Standard Operating Procedure for Formulating Nasal Sprays with Hydrophobic APIs
1) Purpose
This SOP outlines the procedures for formulating nasal sprays containing hydrophobic active pharmaceutical ingredients (APIs). Hydrophobic APIs are typically poorly soluble in water and require special formulation techniques to ensure proper dispersion and stability in nasal sprays.
2) Scope
This SOP applies to all personnel involved in the formulation, preparation, and quality control of nasal sprays containing hydrophobic APIs at [Company Name]. It ensures compliance with internal and regulatory standards for nasal drug delivery.
3) Responsibilities
- Operators: Responsible for formulating nasal sprays with hydrophobic APIs, ensuring proper dispersion and stability of the API in the formulation.
- Quality Assurance (QA): Ensures that the final product meets quality control standards, including particle size distribution, stability, and sterility requirements.
- Maintenance Team: Responsible for maintaining and calibrating equipment used in the formulation process.
4) Procedure
4.1 Selection of Ingredients
4.1.1 Hydrophobic API Selection
- Select a hydrophobic active pharmaceutical ingredient (API) that is suitable for nasal delivery. The API should have poor solubility in water but be dispersible in an appropriate solvent or surfactant system for nasal spray formulation.
- Choose excipients such as surfactants, solvents, or emulsifying agents that enhance the stability of the hydrophobic API and prevent aggregation or sedimentation in the formulation.
4.1.2 Weighing and Handling of Ingredients
- Weigh the API and excipients using a calibrated balance. Ensure that all ingredients are weighed to within ±2% of the target weight. Document the measured quantities in the Batch Manufacturing Record (BMR).
- Ensure the formulation area is free from contaminants to prevent cross-contamination during ingredient handling.
4.2 Mixing and Formulation
4.2.1 Preparing the Aqueous Phase
- Dissolve any water-soluble excipients (e.g., buffers and stabilizers) in Water for Injection (WFI). Stir gently to avoid foam formation and ensure complete dissolution.
- Maintain the solution at a controlled temperature (20-25°C) to ensure proper dissolution of the excipients.
4.2.2 Incorporating the Hydrophobic API
- Disperse the hydrophobic API in the aqueous phase using a surfactant or emulsifier. If necessary, use a homogenizer to achieve uniform particle size distribution and stable dispersion.
- Monitor the particle size of the dispersed API using a particle size analyzer. Ensure that the particle size falls within the target range for nasal spray delivery (typically 1-10 microns). Record the mixing parameters in the BMR.
4.2.3 pH and Osmolality Adjustment
- Measure the pH of the formulation using a calibrated pH meter. Adjust the pH using a buffer solution to ensure compatibility with nasal tissue (typically pH 4.5-7).
- Measure the osmolality of the formulation to ensure it is isotonic or within the acceptable range for nasal administration (typically 280-320 mOsm/kg). Record the pH and osmolality values in the BMR.
4.3 Filtration and Sterilization
4.3.1 Sterilization of Equipment
- Sterilize all equipment used in the formulation and filling process using autoclaving or other validated methods. Document the sterilization process in the cleaning log.
4.3.2 Filtration of the Formulation
- Filter the nasal spray formulation through a 0.22-micron filter to remove any microbial contaminants and ensure sterility. Use a low-pressure filtration system to avoid altering the stability of the dispersed API.
- Record the filtration process and filter integrity test in the BMR.
4.4 Filling and Packaging
4.4.1 Filling Process
- Transfer the sterile formulation to a calibrated filling machine. Fill each nasal spray container with the required volume (e.g., 100 µL per spray), ensuring accuracy and consistency.
- Test the fill accuracy by weighing a sample of 10 filled containers. Ensure that the fill accuracy is within ±5% of the target volume. Record the results in the BMR.
4.4.2 Sealing and Packaging
- Seal the filled containers with sterile spray nozzles or caps. Ensure that the containers are leak-proof and properly labeled with batch numbers, expiration dates, and storage instructions.
- Package the nasal sprays in appropriate secondary packaging that protects the product from environmental factors such as light and humidity.
4.5 Quality Control Testing
4.5.1 Particle Size Distribution Testing
- Perform particle size distribution testing using a laser diffraction analyzer or dynamic light scattering to ensure that the API particles are within the desired range (typically 1-10 microns).
- Record the particle size distribution results in the particle size testing log.
4.5.2 Stability Testing
- Conduct stability testing on the nasal spray formulation under different storage conditions (e.g., 25°C/60% RH and 40°C/75% RH). Ensure that the particle size and API dispersion remain stable over time.
- Record the stability test results in the stability testing log.
4.6 Documentation
- Document all steps of the formulation, mixing, pH and osmolality adjustment, filtration, and filling processes in the BMR.
- Ensure QA reviews and approves all documentation before the product is released for distribution.
4.7 Equipment Cleaning and Calibration
4.7.1 Equipment Calibration
- Calibrate all equipment used in the formulation process, including balances, pH meters, and filling machines, according to the calibration schedule. Record the calibration data in the calibration log.
4.7.2 Cleaning Equipment
- Follow the cleaning validation protocol to clean and sterilize all equipment used in the formulation and filling processes. Document the cleaning process in the cleaning log.
5) Abbreviations, if any
- API: Active Pharmaceutical Ingredient
- QA: Quality Assurance
- BMR: Batch Manufacturing Record
- WFI: Water for Injection
6) Documents, if any
- Batch Manufacturing Record (BMR)
- Particle Size Testing Log
- Stability Testing Log
- Calibration Log
- Cleaning Log
7) References, if any
- ICH Q6A – Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products
- FDA Guidance for Nasal Drug Products
8) SOP Version
Version 1.0
Annexure
1. Particle Size Testing Log Template
| Date | Formulation | Particle Size (µm) | Test Method | Operator Initials | QA Approval |
|---|---|---|---|---|---|
| DD/MM/YYYY | Formulation Name | Particle Size | Method | Operator Name | QA Name |
2. Stability Testing Log Template
| Date | Formulation | Storage Conditions | Time Interval | Stability Results | Operator Initials | QA Approval |
|---|---|---|---|---|---|---|
| DD/MM/YYYY | Formulation Name | Temperature and Humidity | 1 month, 3 months, etc. | Pass/Fail | Operator Name | QA Name |
3. Calibration Log Template
| Date | Equipment ID | Calibration Procedure | Calibration Results | Operator Initials | QA Approval |
|---|---|---|---|---|---|
| DD/MM/YYYY | Equipment Name/ID | Procedure | Pass/Fail | Operator Name | QA Name |
4. Cleaning Log Template
| Date | Equipment ID | Cleaning Procedure | Operator Initials | QA Approval | |
|---|---|---|---|---|---|
| DD/MM/YYYY | Equipment Name/ID | Cleaning Method | Operator Name | QA Name | |