Resolving challenges in reliable and efficient high containment systems in pharma industry

Process equipment are expensive long-term investments, the conundrum for manufacturing is how to address increased safety requirements from ever increasing drug potency.

With current technology, operator exposure levels (OELs) of 10–50 nanogram/m-3 8h Time Weighted Average (TWA) can be readily achieved and should present a reliable outcome. However, over the course of many years, some key failure modes have been observed; including failed OEL measurement during validation, equipment too difficult to work inducing operators to take shortcuts, rapid system deterioration after production use or even lack of budget where there is a need to manufacture high potency compounds without full recognition of the costs.

Fully considering the main influences of the containment failures helps to provide more positive and controlled outcomes.

OEL definition and testing

The key priorities are operator safety and drug quality. When developing drugs, the risks at the early stages are not always fully understood. An ultra-conservative philosophy has to be applied until there is sufficient established data for the product. It is not untypical for a research level of nanogram/m-3 to be relaxed to 1 microgram/m-3 by the production stage.

A common method to establish OEL performance is to use a placebo such as micronised lactose with a d50 at approximately 20 µg for which accredited laboratories can detect at 2 ng. ISPE guidelines are useful directive to follow when measuring OEL, such as the Risk-MaPP (Risk-based manufacture of pharma products) which provides a scientific risk-based approach. This is based on quality risk management, managing the risk of cross contamination in order to achieve and maintain an appropriate balance between product quality and operator safety. It takes into account background prior to testing and potential weak points around the equipment in addition to passing traffic. It will also allow comparable performance.

There has been a trend in recent years to have bands of OEL for facility performance. When validating we need to ensure that we test to the lower level. A regular method is to simulate three operations over say a one-hour period and utilise this result in a TWA consideration.

Utilising an additional 10:1 safety factor, for example 0.1ug/m-³ rather than 1ug/m-³, is questionable. There is already a considerable safety factor built into the initial OEL objective and this additional factor has been used due to unreliable system design. This is not a scientific approach as it would suggest a lack of knowledge and understanding resulting in unnecessary cost and complication.

Where does the risk of failure come from?

When you buy a dryer, mill system or capsule filling machine, you expect it to work. A containment provider has to truly understand all relevant manufacturing processes to ensure that practical and safe solutions are provided to address all potential risks.

The risk of breaching the containment:

• It is obvious that isolator designs need to be workable by an operator: when containment equipment is difficult to work with, operators would tend to attempt shortcuts. Glove boxes and isolators passing an OEL test during site or factory acceptance test (SAT or FAT) will not necessarily perform the same if the defined operating procedure is not strictly followed.

So what is the solution?

Running through all of the operations with full-scale ergonomic models can prevent this risk. Incorporating oval glove ports for an easier operation and less than 550mm (front to back) for single-sided ridged window access are examples of design features making isolators easier to operate.

Working with full scale mock-ups also helps planning the equipment to its exact requirements and ensures there is sufficient space and installation access to the building.

• Robust designs have to be supported by long-term field operations data. These designs also need to consider construction standards for long-term performance. Will 2mm stainless steel bodies perform as well as 4mm in continuing to seal 10 years later? Is the reliance of a single thin flexible barrier sufficient if there is a breach? Disposable flexible containment presents a rapid and cost effective solution, but when manufacturing has to address long-term production programmes of highly potent drugs the risk of breach, in regards to longevity, should not be overlooked.
• An assessment of glove permeability should also be considered. When previously working in production with a substance that attacked the cholinesterase in the blood, the product was found to have permeated the initial glove selection. This was picked up by weekly blood sample checks on the operators and the glove material was then changed to prevent this occurrence.

The risk of cross-contamination and product exposure:

• Powder handling has to work routinely or be sensibly recovered in a contained fashion. An assessment of powder transfer methods and powder handling characteristics should be carried out as well as an evaluation of materials handling including manual or mechanically assisted requirements. The containment provider has to integrate interconnecting systems – determining powder handling through split valves, airlocks, rapid transfer ports (RTPs) and bag-out ports.
• Sampling can be a very difficult challenge if not considered at the start. If sampling raw materials it may be an opportunity to subdivide at the same time to avoid double handling of the raw material drums. Process sampling should assess multi-product processes, as different batch levels would limit a fixed position sampler. An angled sampler, for example can overcome these height differentials.
• Production facilities can involve numerous machineries, which can put operators at risk of injury when operating the equipment. The containment solution needs to incorporate safety switches to avoid windows being opened or hands being placed inside the gloves whilst any part of the machine is operating. Gloves guards are installed for safety protection if someone attempts to access the inside of the isolator.
• Cleaning regimes form an integral part of reducing the risk of cross-contamination. For vessels, reflux cleaning followed by CIP can be very effective reducing levels down to 5ppm or non-detectable. But for isolators and glove boxes the use wipes to pre-clean is preferred, as it provides a concentrated solid waste rather than high volumes of liquid waste which are more costly to treat. CIP should be completed following the wiping technique. Product contact surfaces of 0.4 um Ra are perfectly adequate without electro polishing, which is required for sterile applications. Spraying solvents inside non-pressure vessels, even with purging, is not recommended.

Risk of explosion and solvent ignition

• Where necessary, a modification of process equipment can be performed such as the relocation of internal drives to the isolator’s exterior. Incorporated process equipment such as mills, granulators, blenders or tablet presses requires changes in the control and automation systems to address the ATEX rating. These EU directives describe what equipment and work environment is allowed in an environment with an explosive atmosphere. There is of course a risk of explosion when in the same environment a combustible (gas or dust), a source of ignition (spark or flame) and oxygen meet.
• Safety measures are a critical point to avoid dust explosion or solvent ignition including a nitrogen protection system when applicable. Most organic dust will not ignite below 8-9 per cent oxygen. Aluminium alloys for example will ignite at 2-3 per cent oxygen. Static ignition of solvents in most cases can be prevented below 4 per cent oxygen; however, pyrophoric substances like lithium hydride should be at zero oxygen.
• Laboratory tests can be undertaken on internal and external friction cohesion as well as bulk density (the potential energy to overcome these frictions) in anticipating powder flow. A major installation can fail due to lack of proper powder handling assessment.

Finally a containment provider needs to maintain a long established documentation system with end-users, assuring project efficiency from start to finish. A quality plan and seller document index (listing all documents with a unique reference number and issue status) and a project programme are the documentation part of the qualification and validation of the containment system.

A full documentation package is provided for review prior to commencing final manufacture, and then final assembly and testing can be performed. SAT and IQ/OQ (installation qualification and operation qualification) would normally be included to certify optimum performance of the containment system.5

Comprehensive training of the operation and maintenance personnel on the equipment ensures knowledge to be transferred to the end user, thus minimising risks of a containment breach as seen previously.

How the equipment will be used and maintained throughout the years has a direct impact on the containment level. OEL testing and ISPE guidelines are essential procedures to ensure that a containment system is delivered and installed according to the industry regulations, but how to guarantee a consistent containment level years after its installation despite robust and ergonomic construction, when the human factor is also involved is a challenge in itself.