability, G16 column readiness and testing strategies for affected ethoxylated excipients |
| General Notices 2.20 and 5.40 | Clarifies formatting of official article names and recognises that Identification tests may provide alternative procedural options | Affects interpretation and future structuring of Identification requirements, while currently specified procedures remain applicable |
USP ⟨1664.5⟩ Assessment of Leachables in Oral Drug Products: New General Chapter Proposed
The proposal replaces an earlier draft. USP states that the proposal published in PF 51(5) has been cancelled on the basis of comments received and replaced with this new proposal rather than a revision of the previous text.
Scope of ⟨1664.5⟩
The chapter covers oral dosage forms (ODFs) as defined and described in ⟨1151⟩:
- Liquid oral dosage forms (LODFs), including solutions, suspensions, emulsions, elixirs and syrups
- Semisolid oral dosage forms and pastes (SSODFs)
- Solid oral dosage forms (SODFs), including tablets, capsules, pills, powders, granules and premixes
Two leachables sources are addressed: the manufacturing system used to produce the dosage form, and the container closure system used to package it over its shelf life. Extractables are considered in the context of leachables, as potential leachables. The chapter addresses organic leachables and directs elemental leachables to ICH Q3D.
Oral dosage forms are categorised as a low-risk dosage form for leachables under ⟨1664⟩, Table 1, based on the route of administration and the low probability of packaging component interaction with the formulation.
The chapter restates the position taken in the FDA guidance Container Closure Systems for Packaging Human Drugs and Biologics (May 1999), that patient exposure to leachables in oral dosage forms is comparable to exposure from food packaging and lower in quantity, because the amount of medicine taken is smaller than the amount of food consumed.
Packaging System Requirements for Oral Dosage Forms
A packaging system, or all of its relevant materials of construction, is considered well characterised where:
- It complies with the relevant compendial monographs, including ⟨660⟩ for glass components and ⟨661⟩, ⟨661.1⟩ and ⟨661.2⟩ for plastic components
- It complies with the relevant food contact safety regulations and the use conditions specified therein, for example 21 CFR 174 to 186
- Compliance is adequately justified, including consistency of the proposed use with the food contact regulation, comparison of the leaching propensity of the dosage form against the extraction solvents cited in that regulation, and satisfaction of all specified acceptance criteria
The testing consequences are set out by dosage form:
- SODFs. No additional extractables or leachables testing is required. Fillers, desiccants and other absorbent materials placed in the bottle with the dosage form must also be well characterised.
- Aqueous LODFs containing surfactants, cosolvents or solubilisers. No additional testing is required where the leaching propensity of the formulation is adequately addressed by the extraction solvents used in the cited CFR indirect food regulations. Where it is not, extractables testing is required.
- Extractables outcome. Where all extractables peaks are at or below the analytical evaluation threshold (AET), and no Class 1 substances as defined by ICH Q3E are detected, the leachables risk may be considered minimal and acceptable, and leachables testing is not required.
⟨1663⟩ and ⟨1664⟩ are cited for the design and implementation of any required studies. The chapter states that consultation with the relevant regulatory agency or health authority before implementation may be warranted.
See Also: Types of Pharmaceutical Packaging in GMP
Manufacturing System Requirements for Oral Dosage Forms
The chapter positions orally administered products as fitting the description of traditional or small molecule products in ⟨665⟩, and treats the low-risk dosage form classification as triggering a risk mitigation factor under ⟨1665⟩. The following positions are set out:
- Metallic components require no qualification for organic substances, as they are not a source of organic extractables or leachables. The risk of elemental impurity leaching must be assessed. A high-risk conclusion must be followed by extractables or leachables testing. Where extractables testing does not reveal elements above the applicable control threshold, given as 30 percent of the permissible daily exposure under ICH Q3D(R2), leachables testing of the manufactured product is not required.
- Plastic components used for SODF manufacture require no additional extractables or leachables testing, on the basis that the ability of a solid process stream to leach substances from manufacturing components is low.
