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July, 23 2026

GMP Annex 1 Sterilization of Direct & Indirect Product Contact Parts

GMP Annex 1 and the Sterilization of Direct and Indirect Product Contact Parts: What Manufacturers Need to Know

EU GMP Annex 1, Section 5.5, requires that in aseptic processing, both direct product contact parts (like filling needles and pumps, which the product physically passes through) and indirect product contact parts (like stopper bowls and guides, which don’t touch the product but touch other sterilized surfaces) must be sterilized. This closes a long-standing compliance gap where indirect components were often only disinfected, not sterilized. 

H2: What Does Annex 1 Actually Say? 

The 2022 revision of EU GMP Annex 1, Manufacture of Sterile Medicinal Products, tightened the rules around equipment sterilization in aseptic processing. Section 5.5 draws a clear line between two categories of equipment: 

  • Direct product contact parts: components the product physically passes through during manufacturing, such as filling needles, pumps, tubing, and mixing vessels. 
  • Indirect product contact parts: components that never touch the product itself but come into contact with other sterilized surfaces whose sterility is critical to overall product sterility. An example is a stopper bowl: it doesn’t touch the drug product, but it touches the stoppers that will seal the vial. 

Both categories, according to Annex 1, must be sterilized, not simply cleaned or disinfected. This is a meaningfully higher bar, and it’s one of the areas of the 2022 revision that has caused the most operational disruption across the industry. 

Why This Requirement Is Harder to Meet Than It Sounds 

Prior to this update, many facilities treated indirect contact parts as lower-risk and relied on manual cleaning and disinfection rather than validated sterilization cycles. Annex 1 closed that gap, but doing so exposed a real engineering problem: a lot of installed equipment simply wasn’t built for it. 

Industry surveys following the 2022 revision found that roughly a third of surveyed manufacturers had stopper bowls that were either non-detachable or too heavy to remove for offline cleaning and sterilization, meaning they couldn’t easily comply without redesigning the filling line or investing in new equipment entirely. For newly installed lines, the expectation is now unambiguous: direct and indirect product contact parts should be removable so they can be cleaned and sterilized offline. 

Where parts can’t be removed or redesigned cost-effectively, manufacturers are expected to fall back on a documented, risk-based justification under quality risk management principles (as outlined in ICH Q9) and to demonstrate, with data, that whatever alternative approach they use still delivers an equivalent level of sterility assurance. 

Direct vs. Indirect Product Contact Parts: A Practical Breakdown

CategoryDefinitionExamplesAnnex 1 Expectation
Direct contactProduct physically passes throughFilling needles, pumps, transfer lines, mixing vesselsMust be sterilized; typically autoclaved or sterilized in-line
Indirect contactTouches sterilized surfaces, not the product itselfStopper bowls, guide rails, vial star wheels, some isolator/RABS fixturesMust be sterilized; removable design strongly preferred

Material Excellence: What Belongs on the Line?

Under EudraLex Annex 1, indirect product contact materials (e.g., stopper bowls, delivery chutes, spatulas) are defined as parts that do not touch the drug itself but contact other sterilized surfaces, making their sterility critical. Annex 1 requires these materials to be non-toxic, non-reactive, and cleanable.

To meet these strict European Medicines Agency (EMA) contamination control requirements, the most prevalent materials of construction include:

  • Stainless Steel (316L): The industry gold standard for metal indirect contact parts. It is prized for its highly passive chromium oxide layer, which provides exceptional corrosion resistance, cleanability, and compatibility with harsh Clean-In-Place/Sterilize-In-Place (CIP/SIP) agents.
  • Fluoropolymers (PTFE / Teflon): Utilized for gaskets, seals, and guides in indirect contact paths. They are chosen for their superior chemical inertness, wide thermal operating ranges, and non-stick properties that prevent particulate shedding.
  • Platinum-Cured Silicone & EPDM: Frequently used for tubing and seals located within indirect contact areas. These elastomers are chosen because they withstand repeated autoclave cycles or harsh sterilant exposure without degrading.

