17. Building_10_E_Wing_Level_12_cGMP_Cell_Processing_Lab,_Program_of_Requirement_02-15-2017_FINAL.pdf

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GENESIS ARCHITECTS | ENGINEERS | CONSTRUCTORS

BUILDING 10 E WING LEVEL 12 cGMP CELL PROCESSING LAB

PROGRAM OF REQUIREMENT

15 FEBRUARY 2017

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TABLE OF CONTENTS

PROGRAM OF REQUIREMENTS (Cont.)PROGRAM OF REQUIREMENTS

Appendices

Electrical

Fire Protection

Plumbing

Mechanical

Architecture

GENERAL

Existing Conditions 3 Pre-Design Organization 3 Operational Definitions 3 Conceptual Design 4 Added Program: 5 Continuous Risk Analysis 5 Materials of Construction 5

Applicable Codes, Guidelines and Standards 7 Proposed Classification System 7 Terms, Definitions and Acronyms 7 FDA Application of ISO Classifications 7 Calculation Methodology 7 Design Description 7 System Description 8 Mechanical System Commissioning 12 Preliminary Major Mechanical Equipment List 12

Applicable Codes, Guidelines and Standards 13 General Requirements 13 System Description 13

Applicable Codes, Guidelines and Standards. 16 System Description 16

Scope of Work 18 Standards, Codes and Regulations 18 Engineering and Operation Goals 19 Power Systems Description 19 Uninterruptible Power Supply (UPS) 20 Life Safety 20 Receptacles 20 Lighting 21 Grounding and Lightning Protection 21 Fire Alarm System 21 Telecommunications System 22

Overhead Public Addressing System 22 Access Control System 22 Door Interlock System 22 Audio-Visual System 22 Lab Information Management System (LIMS) 22 Freezer/Refrigeration Equipment Monitoring System 22 Materials of Construction 22 Design Specifications 22

Electrical (Cont.)

APPENDIX A - Architecture 24 A.1 - Floor Plans, Diagrams, and Details 25 A.2 - Equipment List 47 A.3 - NIH Modeling 52 A.4 - Risk Analysis 53 APPENDIX B - Mechanical 70 B.1 - HVAC LOAD Calculations Summary 71 B.2 - Estimated Equipment Heat Loads 72 B.3 - Floor Plans, Diagrams, and Details 79 APPENDIX C - pLUMBING 92 C.1 - Floor Plans and Diagrams 93 APPENDIX D - eLECTRICAL 98 D.1 - Single Line Diagrams 99

APPENDIX E - PROCESS 101

E.1 - Cell Processing Diagrams 102

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listing of potential failures that are of enough concern that a process, an architecture, or both must be designed to reduce the identified risk to a level that is acceptable to NIH and the researchers. The full risk analysis is attached as Appendix A.4.

◦ Process / Facility Integration:

FDA, NIH, Industry Best Practices and Project Team Experience all combine to describe a facility that will keep staff safe and assure product quality. In order to assure consistency of operation, key operating philosophies and intents were identified and integrated with facility design to a assure that the design of the space facilitates proper compliance with SOPs. Gowning, cleaning, material decontamination, protective measures and systems were defined and conceptually documented. These processes dovetail with the layout to assure proper flows of people, material, equipment, samples, waste and product all play a part in the safe and hygienic operation of the facility. See SKA3 through SKA11.

◦ Adjacencies:

There are certain activities that must be adjacent, some for which adjacency would be a benefit but not necessary and some that are best with little or no proximity to each other.

A careful study of these relationships was undertaken as a precursor to the development of the design. The latest version of this adjacency diagram is included herein. See SKA 16.

◦ Cross Contamination Prevention

A system of airlocks and pass-thru(s) have been included to provide separation of spaces, buffer between HVAC zones and provide areas for cleaning and gowning/de-gowning between areas of differing classification or contamination risk. These elements, integral parts of previously described material, personnel and cleaning flows, assist in addressing the risk of cross contamination of product. See SKA17.

C. Operational Definitions

1. Gowning

◦ Plant Uniform:

Donned after removal of street clothes - Personnel in this gown are considered clean and uncontaminated with product. Personnel in this gowning can perform any neutral task (such as labeling or material movement) in Grade CNC or Grade D with appropriate task specific gowning. Personnel in this gown can also work in higher grade areas with appropriate classification specific gowning.

This gown is worn as an under garment for all other gowning.

