Another FDA Warning letter for a facility in Jordan.  This is an interesting observation indeed.  Published in February of this year, it highlights a deficiency in the understanding of the fundamentals of aseptic sterile manufacturing.

 

14^th Feb 2024

Jordan

2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

 

Sterilization of All Equipment that Contacts Sterile Product Constituents

Your firm failed to sterilize multiple pieces of equipment (e.g., hoppers, tracks) that directly contacted (b)(4) constituents of your sterile products, including primary containers and closures. It is essential that sterile equipment is used in the processing of all elements of the sterile product. Conducting only cleaning and disinfection (e.g., (b)(4)) of such equipment is inappropriate, as it is not equivalent to use of (b)(4) (or equivalent sterilization method, such as (b)(4)) sterilization of equipment. Validation of sterilization cycles is based on sterility assurance evaluations that are comprised of rigorous physical and biological measurements.

In addition, it is essential that only sterile instruments are used for aseptic processing line manipulations and in handling of sterilized materials. Between uses, sterile instruments are held under ISO 5 conditions and continuously maintained in a manner that prevents contamination. It is not acceptable to touch the sterile (b)(4) during aseptic production in the manner performed by your personnel.

Annex 1 requires us to ensure that all product contact components and equipment should be sterilized prior to use. This includes raw materials and intermediates and/or bulk solutions, (clause 8.11).  The sterilization process should be validated, both physically, with temperature sensors and where appropriate biologically with a suitable biological indicator challenge.  The whole of the load should be subject to the required sterilant exposure , (clause 8.36).  To ensure this and to deliver a reliable and repeatable sterilisation process the whole of the load should equilibrate to temperature before the sterilization exposure phase commences, (clause 8.52).

If it is not possible to assemble or connect load items aseptically within the Grade A core (Grade B background) then sterilization in place validation process needs to be considered. Preferably intrinsic sterile connection devices should be designed to mitigate risk of contamination, (clause 8.14).

For materials, items, or components necessary for aseptic processing, that are not direct/indirect product contact then validated disinfection and transfer protocols should be in place, they should be protected from recontamination and the pathways for potential contamination should be clearly risk assessed and included within the EM programme, (clause 8.49)

Where items are sterilized in sealed packaging, the packaging must be compatible with the load items and the sterilization process.  The sealing process should be validated to ensure integrity post sterilisation.  Validation should consider integrity of the sterile barrier system and the maximum hold time prior to sterilisation established and the shelf life assigned to each load item or component should be established, (clause 8.48).

Maximum holding times for equipment and component cleaning, drying and sterilization should be documented and validated.  The maximum holding time for sterilized equipment and components can be stored prior to use and during filling should be established and validated, (clause 8.18) & (clause 8.46)

The qualification of the loading configuration and of the wrapping, orientation and location of individual load items should be carefully considered and clearly documented, such that their unwrapping to enable assembly with other direct and/or indirect product contact parts can be achieved aseptically, (clause 8.12).  For moist heat porous hard goods loads, items to be sterilized must be clean, dry and packaged into their protective barrier systems, that comply to relevant parts of ISO 11607.  Orientation to allow effective air removal and rapid steam penetration should be ensured, (clause 8.61). Equally, condensate drainage and confirmation the load items are ‘sensibly dry’ upon cycle completion should be verified both in qualification of the load and in routine operation, (clause 8.56).