is effective for brain-targeted action.

Select excipients that enhance nasal absorption and protect the API during transport to the brain. These may include permeation enhancers, mucoadhesive agents, or surfactants.

4.1.2 Weighing and Preparation of Ingredients

• Weigh the API and excipients using a calibrated balance. Ensure precision within ±2% of the target weight and document the weights in the Batch Manufacturing Record (BMR).
• If necessary, prepare a buffer solution to maintain pH within the range of 4.5-7.0, suitable for nasal administration.

4.2 Mixing and Formulation

4.2.1 Preparing the Aqueous Phase

• Dissolve the excipients (such as permeation enhancers and stabilizers) in Water for Injection (WFI) at room temperature (20-25°C).
• Maintain gentle stirring to prevent foam formation while ensuring complete dissolution of the excipients.

4.2.2 Incorporating the Active Ingredient

• Gradually add the API into the aqueous phase under continuous stirring. Ensure the API is fully dissolved or homogeneously dispersed, depending on its solubility.
• If the API requires homogenization, use a high-shear homogenizer to ensure uniform particle size and even distribution throughout the solution.
• Record the mixing parameters, including speed, time, and temperature, in the BMR.

4.2.3 pH Adjustment

• Use a pH meter to measure the pH of the formulation. Adjust the pH as necessary using a buffer solution to ensure compatibility with the nasal cavity.
• Ensure that the final pH is optimal for brain-targeted delivery and falls within the acceptable range (4.5-7.0). Record the pH adjustment in the BMR.

4.3 Filtration and Sterilization

4.3.1 Sterilization of Equipment

• Ensure that all equipment used in the formulation and filling process, including mixing vessels and filling machines, are sterilized using autoclaving or another validated sterilization method.

4.3.2 Filtration of the Formulation

• Filter the nasal spray formulation through a 0.22-micron sterilizing filter to remove any microbial contaminants. Ensure filter integrity throughout the process.
• Document the filtration process and filter integrity test in the BMR.

4.4 Filling and Packaging

4.4.1 Filling Process

• Transfer the sterile nasal spray formulation into a filling machine. Set the machine to dispense the required volume (e.g., 50-100 µL per spray) depending on the dosage form.
• Test the fill accuracy by weighing 10 randomly selected filled units. Ensure that the fill volume variation does not exceed ±5%. Record the results in the BMR.

4.4.2 Sealing and Packaging

• Seal the filled containers with sterile spray nozzles and caps. Ensure that the containers are leak-proof and that the nozzles provide consistent spray patterns suitable for nasal administration.
• Package the nasal spray bottles in labeled containers with batch numbers, expiration dates, and storage instructions. Use secondary packaging that protects the product from environmental factors such as light and humidity.

4.5 Quality Control Testing

4.5.1 Particle Size Analysis

• Conduct particle size analysis of the nasal spray formulation to ensure that it is within the target range for brain-targeted delivery (typically 1-10 microns).
• Record the particle size distribution in the particle size testing log and ensure it meets product specifications.

4.5.2 Permeation Testing

• Perform permeation testing using an in vitro nasal membrane model to assess the drug’s ability to penetrate the nasal epithelium and reach the brain.
• Document the results of the permeation test in the permeation testing log.

4.5.3 Stability Testing

• Conduct stability testing of the nasal spray formulation under different storage conditions (e.g., 25°C/60% RH and 40°C/75% RH) to evaluate the long-term stability of the product.
• Record all stability test results in the stability testing log and ensure the formulation meets stability requirements before release.

4.6 Documentation

• Document all steps of the formulation process, including ingredient weighing, mixing, pH adjustment, filtration, and filling, in the BMR.
• Ensure QA reviews and approves all documentation before the product is released for distribution.

4.7 Equipment Cleaning and Calibration

• Calibrate all equipment used in the preparation and filling process, such as balances, homogenizers, and filling machines, according to the calibration schedule. Record calibration data in the calibration log.
• Clean all equipment according to the cleaning validation protocol after each batch to prevent contamination. Record 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
• Permeation Testing Log
• Stability Testing Log
• Calibration Log
• Cleaning Log

7) References, if any

• ICH Q1A – Stability Testing Guidelines
• 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. Permeation Testing Log Template

Date	Formulation	Permeation (%)	Test Method	Operator Initials	QA Approval
DD/MM/YYYY	Formulation Name	Permeation %	Method	Operator Name	QA Name

3. 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

4. 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

5. Cleaning Log Template

Date	Equipment ID	Cleaning Procedure	Operator Initials	QA Approval
DD/MM/YYYY	Equipment Name/ID	Cleaning Method	Operator Name	QA Name