Process Transfer from Open ATMP Manufacture to Closed Isolator Technology

[fusion_builder_container type=”flex” hundred_percent=”no” hundred_percent_height=”no” hundred_percent_height_scroll=”no” align_content=”stretch” flex_align_items=”flex-start” flex_justify_content=”flex-start” hundred_percent_height_center_content=”yes” equal_height_columns=”no” container_tag=”div” hide_on_mobile=”small-visibility,medium-visibility,large-visibility” status=”published” border_style=”solid” box_shadow=”no” box_shadow_blur=”0″ box_shadow_spread=”0″ gradient_start_position=”0″ gradient_end_position=”100″ gradient_type=”linear” radial_direction=”center center” linear_angle=”180″ background_position=”center center” background_repeat=”no-repeat” fade=”no” background_parallax=”none” enable_mobile=”no” parallax_speed=”0.3″ background_blend_mode=”none” video_aspect_ratio=”16:9″ video_loop=”yes” video_mute=”yes” absolute=”off” absolute_devices=”small,medium,large” sticky=”off” sticky_devices=”small-visibility,medium-visibility,large-visibility” sticky_transition_offset=”0″ scroll_offset=”0″ animation_direction=”left” animation_speed=”0.3″ filter_hue=”0″ filter_saturation=”100″ filter_brightness=”100″ filter_contrast=”100″ filter_invert=”0″ filter_sepia=”0″ filter_opacity=”100″ filter_blur=”0″ filter_hue_hover=”0″ filter_saturation_hover=”100″ filter_brightness_hover=”100″ filter_contrast_hover=”100″ filter_invert_hover=”0″ filter_sepia_hover=”0″ filter_opacity_hover=”100″ filter_blur_hover=”0″][fusion_builder_row][fusion_builder_column type=”1_1″ type=”1_1″ align_self=”auto” content_layout=”column” align_content=”flex-start” valign_content=”flex-start” content_wrap=”wrap” center_content=”no” target=”_self” hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky” order_medium=”0″ order_small=”0″ hover_type=”none” border_style=”solid” box_shadow=”no” box_shadow_blur=”0″ box_shadow_spread=”0″ background_type=”single” gradient_start_position=”0″ gradient_end_position=”100″ gradient_type=”linear” radial_direction=”center center” linear_angle=”180″ background_position=”left top” background_repeat=”no-repeat” background_blend_mode=”none” filter_type=”regular” filter_hue=”0″ filter_saturation=”100″ filter_brightness=”100″ filter_contrast=”100″ filter_invert=”0″ filter_sepia=”0″ filter_opacity=”100″ filter_blur=”0″ filter_hue_hover=”0″ filter_saturation_hover=”100″ filter_brightness_hover=”100″ filter_contrast_hover=”100″ filter_invert_hover=”0″ filter_sepia_hover=”0″ filter_opacity_hover=”100″ filter_blur_hover=”0″ animation_direction=”left” animation_speed=”0.3″ last=”no” border_position=”all” min_height=”” link=””][fusion_title title_type=”text” rotation_effect=”bounceIn” display_time=”1200″ highlight_effect=”underline” loop_animation=”off” highlight_width=”9″ highlight_top_margin=”0″ title_link=”off” link_target=”_self” content_align=”left” size=”1″ text_shadow=”no” text_shadow_blur=”0″ gradient_font=”no” gradient_start_position=”0″ gradient_end_position=”100″ gradient_type=”linear” radial_direction=”center center” linear_angle=”180″ style_type=”default” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]Process Transfer from Open ATMP Manufacture to Closed Isolator Technology[/fusion_title][fusion_text rule_style=”default” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]

Martin Glättli – ProSys Group, Cork (Ireland)
Correspondence: Martin Glättli,
Address: ProSys Group, IDA Business Park, Carrigtohill Co. Cork, Ireland T45 AP82
E-mail: martin.glaettli@prosysgroup.com

The rapid increase in demand for advanced therapy medicinal products (ATMPs) is driving the shift from production on a laboratory scale to commercial production. But what about ensuring higher levels of sterility in ATMP manufacturing processes, and taking the right approach when redesigning processes for closed technology? With a view to minimizing the impact of a change of operator in terms of product quality, and to improving product purity, the regulations currently in force strongly recommend isolator technology with reproducible H2O2 decontamination. When it comes to making the change to closed manufacturing, careful process re-engineering is essential, with suitable process equipment being re-evaluated from scratch. This is the approach that will ultimately enable a validated system to be presented to the authorities.

