The successful design and realization of a validatable life sciences cleanroom won’t happen by chance. Early and continuous coordination and communication among all parties involved - from process design and scale-up through cGMP layout, pre-construction design review, commissioning, validation, and onsite inspection by regulatory authorities - is essential. The time spent in design optimization in the front end, well in advance of the “bricks and mortar” stage, will be saved many times over.

Manufacturing pharmaceutical and biotechnology products requires that the appropriate level of quality be designed and constructed into the facility, and into the systems that support the production process.

A review of Form 483 observations and warning letters (or Notice of Inspectional Observations) from the Food and Drug Administration (FDA) indicate that “inadequate facility design” and “environmental and personnel monitoring” are good areas for increasing compliance focus.

And, why worry about HVAC? Doesn’t everyone know how to design and build these ubiquitous systems? FDA Inspectional Findings have included some of the following:

“HEPA leak testing criteria, for example, should specify what is considered to be a major leak; smoke studies performed under static and dynamic conditions should demonstrate unidirectional airflow at the critical height of the fill; specifications on HEPA to HEPA variations in air velocity should be established since widely divergent velocities have the potential for turbulent air flows....”

Other common 483 inspectional observations with respect to building and facilities include:

“… There have been documented failures in provisions for separating or defining areas to prevent contamination, cross-contamination, or mix-ups. Inspections have also revealed poorly designed or inappropriate air handling systems, a lack of temperature/humidity monitoring, and poorly designed water systems.”

How do these situations develop? The FDA normally does not dictate how to achieve a specific outcome. Regulatory guidelines specify performance, not methods. For instance, a number of unidirectional flow aseptic fill cleanrooms, once built, proved unable to meet validation requirements. In most of these situations, the aseptic fill application was treated as if it were simply a Class 100 particle count requirement without regard for the critically important airflow patterns and velocity profiles required to ensure that exposed products and components are protected from contamination.

This control aspect, as demonstrated by a suitable and appropriate flow of air that “washes” the surfaces within the critical zone and which exhibits unidirectional flow, is essential for proper performance.

When observing an operation, the FDA assesses whether the design creates potential contamination routes, for example:

  • Does the design adequately incorporate appropriate separation and control measures for the differing levels of air quality required by a particular operation?
  • Are material choices (e.g., composition of material and surface quality) consistent with the need for cleaning, sanitization, and sterilization?
  • Is there a maintenance program that appropriately addresses the gradual breakdowns in facility infrastructure?
The successful design and realization of a cleanroom or containment project does not happen by chance. Time spent preparing as complete a Basis of Design (BofD) as practical will be saved many times over during implementation. The following listed elements are required to establish a BofD document:
  • Process description and process flow diagrams
  • cGMP floor plan and general equipment arrangement
  • Sized major process equipment list with utilities requirements/consumption
  • Sized process support services utilities list (WFI, etc.)
  • Functionality flow diagrams (process, people, product, material, components, waste, and directionality of airflows)
  • HVAC zoning and room classifications, including microbial limits
  • Budget-quality cost-screening estimate
  • Scope of work matrix (Who will design, specify, furnish, install, inspect, test, balance, certify, guaranty, challenge, qualify? Who is responsible for every element of the HVAC, envelope, and process?)
  • Realistic project schedule from kick-off through validation
  • List of the appropriate/applicable regulatory authorities and jurisdictional venues for which the facility will have to be validated.
This BofD information will provide the owner with the information required to support FDA reviews. There are defined hold points during a project when a meeting with the FDA will be enlightening, such as:
  • Design review – concept sketches, flow diagrams, and tentative floor plans (not prior to completion of conceptual design)
  • Pre-construction review – study plans, elevations, HVAC diagrams, all equipment, layouts, and process support services (detail design review)
  • Construction/equipment installation and qualification review– FDA will review portions of the facility on-site while under construction
  • Pre-production review – typical FDA field inspection
One of our clients received the following request for information from the FDA Center for Biologics Evaluation and Research (CBER) Division of Manufacturing and Product Quality (DMPQ), regarding issues to discuss during a pre-facility meeting:
  • An overview of the HVAC system, including a floor plan showing AHU zoning.
  • Floor plan showing pressure differentials for containment/protection.
  • Diagram showing air quality classifications of rooms.
  • Description of the operation of the system (air changes, makeup air, single-pass, etc.).
  • Description of the support systems (WFI, clean steam, gases) and monitoring of these support systems (for instance, frequency and type of monitoring for the WFI system).


