Sterile Manufacturing: Best Practices, Challenges, and Case Study

Sterile manufacturing refers to producing pharmaceutical products in a contaminant-free environment. It is often performed in cleanrooms with strictly controlled environmental conditions to ensure the final product contains no bacterial or fungal contamination. 

Furthermore, this manufacturing process includes an aseptic filling process and a terminal sterilization process. Previously, sterile manufacturing was only used to produce products that needed to be 100% sterile, such as vaccines. However, the scenario has changed. Join Pharma Now to understand the best practices followed and know the challenges to overcome. 

Where is sterile manufacturing used?

Some of the common pharmaceutical products manufactured via sterile manufacturing processes include:

1. Injectable drugs such as intramuscular and subcutaneous injections (e.g., insulin and vaccines), biologics (e.g., gene therapy), cytotoxic and oncologic drugs (e.g., chemotherapy agents), and total parenteral nutrition solutions.
2. Ophthalmic products such as eye drops, eye creams, and eye ointments.
3. Inhalation products such as nebulizer solutions, dry powder inhalers, and asthma medications.
4. Sterile topical products such as wound care solutions and creams.
5. Implantable medical devices such as pain management pumps.
6. Surgical devices such as pre-filled syringes

Because these products are very sensitive and highly consequential, manufacturers must be cautious while developing an in-house sterile manufacturing process. Implementing a new sterile manufacturing process at a facility is not an easy job. In fact, if you don’t have the right pointers, the final product will be compromised.

Considering this importance, we’ve come up with a short list of best practices that pharma manufacturers can follow when implementing sterile manufacturing.

Best practices for implementing sterile manufacturing

Design a strong foundation.

The sterile manufacturing facility must be located on a solid foundation so that it won’t be susceptible to movement. A weak foundation can result in movement, which can cause cracks in key areas like clean rooms. Furthermore, key services, like water, steam, gas, etc., should be appropriately located to ensure they can be serviced without affecting operations. Water, fuel, and air pipelines should be placed in a manner that prevents leakages in aseptic areas.

Focus on air quality compliance.

Regulatory authorities are placing increasing importance on the particulate counts in cleanrooms and aseptic areas in sterile manufacturing facilities. Hence, appropriate heating, ventilation, and air conditioning (HVAC) systems should be designed to maintain required environmental controls. High-efficiency particulate air (HEPA) filters should be installed to maintain particulate counts. In two adjoining areas where air quality requirements are different, pressure differentials must be used to prevent the cross-flow of air.

Pay attention to all details in aseptic filling areas.

Aseptic filling areas are the most critical and need special attention as they define the sterility of the final product. Current designs of aseptic filling areas focus on small sizes that can only allow one operation. Some authorities’ expectations primarily dictate this trend that only a single operation be performed in a single aseptic room to reduce potential contamination between machines.

When designing aseptic filling areas, all finishes to walls, floors, ceilings, and furniture should be non-shedding, non-flaking, and non-cracking to prevent contamination from these materials. These requirements also apply to doors which cannot be made of wood. Furthermore, doors should push into the higher-pressure area to ensure the pressure automatically closes the door. Finally, all entries should be tightly sealed using appropriate sealants to ensure air will not flow in/out through them.

Provide preparation areas.

Preparation areas with high air quality and separate changing facilities must be included in facility design. These areas can also be used for support operations like the washing and preparation of components and equipment. These areas should also be designed using the same quality standards (e.g., no wood, non-shedding finishes, and sealed entries) as aseptic filling rooms to ensure they don’t contaminate the product. These areas should have a higher pressure than the outside but a lower pressure than the adjoining aseptic filling areas to ensure the air does not flow into the filling area.

Design air locks and pass-through hatches.

Another method to prevent contamination and cross-contamination is using airlocks, pass-through hatches, and interlocks.

