Different Approaches for Drug Product Stress Testing

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Overview of Degradation Products
July 22, 2020
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Following are the different strategies for drug product stress testing:

  1. Existing available literature information can be used to avoid any interaction at the initiation of drug product development. Also, do the literature search to avoid known sensitive compounds.

2. In silico approach using sophisticated instruments with software can be used to understand the interaction of drugs with excipients. Due to this interaction, there are chances of formation of potential impurities and it’s primary and secondary degradation impurities in the presence of different excipients.

3. There are a number of software that are helpful to uses the stress stability results obtained from increased humidity and temperature experiments in order to forecast the long-term stability profile.

4. There are following instantaneous solid-state screening methods with their applications were available:

  • Fourier transformed infrared spectroscopy (FT-IR): It is an analytical technique with rapid and non-destructive measurements of chemical and physical components. It can be obtained used to identify organic, polymeric, and, in some cases, inorganic materials.
  • X-ray powder diffraction (XRPD):  The most common use of X-ray powder diffraction (XRPD) is in the identification and characterization of crystalline solids. This technique is useful for distinguishing between amorphous and crystalline material, ID of different polymorphic forms, Quantification of the percent crystallinity of a sample, for non-ambient structural analysis, for stability studies.
  • Thermogravimetric analysis (TGA): The data obtained in TGA is used to determine temperatures of transitions, reactions, and melting points of substances.
  • Differential scanning calorimetry (DSC): Thermogram obtained from the mixtures of the individual excipients with the pure drug signifies the melting point and endothermic or exothermic peaks corresponding enthalpies could show an interaction or incompatibility.
  • Solid-state NMR (ssNMR): NMR spectra is useful to determine the molecular identity and structure of compounds. It is useful to study the physical, chemical, and biological properties of matter.
  • Isothermal microcalorimetry: It provides thermodynamic and kinetic information on various reactions and processes and thus an important device to elucidate their mechanisms. 
  • Hot-stage microscopy (HSM): It is a powerful technique used to visually examine all kinds of thermal transitions.

5. All the above techniques will not give complete information about the basis of degradation. By using these techniques, we can get a clue towards any physicochemical interaction. Analysis by using HPLC, it is specific, precise, and accurate techniques and its ability to elucidate the structure and determine the quantities of impurities in pharmaceutical formulations. HPLC is especially suitable for compounds that are non-volatile, thermally stable, and have high molecular weights. It is a time-consuming approach that does not often address the real ratio between drug substance and excipients in the final formulation and, therefore, the results obtained can be misinterpreted.

6. An additional characteristic is a factorial design of experiment (DoE) with statistical evaluation of numerous potential mixtures of a standard drug product. The relatively complex results obtained are statistically analyzed and could give a ranking or a selection of the most promising combination of drug substances and excipients in terms of compatibility, even if the interpretation of these results is often quite difficult.

7. Primary excipient compatibility studies of formulation testing stretch the evidence relating to elucidating the interaction of several excipients with the drug substance itself in a finished formulation in terms of any compatibility issues. The composition of formulations is not illogically selected as for binary or multi-compatibility experiments and, therefore, these results are supposed to more representative for the long-term storage stability behavior of drug products. At the time of the manufacturing process, these interims are exposed to certain manufacturing process steps (e.g., milling, sieving, mixing, granulation, and compression), which could have a direct impact in terms of physicochemical transformation.

In the final formulation changes in temperature, pressure, humidity, and interaction with excipient may lead to chemical degradation, change in polymorphic form was not representative.

Sample preparation procedure for analysis is critical, if there is any extraction or solubility issue, this may lead to incomplete recovery of the drug and further risk of formation of any impurities. Hence confirmation of the mass balance is believed to be critical.

Conclusion:

Stress testing of the drug substance is useful to identify the probable degradation products, which will support to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved”

References:

  1. ICH. Harmonised Tripartite Guideline: Stability Testing of New Drug Substances and Products Q1A,
  2. ICH. Harmonised Tripartite Guideline: Photostability Testing of New Drug Substances and Products ICH Q1B,
  3. ICH. Harmonised Tripartite Guideline: Stability Testing for New Dosage Forms ICH Q1C,
  4. International Conferences on Harmonization, Draft Revised Guidance on Impurities in New Drug Substances. Q3A,
  5. International Conference on Harmonisation (ICH). Harmonised Tripartite Guideline: Impurities in New Drug Products Q3B,
  6. International Conferences on Harmonization, Impurities–Guidelines for Residual Solvents. Q3C,
  7. Baertschi, S.W., Alsante, K.M., Reed, R.A. (Eds.). (2011). Pharmaceutical Stress Testing: Predicting Drug Degradation. London, UK: Informa Healthcare.
  8. Beni, Z., Szakacs, Z., Santa, Z. (2015). Computer-assisted structure elucidation in NMR. In Szantay, C. Jr (Ed.), Anthropic Awareness: The human aspects of scientific thinking in NMR spectroscopy and mass spectrometry (pp 317–354). Amsterdam, Netherlands: Elsevier.

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