Value Engineering

Value engineering is defined as the systematic analysis of design alternatives that provide maximum value at minimum cost.

In one example of a value engineering trade-off, individual AHUs positioned directly over a clean space will limit ductwork runs but increase structural steel requirements. Instead, one commercial-scale therapeutic protein manufacturing facility utilized a remote equipment loft design. While the system required longer duct runs and larger fan capacity, structural loading for the large clean containment area was reduced and no building columns intruded into the clean space. The operating company prohibited building columns within the controlled area, since columns limit flexibility in the event that a reconfiguration might be required to serve new clients.

In another project, a large robotized lyophilization facility, a capital and operating cost analysis favored the use of a central chilled-glycol system, as opposed to individual air cooled direct expansion units. This was a brand-new greenfield facility. However, capital and operating cost analysis favored quite the opposite conclusion for a sterile-fill suite retrofit project on the same site.

Contamination Control Criteria

Terminal ceiling HEPA units and low wall returns, standard in today’s cleanrooms, eliminate the need for welded stainless steel ductwork. The nominal cfm per filter should be lower than the typical manufacturers’ suggested ratings (say, down to ~350 cfm / filter vs. the manufacturer’s rating of around 600 cfm) in order to place more filters in the ceiling than one would expect for a non-cGMP cleanroom of similar classification.

This derating is an example of “building quality into the room.” By adding more filters than might be expected, we gain:
  • Longer HEPA filter life
  • Lower HEPA filter pressure drop
  • Better air distribution and elimination of drafts and temperature or humidity gradients
In a Class 10,000 Category 3 containment facility, the number of air changes may be reduced to half the conventional value, due to energy savings when forced to utilize 100% once-through fresh air. But in once-through air cleanroom designs, 95% ASHRAE rated pre-filtration is highly advisable.

Additional HVAC Considerations

The need for flexibility, prevention of cross contamination, and the requirement for individual room pressure, temperature, and humidity control often results in a more costly HVAC system for biotechnology facilities as opposed to the classic large volume systems commonly applied in the typical chemical-based pharmaceutical facility. Most biotechnology facilities consist of several suites, each made up of multiple small rooms.

There are no industry standards that dictate air change rates, although the 1987 cGMP guidelines did call out a minimum of 20 ach for controlled areas (typically Class 100K or ISO 8) and EC Regs require a minimum of 20 ach in “every room for which particulate levels must be controlled.” The current FDA guidelines on “Sterile Drug Products Produced by Aseptic Processing,” states “an adequate air change rate should be established for a cleanroom. For Class 100K supporting rooms, air flow sufficient to achieve at least 20 ACPH is typically acceptable ….”

Ach is often treated inappropriately as an independent variable as a result of these regulatory influences, while of course ach is actually calculated:
  • Ach = (Avg. room velocity X 60)/(room height) for a unidirectional flow room, and for a mixed or turbulent flow room, room cfm = (ach X room volume)/60.
    • Note: average room velocity is a very appropriate descriptor for unidirectional flow situations; however for mixed or turbulent flow rooms, there is no truly representative average room velocity, so cfm and ach become the metrics of interest.
Ach clearly lead us to conclude how the room will perform in the event of a contamination excursion (e.g., “recovery time”). However, to be able to place some meaningful performance criteria on the initial room (and in the absence of accurate data on particulate generation, which could allow us to perform a mass balance on particles) we must rely on experience and consider the flow rate through the filter, which is a function of filter face velocity rather than average room velocity.

