SOP for Developing pH-Sensitive Nasal Sprays

Standard Operating Procedure for Developing pH-Sensitive Nasal Sprays

1) Purpose

This SOP outlines the procedures for developing and preparing pH-sensitive nasal sprays. These sprays are designed to deliver active pharmaceutical ingredients (APIs) that release or activate based on the pH levels in the nasal cavity, enhancing therapeutic outcomes.

2) Scope

This SOP applies to all personnel involved in the formulation, testing, and packaging of pH-sensitive nasal sprays at [Company Name]. It ensures compliance with internal and regulatory standards, focusing on pH-dependent drug release formulations.

3) Responsibilities

Operators: Responsible for weighing, mixing, and filling formulations according to pH-sensitive specifications.
Quality Assurance (QA): Ensures that the final product meets quality control standards for pH sensitivity, including release testing and stability.
Maintenance Team: Responsible for cleaning and calibrating the equipment used for production.

4) Procedure

4.1 Selection of Ingredients

4.1.1 Active Ingredient Selection

Select active pharmaceutical ingredients (APIs) that are suitable for pH-sensitive release. These APIs should exhibit stability within a specific pH range and release the active drug upon encountering nasal pH (approximately pH 5.5 to 7.5).
Select excipients such as pH-sensitive polymers or carriers (e.g., chitosan, carbopol, or Eudragit) that can modify drug release depending on the nasal pH environment.

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

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

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

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

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