SOP for Preparation of Nasal Sprays for Targeted Brain Delivery

Standard Operating Procedure for Preparation of Nasal Sprays for Targeted Brain Delivery

1) Purpose

This SOP outlines the procedure for the formulation, preparation, and testing of nasal sprays designed for targeted drug delivery to the brain. Nasal delivery bypasses the blood-brain barrier, making it an effective route for brain-targeted therapies.

2) Scope

This SOP applies to all personnel involved in the formulation, preparation, testing, and packaging of nasal sprays for brain-targeted delivery at [Company Name]. It ensures compliance with internal and regulatory standards.

3) Responsibilities

Operators: Responsible for accurately preparing, mixing, and filling formulations according to the specifications for targeted brain delivery.
Quality Assurance (QA): Ensures that the nasal spray meets quality, safety, and efficacy standards, particularly concerning drug penetration into the brain.
Maintenance Team: Ensures the cleanliness, sterilization, and calibration of equipment used in the process.

4) Procedure

4.1 Preparation of Ingredients

4.1.1 Selection of Active Ingredient

Choose an active pharmaceutical ingredient (API) that is suitable for brain delivery and has been proven to cross the nasal-brain pathway. Ensure that the API has minimal peripheral distribution and

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

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

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

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

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

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