I. Architectural Design The NIH Division of Transfusion Medicine operates in the Clinical Center. They are in need of space for cell processing that will complement the suite of rooms located on Level 2 in the J Wing. Level 12 of E Wing in Building 10 has been identified to fill this need.

A. Existing Conditions The entire E wing of Building 10 is planned to be renovated in the coming years. It is going to be demolished down to bare structure, floor slabs, and exterior walls. Infrastructure to provide Mechanical, Electrical, and Plumbing services has been set, outside the scope of this POR, by a project team consisting of Perkins and Will, Associated Engineers and NIH personnel. This infrastructure is designed to overcome the prevailing floor-to-floor dimension of approximately 12’-0”, for laboratory users on the other floors of the building. Both the floor-to-floor dimensions and the laboratory based solution are less than ideal for a cGMP use, which requires intensive infrastructure. This vertical tightness has pushed the engineers away from the traditional system of serving horizontal ductwork above the ceiling plane from one or two main vertical duct chases to a system including 21 individual duct shafts running vertically through the building. This will allow for greatly reduced duct runs and duct diameters.

This reduction of ductwork, in turn, allows for a higher ceiling than would otherwise be possible. The choice of extensive vertical circulation of utilities to serve the laboratory floors provides an impediment to providing open and unencumbered cGMP spaces with unidirectional flow.

For these reasons, this POR suggests a unidirectional flow of personnel and material running north to south, between these impediments.

The location of the cGMP operation on level 12, directly below the mechanical room serves to mitigate some of the constriction of the low floor to floor height. The mechanical floor on level 13, directly above, provides space for LN2 and CO2 Dewars serving level 12 that would otherwise have to share floor space on that level. Level 13 also provides space to run some conduit and piping that typically found above the ceiling. On the other hand, the additional duct and pipe chases along with the many and large columns on the floor provide a great challenge to designing a floor plan that contains not only the space for equipment and circulation, but also and as importantly, accommodation for airlocks and pass-through boxes in the necessary sizes and locations.

B. Pre-Design Organization Before any walls and doors are drawn, an analysis of the project was done based on

◦ Process Definition:

The cell therapies follow mostly unique paths to completion. Most have one or more periods of rest mid-process for cell culture.

Understanding and documenting the various types of cell processing in terms of durations and equipment being put into use to project how many of a certain combination of therapies can be produced in a 12 month or other period. Genesis has assembled a matrix that details the annual output based on cycles, what formulae can co-exist in the same environment, and those that must be strictly segregated (See A.3 and Process Flow Diagrams).

◦ Risk Assessment:

Based upon the preceding process understanding, Genesis led the project team in identifying those elements that could cause failure, and using a structured methodology to determine the chance of occurrence of a given incident. The end result is a

◦ Grade D Gown

Same as above with shoe cover and Bouffant Cap.

◦ Grade C Gown:

Donned after plant uniform - Personnel in this gowning can perform any neutral task (such as solution preparation or wash) or any low risk task (such as basic cell processing) in Grade C with appropriate task specific gowning. This gown may be doffed when applying Grade B gowning.

Low Shedding Polyester Material, Elastic Wrist and Ankle, Crew Neck

Double

Grade D Only

◦ Cell Therapy Gown:

Personnel in this gown are considered potentially contaminated and are only allowed to move within a cell therapy suite. This gown is shed upon leaving the cell therapy area and disposed of as hazardous waste. Personnel in this gown can work in the highest grade but must use with appropriate task specific gowning when moving between cell lines (gloves and sleeves).

The gloves and sleeves are changed and sanitized frequently.

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2. Cleaning

◦ Unclassified:

Cleaning is expected to be undertaken by Hospital cleaning staff according to NIH procedures. No special chemicals or procedures are anticipated.

◦ CNC:

Cleaning is expected to be undertaken by dedicated as specially trained cleaning staff wearing appropriate gowning and according to DTM/NIH procedures. Special chemicals and procedures are optional.

Cleaning equipment is dedicated and shared only with Grade D areas.

◦ Grade D:

Cleaning is expected to be undertaken by dedicated as specially trained cleaning staff wearing appropriate gowning and according to DTM/NIH procedures. Chemicals are to be diluted with RO/DI or better grade water. Chemicals selected are to be according to the cleaning chemical rotation SOP for all cGMP areas. Cleaning procedures will include hand spray and wipe-down or mop of all surfaces. Due to the low classification of this area cleaning equipment may be shared only with CNC areas.