Where Decontamination Technology Fits In

Annex 1’s requirement for sterilization of contact parts sits alongside, but is distinct from, the broader Contamination Control Strategy (CCS) that governs the entire aseptic environment: the isolator or RABS interior, transfer hatches, and the surrounding Grade A/B cleanroom. Even when contact parts themselves are sterilized by autoclave, the enclosure they sit in still needs a validated, repeatable decontamination cycle to control bioburden before and between production runs.

This is where technologies like SteraMist’s ionized Hydrogen Peroxide (iHP) system are increasingly used inside isolators, RABS, pass-throughs, and small enclosures. The system activates a 7.8% hydrogen peroxide solution through a cold plasma arc, converting it into a fine mist of hydroxyl radicals that achieves a validated six-log reduction against resistant spore-forming organisms such as Geobacillus stearothermophilus. Because the byproduct is oxygen and humidity, cycles avoid the corrosive residue and extended cycle times associated with some traditional vaporized hydrogen peroxide (VPHP) systems, a factor that matters for sensitive equipment surfaces and turnaround time between batches.

This approach is already showing up on the production floor. Bausch + Lomb has implemented iHP in their pharmaceutical fill-line as part of their core aseptic filling operations, using it to support the sterility assurance of indirect product contact parts alongside validated sterilization of the direct contact parts themselves.

For manufacturers navigating Annex 1’s tightened requirements, this generally plays out as a two-layer strategy:

  1. Contact parts (direct and indirect) are sterilized through validated, part-specific methods, most commonly autoclaving of removable components.
  2. The surrounding controlled environment, isolator interiors, RABS, transfer hatches, is decontaminated on a validated, repeatable cycle using a technology like iHP, supporting the Contamination Control Strategy Annex 1 requires as a whole.

Learn about SteraMist iHP sterilization in aseptic environments ➔

Compliance Steps for Aseptic Facilities

  • Audit existing equipment to identify which direct and indirect contact parts are currently removable, and which aren’t.
  • Prioritize redesign or replacement for non-detachable indirect contact parts (like fixed stopper bowls) that can’t be sterilized offline.
  • Document a risk-based rationale under ICH Q9 principles for any equipment that can’t be feasibly redesigned in the near term.
  • Validate enclosure decontamination cycles (isolators, RABS, pass-throughs) separately from contact-part sterilization and ensure both are integrated into your overall CCS.
  • Maintain data-backed evidence, such as cycle logs, biological indicator results, and DQ/IQ/OQ/PQ documentation, for every sterilization and decontamination method in use.

Frequently Asked Questions

Q: What is the difference between direct and indirect product contact parts under GMP Annex 1?

A: Direct product contact parts are equipment components the product physically passes through, such as filling needles or pumps. Indirect product contact parts don’t touch the product itself but touch other sterilized surfaces critical to product sterility, such as stopper bowls or guide rails.

Q: Does Annex 1 require indirect contact parts to be sterilized, or just disinfected?

A: Annex 1 Section 5.5 requires that indirect product contact parts be sterilized, not just cleaned or disinfected. This is a stricter standard than many facilities used prior to the 2022 revision.

Q: What happens if a stopper bowl or other indirect contact part can’t be removed for sterilization?

A: Manufacturers are expected to pursue a risk-based justification, informed by ICH Q9 quality risk management principles, and to provide evidence that an alternative approach delivers equivalent sterility assurance. In practice, many facilities are redesigning lines to use detachable components instead.

Q: Is decontaminating an isolator or RABS the same thing as sterilizing product contact parts?

A: No. Sterilizing contact parts and decontaminating the surrounding enclosure are two distinct, complementary steps within an overall Contamination Control Strategy.

Q: How does SteraMist’s iHP technology support Annex 1 compliance?

A: SteraMist’s ionized Hydrogen Peroxide (iHP) system provides validated, repeatable six-log sterilization for isolators, RABS, pass-throughs, and other small enclosures used in aseptic processing, supporting the environmental control portion of a facility’s Contamination Control Strategy under Annex 1, GMP, and GLP standards.

Speak with a steramist specialist to stay up-to-date with annex 1 compliance ➔