4.1.2 Weighing of Ingredients

• Weigh the API and excipients using a calibrated balance with precision within ±2%. Record all measured quantities in the Batch Manufacturing Record (BMR).

4.2 Mixing and Formulation

4.2.1 Preparing the Aqueous Phase

• Dissolve the pH-sensitive polymer or carrier in Water for Injection (WFI). Adjust the temperature between 20-25°C to ensure proper dissolution of the polymer.
• Maintain gentle stirring to avoid foam formation while ensuring complete dissolution of the polymer.

4.2.2 Incorporating the Active Ingredient

• Slowly add the API to the aqueous phase while continuously stirring. Ensure that the API is homogeneously distributed throughout the solution.
• If necessary, use a homogenizer to create uniform particle distribution within the formulation.
• Record the mixing parameters such as stirring speed, time, and temperature in the BMR.

4.2.3 pH Adjustment

• Measure the pH of the solution using a calibrated pH meter. Adjust the pH using a buffer system, ensuring that the pH is optimal for nasal administration and for achieving pH-dependent drug release.
• Record the pH adjustment process, including the initial and final pH values, in the BMR.

4.3 Filtration and Sterilization

4.3.1 Sterilization of Equipment

• Ensure all equipment used in the mixing, filtration, and filling process is pre-sterilized using validated sterilization methods such as autoclaving.

4.3.2 Filtration of the Formulation

• Filter the nasal spray formulation through a 0.22-micron sterilizing filter to ensure the removal of microbial contaminants.
• Ensure the integrity of the filter is verified before and after filtration, and record this process in the BMR.

4.4 Filling and Packaging

4.4.1 Filling Process

• Transfer the sterile formulation to a filling machine calibrated for the desired volume per spray (e.g., 50 µL or 100 µL per spray).
• Test the fill accuracy by weighing 10 randomly selected filled containers. The variance should not exceed ±5% 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 all containers are leak-proof and labeled with batch numbers, expiration dates, and storage instructions.
• Ensure that the packaging is appropriate for pH-sensitive formulations, such as containers that prevent environmental exposure to factors like humidity or light that could affect pH stability.

4.5 Quality Control Testing

4.5.1 pH Sensitivity Testing

• Test the pH sensitivity of the formulation by exposing it to different pH environments and measuring the release of the active ingredient. Ensure that the release profile matches the product specifications.
• Document the pH sensitivity test results in the pH sensitivity testing log.

4.5.2 Stability Testing

• Conduct stability testing under varying storage conditions (e.g., 25°C/60% RH and 40°C/75% RH) to assess the stability of the pH-sensitive formulation over time.
• Record the results in the stability testing log, ensuring the product remains stable throughout its shelf life.

4.5.3 Microbial Testing

• Perform microbial testing to ensure that the product remains free from contamination. Record the results of sterility and endotoxin testing in the microbial testing log.

4.6 Documentation

• Document all steps of the formulation, mixing, pH adjustment, filtration, and filling processes in the BMR.
• Ensure QA reviews and approves all records before the batch is released for distribution.

4.7 Equipment Cleaning and Calibration

• Calibrate all equipment used in the formulation process, including pH meters, balances, and filling machines, according to the calibration schedule. Record calibration data in the calibration log.
• Follow the cleaning validation protocol to clean and sterilize all equipment after each batch. 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)
• pH Sensitivity Testing Log
• Stability Testing Log
• Microbial 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. pH Sensitivity Testing Log Template

  

    
Date
    
Formulation
    
Tested pH
    
API Release (%)
    
Test Method
    
Operator Initials
    
QA Approval
  
  

    
DD/MM/YYYY
    
Formulation Name
    
Tested pH
    
API Release
    
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. Microbial Testing Log Template

  

    
Date
    
Formulation
    
Microbial Test
    
Results
    
Operator Initials
    
QA Approval
  
  

    
DD/MM/YYYY
    
Formulation Name
    
Microbial Test
    
Results
    
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