The approval of Rybelsus®, which contains the GLP-1 agonist, semaglutide, by the EMA in April 20201 is of special interest because, unlike other biologics that are mostly parenterally administered, it was formulated as an immediate release tablet for oral administration. It is likely that this product may also be registered by the SAHPRA in the very near future. Being a tablet, makes it subject to release and shelf-life specifications associated with the quality control (QC) of pharmaceutical preparations such as dissolution, hardness, disintegration, friability, etc. Dissolution is a critical quality attribute for all solid oral dosage forms as the rate at which the active substance is released and goes into solution in the gastrointestinal fluid determines the amount of the dose that is absorbed, i.e., its bioavailability and, thus, its efficacy.
Semaglutide is a peptide composed of only 31 amino acids; hence, it can be manufactured by total chemical synthesis. As a synthetic drug, semaglutide would be classified as a pharmaceutical substance or active ingredient. It should be noted, however, that the semaglutide used in the development of Rybelsus®, was produced using recombinant DNA technology1, which according to the definition of a biologic in the SAHPRA’s biosimilar guideline2, would be regarded as a biologic.
There are obvious advantages for companies to register copies of Rybelsus® as generics once its patent has expired (between 2029 and 2034 depending on the jurisdiction). This is because a comparative efficacy trial would not be necessary, and the requirement for an extensive comparability report in which the candidate generic is compared with the reference listed drug (RLD) on a physical, chemical, and biological level, would likely also be waived.
For the registration of generics, the biobatch is of pivotal importance as it is the batch of the generic product that was shown to be bioequivalent in a bioequivalence study against the RLD. Consequently, the dissolution profile of the biobatch is used to set dissolution specifications for the generic product to ensure that all commercial scale batches of the generic will exhibit the same dissolution characteristics as the RLD. It is important to remember that the biobatch is a living batch against which all subsequent changes to the product must be validated to ensure batch-to-batch consistency of future batches with the biobatch. Another important point is that the relationship with the biobatch should be guaranteed throughout the shelf life of the finished product. A wider shelf-life dissolution limit is, therefore, not acceptable if a decreasing trend in dissolution is seen from stability data.
The acceptance criterion for a dissolution specification is defined by a Q value, which is the average quantity of active substance dissolved at a given time point. The Q value is usually set in the range of 75 % to 85 % (5 % intervals) to demonstrate discriminatory power between acceptable and nonacceptable batches. A limit greater than 85 % is not relevant (as 85 % represent rapid dissolution if the timepoint is 30 min or less). Usually timepoints of 15, 30, and 45 min are sufficient, although other timepoints may be acceptable if adequately justified. Timepoints less than 15 minutes are not considered relevant as the variability in results will be high.
The USP and EP define three stages (S1, S2, and S3) for setting specifications for dissolution testing. A typical acceptance criterion for an immediate release tablet is 80 % (Q) in 30 min, and using this as an example, the three stages can be interpreted as indicated in the Table below.
Interpretation (acceptance criteria expressed as Q), e.g.,
NLT 80 % (Q) of labelled amount is dissolved in 30 minutes.
Batch results showing compliance with stage S1, S2 and S3 (Ph. Eur. 2.9.3.) are acceptable. The specification should be set in such a way so that during routine manufacture and testing it would be expected that compliance with S2 is attained.
As stated earlier, acceptance criteria for setting QC dissolution specifications for batch release and stability testing are derived from the biobatch profile data. The average of 12 units (tablets) are calculated (no decimals) at timepoints of either 15, 20, 30, 45, or 60 minutes. The actual timepoint selected is the one where the relative standard deviation (RSD) is less or equal to 10 %. Below is a stepwise procedure that can be followed for setting QC dissolution limits3.
- Find the first timepoint in the profile where mean release is ≥ 85 %
- Set this time = T
- The RSD at T must be ≤ 10 %
− If not, consider the next time point as T
- Subtract 10% from the mean value at time point, T
- Round the result to the closer of 75 % or 80 % = V%
- Suggested limit is NLT V % (Q) at time, T
- Acceptance criterion:
NLT 75% (Q) or NLT 80 % (Q) after 15 or 20 or 30 or 45 min
As an example, consider the percentage API released from each of 12 tablets at 5 min intervals over a period of 45 minutes.
The timepoint where the mean value is at least 85 % is at 15 min. Since the RSD is 2 (i.e., < 10%), T = 15 min. If 10% is deducted from the mean value at this timepoint, we have 85 – 10 = 75 %, which is V. Thus, the dissolution limit is NLT 75 % (Q) at 15 min.
Readers may wonder why a value of 10 % is deducted from the average dissolved quantity to obtain the Q-value. This is because similar dissolution of two batches may be assumed in case of a difference of less than 10 % of the label claim (of the active ingredient) in their mean results3.
For relatively fast dissolving immediate-release products, one timepoint is usually adequate as in the above example. In the case of “slower” dissolving immediate-release tablets or capsules, a second timepoint may be warranted, e.g., 55 % (Q) in 45 min plus 80 % (Q) in 90 min.
Finally, readers are referred to Decision Tree #7 of ICH 6A (reproduced below), for setting acceptance criteria for drug product dissolution.
- European Medicines Agency. Assessment report. Rybelsus. 30 January 2020. EMA/95374/2020. https://www.ema.europa.eu/en/documents/assessment-report/rybelsus-epar-public-assessment-report_en.pdf.
- Biosimilar Medicines: Quality, Non-clinical and Clinical requirements. August 2014. https://www.sahpra.org.za/wp-content/uploads/2020/08/SAHPRA-BIOSIMILARS-MEDICINES-GUIDANCE.pdf.
- European Medicines Agency. Reflection paper on the dissolution specification for generic solid oral immediate release products with systemic action. 10 August 2017. Reflection paper on the dissolution specification for generic solid oral immediate release products with systemic action (europa.eu)