◦ Grade C:

Cleaning is expected to be undertaken by dedicated as specially trained cleaning staff wearing appropriate gowning and according to DTM/NIH procedures. Chemicals are to be diluted with WFI. Chemicals selected are to be Cleaning equipment is dedicated to these areas. These areas may be sanitized with vaporized hydrogen peroxide on a very occasional basis.

◦ Grade B:

Cleaning is expected to be undertaken by dedicated as specially trained cleaning staff wearing appropriate gowning and according to DTM/NIH procedures. Personnel shall clean each suite entering and leaving via unidirectional flow. Chemicals are to be diluted with WFI. Chemicals selected are to be Cleaning equipment is dedicated to these areas. These areas may be sanitized with vaporized hydrogen peroxide on a periodic (regular) basis.

◦ Grade A:

Grade A biological safety cabinets (BSC) will be cleaned with their surrounding Grade B room. Only fresh, disposable cleaning materials and chemicals may be used in cleaning Grade A areas. Gloves and Sleeves will be changed before and after cleaning each BSC.

◦ Chemicals and Compatibility:

Cleaning chemicals within this facility may include the following:

a. Steris Product Names

◦ Vesphene

◦ LpH

◦ SporKlenz

◦ Septihol

◦ ProKlenz

◦ Process NPD

◦ Coverage NPD

◦ Coverage Plus

Gross Area: 15,173 SF

Rentable area: 13,311 SF

Net Assignable Area: 10,288 SF

Donor interview 76

Future office 121

Office (Hann) 122

Office (Joe) 122

Office (Product Team Leader) 127

Office (Stroncek) 121

Open Admin Office 1033

Records / Storage 78

Clean Janitor Closet 69

Dirty Janitor Closet 65

Air Lock 153

Supply Room 373

Assay Laboratory 242

Clean Corridor 815

Core Laboratory 457

Freezers room 790

Product development 1014

Tissue Culture 1 270

Tissue Culture 2 251

Tissue Culture 3 251

Tissue Culture 4 251

Required Program Areas in square feet from original predesign:

b. Generic Names

◦ 6% H2O2

◦ 10% NaOCl

◦ 10% NaOH

◦ 10% Peroxyacetic Acid

◦ Quaternary Ammonium Compounds

◦ Phenolics

◦ Glutaraldehyde

◦ 70% IPA

◦ 70% Ethanol

◦ Vaporized Hydrogen Peroxide

3. Biosafety

◦ BSL-1:

All areas outside of the BSL-2 boundary are considered BSL-1. No pathogens handled and no viral vectors are open. Apheresis materials are within closed systems. Samples and vectors are within over-wraps.

◦ BSL-2:

Areas within the BSL-2 boundary. No pathogens are handled and viral vectors are handled within BSCs or closed systems. Apheresis materials are within closed systems or handled within BSCs. Samples are put into wraps within these spaces. No use of BSL-3 materials is expected.

◦ Infectious:

This suite is the same as other areas within the BSL-2 boundary;

however apheresis materials which are not cleared may be handled in this dedicated area. This area has a dedicated incoming material path which may be used as a dedicated product path, as required. No use of BSL-3 materials is expected.

4. Material Movement and Sanitation

◦ Incoming Apheresis Materials

Enter the CNC Log-in area through a pass-through box.

The outer bag is sanitized within the pass-thru.

◦ Equipment

Enters the Grade C corridor through the east material airlock. The equipment is sanitized within the air lock and passed across the line after cleaning, for pickup by personnel within the cGMP area.

◦ Consumables

Enters the deboxing area where corrugated cardboard is removed and disposed of. Materials then enter the storage area for holding prior to release or for capacity. Released materials enter the Grade C clean storage area the material airlock. The materials are sanitized within the air lock and passed across the line after cleaning, for pickup by personnel within the cGMP area.

◦ Apheresis Materials to cGMP Corridor

Enter the Grade C Corridor through a pass-through box.

The outer bag is sanitized again within the pass-thru.

◦ Consumables and Apheresis Materials to Basic Cell Processing

Are hand carried through the door to the basic cell processing room or to the solution preparation area.

◦ Consumables and Apheresis Materials to Advanced Processing

Enter a suite through a pass-through box. The outer bag is sanitized again within the pass-thru.

