Sterile Manufacturing In Pharma: Best Practices, Automation & Regulatory Trends For 2025

The air feels almost unreal inside a sterile manufacturing facility—silent, filtered, and untouched by the outside world. Every technician moves with deliberate precision, every surface gleams, and not a single particle is left to chance. This is where life-saving medicines are born.

Once reserved for producing only the most sensitive products—like vaccines—sterile manufacturing has evolved into a cornerstone of modern pharma. In these tightly controlled cleanrooms, aseptic filling and terminal sterilization protect medicines from bacteria, fungi, and even the tiniest speck of dust.

Today, the process is no longer just about sterility—it’s about scaling precision, meeting rising demand, and navigating an increasingly complex regulatory landscape. This article takes you inside the world of sterile manufacturing, uncovering the best practices, new innovations, and pressing challenges shaping its future.

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

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 difficult. The final product will be compromised if you don’t have the right pointers. Considering this importance, we’ve compiled a list of best practices pharma manufacturers can follow when implementing sterile manufacturing!

Best practices for implementing sterile manufacturing

1) 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.

2) Focus on Air Quality Compliance: Regulatory authorities are increasing the importance of 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.

Image Source: Allied Cleanrooms

3) 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 that 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.

4) 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 washing and preparing 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.

5) Use of Isolators & RABS: In sterile pharmaceutical manufacturing, isolators and Restricted Access Barrier Systems (RABS) help protect products from contamination. Isolators are fully enclosed systems with airtight barriers, glove ports, and controlled airflow, allowing operations without direct human contact and providing the highest sterility assurance. 

RABS, while not completely sealed, use rigid walls or panels with glove ports to reduce contamination risk and operate within high-grade cleanrooms using strict aseptic techniques. Both systems improve product safety, but isolators offer greater protection, with the choice depending on product type, process needs, and facility design.

6) Design Air Locks, Pass-Through Hatches & Interlocks: 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 to 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 tricky—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 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.

What Is The Difference Between Aseptic And Terminal Sterilization?

In sterile pharmaceutical manufacturing, two primary methods ensure products are free from microorganisms: aseptic processing and terminal sterilization. Terminal sterilization involves filling the product into its final container and then sterilizing the sealed unit, usually by heat, but sometimes by radiation or gas. It is highly reliable, easier to validate, and preferred by regulators, but unsuitable for heat- or radiation-sensitive products and may affect stability.

Aseptic processing sterilizes the product and container separately, then combines them in a controlled sterile environment. It is ideal for heat-sensitive drugs but requires strict environmental control, skilled operators, and constant monitoring, making it more complex and costly. 

Regulatory agencies recommend terminal sterilization whenever possible, with aseptic processing reserved for products that cannot tolerate the terminal method. The choice depends on the product’s stability, characteristics, and safety requirements.

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.

Global Regulatory Trends In Sterile Manufacturing

1) Stricter Focus On Contamination Control

Regulatory bodies such as the US FDA, EMA, and WHO increasingly emphasize contamination control strategies (CCS) to ensure sterile products remain free from microbial and particulate contamination. The revised EU GMP Annex 1, implemented in 2023, has set a new benchmark by requiring a comprehensive, integrated approach that includes facility design, process control, environmental monitoring, and rigorous operator training. Manufacturers must demonstrate a clear, documented strategy that proactively prevents contamination rather than relying solely on end-product testing.

2) Adoption Of Advanced Technologies

Modern technologies such as isolators, restricted access barrier systems (RABS), and automation are being strongly encouraged by regulators. These systems minimize human interaction in critical manufacturing zones, thereby reducing the risk of contamination. Automation enhances sterility assurance and improves manufacturing efficiency and consistency, helping companies meet regulatory expectations for high-quality sterile products.

3) Risk-Based & Science-Driven Approaches

Current regulatory trends emphasize a risk-based framework for sterile manufacturing, where decisions are guided by scientific evidence and comprehensive risk assessments. Manufacturers are expected to identify potential contamination risks, implement control measures, and continually monitor processes throughout the product lifecycle. This approach promotes continuous quality improvement, ensuring safety and efficacy are maintained at every stage.

4) Global Harmonization of Standards

Efforts are underway to align sterile manufacturing requirements across different markets through organizations like the International Council for Harmonisation (ICH). This harmonization helps streamline the international supply process, reducing the burden of meeting multiple, sometimes conflicting, requirements. However, regional differences still exist, and companies must stay informed about country-specific guidelines to avoid regulatory delays.

5) Expectations Beyond Basic Compliance

Regulators now expect manufacturers to go beyond simply meeting minimum requirements and to establish robust, proactive quality systems. These systems should be capable of consistently producing sterile products that are safe, effective, and compliant, even under challenging circumstances. The focus is on building a quality culture, adopting innovative manufacturing solutions, and maintaining a state of inspection readiness at all times.

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!

FAQs

Q1. What is sterile manufacturing in pharmaceuticals?

Sterile manufacturing refers to the production of pharmaceuticals in a contaminant-free environment, utilizing cleanrooms, aseptic filling processes, and terminal sterilization to ensure products are free from microbial contamination.

Q2. Which pharmaceutical products require sterile manufacturing?

Sterile manufacturing is essential for injectable drugs such as insulin and vaccines, ophthalmic products like eye drops and ointments, inhalation products including nebulizer solutions and asthma medications, sterile topical products for wound care, implantable medical devices such as pain management pumps, and surgical devices like pre-filled syringes.

Q3. What are the best practices for maintaining sterility in pharmaceutical manufacturing?

Best practices include establishing a strong foundation with air quality compliance using HVAC systems and HEPA filters; ensuring aseptic filling areas have non-shedding, non-flaking finishes on walls, floors, ceilings, furniture, and doors; preparing areas with high air quality and separate changing facilities; and implementing air locks, pass-through hatches, and interlocks to prevent contamination and cross-contamination.

Q4. What challenges are commonly faced in sterile pharmaceutical manufacturing?

Maintaining a sterile environment is challenging due to human microbes, inadequate cleaning procedures, poor disinfection practices, improper airflow management, unbalanced pressure differentials, time-consuming and expensive continuous monitoring of air, surfaces, and personnel, as well as risks from improper handling that compromise cleanroom sterility.

Q5. How did PharmTech overcome challenges in expanding sterile manufacturing capabilities?

PharmTech hired consultants to implement a phased approach including constructing ISO-certified cleanrooms, acquiring automated equipment to reduce contamination risks, and conducting workforce training. This strategic plan helped them address expertise gaps, regulatory compliance issues, facility requirements, and high investment costs.

Q6. Why are pharmaceutical companies increasingly adopting sterile manufacturing?

Pharmaceutical companies are adopting sterile manufacturing to meet tightened regulatory standards that demand higher levels of product safety and contamination control. This trend ensures compliance with regulations while delivering safe injectable drugs and other sterile products to patients.