4.2 Mixing and Formulation

4.2.1 Mixing the Aqueous Phase

• Prepare the aqueous phase by dissolving excipients such as buffers and stabilizers in water. Use pre-sterilized water for injection (WFI) to ensure sterility.
• Maintain the mixing temperature between 20-25°C to avoid degradation of sensitive ingredients.

4.2.2 Incorporating the Active Ingredient

• Slowly add the API to the aqueous phase while stirring continuously. Ensure that the API dissolves completely and uniformly.
• Use a homogenizer if necessary to ensure even distribution of the API throughout the solution.
• Record the stirring speed, time, and temperature in the BMR.

4.2.3 pH Adjustment

• Adjust the pH of the formulation using pre-approved buffers. Ensure that the final pH is within the specified range (typically pH 4.5-7) for pediatric nasal administration.
• Test the pH and record the results in the BMR.

4.3 Filtration and Sterilization

4.3.1 Filtration Process

• Filter the prepared formulation through a 0.22-micron sterilizing filter to remove any microbial contaminants or particulates.
• Document the filtration process, including the filter integrity test, in the BMR.

4.3.2 Sterilization

• Ensure that all equipment, containers, and closures used in the filling process are pre-sterilized using autoclaving or another validated sterilization method.

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 pediatric dose (e.g., 50 µL per spray).
• Test the fill accuracy by weighing 10 randomly selected filled containers. Ensure that the variation does not exceed ±5% of the target volume.
• Document the fill weight results in the BMR.

4.4.2 Packaging and Labeling

• Seal the containers with sterile nasal 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 child-resistant secondary packaging to ensure safety during storage and handling.

4.5 Quality Control Testing

4.5.1 Microbiological Testing

• Conduct microbiological testing to ensure the pediatric nasal spray is free from microbial contamination. Perform tests such as total microbial count and endotoxin testing.
• Record the results in the microbiological testing log.

4.5.2 Dosage Testing

• Test the dosage accuracy of the nasal spray by dispensing a set number of sprays into a graduated cylinder. Ensure that the dose falls within the specified range for pediatric use.
• Document the dosage test results in the dosage testing log.

4.6 Documentation

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

4.7 Equipment Cleaning and Calibration

• Calibrate all equipment, including balances, homogenizers, and filling machines, according to the calibration schedule. Document the calibration results in the calibration log.
• Clean and sterilize all equipment according to the cleaning validation protocol to prevent cross-contamination between batches.

5) Abbreviations, if any

• API: Active Pharmaceutical Ingredient
• QA: Quality Assurance
• BMR: Batch Manufacturing Record

6) Documents, if any

• Batch Manufacturing Record (BMR)
• Microbiological Testing Log
• Dosage Testing Log
• Calibration Log
• Cleaning Log

7) References, if any

• ICH Q1A – Stability Testing Guidelines
• FDA Guidance for Nasal Drug Products
• Pediatric-specific Regulatory Guidelines

8) SOP Version

Version 1.0

Annexure

1. Microbiological Testing Log Template

  

    
Date
    
Formulation
    
Microbial Test
    
Results
    
Operator Initials
    
QA Approval
  
  

    
DD/MM/YYYY
    
Formulation Name
    
Microbial Test
    
Results
    
Operator Name
    
QA Name
  
  

    
 
    
 
    
 
    
 
    
 
    
 
  

2. Dosage Testing Log Template

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Date
    
Formulation
    
Dosage Volume (µL)
Test Method
    
Operator Initials
    
QA Approval
  
  

    
DD/MM/YYYY
    
Formulation Name
    
Volume
    
Method
    
Operator Name
    
QA Name
  
  

    
 
    
 
    
 
    
 
    
 
    
 
  

3. Calibration Log Template

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Certainly! Below is the SOP for Manufacturing Nasal Sprays for Pediatric Use rewritten:

SOP for Manufacturing Nasal Sprays for Pediatric Use
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Standard Operating Procedure for Manufacturing Nasal Sprays for Pediatric Use
1) Purpose
The purpose of this SOP is to describe the step-by-step process for the preparation, formulation, and packaging of nasal sprays designed specifically for pediatric patients, ensuring safety, proper dosage, and regulatory compliance for this sensitive age group.
2) Scope
This SOP applies to all personnel responsible for the formulation, testing, and packaging of pediatric nasal sprays at [Company Name]. It ensures that formulations meet the pediatric safety and efficacy standards set forth by regulatory bodies.
3) Responsibilities

    
Operators: Responsible for measuring, mixing, and filling ingredients according to pediatric-specific requirements.
    
Quality Assurance (QA): Ensures product meets quality and safety standards, including microbial and chemical stability, before product release.
    
