Emissions Control and Extraneous Materials Containment

The recently released FDA guideline on extraneous materials will obviously cause much consternation for Quality Organizations. Questions will need to be asked, and answered, beyond normal processing parameters which have never been formally addressed. Using a Risk-MAPP approach may result in a series of heretofore unasked questions about cross-contamination from the workplace – and associated answers, e.g.

  1. How low must trace analyses perform (percentile, ppm, ppb,or nano-concentrations)
  2. How efficient is sampling and analysis at trace levels on both internal process surfaces and external exposed surfaces (what is the sample recovery from different surfaces)
  3. What are the user costs of sampling and analysis method development at the trace level for a multitude of materials potentially surrounding a process (ballpark figures for each moiety are ~$35,000 to $60,000 per molecule at the ppm level, and increasing by an order of 2 – 5 successively sensitivity improvements)(ca.2014)
  4. What does it cost a user per sample (>$500 for a single sample and decreasing to ~$175 – $250 for samples in excess of 24 for each component analyzed) (ca. 2014)
  5. How rapidly can sampling be achieved, and how fast is sample turnaround and data approval
  6. Must all sampling be performed by certified (or Quality) personnel
  7. How effective are current room cleaning techniques
  8. Must cleaning be performed by certified personnel
  9. How long does cleaning take
  10. How long before Quality release
  11. The extent of materials migration both into and out of a process train
  12. How effective is surface cleaning at process equipment boundaries
  13. How effective is the Personal Protective Equipment (PPE) both for protecting the employee and the process
  14. Are PPE removal and employee decontamination adequate
  15. Are current process and PPE waste handling practices adequate
  16. Are equipment movement procedures for tear-down, inspection, permitted pass through adjacent rooms, shared hallways, and storage
  17. Are dedicated isolated areas required for shared equipment cleaning and storage adequate
  18. How long will a cleaning cycle last before release to production
  19. How long will a cleaning cycle last before release for batch production
  20. How long will cleaning and equipment release take between product changes
  21. Will Quality have to release the process for further manufacturing
  22. Frequency of re-validation to ensure an operational facility
  23. What is the cumulative cost of any combination of efforts needed to ensure acceptable migration limits
  24. The alternative costs of engineering controls to mitigate or minimize efforts to ensure absence of materials migration (airflow controlled, rigid containment, flexible containment solutions)
  25. Are the engineering controls functional across different processing batches to achieve an economic solution (how cleanable, or disposable, are surfaces within the engineering solution boundary
  26. Do shared facilities, e.g. dispensing contribute to contaminant build up

The issue of cost can be significant. Materials leakage (spontaneous or continuous emissions) from a processing flight which results in dispersion within a processing suite incurs multiple costs of manufacturing, and inevitably affects the useful cycle time of a processing rig. Lost production, and product lot rejection, and rework add significantly to manufacturing costs.

Recent contamination issues around generic drugs shipped from third world manufacturers have given rise to the new guidance criteria. It doesn’t take much crystal ball gazing to anticipate questions that will be asked during an Agency inspection. Both the initial licensed patented drug manufacturer, contract manufacturers, and subsequent generics manufacturers will be required to detail identities of process and acquired contaminants (extraneous materials) in their product. This will afford agencies a database which can be used for policing third party and toll manufacturers as well as policing counterfeit drug imports.

The cumulative user costs for performing such analyses on a product will not be insignificant. Add to this the many other potential surfaces to be identified as contaminant sources and the costs become staggering. It doesn’t take long to realize that Quality Control Laboratories can rapidly become overwhelmed and in need of incremental growth at all levels.

As sampling and analytical methodology improves, the adequacy of existing cleaning practices will be raised. Current cleaning practices for surfaces outside the processing equipment may be adequate for today’s criteria but found insufficient to address the new criteria. Cleaning method developments such as those placed in practice by a few of our partners will be needed. While the methods are more efficient and result in a lower waste burden, their development was at a high cost. FabOhio, Inc. has participated with clients cleaning method development and implementation for many years. As such, our cleaning knowledge across a wide range of environments can be invaluable to our clients.

