Sterile API Manufacturing FAQs

The manufacture of sterile products is a complex activity that requires specific controls and measures to ensure the
quality of products manufactured.

The key principles of sterile product manufacturing include minimizing the risk of microbial, particulate, and endotoxin
contamination through appropriate facility and equipment design, qualified personnel, validated processes, and robust
monitoring systems. Quality Risk Management (QRM) and a documented Contamination Control Strategy (CCS) should
be applied throughout all operations.

Sterile APIs may be required for several types of pharmaceutical formulations, including:

• Injectables
• Inhalation products
• Implants
• Ophthalmic formulations

Active pharmaceutical ingredients (APIs) can be sterilized using several terminal sterilization methods, including dry
heat, moist heat, radiation, and other validated approaches. These methods are suitable when the API remains stable
under the required sterilization conditions and its molecular structure and impurity profile are not adversely affected.

Where terminal sterilization of the APIs is not feasible, sterilization by filtration followed by aseptic processing under
validated and controlled conditions is the option of choice.

When terminal sterilization is not feasible, sterile filtration followed by aseptic processing is the primary alternative. This specialized manufacturing approach ensures sterility by preventing contamination throughout the full production workflow and process rather than sterilizing the product at the final stage.

Aseptic processing is intended to prevent microbial, particulate, and endotoxin contamination. These controls help
ensure that the final API meets the sterility requirements necessary for use in sterile pharmaceutical formulations.

Sterility during aseptic processing is ensured through the application of Quality Risk Management (QRM) across all
stages of aseptic API production. This includes facility design, equipment qualification, process and controls design,
system implementation, and operational procedures. QRM provides a structured framework for identifying, assessing,
and controlling risks associated with sterile manufacturing. It supports consistent process performance and helps
ensure that the final API meets stringent sterility and quality requirements.

Aseptic capabilities should comply with the latest international regulatory requirements. The principal applicable
standards include:

• EU GMP Annex 1
• FDA Guidance for Industry: Sterile Drug Products. Current good Manufacturing Practices
• FDA guidelines (21 CFR Part 11)
• ISO standards, including ISO 13408 and ISO 14644
• PDA technical reports (TR), including TR 28 and TR 27
• USP <1116>

Together, these frameworks provide general guidance for the design and control of facilities, equipment, systems, and
procedures used in sterile product manufacturing, while reinforcing the application of Quality Risk Management (QRM)
principles.

Key requirements for premises and cleanroom design include the following:

• Controlled environments: Sterile manufacturing should be carried out in cleanrooms equipped with HEPA-filtered air to prevent microbial ingress. Appropriate airlocks and physical separation are required to maintain environmental control. Cleanrooms are classified into four grades (A–D), each with defined requirements.
• Closed systems and automation: Manufacturing systems should be designed to minimize human intervention. Barrier technologies such as RABS and isolators, together with automation, are recommended to reduce contamination risk.
• Equipment and utilities: Equipment should support effective cleaning and minimize contamination risk. Critical utilities, including water, gases, and steam, must be controlled, qualified, and periodically monitored.

Effective aseptic API processing control depends on the following elements:

• Personnel requirements: Only qualified and trained personnel should be permitted to enter cleanrooms. Gowning and hygiene requirements must be defined according to cleanroom grades. Continued training, qualifications, and routine monitoring should be supported by formal procedures for disqualification and retraining when needed.
• Environmental monitoring: Comprehensive monitoring of viable and non-viable particles is required, with alert and action limits established according to cleanroom grade. Routine trend analysis should be used to identify shifts that may affect process control. Cleanrooms should also be qualified and periodically requalified.
• Process monitoring: Robust validated procedures are required to demonstrate control of aseptic operations. These should include media fill runs designed to simulate worst case conditions. Periodic verification of the effectiveness of the controls in place for aseptic processing should include Aseptic Process Simulation (APS), also referred to as media fill. APS should be performed as part of the initial validation and periodically executed. Additional controls, such as sterilizing filter integrity testing and glove integrity monitoring, should also be included.
• Quality control (QC): Quality control should include expertise in microbiology, sterility assurance, and particulate control. Bioburden and endotoxin testing must be performed at defined stages. Sterility testing is the final verification step, but it should not be considered the sole assurance of sterility. Personnel, Environmental and process monitoring results and trend data should be reviewed as part of batch release.
• Adherence to the Pharmaceutical Quality system (PQS): the manufacturer’s PQS should encompass and address the specific requirements of sterile product manufacture and ensure that all activities are effectively controlled so that the risk of microbial, particulate and endotoxin/pyrogen contamination is minimized in sterile products.

