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Designed, Sealed and Delivered


To run a successful prefilled syringe manufacturing operation, there is an increasing need to integrate quality by design into the assessment of a sterile manufacturing facility. The design, engineering and construction of high technology pharmaceutical space for prefilled syringes is technically uncompromising, requires significant financial investment, and demands the careful attention of knowledgeable people if it is to meet and anticipate the standards demanded by regulators, manufacturers and ultimately by caregivers and patients. When designed and executed correctly, however, a well-maintained facility and infrastructure promotes the precise control of product quality, and ultimately helps a supplier achieve optimum cost for a product throughout its marketed life.

As with a quality by design (QbD) approach to drug development, those designing a sterile pharmaceutical prefilled syringe fill and finish facility and infrastructure will first need to identify the critical attributes required of both the product or products and the requirements and any limitations of the facility where they are to be produced. The designer will ensure that the facility is somewhat flexible and expandable, but at the same time that the critical to quality attributes (CQAs) necessary to meet and maintain standards are ‘designed in’ from the outset.

An indication of the strength and suitability of a sterile fill and finishing outsourced solution can be determined by looking in depth at the facility and its infrastructure. A facility design space, somewhat like QbD’s formulation design space, is a multidimensional combination of input variables, and process parameters that have been previously demonstrated as key in indication of the strength and suitability of a sterile fill and finishing outsourced solution can be determined by looking in depth at the facility and its infrastructure. A facility design space, somewhat like QbD’s formulation design space, is a multidimensional combination of input variables, and process parameters that have been previously demonstrated as key in providing assurance of the desired quality. As the expectations of output are many and varied, it is incumbent on the design authority to assemble multidisciplinary teams to balance the needs of the product and attributes required in the facility at the design phase, and so execute CQAs.

Current good manufacturing practice (cGMP) and other regulatory guidance does a good job defining ‘what’ is required from a facility and its infrastructure, and allows flexibility in ‘how’ this is to be achieved. Pharmaceutical and biotechnology companies outsourcing sterile filling and finishing of their products should therefore critically examine potential partners against how compliance to the regulations has been met during the qualification phases, and, as importantly, how they demonstrate and maintain ongoing compliance.

Evaluating an Outsource Partner

Start by reviewing the architectural design of the prefilled syringe provider. A purpose-built, sterile fill/finishing facility will have shown consideration of multiple aspects such as the flow of product and people, and specific product and process requirements, including equipment and equipment infrastructure.

A good architectural design will likely have a product flow that is clear, and will have outstanding separation for different processes. If it is logical, then it can be easily explained. Look for a ‘Main Street’ or a common corridor, which is frequently used to allow entry and exit from process areas and at the same time separate these areas. Optimising the movement of people and product at the design phase not only enhances productivity by eliminating wasted movement, it also minimises the potential for contamination.

Access Control

People flow can be further controlled by employing badge access or other similar security practices. When combined with a common corridor approach, this helps ensure that only trained and qualified personnel with a genuine need to enter controlled areas can actually do so. Today, there are several voice and closed-circuit technology tools available to support such initiatives and thus to minimise unnecessary ‘traffic’ entering clean production areas. To reduce the need to enter a controlled environment, processes and personnel should be easily observable from viewing areas within the common corridor.

Pay particular attention to pass-through areas or air locks designed for entry and exit of equipment and materials. A strong prefilled syringe facility and quality system will have a written preventative maintenance and cleaning plan with specific reference to such pass-through areas. Pass-through chambers, like the production areas themselves, should have no recesses that cannot be cleaned and have only the minimal storage space and shelving necessary for efficient handling.

Watch for Process Waste

When selecting a fill and finish supplier, watch for signs of multiple handling, or wasteful people or material movement. Observations like these can indicate sub-optimal facility design or execution. As well as contributing to excess cost, an improper flow increases the potential for product damage or loss. The product should be manipulated only if and as value is added to it. Also watch for non-moving materials. Anything but essential line storage or ‘work in process’ can suggest waste and also increases the potential for damage, loss or misdirection, another indication of improperly designed flow or execution.