• Airlocks are controlled transition zones that prevent contamination from moving between areas. These areas maintain pressure differentials, preventing contaminants from entering clean rooms. Airlocks should preferentially be included in areas where machinery needs to be transported because doors are open for a long time during such operations.
• Pass-through hatches are sealed enclosures used to transfer materials between areas. They are ideal for situations where only an object needs to be transported into or outside the cleanroom. The item can be transferred through the hatch, avoiding unnecessary movement of personnel.
• Interlocks prevent both doors from opening together. They should be integrated into all facilities because they can prevent large quantities of air from escaping or entering the cleanrooms. When two doors are simultaneously opened, the pressure differential drops significantly, compromising the air quality.

After opening, air should be purged into the room to maintain sterility. Many sites integrate timer or delay switches to ensure sufficient time between door closing and purging.

These are only some of the best practices for sterile manufacturing. The design of sterile facilities requires strict adherence to regulatory guidelines and good manufacturing practices. Hence, pharma manufacturers often face many challenges.

Common challenges in implementing sterile manufacturing

Sterile manufacturing faces many challenges; three top challenges include:

Challenge: Constantly maintaining a sterile environment is challenging.

While sterile environments are necessary in such manufacturing facilities, maintaining them is extremely difficult. Humans carry thousands of microbes, making them a huge contaminant risk. Strict hygiene and cleanliness protocols need to be implemented, which is problematic. Furthermore, contaminants are also introduced due to inadequate cleaning or poor disinfection protocols, which happen more often than expected. Finally, poor airflow and unbalanced pressure differentials in cleanrooms can also introduce contaminants. Consequently, maintaining sterility is a never-ending battle.

Challenge: Continuous monitoring of air, surfaces, and personnel to prevent contamination is time-consuming and expensive.

Real-time contaminant monitoring technologies are not always integrated into facilities, which makes contaminant detection difficult. When such technologies are integrated, they can provide false positives, leading to unnecessary batch rejections. Continuous monitoring of all surfaces and personnel is also difficult—dedicated personnel may need to be hired, which increases the overall operational cost.

Challenge: Improper handling can compromise the sterility of cleanrooms.

While all personnel working in cleanrooms are provided extensive training, human errors are unavoidable, and they are the primary source of contamination. Improper gowning or compromising on a protocol can create contamination risks. For example, a single operator’s failure to properly secure their gloves can contaminate several product batches. Such minor handling errors aren’t always predictable or unavoidable.

In addition to these challenges, manufacturers must overcome hurdles such as regulatory guidelines (which are constantly shifting), technological implementation gaps, and contamination risks from raw materials, which are unavoidable from a manufacturer’s point of view. Here’s a case study of a pharma company that successfully implemented sterile manufacturing.

Case study: PharmTech’s implementation of sterile manufacturing

PharmTech, an oral solid dosage manufacturing company, expanded its portfolio by integrating injectable solutions (saline). During implementation, it faced four significant challenges:

1. Lack of expertise: PharmTech’s lack of knowledge in sterile manufacturing meant its existing workforce was not trained in the necessary protocols.
2. Regulatory challenges: PharmTech did not understand how to meet the stringent cleanroom requirements, which called for an operational redesign.
3. Facility challenge: The existing infrastructure was not equipped with ISO-classified equipment.
4. High investment: PharmTech needed to purchase specialized equipment like advanced filling lines, which was expensive.

Solution: PharmTech hired consultants who suggested a phased approach:

• Design and install ISO-certified clean rooms, pass-through hatches, airlocks, and HEPA filters.
• Select and purchase automated equipment that reduces human intervention and human contamination.
• Exhaustively train the existing workforce on aseptic protocols.
• Prepared for and passed initial regulatory inspections.

Consequently, PharmTech obtained regulatory approvals and manufactured sterile injectable solutions within 2.5 years.

Conclusion

In recent years, regulatory bodies have tightened pharmaceutical product quality and safety standards. Therefore, pharmaceutical companies have started integrating sterile manufacturing processes to meet regulatory requirements. However, the implementation of such methods is quite challenging and time-consuming. For a mid-sized company, the transition from non-sterile to sterile manufacturing is daunting, expensive, and hazardous because of the many pitfalls present. We’ve highlighted some best practices in this article to aid in this transition. If we’ve missed anything, let us know in the comments!