The characteristics of many ATMPs mean that final sterilization is not possible – the long-established process of heat sterilization that is reliably used for many parenterals would simply destroy them. Another common method for final sterilization is the sterile filtration used in aseptic fill and finish, but this method must also be ruled out due to the characteristics of the products involved. The entire manufacturing process demands the highest level of quality assurance, i.e. aseptic processing and a safe environment from thawing to filling. The primary goal is to ensure closed processes, production facilities and systems for cell culture, harvesting, cell purification, production of viral vectors and all other units involved in ATMP production for which a closed isolator environment is essential. Systems of this kind are being developed in parallel with the advances in therapies.

One of the key parameters is that the process, driven by the quantity of product required or the short lead time, moves clearly away from laboratory scale and towards commercial production. Cases of especially short process times apply for example in personalized medicine, with the recipient waiting in the treatment room between collection and administration, or when cells with short survival times are processed. Traditionally, the move would have been away from the bench in the laboratory, and into a series of biosafety cabinets. Regardless of batch size, production must be carried out under aseptic conditions. When it comes to minimizing costly operator errors, the decision to make the move to established isolator technology is a logical one. Such a move is typically rewarded with a 10- to 100-fold increase in sterility assurance level (SAL). What is more, the containment also provides protection for personnel and the environment from Biosafety Level (BSL) 2 material such as live viruses. The use of a decontamination system that is possible in containment barrier systems also offers the advantage of an inactivation cycle with H2O2 at the end of production. Even before the official release of the new EU GMP Annex 1, implementation was already a key issue in the relevant committees and symposia. Above all, however, the focus was on its impact on the manufacture of ATMPs. The main thrust has been clearly defined and set out in various standards, regulations and guidelines: new aseptic production facilities should be designed using closed barrier technology wherever possible. Isolator technology allows for strict separation of operator and process, as well as 6-log bioburden reduction. Overall, these properties make it possible to simplify the measures in the Contamination Control Strategy (CCS), and ultimately ensure increased product safety with regard to contamination by humans and the environment. The process redesign of the manufacturing steps and the closed environment also allow for an improvement in product quality in terms of cross-contamination, and a strict hygienic design allows for thorough cleaning validation. Employee comfort is another important issue – many of the manual production stages in ATMP production require highly skilled and reliable personnel, making them an important element when it comes to risk assessment. It is essential, therefore, to be able to offer good working conditions. Working in a Grade C cleanroom environment is significantly more comfortable than Grade B in terms of clothing requirements, and personnel availability at the workstation is considerably higher. On top of this come the well-known factors that the cost of operating a Grade B clean room is much higher than Grade C due to energy consumption, cleanroom monitoring and clothing. As a result of these factors, the higher investment costs of an isolator-based manufacturing concept are generally recouped after just one to three years of production. The combination of a higher quality of work and a lower total cost of ownership (TCO) is thus a further argument in favour of integrating the ATMP manufacturing process in closed isolator technology (Fig. 1).

[/fusion_text][fusion_imageframe custom_aspect_ratio=”100″ lightbox=”no” linktarget=”_self” align_medium=”none” align_small=”none” align=”center” hover_type=”none” caption_style=”resa” caption_align_medium=”none” caption_align_small=”none” caption_align=”center” caption_title_tag=”4″ animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky” filter_hue=”0″ filter_saturation=”100″ filter_brightness=”100″ filter_contrast=”100″ filter_invert=”0″ filter_sepia=”0″ filter_opacity=”100″ filter_blur=”0″ filter_hue_hover=”0″ filter_saturation_hover=”100″ filter_brightness_hover=”100″ filter_contrast_hover=”100″ filter_invert_hover=”0″ filter_sepia_hover=”0″ filter_opacity_hover=”100″ filter_blur_hover=”0″ image_id=”4163|thumbnail” caption_title=”Figure 1″ caption_text=”Decontaminable autoclaves in a Grade A isolator for ATMP production “]https://www.prosys.com/wp-content/uploads/2023/05/ATMP-CASE-STUDY-1–253×160.png[/fusion_imageframe][fusion_title title_type=”text” rotation_effect=”bounceIn” display_time=”1200″ highlight_effect=”circle” loop_animation=”off” highlight_width=”9″ highlight_top_margin=”0″ title_link=”off” link_target=”_self” content_align=”left” size=”2″ text_shadow=”no” text_shadow_blur=”0″ gradient_font=”no” gradient_start_position=”0″ gradient_end_position=”100″ gradient_type=”linear” radial_direction=”center center” linear_angle=”180″ style_type=”default” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]3. Ergonomic transfer of a manual or semiautomatic ATMP process into an isolator[/fusion_title][fusion_text rule_style=”default” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]