Some products may require temperature, humidity or other controls, special lighting and other unique processes. The facility design must deliver on these attributes, but at the same time, these special needs must not interfere with other design space standards, such as cleanliness, human comfort or logical product flow.

Look ‘Beneath the Skin’ of the Facility

Besides the easily observable attributes of overall facility design and the flow of people and product, there are several attributes that are not so easily assessed without specific reference, which can give an indication of the prefilled syringe supplier’s ability to produce sterile products reliably. It goes without saying that all compliance elements warrant attention, but three items will be discussed further here: mechanical utilities such as heating, ventilation and air conditioning (HVAC); design for sterility; and maintainability.

Mechanical utilities, especially HVAC, are key infrastructure enablers in maintaining product cleanliness, helping to prevent cross-contamination, and delivering appropriate people and product temperature requirements.

Confirm that there are independent and segregated HVAC systems for different processes and products to prevent cross contamination potential, and provide for employee comfort. Maintenance and calibration of HVAC equipment, continuous feedback and alarm systems for air balances to ensure appropriate pressure cascades and calibration of high efficiency particulate air (HEPA) filters are appropriate and critical measures of adequate design and ongoing control.

Any outsourced prefilled syringe facility should be able to demonstrate outstanding performance at meeting and exceeding compliance standards by providing adequate design margins, performing timely maintenance and calibration, and utilising real-time alarms along with statistical process control monitoring. Review of a site’s HVAC systems’ performance, including exception handling, standard operating procedures for excursions or one time events, along with escalation practices, are useful to determine the robustness of this critical sub-system.

Design for sterility is particularly important when considering how the facility will support process equipment clean in place (CIP), sterilise in place (SIP) or operational usage. From a facility point of view, always check drain design and handling of excess process water and steam, as they are serious potential contaminant sources.

When completing an overview assessment of a fill and finish supplier, a useful practice is to pick one or two critical utilities (process gasses, clean dry air (CDA), process chilled water, water for injection (WFI) and/or de-ionised water) and actually ‘walk the line’. Is it ‘designed for sampling’, meaning accessible? Does it come to the work space via the most direct route? Do the facility prints match the physical reality? Can you observe any dead legs or inappropriate materials? Again, good incorporation of utilities is evidence of superior facility and infrastructure design and so can greatly enable reliable sterility performance.

Finally, when selecting a sterile fill and finish prefilled syringe supplier, the maintainability of the site and infrastructure becomes critical. A strong facility design will enable inspections, controls and as many preventative maintenance and repair tasks as possible to be completed from outside the clean areas.

In-house maintenance staff are common at pharmaceutical fill and finishing plants, but contracted resources are inevitably required for some specialist tasks. Look for a programme that specifies training, management and supervision of these resources.

A facility and its infrastructure are always changing, be it continuous improvement, growth, new technology, addressing obsolescence or any number of other factors. Fill/finishers demonstrating change discernment will be able to share their process results which should minimally include: technical risk assessments, well-written change controls, and qualifications and validations for completed and/or in-process changes.

Conclusion

Lack of good facility design or ongoing facility controls can and has resulted in recalls, regulatory findings, and reputation damage. Good results can be obtained with prefilled syringe fill finishers who comply with regulations by designing in facility and infrastructure adherence to QbD-like attributes for their facility and infrastructure to ensure high value, safe and effective drug products.

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Kay Schmidt joined Catalent Pharma Solutions as Sterile R&D Platforms Director in 2009. Based in Catalent’s Woodstock, IL facility in the US, Kay is responsible for the development of Catalent’s portfolio of sterile injectables products and services and its blow-fill-seal product ranges. Prior to joining Catalent Pharma, Kay held medical device research and operations leadership positions and has 25 years of experience of the development of clean room facilities from ‘green field’ and within existing premises. Kay holds a BSc and MSc and is a certified Six Sigma Green Belt.
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