Stages of Dissolution Acceptance (USP)

In pharmaceutical manufacturing, the effectiveness of a tablet depends entirely on how well it dissolves. Factors like binders, granulation techniques, mixing, and tablet coating can all significantly impact how a drug is released in the body.

The Dissolution Test is the standard laboratory procedure used to verify the release of an active pharmaceutical ingredient (API) from its dosage form.

What is "Q" in Dissolution Testing?

In a dissolution test, the amount of dissolved active ingredient is represented by the symbol "Q".

The value of Q is not universal; it is specified in the individual monograph of a drug (such as USP, BP, or IP) and depends on the nature of the formulation. The test is typically performed using 6 dosage units (tablets or capsules) in the initial stage.

The Three Stages of Dissolution Acceptance (USP)

To provide statistical flexibility while ensuring patient safety, regulatory bodies have established a three-stage testing process: S1, S2, and S3. If a sample fails one stage, it proceeds to the next.

Stage 1: S1 Stage (Initial 6 Units)

In the first stage, six units are tested.

Acceptance Criteria: Each individual unit must not be less than Q + 5%.
Example: If the monograph states $Q = 75\%$ , then every single tablet must show at least $80\%$ dissolution. If any unit fails this, we proceed to S2.

Stage 2: S2 Stage (Additional 6 Units)

Six more units are tested, bringing the total to 12 units.

Acceptance Criteria: 1. The Average of 12 units (S1 + S2) must be greater than or equal to Q.2. No single unit should be less than Q - 15%.
This stage offers flexibility by allowing the average to meet the requirement even if some individual tablets are slightly lower than the target.

Stage 3: S3 Stage (Additional 12 Units)

If the sample fails S2, twelve additional units are tested, totaling 24 units.

Acceptance Criteria:

The Average of 24 units (S1 + S2 + S3) must be greater than or equal to Q.
Only two units can be less than Q - 15%.
No unit should be less than Q - 25%.

Summary of Acceptance Table

Stage	Number Tested	Acceptance Criteria
S1	6	Each unit is not less than Q + 5%
S2	6	Average of 12 units (S1+S2) is ≥ Q; no unit < Q - 15%
S3	12	Average of 24 units ≥ Q; max 2 units < Q-15%; no unit < Q-25%

Why are these Stages Important?

The staged approach is globally recognized by regulatory bodies like the FDA and EMA. It accounts for the inherent variability in pharmaceutical manufacturing.

While the goal is always for a drug to release its active ingredient consistently, factors like particle size distribution or compression force can cause minor outliers. The S1, S2, and S3 stages ensure that a batch isn't unfairly rejected due to minor variations, provided the overall average meets the safety and efficacy standards.