Process changes rarely come without certain hurdles that need to be tackled as part of the process re-engineering. This is especially true when a manual process that has been validated on a laboratory scale and under laboratory cleanroom conditions is now to be transferred to a closed process. Another hurdle – but one that can also be seen as an opportunity – is the question of (partially) automating or at least modernizing the manufacturing process at the same time. Work in the laboratory is generally defined by the positioning of personal workstations, followed by the location of process equipment, and finally by the arrangement of media columns and possibly biosafety cabinets (BSCs) or laminar air flow (LAF) workbenches. This means that the workflow is dictated by the laboratory planner, and not by the process planner. First of all, therefore, process re-engineering is carried out in close cooperation with the process owner and subject matter experts (SMEs) with the aim of designing the process flow according to cGMP, ideally in a step-by-step approach that avoids the repetition of a specific step in the same location. Under certain circumstances, however, such repetitions are acceptable when it comes to using process equipment permanently integrated in the isolator for different process steps. Feasibility must be confirmed with a risk analysis. Process ergonomics must also be considered in terms of the number of operators, with a view to designing the steps in such a way that as few operators as possible are required, and that they can assist each other. Ergonomics from a health, safety and environment (HSE) perspective thus play a role when it comes to ensuring accessibility, especially to equipment integrated in the rear wall, and also allowing for manual cleaning in the closed isolator. The challenge of ergonomics is further complicated by the fact that the overall system must be designed for personnel of various heights and builds. The operators must also be included in the design process, especially in view of the fact they will have to deal with being unable to move sideways as their arms are in the glove ports. Involving operators at an early stage also helps to improve acceptance, in turn allowing for shorter induction times and throughput times in production.

The selection and definition of the process equipment – the incubator, the centrifuge and later the filling station – play a central role. In many manufacturing processes, the equipment is already defined during process validation and can often only be changed with a final revalidation, which in turn involves a significant amount of additional work. The process equipment should therefore be retained if possible, but this can be done only under certain circumstances, i.e. when suitability has been thoroughly clarified, tested and approved. The following points must be taken into account in such a situation:

a) Feasibility of mechanical integration: for reasons of operator ergonomics, large process equipment cannot be placed completely in the isolator, but must be installed in the rear wall, side wall or base plate and be fitted with a gas-tight flange.

b) Ergonomics and ease of use with gloves in the isolator: doors and covers must be openable in a confined working environment.

c) Chemical resistance to vaporized H2O2: surface materials must be declared by the manufacturer and suitability confirmed in order to avoid the need for expensive testing.

d) Surface properties for the killing of biological materials with the aid of H2O2 and its validability: the surfaces must be of sufficient quality for H2O2 decontamination – a build-up of spores would make them unreachable for killing by H2O2. Furthermore, the materials must not absorb H2O2, which would subsequently outgas and result in long decontamination times.

e) Aerodynamics: the directional air flow in the working chamber must be optimal, and must not be disrupted in a way that creates dead space or vortices.

f) Hygienic design: as work is often also carried out with hazardous substances, typically viral vectors, it should also be possible to clean the work area before opening the front isolator door. Among many other factors, this means ensuring flat surfaces and avoiding ball corners, blind holes and socket head screws.

g) Leak-tightness: to protect the operator and the environment, a leak test is performed before the start of a decontamination cycle to warn of any possible leaks. All process equipment must therefore pass the required leak test.

h) Control panel: it must either be possible for the panel to be operated inside the isolator with gloves, or it must be positioned externally, i.e. separate from the process equipment.

i) Control system: 21cfr Part 11 compliant data handling requirements are becoming the standard. Data must be recorded in a complete batch report, and integration of process equipment is essential in this regard.

