Introduction
Nowadays Isolators play important role in sterile pharmaceutical manufacturing industries. Being sterile production, aseptic conditions are prerequisites for sterile dosage forms. So to maintain the aseptic environment, Isolators are being used in sterile pharmaceutical industries.
Normally to maintain aseptic environment HEPA filters are used. These filters are providing clean air vertically or horizontally. But due to man and material interference, the external air can contaminate the clean area leading to sterility failure. So to overcome this sterility failure, the use of Isolators is mandatory. In this post we will come to know that, what are Isolators and how they work.
Pharmaceutical isolators play a crucial role in establishing a protective barrier during the production of drug products, thereby reducing the risk of contamination. These sophisticated systems are vital for ensuring that the products meet safety and quality standards. The primary function of a pharmaceutical isolator is to protect the product from the operator, creating a sterile environment that is essential for handling sterile dosage forms. In recent years, there have been significant advancements in the functionality and adaptability of isolators, solidifying their importance in both drug manufacturing and research. This guide will explore the technical characteristics, applications, and advantages of isolators, aiming to elucidate all their essential aspects for practical use within the pharmaceutical sector.
The pharmaceutical isolator is engineered to fulfill two critical functions:
Containment
In manufacturing facilities, an isolator facilitates the containment of pharmaceutical operations. It necessitates a safeguarded environment devoid of viable microorganisms. The isolator effectively separates the production area from personnel and the surrounding environment, thereby preventing the spread of contamination between these zones. This technology offers a superior level of containment compared to conventional clean rooms and incorporates an integrated decontamination system. Typically, the isolator is decontaminated using a sterilizing gas, such as hydrogen peroxide (H2O2). It employs highly efficient filters to ensure optimal protection of the product. These systems are designed to eradicate microbes and particles from all potential contamination sources, including the external environment and operators.
Product Transfer
When products are either introduced into or removed from the isolator, it is crucial to maintain containment and protect the atmosphere from contamination. This is achieved through the use of a transfer lock. This system not only facilitates the movement of products and materials but also streamlines the disposal of waste, ensuring that the aseptic conditions of the environment are consistently upheld. Isolators utilized in the pharmaceutical sector must adhere to Class A Standards as specified in the EU GMP Classification OJ 07/01/97. Additionally, the isolator can be outfitted with various optional accessories, including hooks on docking bars, welders, cooling trays, and cleaning tools.
It usually consists of a shell, viewing window, glove/sleeve assemblies, supply and exhaust filters, light (s), gauge (s), Input and Output openings (equipment door airlocks, Rapid Transfer Ports (RTPs), etc.), and various other penetrations.
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How Pharmaceutical Isolators Work ?
Aseptic isolators should be free of microorganisms out of the environment and therefore need to operate under positive pressure air delivered through HEPA filters. However few isolators will work on negative pressure also.
1. Preparation & Material Transfer
This phase ensures all materials introduced into the isolator are either sterile or decontaminated:
- Material Loading: Items like vials, stoppers, instruments, and media are loaded using:
- Rapid Transfer Ports (RTPs): These provide a sterile docking interface for bags or containers.
- Mouseholes: Small, controlled-access entry points for tools or supplies.
- Decontamination Chambers: Mini-chambers attached to the isolator where materials are sterilized before entry.
- Decontamination Process:
- Items pass through Vaporized Hydrogen Peroxide (VPHP) decontamination cycles.
- Alternatively, some materials may undergo pre-sterilization (gamma irradiation, autoclaving) before transfer.
- Bioburden Reduction Strategy:
- Preference is given to pre-assembled, pre-sterilized components (e.g., Ready-to-Use/Ready-to-Sterilize components) to minimize contamination risk.
2. Decontamination Cycle
Once all materials are inside, the entire isolator is sterilized:
Sealing: The isolator is sealed to create an airtight chamber.
VPHP Cycle Steps:
- Injection: Liquid hydrogen peroxide is injected into the vaporizer.
- Vaporization: It is turned into vapor and uniformly distributed.
- Dwell Phase: This biocidal phase ensures lethal exposure time to microbial contaminants.
- Aeration: The vapor is neutralized and removed using catalytic converters or air exchange.
