Standard Operating Procedure for Dose Selection Criteria in BA/BE Studies
| Department | BA-BE Studies |
|---|---|
| SOP No. | SOP/BA-BE/005/2025 |
| Supersedes | SOP/BA-BE/005/2022 |
| Page No. | Page 1 of 12 |
| Issue Date | 17/04/2025 |
| Effective Date | 20/04/2025 |
| Review Date | 17/04/2026 |
1. Purpose
To establish a standardized process for selecting the appropriate dose strength for conducting Bioavailability and Bioequivalence (BA/BE) studies in alignment with regulatory guidance, product development goals, and safety considerations for study participants.
2. Scope
This SOP applies to all BA/BE studies involving oral or non-oral dosage forms requiring dose strength selection for regulatory submissions, including USFDA, EMA, CDSCO, TGA, and WHO markets.
3. Responsibilities
- Regulatory Affairs: Identifies regulatory guidance for recommended strength to be studied.
- Clinical Pharmacologist: Evaluates pharmacokinetics and linearity across strengths.
- Medical Writer: Documents the rationale in the protocol and study synopsis.
- Biostatistician: Verifies design suitability and statistical power for selected strength.
4. Accountability
The Head of Clinical Research is accountable for ensuring that dose strength selection is scientifically justified, ethically sound, and appropriately documented in regulatory filings and clinical study protocols.
5. Procedure
5.1 Identification of Available Strengths
- List all proposed marketed strengths of the test product.
- Identify the corresponding strength(s) of the Reference Listed Drug (RLD) or Reference Medicinal Product (RMP).
- Confirm availability of reference strength in the relevant jurisdiction (e.g., Orange Book, EMA register).
5.2 Review of Regulatory Guidance
- Consult country-specific guidelines and product-specific guidance (PSG), if available.
- Follow agency recommendations on whether:
- One strength is sufficient (linear PK, BCS Class I)
- Multiple strengths require BE studies (non-linear PK, NTI drugs)
- For US submissions, refer to FDA’s Draft or Final PSG and 21 CFR 320.25.
5.3 Scientific Considerations for Dose Selection
- Evaluate the following factors:
- Pharmacokinetic linearity across strengths
- Solubility and dissolution profile
- Safety and tolerability in healthy volunteers
- Inter- and intra-subject variability
- Avoid very high doses for safety and very low doses that may challenge assay sensitivity.
5.4 Biopharmaceutics and Ethical Considerations
- Ensure dose selected meets biowaiver eligibility (if applicable) per BCS classification.
- Prefer the highest strength if:
- Formulation is linear
- Proportional composition confirmed
- It allows extrapolation to lower strengths
- Consult ethics committee for dose justification in cases of concern.
5.5 Documentation and Review
- Fill out Dose Selection Justification Form (Annexure-1).
- Include the rationale in the Clinical Study Protocol (Annexure-2) and study synopsis.
- Submit for internal review and archive in eTMF under the “Dose Selection” folder.
6. Abbreviations
- BA: Bioavailability
- BE: Bioequivalence
- PK: Pharmacokinetics
- RLD: Reference Listed Drug
- PSG: Product Specific Guidance
- NTI: Narrow Therapeutic Index
- BCS: Biopharmaceutics Classification System
7. Documents
- Dose Selection Justification Form – Annexure-1
- Excerpt from Protocol Dose Justification Section – Annexure-2
- Agency Guidance Excerpt (if applicable) – Annexure-3
8. References
- USFDA Product Specific Guidance – https://www.accessdata.fda.gov
- EMA Guideline on the Investigation of Bioequivalence
- ICH M9 Biopharmaceutics Classification System-Based Biowaivers
- WHO Technical Report Series 1003 (2021)
9. SOP Version
Version: 2.0
10. Approval Section
| Prepared By | Checked By | Approved By | |
|---|---|---|---|
| Signature | |||
| Date | |||
| Name | |||
| Designation | |||
| Department |
11. Annexures
Annexure-1: Dose Selection Justification Form
| Product Name | ABC Tablet |
|---|---|
| Strength Selected | 100 mg |
| PK Justification | Linear across 25–100 mg |
| Regulatory Reference | USFDA PSG Feb 2023 |
| Safety Notes | Well tolerated at 100 mg |
Annexure-2: Excerpt from Protocol Dose Justification
| Section | 3.1 Rationale for Dose Selection |
|---|---|
| Summary | The 100 mg strength was selected based on linear pharmacokinetics, proportional formulation, and FDA PSG recommendations. |
Annexure-3: Regulatory Guidance Excerpt
| Agency | Document Title | Published | Key Guidance |
|---|---|---|---|
| USFDA | Product Specific Guidance | 12/2023 | Conduct study on highest strength (100 mg) |
Revision History:
| Revision Date | Revision No. | Details | Reason | Approved By |
|---|---|---|---|---|
| 10/01/2022 | 1.0 | Initial SOP Release | New SOP | QA Head |
| 17/04/2025 | 2.0 | Updated for BCS-based biowaiver and annexures added | Annual SOP Review | QA Head |