Issue
What precautions should be taken when loading and unloading multiple lyophilizers from a common corridor?
This guidance should address questions raised by lyophilization (freeze drying) facilities involving in using of automated loading and unloading systems for new lyophilizer installations. The options described in this guidance assume the use of such an automated system. Maximum operational flexibility and capacity with these systems is desired without compromising product quality. As such, it is desirable to simultaneously load and unload product from different dryers. This can be accomplished with a pass-through freeze dryer design or with appropriate control of the operation from a single-side freeze dryer design. A review of regulatory guidances and internal standards does not find any prohibition to the recommendations made in this guidnace. A review of the barriers to contamination is provided to support the recommendation that the loading and unloading of the same product can be conducted with a single transfer cart without cleaning or sanitization between each shelf loading cycle within a batch. Further, with separate carts dedicated to loading and unloading, different products can be simultaneously loaded and unloaded in the same transfer corridor.
A single cart should not be used to load and unload different products without cleaning between these uses. Cleaning and sanitization validation, airflow pattern studies, environmental monitoring program, as well as satisfactory sterile process simulations (media fills), are required to support any operating mode chosen. Products containing penicillin, cephalosporins, sex hormones, cytotoxic compounds or live biological agents are excluded from consideration and require more rigorous isolation thorough separate facilities or dedicated equipment.
Introduction
Generally, filling and primary packaging lines for lyophilized products are constructed to be separate from each other to avoid issues of cross contamination and product mix-up. The use of multiple freeze dryers and the extended nature of lyophilization cycles offer the possibility to run the filling line separate from the capping line to optimize the capacity of the workcenter.
One method to separate these functions is to use a pass-through dryer design, loading from one side and unloading from another. Regulatory and internal standards do not require this option and alternative options may be considered. The options described below address conditions using single and multiple transfer carts and situations with multiple lots of the same product as well as operations involving different products utilizing freeze dryers which involve loading and unloading from the same side.
For any option to be used successfully, the concerns of contamination (microbiological and chemical cross-contamination) as well as potential product mix-up must be addressed.
For the purposes of this discussion, the definition of same product includes different strengths of a product containing the same active ingredient.
Regulatory Guidance
The FDA, in its Guidance for Industry: Sterile Products Produced by Aseptic Processing – Current Good Manufacturing Practice requires that “ … partially closed sterile product should be transferred only in critical areas. Facility design should ensure that the area between a filling line and the lyophilizer provide for Class 100 (ISO 5) protection. Transport and loading procedures should afford the same protection.”
The FDA set similar requirements in their earlier Guide for Inspection of Lyophilization of Parenterals. Here, they state “The transfer and handling, such as loading of the lyophilizer, should take place under primary barriers, such as the laminar flow hoods under which the vials were filled. Validation of this handling should also include the use of media fills.”
The EC also requires that “Prior to completion of stoppering, transfer of partially closed containers, as used in freeze drying should be done either in a grade A environment with a grade B background or in sealed transfer trays in a grade B environment.
No requirements are stated for unloading the dryers. Here, with internal stoppering, the stoppers have been fully seated within the protection of the closed dryer. No requirements are stated for separation (in time or space) of loading and unloading activities or between multiple dryers.
A search of FDA Warning Letters on the FDA website (from November 1996 to date) found one reference to lyophilization or freeze dryer loading and unloading. This letter contained an observation that “The partially stoppered vials are not kept in a class 100 environment during mobile cart transfer process to the lyophilizer”. This observation references 21CFR 211.42b.
Finally, products containing penicillin, cephalosporins, sex hormones, cytotoxic compounds or live biological agents are excluded from consideration and require more rigorous isolation through separate facilities or dedicated equipment.
Recommended Standards
It can be recommended that transferring to (the) lyophilizer and loading into and unloading from the lyophilizer shall be processed using aseptic technique in a Grade A environment with a Grade B background. The stoppered vials shall remain in a Grade B environment and shall be conveyed to the stopper/sealer under Grade B conditions.
Barriers to Contamination
Multiple barriers exist to protect the product from microbial ingress and chemical cross-contamination during product transfer and dryer loading and unloading. As stated by the
regulatory authorities, transfer from the filling line and loading should take place in a very clean and controlled environment; Grade A with a Grade B background. Unloading requirements are not specified by the regulatory authorities.
The separation of adjacent operations can be improved through the use of barrier technologies around the transfer cart such as that provided by an isolator or a restricted access barrier system (RABS). The isolator is enclosed on all sides while the RABS is open only below the work surface. In both cases, an overpressure protects any openings against particulate ingress. It may also be possible to provide adequate protection with a hermetically sealed cart. A slot door (“pizza door”) is used on new dryers to limit exposure to a single shelf during loading and unloading and to minimize disruption of the airflow surrounding the transfer operations.
Further protection is provided by the use of lyo-stoppers to partially close the vial during transfer to the dryer (providing a tortuous path to particulate entry). Stoppering of the vials inside the dryer provides fully closed vials for unloading and transfer to capping.
A potential source of cross contamination can arise from dried product which is exposed during unloading. Such product can come in small amounts from splashes and breakage during filling and loading and vapour deposition and vial breakage during lyophilization. HEPA filtration in the room and on the cart(s) should be designed to prevent the transfer of dried product. Smoke testing should be used to demonstrate air exhausted from one cart is not transferred to another.
Further control of cart movement and their relative proximity can be programmed with an automated system if smoke testing reveals such control is necessary.
Validated washing and sanitization procedures are used to assure successful chemical and microbiological cleaning of the transfer cart(s) between batches. The dryers are cleaned and sterilized between each use so they should not offer a source of contamination to the cart(s).
Finally, if a single cart will move between the unloading accumulator, dryers and the loading accumulator, both the loading and unloading accumulators must be maintained in a Grade A environment so as not to contaminate the cart.
Loading/Unloading Options and Recommendations
The following options apply to the use of an automated or semi-automated loading system and assume the system has been validated to deliver and retrieve vials from the selected dryer and shelf to prevent product mix-up.
Option 1: A single cart is used to load and unload two batches of the same product. Acceptable, With both the loading and unloading accumulator in Grade A environment and provision for verification of vial clearance between cycles (e.g. transfer of a single shelf of vials) to prevent product mix-up.
Option 2: Two carts, one dedicated to loading and the other to unloading are used to load and unload two batches of the same product at different times or simultaneously. Acceptable, Carts are washed and sanitized after completion of each batch.
Option 3: Two carts, one dedicated to loading and the other to unloading are used to load and unload two batches of different products at different times or simultaneously. Acceptable, but limited to isolator and RABS cart designs to provide an additional barrier to chemical cross contamination. Carts are washed and sanitized after completion of each batch.
Option 4: A single cart is used to load and unload two batches of different products. Not Acceptable, Risk of contamination of liquid product (being loaded) by dried product from spill or breakage on vials being unloaded too great. Contamination may transfer via table surface in cart.