Proposed Changes to EU Annex 1 – Manufacture of Sterile Medicinal Products
The EU Annex 1 guidance for the manufacture of sterile medicinal products was first published in 1971 and was then updated with very specific topics up until 2008 which is when the last update was published. Since then, much has changed in the industry and in 2018, the EU finally issued a proposed change to that document which is a major re-write. The new version is 50 pages long vs the current version which is only 16 pages. Comments from industry were due back by March 20th and the final publish date has not been announced. ISPE published their comments (here) and those comments alone comprise 60 pages, so I wouldn’t expect the final version of this document to be published anytime soon.
So, what are the proposed changes? It is difficult in the space here to list all the changes since almost no part of the document remains untouched. You will see in the summary below (which certainly is not exhaustive) that many of these changes are just documenting current cGMP practices throughout the industry, but some new ideas are introduced as well. Here are some of the more significant proposed changes that I see.
Starting with the table of contents, you will see several new sections that have been added including scope, utilities, environmental and process monitoring.
This revision introduces the concept of Quality Risk Management (QRM) which has been around for many years now, especially here in the US. The entire document was restructured to give it a more logical flow and detail was added to many of the sections in an (although not altogether successful) attempt to provide more clarity. “Media Fill” has been changed to “Aseptic Process Simulation” throughout the document.
A major change that will require some thought, if in the final document, is the requirement for a written Contamination Control Strategy. In the proposed revision, there are suggested sections to include when developing this strategy and these sections include both facility and process considerations. A few of the areas to consider include the design of the facility and process, raw materials control, vendor approval, risk assessments, validation, maintenance, cleaning, monitoring, and continuous improvement.
The Premises section has been expanded and been tweaked a bit. Grade A air velocity guidance values of 0.36-0.54 m/s are still here, but now say that those readings may be taken at either the filter face or the working height as long as you have written justification for which are using. The idea of unidirectional airflow at the working height is still an expectation. One change (among many) that ISPE took exception to is the statement that “only Grade C cleanrooms should interface with Grade B aseptic processing areas”. This is new and if it stays, will require facility changes throughout the world. Separate entry and exit changing rooms previously were stated to be “sometimes desirable”. With the update, it is now stated as “generally desirable”. Also new in the premises section is a section for material airlocks. A major change here is a statement that says pass through hatches without an active air supply should be avoided. I think this is generally a good idea, but again, this will require many companies to make changes to existing facilities to comply. Lastly, the new document clarifies that airlocks into grade A/B areas should be interlocked while doors to lower grades can be alarmed instead. Currently, the guidance says that all airlocks should be interlocked or alarmed without specificity.
The current guidance document includes a section titled “Isolator Technologies”. In the revision, this has been changed to include Restricted Access Barrier systems (RABs) and has been renamed as “Barrier Technologies”. Changes in this section were mainly to add some clarity to required background environments, glove system integrity testing, and pressurization recommendations.
The section titled Clean Room and Clean Air Device Qualification (formerly Classification) have been updated in accordance with the latest revision of ISO 14644. The new document removes requirement to measure particles greater than or equal to 5 micron for classification and qualification (in accordance with the new revision of ISO 14644) but section 9 (environment and process monitoring) keeps the requirement for monitoring in place. The revision adds ISO classifications for each room grade:
Grade A – ISO 5/5 (in operation/at rest)
Grade B – ISO 5/7
Grade C – ISO 7/8
Grade D – ISO 8/8
Additionally, Microbial contamination limits for Grade A have been changed from <1 cfu to 1 cfu with a note saying the expectation should be 0, and any recovery of 1 cfu or greater should result in an investigation. Also new is the specification for requalification periods for clean rooms as follows:
Grade A/B – maximum time interval 6 months
Grade C/D – maximum time interval is 12 months
In the Equipment section there is a new requirement for a written description of the equipment design that includes product, fluid, and gas pathways and controls. It also calls for qualification of particle counters and its associated sample tubing. Sterile product contact surfaces are specifically called out and validated cleaning processes are described in more detail than before.
A new section on Utilities has been added. Risk assessment is mentioned as a method for determining the level of qualification for each utility, and critical parameters of high risk systems are required to undergo trend analysis. One point that ISPE has commented on in the Water for Injection (WFI) section is where the new guidance says that the feed water for WFI systems “should be” purified water. ISPE is recommending that it be changed to “should be produced according to current EP monograph, USP, or WHO requirements”. Steam used for sterilization should be assessed for non-condensable gasses, dryness fraction, superheat, and steam condensate quality. Compressed gas systems require backflow prevention.
In the Production and Specific Technologies portion, there are new sections for Finishing of Sterile Products, Form-Fill-Seal, Lyophilization, Closed Systems, and Single Use Systems (SUS). These all go into some detail regarding these technologies, many of which were not in existence back in 1971 or even in 2008.
There is no need to panic just yet though. As previously mentioned, this guidance is still in draft form and comments that were received from the industry will be considered. All in all though, I would say that this much needed update is a significant improvement on the current version. It provides a lot more detail and should result in less inspector interpretation differences for companies to deal with. There are still ambiguities in the document, but that is out of necessity as with all regulations.