Introduction
In the pharmaceutical industry, it is not enough to simply test the final product. It must also be ensured that manufacturing processes consistently produce products of the required quality. This assurance is achieved through a systematic approach known as validation. Validation provides documented evidence that a process, equipment or activity will reliably give the expected results every time.
Validation includes various activities such as equipment qualification, facility validation, cleaning validation, process validation, analytical method validation, packaging validation and cold chain validation. Regulatory agencies like the US FDA require proper validation as part of Good Manufacturing Practices.
What Is Validation?
Validation is the process of establishing documented proof that a process or system performs as intended and consistently delivers products meeting predetermined specifications.
Process validation involves collecting and evaluating data from the process design stage through full-scale production to ensure that the process is capable of consistently producing high-quality products.
Since sterilization is a critical activity for many pharmaceutical products, it also requires validation. Effective sterilization cannot rely on finished product testing alone due to limitations in sampling. Instead, validation ensures that the sterilization method consistently achieves microbial destruction.
Controls Required for Sterilized Products
Products labelled as sterile must undergo strict controls, including:
- Control of the sterilization process using sterilization indicators
- Sterility testing of the final product
Monitoring of sterilization cycles is done using physical, chemical and biological indicators, each providing different types of evidence about process effectiveness.
1. Physical Indicators
Physical indicators measure sterilization conditions such as time, temperature and pressure. They are widely used for steam, dry heat, radiation and gaseous sterilization.
i) Moist Heat Sterilization
A master process record (MPR) is prepared for each autoclave, covering load configuration and sterilization parameters. During routine runs, a batch process record (BPR) is compared with the MPR. Modern autoclaves use microprocessor-controlled sterilization cycles. Pressure is monitored using gauges or pressure transducers.
ii) Dry Heat Sterilization
Each sterilization cycle produces a temperature record chart which is compared with a master temperature record to ensure proper heat distribution.
iii) Radiation Sterilization
Plastic dosimeters accurately measure the absorbed radiation dose and are used as the primary physical control for gamma and electron-beam sterilization.
iv) Gaseous Sterilization
For ethylene oxide and other gases, temperature probes, leak tests, gas-tight seals, and gas concentration measurements are used. Humidity and pressure are also recorded.
v) Filtration Sterilization
A bubble-point pressure test is performed to check filter integrity. The filter is soaked in a suitable liquid, and pressure is applied. The pressure at which the first air bubble passes indicates the maximum pore size.
2. Chemical Indicators
Chemical indicators change colour or physical properties when exposed to certain sterilization conditions such as heat, steam, radiation or gases.
i) Browne’s Tubes
These sealed tubes contain a chemical mixture and indicator dye. Exposure to a specified time and temperature results in a colour change from red to yellow-brown to green.
ii) Witness Tubes
These contain crystalline substances with known melting points, such as sulphur or benzoic acid. When the sterilization temperature is reached, the crystals melt, serving as a simple indicator.
iii) Heat-Sensitive Tape
Used in the Bowie-Dick test to confirm steam penetration and removal of air from dressings. All tape bars must change colour to indicate full steam penetration.
iv) Royce Sachet
A chemical indicator for ethylene oxide sterilization. Exposure produces ethylene chlorohydrin, leading to a colour change from yellow to purple.
v) Chemical Dosimeters
Used for radiation sterilization. These dosimeters measure absorbed radiation levels. Radiosensitive chemical indicators also change colour during irradiation.
3. Biological Indicators
Biological indicators are the most reliable tools for sterilization validation. They use highly resistant, non-pathogenic bacterial spores deposited on carriers.
Indicators are placed at various positions within the sterilization load. After sterilization, they are removed and cultured to check for microbial survivors.
Ideal Characteristics of Biological Indicators
- High and reproducible resistance to the sterilizing agent
- Genetic stability
- Easy characterization
- Non-pathogenic nature
The viability of spores, storage conditions and culture methods must be standardized before using biological indicators.
Role of Biological Indicators
They are used for:
- Validation: To ensure the sterilization process is effective under worst-case conditions
- Routine monitoring: To confirm that the sterilizer continues to operate correctly
Key Points
- Validation provides documented assurance that a process consistently produces expected results.
- Sterilization processes must be validated using physical, chemical and biological indicators.
- Biological indicators are the most accurate tools for verifying microbial destruction.
- Regulatory bodies require validation as part of quality assurance for sterile pharmaceutical products.
Detailed Notes:
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