Validation Activities

Validation is a rigorous, documented process used to ensure that a specific procedure, process, or equipment will consistently produce a result meeting its predetermined specifications.

A. Sterilization Validation Process For

Gamma-

Gamma validation focuses on finding the “target dose” that kills microorganisms without destroying the product’s material (polymers).

Establishment of Dose: Use Method 1 (based on bioburden) or VDmax (Substantiation of 25 kGy or 15 kGy).
Bioburden Testing: Determining the number and type of microorganisms on the product before sterilization.
Verification Dose Experiment: Irradiating a small sample at a lower dose to verify the lethality.
Dose Mapping: Identifying the “Cold Spot” (minimum dose received) and “Hot Spot” (maximum dose received) within a fully loaded pallet.
Quarterly Dose Audits: Repeated every 3 months to ensure the bioburden hasn’t changed.

Eto- Ethylene Oxide (EtO) (ISO 11135)

Eto is a gas-based chemical sterilization for heat-sensitive devices.

The Overkill Method: The most common approach. You prove that a Half Cycle (50% exposure time) kills $10^6$ spores of Bacillus atrophaeus. If the half cycle works, the “Full Cycle” is guaranteed to be effective.
Physical PQ: Monitoring Temperature, Humidity, and Gas Concentration inside the chamber using sensors.
Aeration Study: Measuring how long it takes for toxic EtO gas residues to “off gas” from the product so it is safe for human use.

Aseptic filling-

Media Fill: Replacing the actual drug with a nutrient medium (like Soya Bean Casein Digest Medium).
The machines function under actual production conditions, which include testing their performance during extreme operational scenarios when they have to handle situations which require them to resolve a stopped production halt and to manage operational transitions.

The incubation process requires all filled vials to undergo a 14-day testing period. The testing results will meet acceptance criteria when there is no contamination because all tested vials show no growth.

Moist Heat (Autoclave) –

Used for steam-stable items like liquids, glass, or surgical tools.

Heat Distribution: Placing 10–12 probes in an empty chamber to ensure no “cold pockets” exist.
Heat Penetration: The method requires inserting probes into products which include bottles of saline to verify that the core temperature reaches 121.
Calculation: The process requires measurement of total lethality which occurs throughout the duration of the procedure.
Biological Indicators: The method uses Geobacillus stearothermophilus strips as biological indicators to demonstrate the process achieved complete microbial elimination.

B. Cleaning process Validation (Machine and Equipment)

This ensures that the cleaning SOP effectively removes active drug residues, detergents, and microbes to prevent cross-contamination.

Worst-Case Selection: The process requires researchers to find two products which include the “Hardest to Clean” product that depends on its solubility and the “Most Toxic” product.
Sampling Methods:
- Swab Sampling: Physically rubbing area of the machine surface. Good for “hard-to-reach” spots.
- Rinse Sampling: Analysing the final rinse water. Good for large tanks or internal piping.
Acceptance Criteria:
- Visual Cleanliness: No visible residue (first check).
- 10 ppm Limit: No more than 10 parts per million of the previous drug in the next batch.
Hold Time Studies:
- Dirty Hold Time (DHT): How long can a machine sit dirty before cleaning becomes impossible?
- Clean Hold Time (CHT): How long can a cleaned machine sit before it grows Mold or bacteria?

c. Process Validation

Modern Process Validation is not a one-time event; it is a three-stage lifecycle.

Stage	Name	Key Activity
Stage 1	Process Design	Defining the CPP (Critical Process Parameters) like mixing speed or temperature, and CQA (Critical Quality Attributes) like tablet hardness.
Stage 2	Process Qualification	Often called the PPQ (Process Performance Qualification). You run 3 consecutive commercial scale batches to prove the process is stable and repeatable.
Stage 3	Continued Process Verification	Ongoing monitoring of every batch. You use statistical charts (Trend Analysis) to ensure the process doesn't "drift" over time.

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