Perfiles de disolución - Parte 4 - Métodos FDA y NOM-177

Dissolution Profile Calculations: FDA vs. Norma Oficial Mexicana

Key Concepts:

• Dissolution profile
• Efficiency
• Mean dissolution time
• FDA (Food and Drug Administration)
• Norma Oficial Mexicana (NOM)
• COFEPRIS (Comisión Federal para la Protección contra Riesgos Sanitarios)
• Reference product (R)
• Test product (T)
• f1 and f2 tests
• Percentage of dissolved dose

Methodologies: FDA vs. Norma Oficial Mexicana

The video focuses on the differences between the FDA and the Norma Oficial Mexicana (NOM-177) methodologies for dissolution profile calculations, specifically regarding the data points considered for further analysis (f1 and f2 tests). The speaker emphasizes that these are legal requirements, and changes in government or location can lead to modifications.

• FDA (United States): Has its own set of rules for dissolution testing.
• Norma Oficial Mexicana (Mexico): Governed by the Secretaría de Salud in conjunction with COFEPRIS and published in the Diario Oficial de la Federación. It shares similarities with the European Medicines Agency (EMA) guidelines.

The speaker highlights the importance of understanding both methods because a drug might be approved in one country (e.g., the US) but not in the other (e.g., Mexico) due to these methodological differences.

Discarding Data Points: 85% Dissolution Rule

The core concept revolves around the idea that the later time points in a dissolution profile, after a significant portion of the drug has dissolved, are less relevant. Both the FDA and NOM-177 have rules based on the 85% dissolution mark.

• The speaker uses an example of a 200mg drug, arguing that the last few milligrams dissolving after a considerable amount of time might not significantly impact the drug's overall effect in the body.

Norma Oficial Mexicana (NOM-177) Approach

The NOM-177 focuses solely on the reference product (R) to determine which data points to include.

• Process:

  1. Calculate the percentage of the dose dissolved at each time point for both the reference (R) and test (T) products. This is done by dividing the concentration (in milligrams) at each time point by the total dose (200mg in the example) and multiplying by 100.
  2. Identify the time point when the reference product (R) reaches or exceeds 85% dissolution.
  3. Include data up to one additional time point after the reference product (R) has reached 85% dissolution.
  4. Discard all subsequent data points for the f1 and f2 calculations.

• Example:

  • If the reference product (R) reaches 90% dissolution at 25 minutes, the NOM-177 methodology would include data up to the 30-minute time point (one additional time point).

• Quote (from NOM-177): "Calcular el valor de f2 en cada uno de los medios de disolución, comparar los valores promedio desde el primer tiempo de muestreo hasta máximo un tiempo de muestreo después de que el medicamento de referencia ha alcanzado el 85% de fármaco disuelto." (Calculate the value of f2 in each of the dissolution media, compare the average values from the first sampling time up to a maximum of one sampling time after the reference drug has reached 85% of the drug dissolved.)

FDA Approach

The FDA methodology is more stringent, requiring both the reference (R) and test (T) products to reach 85% dissolution before determining the data cutoff.

• Process:

  1. Calculate the percentage of the dose dissolved at each time point for both the reference (R) and test (T) products.
  2. Identify the time point when both the reference (R) and test (T) products have reached or exceeded 85% dissolution.
  3. Include data up to one additional time point after both products have reached 85% dissolution.
  4. Discard all subsequent data points for the f1 and f2 calculations.

• Example:

  • If the reference product (R) reaches 90% dissolution at 25 minutes, but the test product (T) only reaches 91% dissolution at 40 minutes, the FDA methodology would include data up to the 50-minute time point (one additional time point after both have exceeded 85%).

• Quote (from FDA guidance): "Solo se deberá considerar una medición después de la disolución del 85% de ambos productos." (Only one measurement should be considered after the dissolution of 85% of both products.)

Practical Implications and Data Reduction

The video illustrates how these different methodologies lead to different datasets being used for the f1 and f2 calculations. The FDA method typically results in a smaller dataset compared to the NOM-177 method.

• The speaker provides visual examples of how the original dissolution profile is "cut" differently depending on whether the FDA or NOM-177 methodology is applied.

Conclusion

The video concludes by emphasizing that the differences in these methodologies are simply due to different regulatory requirements. The speaker stresses the importance of staying updated on the latest versions of these guidelines, as they can be subject to change. The next video will demonstrate the actual f1 and f2 calculations using these truncated datasets. The main takeaway is that understanding these regulatory nuances is crucial for drug development and approval processes in different countries.