Aseptic processing for sterile APIs is a highly controlled, complex activity that relies on purpose-built facilities, qualified personnel, validated processes, and robust monitoring to minimize risks of microbial, particulate, and endotoxin contamination. By leveraging validated aseptic processes, routine environmental and process monitoring, and
integrated microbiological expertise, a CDMO helps ensure consistent sterility assurance aligned with global regulatory expectations, while reducing the need for significant internal investment and accelerating timelines to clinical or commercial supply.

Curia’s center of excellence for aseptic API processing is in Valladolid, Spain. The site operates two aseptic processing lines, with product families split by suite: one line is segregated for steroid APIs and the second handles non-steroid APIs. Both suites run closed processing with barrier isolators as primary containment.

The suites are supported by an in-house microbiology laboratory (sterility, endotoxin and bioburden testing), environmental monitoring of viable and non-viable particles, water and steam monitoring, container closure integrity testing and stability chambers. A pilot plant and non-GMP suite mimic the aseptic capabilities for development work.

Yes. Curia completed a $4 million upgrade of the two API aseptic suites at Valladolid in 2025. The upgrade introduced fully closed processing and new isolators, together with improvements to HVAC, pharmaceutical utilities, automation and sterilization-in-place processes, in line with the current EU GMP Annex 1.

Sterility assurance at the site is built into process design and controls rather than relying on finished-API testing alone: gowning and hygiene requirements, aseptic process simulation (media fills), filter integrity testing, glove and half-suit integrity monitoring, container closure integrity testing and final API testing for sterility, endotoxins and particulate matter.

Curia’s catalogue includes more than ten commercial sterile APIs. Products manufactured at Valladolid include budesonide sterile for inhalation, betamethasone acetate and betamethasone dipropionate for long-acting injection, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone sodium succinate and methylprednisolone acetate for injection, medroxyprogesterone acetate for injection, hydrocortisone aceponate for otic suspension and loteprednol etabonate sterile micronized for ophthalmic suspension. Aztreonam sterile is manufactured at Tonneins, France. Several carry US DMF, EU DMF or CEP filings, listed product by product in the Sterile API Catalogue.

A worked example is budesonide. Where terminal sterilization by heat or radiation is not suitable for the molecule, as with budesonide, Curia uses sterile filtration as the preferred sterilization strategy: the API is dissolved, passed through a double 0.22 micron sterilizing filter, then crystallized, isolated, dried and packaged under aseptic conditions, with filter integrity verified as part of quality assurance. The approach is described in Curia’s insight on sterile filtration of budesonide.

The full list is published in the Sterile API Catalogue.

Curia sterilizes both steroid and non-steroid APIs. Steroids and hormones are the longest-standing family: Curia has over 20 years of experience in aseptic processing with a dedicated line segregated for steroids, and its sterile catalogue covers corticosteroids such as budesonide, betamethasone, hydrocortisone, methylprednisolone and loteprednol, and hormones such as medroxyprogesterone acetate. The second Valladolid line handles non-steroid APIs, and the Tonneins site in France operates a dedicated sterile line for the monobactam antibiotic aztreonam.

Across families, Curia combines sterility assurance with solid-state control: aseptic crystallization, milling and micronization under aseptic conditions, and a range of qualified aseptic packaging configurations to maintain sterility during transfer to the drug product site. This supports injectable suspensions, pre-filled syringes, implants, inhalation and ophthalmic products.

The API is dissolved and the solution passes through a sterilizing filter. The API is then crystallized, isolated, dried and packaged under controls designed to maintain sterility. Milling or micronization may be included where required.

The crystallization stage sets the product’s physical properties, including crystal form, polymorphic form and particle size, through methods such as anti-solvent addition, cooling, controlled distillation and sterile seeding. Drying is adapted to each solvent and to hygroscopic APIs, and all operations are carried out through isolators.

Curia has completed a $4 million upgrade to the two API aseptic suites at Valladolid and is investing more than $28 million in additional sterile API capacity for steroid and non-steroid products at the site. The expansion began in Q3 2026, with project completion scheduled for Q4 2028.

The additional capacity will complement the site’s existing work in aseptic crystallization and particle size control, and will add a new suite alongside the two existing aseptic lines. It continues an expansion path that began with the first sterile crystallization building for steroid APIs in 2005 and the extension to non-steroid APIs in 2018.

Curia manufactures sterile APIs at Valladolid from gram scale to hundreds of kilograms, with variable batch sizes and closed-system capabilities. The appropriate batch size depends on the product and the aseptic processing route. Curia’s team can assess the available equipment against clinical or commercial supply requirements.