[/fusion_text][fusion_title title_type=”text” rotation_effect=”bounceIn” display_time=”1200″ highlight_effect=”circle” loop_animation=”off” highlight_width=”9″ highlight_top_margin=”0″ title_link=”off” link_target=”_self” content_align=”left” size=”2″ text_shadow=”no” text_shadow_blur=”0″ gradient_font=”no” gradient_start_position=”0″ gradient_end_position=”100″ gradient_type=”linear” radial_direction=”center center” linear_angle=”180″ style_type=”default” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]5. Overcoming hurdles, and final integration solutions[/fusion_title][fusion_text rule_style=”default” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]Evaluating process equipment in terms of suitability involves increased effort and demands considerable expertise and experience in H2O2 decontamination. Should an item of equipment be declared unsuitable as a result of the evaluation, modifications may be requested from the original manufacturer, or a suitable version may be obtained. This can, for example, be a stainless steel model or one with a flange interface. If this is not possible, the only remaining option is modification by the integrator, provided it has the necessary capability. In most cases this is highly unattractive for the further life cycle, however, as warranties are denied by the original manufacturer, which means that any warranty claim must be accepted by the integrator. Modifications may also include, for example, providing a centrifuge with a specially designed gas-tight enclosure to ensure leak-tightness (Fig. 2).

[/fusion_text][fusion_imageframe custom_aspect_ratio=”100″ lightbox=”no” linktarget=”_self” align_medium=”none” align_small=”none” align=”center” hover_type=”none” caption_style=”resa” caption_align_medium=”none” caption_align_small=”none” caption_align=”none” caption_title_tag=”2″ animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky” filter_hue=”0″ filter_saturation=”100″ filter_brightness=”100″ filter_contrast=”100″ filter_invert=”0″ filter_sepia=”0″ filter_opacity=”100″ filter_blur=”0″ filter_hue_hover=”0″ filter_saturation_hover=”100″ filter_brightness_hover=”100″ filter_contrast_hover=”100″ filter_invert_hover=”0″ filter_sepia_hover=”0″ filter_opacity_hover=”100″ filter_blur_hover=”0″ image_id=”4164|thumbnail” caption_title=”Figure 2 ” caption_text=”Fully integrated centrifuge, validated for H2O2 decontamination “]https://www.prosys.com/wp-content/uploads/2023/05/ATMP-CASE-STUDY-2–253×160.png[/fusion_imageframe][fusion_title title_type=”text” rotation_effect=”bounceIn” display_time=”1200″ highlight_effect=”circle” loop_animation=”off” highlight_width=”9″ highlight_top_margin=”0″ title_link=”off” link_target=”_self” content_align=”left” size=”2″ text_shadow=”no” text_shadow_blur=”0″ gradient_font=”no” gradient_start_position=”0″ gradient_end_position=”100″ gradient_type=”linear” radial_direction=”center center” linear_angle=”180″ style_type=”default” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]6. Validation of process equipment for 6-log H2O2 decontamination[/fusion_title][fusion_text rule_style=”default” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]

Once it has been decided that the manufacturing process will be based on closed barrier technology, the highest GMP level is also expected.

Technical and organizational compliance with the corresponding requirements should be thoroughly tested and documented, so that final process validation can take place. Process risk analysis plays a supporting role in this regard – particular attention is paid to the complete and thorough validation of the decontamination of the interior, including all surfaces of the process equipment. In the practical implementation of validation activities, especially in the preceding steps such as cycle development, it is of course helpful to use a decontamination system that can handle changing external influences such as load, materials and temperatures. It is also essential to ensure simple and reliable distribution of the H2O2 vapour, which also allows for deep penetration into horizontal protrusions such as the incubator. The task of developing and deploying such a decontamination system clearly falls into the category of “quality by design”, or QbD. The suitability of process equipment for decontamination with H2O2 must also be evaluated and tested if necessary. In case of initial unsuitability, such as leaky housing or shaft bushing, a solution must be found to prevent air backflow in certain operating modes or during manipulation. This is due not least to the fact that such areas are not easy to decontaminate and carry the risk of contamination during operation. This can be remedied by a specially calculated flow with H2O2. Finally, proof of efficiency is provided in the traditional manner by means of bioindicators, which must be placed at all worst-case locations identified in advance.