Current PPE usage incurs many costs to maintain an in-house program including operator training, routine testing, storage and shipping costs, qualified equipment repair, decontamination and waste handling. Any incremental PPE procedure and/or devices will be accompanied by new programs and practices at all levels of the program – also at incremental cost.

By controlling material migration from external sources you can eliminate most of the above concerns! What are the alternatives?

Localized Airflow Containment (a form of Ventilation Control) is a highly efficient method of particle redistribution, especially for small particle sizes, e.g. milled materials handled in bulk packaging, dispensing, final product formulation and packaging, and equipment teardown and cleaning.

Total body covering using appropriate PPE, and associated decontamination and waste disposal are required.

Capital costs are high for shipping and handling, installation, and system balancing.

Operating costs include large volumes of conditioned make-up air along with the energy consumed by blowers operating at a relatively high pressure differential due to the need for UHEPA (Ultra High Efficiency Particle Air &/or absorption) filtration.

Design and fabrication can become a long process. Use of an existing design can shorten the process. Design to finished delivery and installation can take several months. Maintenance is moderately high for maintaining balanced flow as filters blind, and filter change-out and disposal during a scheduled outage.

Once a ventilation control system is installed, there is Agency expectation that system performance testing be incorporated into operational parameters within a manufacturing document, e.g. a New Drug Application, with formal documentation of remedial measures.

Rigid Containment which is particularly effective for processing materials expected to have a long production life in a dedicated manufacturing suite.

The high initial cost is offset by the fact that both process performance and cleaning efficacy only need be performed initially and after equipment maintenance or configuration change.

A clear advantage is the virtual elimination of need for PPE. Conventional protective clothing is adequate since product contact is eliminated.

Cleaning performance testing may need to be upgraded from the current Riboflavin/UV light method (sensitivity of fluorescence ~1%) to the more sensitive Acid Yellow/UV method(sensitivity of fluorescence ~40 ppb) practiced by some of our clients. Surprises may result from such testing when used for Cleaning Validation in preparation for a new product.

It may be that Rigid Containment proves unsuitable for multiple product use without extensive downward and some surface conditioning, e.g. acid polishing, electro-polishing, or surface coating.

Because Rigid Containment systems are such an integral part of manufacturing, they are normally included in the manufacturing criteria and documentation subject to Agency Inspection, e.g. operating pressure ranges, filter change-out records, filter leakage testing frequency and performance, cleaning performance, etc.

Incorporation of Rigid Containment can take up to a year from initial concept, through design and Design Qualification (DQ), prototype mock-up, fabrication, factory testing and Installation Qualification (IQ), on-site setup and Operational Qualification (OQ), Performance Qualification (PQ) with surrogate, before being placed in service along with Process Performance Qualification (PPQ). Any failures noted along the Qualification path require remedial action and further Qualification testing. All documentation is archived for Agency review as part of the manufacturing compliance record.

Flexible Containment displays multiple advantages for a manufacturer who has a need for rapid equipment turnaround, and especially when deploying older equipment. Much equipment in laboratories, production, and storage, was placed in use before newer demands of potent compound manufacturing. This is common across the board, ranging from the major players to the most recent entrants.

Flexible Containment can be configured in any size from localized enclosure for piping flanges and small storage containers, e.g. individual Petri dish culture segregation, to full scale manufacturing suites with multiple rooms and either single or dual manway portals with robing, disrobing, and decontamination within a single assembly.

Flexible Enclosures have been demonstrated (third party testing) to deliver an isolation factor in excess of 15,000,000 between the inner and outer containment surfaces during development and production cycles.

With high tensile strength, and elongation to over 6 times the relaxed dimension, polyurethane Enclosures are able to perform under both positive (>20” water gage) and negative pressures when mounted upon a rigid frame with appropriate attachment. Puncture resistance is high requiring high effort with a sharp tool or object, or intentional cuts, before damage occurs.