- Plastic components used for LODF manufacture may be considered qualified without testing where the components comply with relevant regional food contact safety regulations, the manufacturing process conditions are consistent with the testing performed to establish that compliance, and the leaching propensity of the product does not exceed that identified in the food contact regulation. Where these criteria are not met, extractables testing applies, with the same AET and Class 1 decision logic, and the semi-quantitative extraction method must be qualified consistently with ⟨1663⟩ and ⟨1664⟩.
- Where the active ingredient in an oral dosage form is a biologic, extractables testing of polymeric manufacturing components should be considered under ⟨665⟩ and ⟨1665⟩.
The chapter also notes that processing temperatures for semisolid oral dosage forms are typically higher than for liquids or solids, and that these temperatures can increase the risk of leachables from polymeric processing components.
Nitrosamine Risk Assessment for Oral Drug Product Packaging
The chapter identifies certain packaging systems as potential nitrosamine sources, citing the use of nitrocellulose in blister lidding foil. Packaging systems for oral dosage forms are to be risk assessed as potential nitrosamine sources in accordance with the FDA guidance Control of Nitrosamine Impurities in Human Drugs, Revision 2, September 2024.
Where a low risk of nitrosamines leaching from packaging cannot be established from existing information, nitrosamine testing of controlled extracts or of the packaged product is recommended.
Auxiliary Dispensing Devices for Liquid Oral Dosage Forms
Oral syringes, dosing cups, dropper bottles and pump dispensers are identified as potential leachables sources despite transient contact with the product. Materials of construction must comply with the relevant compendia. Extraction studies may be required on a case-by-case basis, and where materials are well characterised, including compliance with food contact safety regulations, extractables and leachables studies may not be required.
Leachables testing is limited to targeted assessment of a specific extractable already shown to present a potential patient safety risk. Consultation with the relevant regulatory agency or health authority before eliminating extractables testing may be warranted.
USP ⟨469⟩ Ethylene Glycol, Diethylene Glycol and Triethylene Glycol in Ethoxylated Substances: Procedure 1B Added
The proposal is based on the version of the chapter officially published as of 1 December 2014. USP identifies ethylene glycol and diethylene glycol contamination in high-risk excipients as a public health issue dating from 1937, and cites a letter from FDA dated 10 February 2023 as the trigger for the current programme of revisions. Two proposals preceded this one:
- PF 50(5) proposed a new general chapter, ⟨470⟩ Determination of Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Polyethylene Glycol, addressing contamination risk in polyethylene glycol
- PF 51(3) proposed revising the Polyethylene Glycol 40 Castor Oil monograph to include a validated ethylene glycol and diethylene glycol test and move it into the Identification section. That revision was published by Interim Revision Announcement and became official on 1 January 2026.
USP states that the current proposal responds to multiple further requests to revise the glycol test in ethoxylated excipients.
What Changes in ⟨469⟩
- Procedure 1B is added. The new procedure uses a G16 column and is described as employing more user-friendly conditions. For Polyethylene Glycol 40 Castor Oil, Procedure 1B is stated to be suitable for the Identification test, as requested by FDA.
- The existing procedure is relabelled Procedure 1A and its list of applicable substances is revised. Polyoxyl 60 hydrogenated castor oil is added to that list.
- Editorial changes align the chapter with current USP style.
USP states that additional monographs will be updated as further ethoxylated substances are validated using the new method.
The chapter text lists Procedure 1B as suitable for polyethylene glycol 40 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, and polyoxyl 15 hydroxystearate. The briefing narrative lists polyethylene glycol 40 castor oil twice and does not name polyoxyl 40 hydrogenated castor oil. Users should verify the applicability list with USP before relying on it for planning purposes.
