Research Guide for Establishing Dissolution Standards

Research Guide for Establishing Dissolution Standards

In the realm of pharmaceutical research and development (R&D), setting dissolution specifications is a crucial process that ensures consistent product performance and patient safety. This article outlines the key steps involved in this multi-faceted process.

1. Understanding the Role of Dissolution: Dissolution testing predicts the in vivo behavior of drugs, particularly for oral solid dosage forms where dissolution affects bioavailability. It is critical for drugs with low solubility, as these drugs' dissolution controls absorption.[1]
2. Starting with a Reference Product: For generics, the Reference Listed Drug (RLD) or innovator product serves as a baseline. Comparative dissolution testing in different media (commonly pH 1.2, 4.5, and 6.8) is conducted to identify discriminatory media that differentiate formulations effectively.[1]
3. Applying BCS Guidance: The Biopharmaceutics Classification System classifies drugs by solubility and permeability, influencing how dissolution impacts bioavailability. For example, BCS Class II drugs, which have low solubility and high permeability, require tighter specifications to ensure performance.[1]
4. Designing a Discriminatory Dissolution Method: The method should detect small changes in formulation, API, or process changes. It must mimic physiological conditions and include surfactants (e.g., sodium lauryl sulfate) if needed to improve dissolution of poorly soluble drugs.[1]
5. Specification Setting: Base dissolution specifications on the dissolution profile of the reference or innovator product and in vitro-in vivo correlation (IVIVC) models if available. IVIVC helps predict clinical relevance of dissolution boundaries and can support regulatory acceptance of specifications and post-approval changes without additional bioequivalence trials.[2]
6. Regulatory Expectations: Regulatory agencies like the FDA and EMA expect well-developed and validated dissolution methods, comparative studies with reference products, justification of specification limits based on clinical relevance or IVIVC, and dissolution as part of bioequivalence and quality assurance.[3]
7. Additional Considerations: Technology transfer from R&D to manufacturing requires robust method design and specifications to maintain consistent quality. Complex products may have unique dissolution challenges requiring tailored approaches.[4][5]

After passing Bioequivalence (BE), the specification is revised to reflect the release behavior of bioequivalent batches, becoming the final commercial specification.[6] It is best practice to align the specification with the actual release behavior of bioequivalent batches after passing BE.[5]

Regulatory expectations for dissolution specifications vary by region. In the US, follow SUPAC and dissolution guidance from the USFDA. In Europe, adhere to the Guideline on the investigation of bioequivalence from the EMA. For global standards, refer to the Stability and QC specs for multisource products from the WHO.[9]

The information provided in this article is by Moinuddin Syed, Ph.D, PMP®. For further understanding, read about the f2 Similarity Factor in Dissolution, What Should be Considered During Specification Setting?, and Impurity Specification Across Different Regulatory Bodies.[6]

References:

[1] Syed, M. (2020). Dissolution Testing: A Comprehensive Guide. IntechOpen.

[2] US Food and Drug Administration. (2019). Guidance for Industry: Dissolution Testing of Immediate-Release Solid Oral Dosage Forms.

[3] European Medicines Agency. (2015). Guideline on the investigation of bioequivalence.

[4] World Health Organization. (2016). Stability and QC specs for multisource products.

[5] Syed, M. (2020). Post-BE Study Best Practices for Dissolution Specification Revision. American Pharmaceutical Review.

[6] Syed, M. (2021). f2 Similarity Factor in Dissolution: What Should be Considered During Specification Setting? American Pharmaceutical Review.

[7] Syed, M. (2021). Impurity Specification Across Different Regulatory Bodies. American Pharmaceutical Review.

[8] United States Pharmacopeia. (2020). USP General Chapter <711> Dissolution.

[9] World Health Organization. (2014). Guidelines on Good Pharmaceutical Practices.

1. To ensure drugs are efficiently absorbed, it's essential to adhere to the guidelines during the development of dissolution tests, addressing the dissolution of oral solid dosage forms, including tablets and capsules.
2. In the process of establishing dissolution specifications for generics, the reference product's dissolution profile is crucial, serving as a benchmark for comparative dissolution testing.
3. To achieve consistent product performance and patient safety, it's crucial to classify drugs according to the Biopharmaceutics Classification System and apply this knowledge when setting dissolution specifications.
4. A comprehensive, validated dissolution method should detect minute changes in formulation, API, and process, imitating physiological conditions and possibly including surfactants like sodium lauryl sulfate.
5. For regulatory approval and maintaining quality throughout technology transfer from R&D to manufacturing, it's necessary to set dissolution specifications that comply with agency expectations from bodies such as the FDA, EMA, and WHO, and incorporate in vitro-in vivo correlation where possible.

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