[/fusion_text][fusion_imageframe custom_aspect_ratio=”100″ lightbox=”no” linktarget=”_self” align_medium=”none” align_small=”none” align=”center” hover_type=”none” caption_style=”resa” caption_align_medium=”none” caption_align_small=”none” caption_align=”none” caption_title_tag=”2″ animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky” filter_hue=”0″ filter_saturation=”100″ filter_brightness=”100″ filter_contrast=”100″ filter_invert=”0″ filter_sepia=”0″ filter_opacity=”100″ filter_blur=”0″ filter_hue_hover=”0″ filter_saturation_hover=”100″ filter_brightness_hover=”100″ filter_contrast_hover=”100″ filter_invert_hover=”0″ filter_sepia_hover=”0″ filter_opacity_hover=”100″ filter_blur_hover=”0″ image_id=”4165|thumbnail” caption_title=”Figure 3 ” caption_text=”ATMP fill & finish isolator with semi-automatic filling of nested vials.”]https://www.prosys.com/wp-content/uploads/2023/05/ATMP-CASE-STUDY-3–253×160.png[/fusion_imageframe][fusion_title title_type=”text” rotation_effect=”bounceIn” display_time=”1200″ highlight_effect=”circle” loop_animation=”off” highlight_width=”9″ highlight_top_margin=”0″ title_link=”off” link_target=”_self” content_align=”left” size=”2″ text_shadow=”no” text_shadow_blur=”0″ gradient_font=”no” gradient_start_position=”0″ gradient_end_position=”100″ gradient_type=”linear” radial_direction=”center center” linear_angle=”180″ style_type=”default” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]7. Conclusion[/fusion_title][fusion_text rule_style=”default” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]Taking the right approach the first time means that the following points can be fulfilled:

The process integrator is proactively involved in the project and is able to accurately understand the process.
The process integrator is familiar with the rules and regulations and translates them into process ergonomic solutions.
The process integrator suggests process improvements and equipment pre-tests and simplifies processes, thereby helping to ensure quality by design.
The process integrator is available on site from commissioning to auditing and maintenance, and takes responsibility for the CCS of the system.
The process integrator provides a process with the required ergonomic flexibility and ensures the full integration of the process equipment (Fig. 3).

[/fusion_text][fusion_title title_type=”text” rotation_effect=”bounceIn” display_time=”1200″ highlight_effect=”circle” loop_animation=”off” highlight_width=”9″ highlight_top_margin=”0″ title_link=”off” link_target=”_self” content_align=”center” size=”2″ text_shadow=”no” text_shadow_blur=”0″ gradient_font=”no” gradient_start_position=”0″ gradient_end_position=”100″ gradient_type=”linear” radial_direction=”center center” linear_angle=”180″ style_type=”double solid” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” sticky_display=”normal,sticky”]Author[/fusion_title][fusion_person name=”Martin Glättli” title=”Aseptic Subject Matter Expert ” linktarget=”_self” hover_type=”none” social_icon_colors=”var(–awb-color1)” social_icon_colors_hover=”var(–awb-color1)” social_icon_boxed_colors=”var(–awb-custom15)” social_box_colors_hover=”var(–awb-color6)” show_custom=”yes” animation_direction=”left” animation_speed=”0.3″ hide_on_mobile=”small-visibility,medium-visibility,large-visibility” picture=”https://www.prosys.com/wp-content/uploads/2023/05/ATMP-CASE-STUDY-4–253×160.png” picture_id=”4166|thumbnail” linkedin=”https://www.linkedin.com/in/martin-gl%C3%A4ttli-a2390911″ email=”martin.glaettli@prosysgroup.com” icon_position=”bottom” pic_style=”bottomshadow” social_icon_boxed=”yes” social_icon_tooltip=”Right” social_icon_color_type=”custom” content_alignment=”center”]Martin Glättli works in Basel, Switzerland, as SME
Aseptic Solutions for ProSys Group. He has spent
over 24 years in the pharmaceutical industry,
20 of which have been closely involved with the
development of isolator technology. He is passionate
about helping to bring about a fusion of
engineering, microbiological and commercial
aspects to create a solution that will convince
future process owners and users, and help keep
their desks free of deviation reports.
Either[/fusion_person][fusion_global id=”3979″][fusion_global id=”4776″][/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

Process Transfer from Open ATMP Manufacture to Closed Isolator Technology

QUICK LINKS