Procedure 1A and Procedure 1B Compared
| Parameter | Procedure 1A | Procedure 1B |
|---|---|---|
| Column phase | G3, 0.53 mm x 30 m, 1.0 µm film | G16 fused silica, 0.53 mm x 30 m, 1.0 µm film |
| Injection port / detector | 270° / 290° | 250° / 250° |
| Oven programme | 40° to 280°, three ramps | 80° to 230°, two ramps |
| Carrier gas flow | Helium, 5.0 mL/min | Helium, constant flow, 8.0 mL/min |
| Injection | Split, 2:1 | Split, 2:1 |
| Sample solution | 40 mg/mL | 20 mg/mL |
| Standard, ethylene glycol | 25 µg/mL | 12.4 µg/mL |
| Run time | 26 min standard; 86 min sample and diluent | 40 min |
| Sensitivity solution | Not specified | 1.2 µg/mL, signal to noise NLT 10 |
| Ethylene glycol RRT | 0.45 | 0.83 |
Procedure 1A requires an 86 minute run for the sample solution and diluent, including a 60 minute hold at 280 degrees. Procedure 1B completes in 40 minutes at a lower maximum oven temperature and half the sample loading.
Under the G16 phase, ethylene glycol elutes at a relative retention time of 0.83 against 1.00 for the butane-1,3-diol internal standard, compared with 0.45 under Procedure 1A. Procedure 1B introduces a sensitivity solution and a signal to noise requirement of not less than 10 for each of the four peaks, which Procedure 1A does not contain.
Resolution, tailing factor and relative standard deviation requirements are the same in both procedures: resolution not less than 20 between adjacent peaks, tailing factor 0.8 to 1.8, and relative standard deviation not more than 5.0 percent for the peak response ratio to the internal standard.
Both procedures use the same reference standards: USP Butane-1,3-diol RS, USP Diethylene Glycol RS, USP Ethylene Glycol RS and USP Triethylene Glycol RS.
USP General Notices Revision: Sections 2.20 and 5.40
USP describes the proposal as the first in an intended series to modernise and revise the General Notices for additional clarity. It is based on the version official as of 1 August 2025 and contains two substantive revisions together with editorial alignment to current USP style.
Section 2.20 Official Articles
The revision formalises the general practice of using initial capital letters when referencing an official article, with Acetaminophen Oral Solution given as the example. USP states the intent is to clarify the distinction between references to official articles, generally formatted with initial capital letters, and references to chemical names or active moieties of substances contained in official articles, generally formatted in lowercase.
Section 5.40 Identification
The revision:
- Retains the requirement that all requirements of specified procedures under the Identification test must be met
- Removes the word “all” before “specified procedures” in two places
- Adds language recognising that Identification tests may include more than one option for procedures for meeting the requirements of the test
- Is stated by USP to encourage future acceptance of advanced technologies for confirming the identity of an article
The provision that failure to meet the requirements of the specified procedures indicates that the article is mislabelled, adulterated, or both, is retained.
Commenting on PF 52(5)
Comments on all three proposals are submitted through the USP Pharmacopeial Forum commenting platform. The window closes on 30 November 2026. Contacts listed in the auxiliary information are Ravikiran Kaja for ⟨1664.5⟩, Documentary Standards Support for ⟨469⟩, and Elena Gonikberg for the General Notices, with the responsible expert committees being Packaging and Distribution, Excipient Chapters, and the Council of Experts, respectively.
Summary
PF 52(5) proposes a new informational chapter setting out how leachables are assessed for oral dosage forms, a second and shorter gas chromatographic procedure for glycol impurities in ethoxylated excipients, and the first of a planned series of General Notices revisions.
⟨1664.5⟩ establishes compendial and food contact compliance, with documented justification, as the qualification route for oral product packaging and manufacturing systems, with extractables testing reserved for cases where that route does not apply.
The ⟨469⟩ revision adds Procedure 1B for four ethoxylated substances and expands the Procedure 1A applicability list. The General Notices revision formalises capitalisation of official article titles and recognises that Identification tests may offer more than one procedural option. All three proposals carry a proposed official date of 1 December 2027.