Maintenance Team: Ensures all equipment used in the formulation is sterilized, calibrated, and functioning properly.
4) Procedure
4.1 Preparation of Materials
4.1.1 Selection of Ingredients

    
Choose pediatric-safe active pharmaceutical ingredients (APIs) with known safety and efficacy profiles for this age group.
    
Use excipients that are non-toxic and do not cause irritation in pediatric patients. Preservatives should be minimized or avoided when possible.
4.1.2 Weighing of Ingredients

    
Weigh the API and excipients using a calibrated balance with precision. Ensure the concentration of the API is appropriate for the pediatric population and document it in the Batch Manufacturing Record (BMR).
4.2 Mixing and Formulation
4.2.1 Preparing the Aqueous Phase

    
Mix the excipients such as buffers and stabilizers into Water for Injection (WFI) in a sterile vessel.
    
Maintain the solution at a controlled temperature (20-25°C) to prevent degradation of sensitive ingredients.
4.2.2 Incorporation of API

    
Gradually add the API into the aqueous phase while continuously stirring. Ensure that the API is fully dissolved or dispersed in the formulation.
    
Use a homogenizer if necessary to achieve uniform distribution of the API.
    
Record the mixing parameters such as speed, time, and temperature in the BMR.
4.2.3 pH Adjustment

    
Adjust the pH of the formulation to fall within the acceptable range for nasal administration (typically pH 5.5 - 6.5 for pediatric use) using pre-approved buffers.
    
Record pH adjustments and the final pH in the BMR.
4.3 Sterilization and Filtration
4.3.1 Sterilization of Equipment

    
Ensure that all equipment used in the formulation process is sterilized, including vessels, filling machines, and storage containers. Use autoclaving or other validated sterilization methods.
4.3.2 Filtration

    
Filter the nasal spray solution using a 0.22-micron filter to remove any microbial contaminants. Ensure the filter integrity is maintained throughout the process.
    
Document the filtration process in the BMR, including the filter integrity test.
4.4 Filling and Packaging
4.4.1 Filling the Nasal Spray Containers

    
Transfer the sterile formulation into a filling machine pre-calibrated for pediatric doses (e.g., 50 µL per spray).
    
Test the fill accuracy by randomly selecting and weighing 10 filled containers. The variation must not exceed ±5% of the target dose. Document the results in the BMR.
4.4.2 Sealing and Packaging

    
Seal the filled containers with pre-sterilized nozzles or caps. Inspect for any leaks or defects before proceeding to packaging.
    
Label each container with the appropriate batch number, expiration date, and storage instructions, ensuring child-resistant packaging is used to prevent accidental exposure.
4.5 Quality Control Testing
4.5.1 Microbial Testing

    
Conduct microbial tests, including sterility and endotoxin tests, to ensure the nasal spray meets pediatric safety standards.
    
Record all microbial test results in the microbial testing log.
4.5.2 Dosage Accuracy Testing

    
Perform dosage accuracy tests by dispensing a set number of sprays into a graduated cylinder. Ensure that the dispensed volume is within the accepted range for pediatric dosage.
    
Document the dosage accuracy results in the dosage testing log.
4.6 Documentation

    
Document all formulation steps in the BMR, including ingredient weighing, mixing, pH adjustment, filtration, and filling.
    
QA must review and approve all documents before the batch is released for distribution.
4.7 Equipment Cleaning and Calibration

    
Calibrate equipment such as balances, homogenizers, and filling machines according to the calibration schedule. Document the calibration in the calibration log.
    
Follow the cleaning validation protocol to ensure all equipment is sterilized before and after use, preventing contamination between batches. 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)
    
Microbial Testing Log
    
Dosage Testing Log
    
Calibration Log
    
Cleaning Log
7) References, if any

    
ICH Q1A - Stability Testing Guidelines
    
FDA Guidance for Nasal Drug Products
    
Pediatric-specific Regulatory Guidelines
8) SOP Version
Version 1.0
Annexure
1. Microbial Testing Log Template

  

    
Date
    
Equipment ID
    
Calibration Procedure
    
Calibration Results
    
Operator Initials
    
QA Approval
  
  

    
DD/MM/YYYY




    
    
    

















































































  

    
Date
    
Formulation
    
Microbial Test
    
Results
    
Operator Initials
    
QA Approval
  
  

    
DD/MM/YYYY
    
Formulation Name
    
Microbial Test
    
Results
    
Operator Name
    
QA Name
  
  

    
 
    
 
    
 
    
 
    
 
    
 
  

2. Dosage Testing Log Template

  

    
Date
    
Formulation
    
Dosage Volume (µL)
    
Test Method
    
Operator Initials
    
QA Approval
  
  

    
DD/MM/YYYY
    
Formulation Name
    
Volume
    
Method
    
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