Individual Flexible Enclosure width design typically takes into account full access based on a glovesleeve reach of 21 inches (American Glovebox Society Publication Guideline for Gloveboxes AGS G-001) from either a single side or 42 inch for two side of access. Horizontal enclosure length can be extended by providing multiple glovesleeves along its length. Flexure of an enclosure allows these limits to be exceeded.

Flexible Enclosure designs allow for operation using conventional coverings used in a manufacturing or laboratory environment. PPE is not required for operation.

Flexible Manufacturing Suites have the same structural capability but design is virtually limitless. Functional designs enclosing two levels have been operated.

Flexible Suites can be operated in both positive and negative pressure modes, limited by the support design and attachment. When used under ambient conditions, they continually flex to accommodate pressure perturbations based on people and materials movement, and fluctuations due to equipment operation, e.g. packaging, jet mill venting, etc.

Since Flexible Suites function by containing the entire equipment train used to manufacture the product, it is necessary for the operator to work within the enclosure fully protected by PPE. This requires gowning, and degowning with decontamination. A full PPE program is required along with contained decontamination and waste disposal. Single entry suites have been used and tested with success, but require vigilance for the decontamination procedure, and is best suited for a single short campaign such as in a Pilot Plant during development and scale-up. A uni-flow access using separate gowning entry and a decontamination and degowning egress is the preferred method and is better suited for a negative pressure dependent control system.

Flexible Enclosures are often used in developing conceptual designs for Rigid Containment systems because they can be instantly modified as operator critique is received. This is also an excellent way to gain operator buy-in since the product of their input can be immediately demonstrated for them to re-evaluate. This overcomes a major obstacle for several reasons: a) the operator(s) begin to develop buy-in when the design incorporates their ideas, b) hard material mock-ups are not readily modified (and certainly not immediately), c) operators can exercise a functional feel not provided by a rigid mock-up, d) when operators are presented with a finished product without prior review some level of rejection has been observed, e) the cost is minimal – typically <$1,000, and f) design, fabrication, and delivery is within a short time – often within 4 – 5 weeks of acceptance of the design concept.

Flexible Enclosure and Suites, unlike Rigid Containment, flex to absorb stress induced by pressure changes and operator access. They readily adaptable using several mounting methods to accomodate multiple operators – petite, tall, short arms, long arms, large girth, vision impairment, etc. without placing stress on the operator. This makes them a friendlier solution, easier to use, and less tiring. Lighting is provided from an external source. They are capable of inert gas operation, and can be delivered particle and viable organism free.

Unless mandated by the Quality Organization, it is best to exclude them from the manufacturing ticket since product contact is not the intent. Any materials leaving the process and settling in the Flexible Enclosure is discarded.

Polyurethane formulation is self catalysing and does not require additives unless antistatic material is necessary. Everything has a vapor pressure, but the volatility of the polyurethane used for fabrication is extremely low and is not considered an issue for manufacturing cross-contamination. The formulation is the same as that used in the automotive industry and does not support combustion, as required for automotive safety. Antistats do contribute a vapor pressure potential and these formulations should be researched as a cross-contamination risk. Other polymers such as polyethylene and polyvinyl chloride are catalysed and typically have a plastizer in their formulation, as well as antistat additives.

The economics of Flexible Enclosure and Suites usage are benefited by low decommissioning costs. Cleaning is not recommended. The use of disposable tools is encouraged since they can be disposed of within the enclosure. The enclosures are collapsed by expelling the air (or inerting gas) through the-built-in vent filters, then rolling the enclosure to fit inside a disposal storage container. The container is then shipped to the destruction site along with your waste manifest.

Performance testing is a simple, albeit expensive (user costs of >$2,500 for sampling and analysis alone). The FabOhio, Inc. database includes statistically robust engineering performance data which is readily repeated for both surrogate and process performance studies. The use of an engineering protocol, rather than the ISPE/SMEPAC pseudo-Occupational Health protocol, is recommended because it can deliver reliable and repeatable statistical data on containment performance.

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