With the release of the Annex 1 draft in December 2017 several new topics and additions were introduced for the production of sterile medicinal products. Several issues were raised and answered in the new revision, targeting processes, equipment, and personnel. New content was added including the introduction of a holistic contamination control strategy, a redefinition of the “media fill”, changed specifications for particle concentrations in clean rooms, and new requirements for personnel. As a consequence, the content increased from 16 pages (127 articles) to 50 pages (269 articles). The main focus of the document shifted towards risk management and the pharmaceutical quality system. In addition, the new revision incorporates the guidance’s of ICH Q9 and Q10 resulting in a rewrite rather than a simple update. A breakthrough is the annotation for annex 1 not being limited to sterile production solely, rather be a guideline for all pharmaceutical productions. This is supposed to enhance the quality system and help to preventively contain microbial, particulate and pyrogen contamination.
A new contamination control strategy
A major change for the production of steril medical products is the introduction of a facility-wide conatmination control strategy. This new control instrument monitors and displays the contamination controll along the whole value chain, starting from the supplier, along the production line, up to the finished product. The strategy is a fundamental element in the quality management system and includes monitoring of the environment, processes, as well as personnel and controlls the degree of implementation of out of specification (OOS) deviations. Every aspect affecting the product quality will be recorded, analysed, and controlled from a holistic perspective.
Aseptic Process Simulation (APS)
The newly introduced „aseptic process simulation (APS)” replaces the former “Media Fill” and expanding the chapter with new content. There are clear recommendations in place in what intervals and under which circumstances an ASP should be performed. Given examples recommend to perform an APS as part of the revalidation, after a “major facility shut down” or in addition to each aseptic process and filling line at least annually for each operator. Consideration should be given to performing an APS after the last batch prior to shut down, before long periods of inactivity, before decommissioning or relocation of a line. This should rise attention to the risk during inactivity and confirm the compliance of the last production period.
Specification of validated systems
An update is the addition of systems such as “single use systems”, “lyophilization”, or “blow-fill-seal”, together with new detailed specifications for other validated systems. The new annex 1 finally incorporates the cleaning validation of equipment and extends the recommendations for validations. This includes a validated maximum duration for each aspect of the aseptic manufacturing process or to consider any transportation or shipping requirements in the validation of the “container closure integrity”. Additionally, annex 1 lists parameters for moist heat sterilization, such as exposure time, correlation of pressure and temperature, together with a maximum temperature range during exposure for porous cycles and temperature. Furthermore, acceptance criteria are required for these.
Several changes concern the chapters “premises” and “production and specific technologies” (former “processing”). This includes specific requirements such as a qualification list for materials and equipment to be transferred into grade A/B areas via air lock or pass through. Or to use microbial ingress studies (or alternative methods) to determine the acceptable stopper height displacement for capping vials. A major impact will have the identification of microorganisms isolated from contaminated units to (at least) the genus. Raising the challenge for each process step.
Dr. Florian Blauert