4.1.2 Weighing of Ingredients

• Weigh APIs and excipients using a calibrated balance, ensuring that the measured quantities fall within ±2% of the target weight. Record the weight in the Batch Manufacturing Record (BMR).

4.2 Mixing and Formulation

4.2.1 Preparing the Aqueous Phase

• Dissolve the excipients (e.g., permeation enhancers, stabilizers, mucoadhesive agents) in Water for Injection (WFI) at room temperature, ensuring all excipients are fully dissolved.
• Stir gently to avoid introducing air bubbles into the formulation.

4.2.2 Incorporating the API

• Add the brain-targeted API to the aqueous phase while stirring continuously. Use a homogenizer or sonicator to ensure uniform dispersion of the API in the solution.
• If necessary, use nanoparticle encapsulation or liposomal carriers to enhance drug delivery efficiency. Record the mixing parameters, such as time, speed, and temperature, in the BMR.

4.2.3 pH and Osmolality Adjustment

• Measure and adjust the pH to fall within the physiological range (pH 5.5-7.0) suitable for nasal administration. Use a calibrated pH meter.
• Check the osmolality of the solution to ensure it is isotonic (280-320 mOsm/kg) for safe nasal administration.
• Record the pH and osmolality adjustment processes in the BMR.

4.3 Filtration and Sterilization

4.3.1 Filtration Process

• Filter the nasal spray formulation through a 0.22-micron sterile filter to remove any microbial contamination.
• Record the filtration process and the filter integrity test results in the BMR.

4.4 Filling and Packaging

4.4.1 Filling Process

• Transfer the sterile formulation to a calibrated filling machine. Ensure that the machine is set to dispense the appropriate volume per spray (e.g., 50 µL or 100 µL).
• Weigh 10 randomly selected filled containers to check fill accuracy, ensuring that the variance is within ±2% of the target volume. Record the results in the BMR.

4.4.2 Sealing and Packaging

• Seal the filled containers with pre-sterilized nasal spray nozzles or caps. Ensure the packaging is secure, leak-proof, and labeled with batch numbers, expiration dates, and instructions for use.
• Package the nasal sprays in secondary packaging with appropriate storage and transportation instructions.

4.5 Quality Control Testing

4.5.1 Drug Release Profile Testing

• Test the in-vitro release profile of the API using an appropriate nasal delivery simulation to confirm that the drug is released in a controlled manner for targeted brain delivery.
• Record the drug release profile data in the release profile log.

4.5.2 Stability Testing

• Conduct stability testing under various environmental conditions to ensure the formulation remains 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, filling, and packaging processes in the BMR.
• Ensure QA reviews and approves all documents before the product is released for distribution.

4.7 Equipment Cleaning and Calibration

4.7.1 Equipment Calibration

• Calibrate all equipment, including balances, pH meters, osmometers, and filling machines, as per the calibration schedule. Record the calibration data in the calibration log.

4.7.2 Cleaning Equipment

• Clean and sterilize all equipment used in the formulation and filling processes according to the cleaning validation protocol. 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)
• Drug Release Profile 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. Drug Release Profile Log Template

  

    
Date
    
Formulation
    
Release Time (hours)
    
Released API (%)
    
Test Method
    
Operator Initials
    
QA Approval
  
  

    
DD/MM/YYYY
    
Formulation Name
    
Time
    
API Released
    
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
    
Procedure
    
Operator Name
    
QA Name