Validation:
- Biological Indicators (BIs) using Geobacillus stearothermophilus spores confirm ≥6-log microbial kill.
- Chemical Indicators (CIs) show proper vapor distribution.
- Residual Peroxide Testing ensures peroxide levels drop below regulatory limits (e.g., <1 ppm) before initiating operations.
3. Environmental Monitoring Setup
Monitoring ensures that aseptic conditions are maintained throughout the fill process:
Non-viable Particle Monitoring:
- Continuous air sampling is done using particle counters placed inside the isolator.
- Must comply with ISO 5 cleanroom limits (e.g., ≤3520 particles ≥0.5μm/m³).
Viable Particle Monitoring:
- Settle Plates: Collect microorganisms from air settling over time.
- Contact Plates: Pressed against surfaces/glove sleeves to check surface contamination.
- Active Air Samplers: Draw and impact air onto nutrient media for microbial detection.
Leak Testing:
- Each use requires a pressure decay test or helium integrity test to verify isolator integrity and containment.
4. Filling and Stoppering
The critical fill process is fully automated and takes place inside a sterile enclosure:
Robotic Systems:
- Automated arms perform precise filling operations, reducing human involvement.
- Machines may include rotary or linear vial fillers integrated within the isolator.
Sterile Conditions:
- Laminar airflow ensures unidirectional, filtered air supply at the fill zone.
- ISO 5 classification is strictly maintained at the point of fill.
Stoppering and Sealing:
- Happens immediately after fill to prevent microbial ingress.
- Ensures a closed container system ready for terminal sterilization or direct packaging.
5. Operator Interaction (Glove Ports)
Though isolated, operators still interact with the system:
Glove Ports:
- Installed throughout the isolator to allow manipulation without breaching sterility.
- Glove and sleeve systems must pass routine integrity tests (e.g., pressure decay, electrical conductivity, or vacuum decay methods).
Zero Contact Principle:
- Operators never directly touch the product—barrier integrity is absolute.
6. Exit of Product
Sterile products exit the isolator using controlled, sterile pathways:
Exit Mechanisms:
- Exit RTPs: Used to dock with external containers for sterile removal.
- Pass-Boxes or tunnels: May be used to maintain separation during exit.
Contamination Prevention:
- One-way transfer with airlocks or decontaminated pathways ensures no back-contamination.
7. Cleaning & Re-Decontamination
Post-batch activities are essential to maintain sterility for future runs:
Manual or Automated Cleaning:
- All internal surfaces are cleaned using sporicide or a validated detergent to remove residue and potential contaminants.
Repeat VPHP Decontamination:
- Another full sterilization cycle ensures the system is reset for the next batch.
Media Fill Simulations:
- Periodic simulation runs using nutrient media (not actual drug product) test the aseptic process.
- If no microbial growth occurs post-incubation, the process is validated.
Conclusion
- Pharmaceutical isolators have revolutionized aseptic manufacturing by offering a controlled, contamination-free environment that enhances both product safety and operator protection. By integrating advanced barrier systems, automated decontamination cycles, and rigorous environmental monitoring, isolators ensure consistent compliance with global regulatory standards like FDA, EU GMP, and PIC/S. Each step—from material transfer to final product exit—is meticulously designed to maintain sterility and prevent cross-contamination.
- Their use in sterile drug production, especially in high-risk or high-potency scenarios, not only improves product quality and patient safety but also streamlines operations and reduces the dependency on human intervention. As pharmaceutical processes continue to evolve towards automation and precision, isolator-based manufacturing is becoming the gold standard for ensuring aseptic integrity across the production lifecycle.
Sagar Pawar
Sagar Pawar, a Quality Specialist at Zamann Pharma Support, brings over 11 years of experience in Quality domain for the pharmaceutical and medical technology industries. Specializing in qualification, validation, Computer System Validation (CSV), and Nitrosamine activities, Sagar is currently focused on enhancing the Zamann Service portfolio by developing and implementing robust strategies to address Nitrosamine-related challenges. Outside of work, Sagar enjoys trekking and cooking. Connect with Sagar on LinkedIn to discuss topics related to equipment qualification, GMP Compliance and Nitrosamine-related challenges.
