💊 Uniformity of Dosage Units

Pharma Ph.Eur. 2.9.40

Overview

PHARMACOPOEIA CHAPTER AND HARMONISED TEXTS. Chapter 2.9.40 of the European Pharmacopoeia is harmonised with chapter 6.02 of the Japanese Pharmacopoeia and chapter <905> of the United States Pharmacopeia. ICH guideline Q4B, Annex 6, recognises these three texts as interchangeable in the ICH regions and the acceptance criteria as harmonised — with conditions: mass variation as an alternative to content uniformity is interchangeable only when the 25 mg / 25 % threshold is met; dosage forms marked in the pharmacopoeias as local text are not covered by interchangeability; a correction factor (when the assay of the batch and the uniformity test use different procedures) must be specified and justified in the application dossier. In the European Union the Ph. Eur. monographs are mandatory.

TWO METHODS. Content uniformity: at least 30 units are selected and the content of the active substance is determined in 10 of them, individually, using an appropriate analytical method. For liquid and semi-solid dosage forms, the well-mixed material from an individual container, withdrawn under normal conditions of use, is assayed and the result is expressed as the delivered dose. Mass variation — an alternative permitted at the threshold of 25 mg of active substance and 25 % of the unit mass; Ph. Eur. and the Japanese Pharmacopoeia also have an exception to this threshold at an RSD of not more than 2 %, which the FDA does not accept (in the USA, content uniformity is tested below the threshold).

ACCEPTANCE VALUE (table 6.02-2 of the harmonised text). AV = |M − X̄| + ks, where X̄ — mean content in % of label claim, s — sample standard deviation, k — acceptability constant: 2.4 for n = 10 and 2.0 for n = 30. Reference value M when T ≤ 101.5 %: if 98.5 % ≤ X̄ ≤ 101.5 %, M = X̄ (AV = ks); if X̄ < 98.5 %, M = 98.5 %; if X̄ > 101.5 %, M = 101.5 %. When T > 101.5 %: if 98.5 % ≤ X̄ ≤ T, M = X̄; if X̄ < 98.5 %, M = 98.5 %; if X̄ > T, M = T. T is the target content per unit at the time of manufacture, in % of label claim — unless otherwise stated, 100.0 % or approved by the manufacturer.

CRITERIA. The requirement is met if the AV of the first 10 units does not exceed L1 = 15.0. If it does, the next 20 units are tested; the requirement is met if the AV of all 30 units does not exceed L1 = 15.0 and no individual content is less than (1 − L2 × 0.01)·M or more than (1 + L2 × 0.01)·M, with L2 = 25.0 — i.e. every unit lies between 0.75·M and 1.25·M. L2 is not an AV limit for 30 units.

WHAT WE DO NOT GIVE HERE. The table assigning the method to the dosage form (content uniformity or mass variation), the procedure of the mass variation method and the provisions for dosage forms covered by local text — we have not read this part of the chapter. The assay method (e.g. chromatography) and sample preparation are specified by the product monograph or the application dossier, not by chapter 2.9.40.

Method principle

Uniformity of dosage units is demonstrated by one of two methods: content uniformity — by assaying the active substance in individual units — or mass variation, when the threshold of 25 mg of active substance and 25 % of the unit mass is met. From the results for individual units (in % of label claim) the mean X̄ and the standard deviation s are calculated, and from them the acceptance value AV = |M − X̄| + ks.

The test has two stages: first 10 units (k = 2.4; requirement: AV ≤ 15.0) and, if AV exceeds 15.0, an additional 20 units (k = 2.0 for all 30; requirement: AV ≤ 15.0 and every unit within 0.75·M–1.25·M).

Applications

• Quality control of dosage forms dosed in units — tablets, capsules, liquid and semi-solid forms in single-dose containers — according to the Ph. Eur. monographs and the application dossier
• Choice between content uniformity and mass variation (25 mg / 25 % threshold)
• Application dossiers in the ICH regions — interchangeability of the texts Ph. Eur. 2.9.40, JP 6.02 and USP <905> under the conditions of ICH guideline Q4B, Annex 6

Key parameters

Standard

Standard number

European Pharmacopoeia 2.9.40

Title (PL)

Jednorodność jednostek dawkowania

Title (EN)

Uniformity of dosage units

Step-by-step procedure

1. Choice of method and selection of units

   Establish whether the test is performed by content uniformity or by mass variation (25 mg / 25 % threshold, table of chapter 2.9.40). For content uniformity, select at least 30 units.

2. Assay of 10 units

   Solid dosage forms: assay 10 units individually using an appropriate method. Liquid and semi-solid dosage forms: assay well-mixed material withdrawn from an individual container under normal conditions of use; the result as the delivered dose. When the assay of the batch and the uniformity test use different procedures, a correction factor may be needed.

3. Calculation of AV for 10 units

   X̄ and s from the results in % of label claim; M according to the table (when T ≤ 101.5 %: X̄, 98.5 % or 101.5 %); AV = |M − X̄| + 2.4·s.

4. Evaluation — stage 1

   AV ≤ 15.0 — the requirement is met. AV > 15.0 — proceed to stage 2.

5. Stage 2 — 20 further units

   Assay the next 20 units and calculate AV for 30 units with k = 2.0. The requirement is met if AV ≤ 15.0 and no unit is less than 0.75·M or more than 1.25·M.

Required equipment and apparatus

Reagents, media and consumables

Health and safety (OHS)

• Chapter 2.9.40 gives no safety requirements — the rules for working with the active substance and reagents are set by the laboratory on the basis of the safety data sheets and the monograph

Frequently asked questions