Equally important is the placement of returns, to be able to achieve suitable airflow sufficient to sweep particulates away from the product. Dynamic flow modeling will provide a useful check on the validity of the proposed system configuration.

Direct Impact Systems

Direct impact systems are those that directly affect product quality, and these must be validated. All other systems (e.g., indirect impact and no impact) need be commissioned only. Indirect impact systems support direct impact systems.

For systems that need to be validated, this occurs by executing protocols that serve to qualify those particular systems. If the commissioning activities for these direct impact systems are executed properly, much of the work done to commission these systems can also be used to qualify the systems. For indirect and no-impact systems that do not require formal protocols, commissioning can utilize standard SMACNA, IEEE etc., checklists and forms. Vendors of packaged equipment can often satisfy large portions of their commissioning requirements through FAT and SAT execution.

Conclusion

Facilities are always asked to provide greater throughput and are utilized longer than originally anticipated. It is increasingly difficult to predict whether or not today’s plant will meet tomorrow’s facility requirements. A properly designed, controlled, and maintained HVAC system, as well as an appropriate facility monitoring system is crucial for demonstrating and maintaining control. Without the implementation of proper front-end assessment and planning, no project will be successful. Cleanroom facilities delivery requires a systematic methodology from concept through commissioning.ES

For Further Reading

PDA Draft Technical Report, Points to Consider for Aseptic Processing

PDA Technical Report No.13, Fundamentals of an Environmental Monitoring Program

EC Guide to Good Manufacturing Practice, Revision to Annex 1

Food and Drug Administration,http://www.fda.gov/foi/warning.htm

Food and Drug Administration 21 CFR (Code of Federal Regulations) Parts 210 and 211. Current Good Manufacturing Practice.

Food and Drug Administration, “Sterile Drug Products Produced by Aseptic Processing

“Risk Factors in Aseptic Processing”, Richard L. Friedman & Stephen C. Mahoney, Food & Drug Administration, Center for Drug Evaluation and Research, American Pharmaceutical Review, Spring_2003
USP 26 <1116> Microbiological Evaluation of Cleanrooms and other Controlled Environments, Rockville, MD

Product Quality Research Institute, Aseptic Processing Work Group, Final Report, March 12, 2003

Federal Standards, FED-STD-209E, Airborne Particle Cleanliness Classes in Clean Rooms and Clean Zones”, September 1992

ISO-14644-1, Cleanrooms and Associated Controlled Environments, Part 1: Classification of Air Cleanliness

ISO-14644-2, Cleanrooms and Associated Controlled Environments, Part 2: Testing and Monitoring to prove Compliance with ISO 14644-1

ISPE Baseline Guide, Vol. #3, Sterile Manufacturing Facilities

ISPE Baseline Guide, Vol #6, Biopharmaceutical Manufacturing Facilities

ISPE Baseline Guide, Vol #5, Commissioning and Qualification



Sidebar: Commissioning

Commissioning is the process of ensuring that all building and process systems are designed, installed, functionally tested, and capable of operation in conformance with the design intent. Commissioning process steps generally include system documentation, equipment start-up, control system calibration, testing and balancing, performance testing, and release of the systems to the owner for validation.

Elements of a commissioning plan:
  • Hydronic balance testing
  • Sound measurement testing
  • Vibration testing
  • Alarms and interlocks testing
  • Airflow rate testing in ductwork
  • Air volume supply and return, testing, and balancing
  • Fan rpm and amperage
  • Temperature, humidity (coil duties), and static pressure testing (duct leakage)
  • Differential pressure testing and balancing
  • Loop checks
  • HEPA filter integrity testing
  • Verification of the proper operation of coils, air handlers, fans and filters, including test sequences, shut-down, and start-up
  • P&ID walkdown, resulting in an “as-built” P&ID
  • Utilities check
  • Instrument calibration
  • Electrical power tests
  • Motor run tests
  • Lubrication checks
  • Isometric drawing checks
  • Safety checks