◦ Apheresis Materials in Processing

The outer bag is removed within a BSC

◦ Products and Intermediates

An over-wrap is applied within or just outside of a BSC

◦ Equipment to Cell Processing

Enters the suite through the personnel airlock. The equipment is sanitized within the air lock and passed across the line after cleaning, for pickup by personnel within the cGMP area. This operation is undertaken prior to operations, except in emergency cases.

◦ Products, Samples and Intermediates to Return Corridor

Enter the Grade D Corridor through a pass-through box.

The outer bag is sanitized within the pass-thru.

D. Conceptual Design Once these pre-design topics have been explored, addressed, and documented, the design team was able to consider how these items physically fit into the floor plate that has been assigned to this project.

Available area in Building 10, Level 10E:

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F. Continuous Risk Analysis As ideas from the team are offered on how to improve any aspect of the project, they were run through risk analysis to confirm that adopting the idea would not in itself raise a risk and that it would not magnify an otherwise low level risk. This process should continue through later stages of design.

Increasing the efficiency and flexibility of the cell processing suites was studied in two separate instances. An early iteration of the floor plan contained bi-directional Air Locks for Low risk as well as for Basic Cell processing. It was noted there may be a time when additional Advanced Cell processing is called for. By converting the Low Risk rooms into unidirectional flow spaces, these can house advanced cell processing, increasing the flexibility of the space without increasing area or risk. In fact, the conversion to uni-directional flow will have the effect of reducing the risk of cross-contamination, one of important headings in the risk analysis report.

G. Materials of Construction The intense need for cleanliness, personnel safety and the avoidance of cross-contamination of product eliminates a large number of finishes and materials that do not hold up under the repeated cleanings or have surfaces that are too uneven for efficient full cleaning.

Materials with any amounts of wood fiber should be avoided.

1. General:

• Within the cGMP perimeter all finishes will be smooth and monolithic to be easily cleaned and reduce crevices and horizontal surfaces.

• All joints between materials and systems will be flush wherever possible and will be gasketed or sealed.

• Inside and outside 90 degree corners will be coved or eased for enhanced cleaning and finish adhesion.

2. Flooring:

• GRADE B and GRADE C Spaces: Floors shall be monolithic seamless material that is Urethane top-coated Broadcast and troweled Epoxy with integral base except at air walls which will have a pre-molded base by wall manufacturer. Some spaces will not require the hardness and chemical resistance of troweled epoxy. Here, Mipolam BioControl, Armstrong Medintech, or similar welded seam sheet vinyl should be considered for maintenance and repair benefits. All floor-to-wall intersections shall be treated with integral coved bases. Cove to wall interface should be smooth and flush, without lip or reveal.

• Grade D and CNC Areas: There will be seamless rubber floor with coved integral base.

• Unclassified Areas: Shall be consistent with the balance of the building, with the exception of the locker rooms, which shall be seamless rubber floor with coved integral base.

3. Walls:

• GRADE B, GRADE C, and Grade D Spaces: Walls will be 2” cleanroom wall system and where there is an existing framed wall to work with, there will be cleanroom liner panel laminated.

Exterior walls will receive cleanroom liner panel for cleanability

Tissue Culture 5 251

Tissue Culture 6 251

Tissue Culture 7 251

Tissue Culture 8 251

Unclassified Corridor 871

Air Lock 1 110

Air Lock 2 105

Change Room 50

Change room 36

Clean Supply 296

De-gowning room 152

Equipment room 367

Gowning Room 116

Labeling / Accession / Sample 233

Material / Equipment air Lock 113

TOTAL 10,235

Using this program as a guideline, but adding the necessary air locking arrangement that would garner FDA approval along with other adjustments including an additional tissue culture room to fully accommodate the cell processes put the program space well over what the floor plate would accommodate. Approval for the elimination of the public corridor that further split the department was a much needed help but additional space was still needed.

It was decided that there were some functions that could operate not directly adjacent to the Cell Processing section. This included Product Development, a significant portion of Administration, Donor Interview. Space from Director’s Reserve has been requested on Level 7 to house these programmatic needs.

The program space on level 12 is as follows with SF:

West Entry -1* 165

West Entry – 2* 59

Men’s Locker 205

Women’s Locker 193

Shoes 166

Log-in Office 408

QC Assay Lab 508

Freezers 635

CNC Air Lock 124

CNC MAL 55

Office Corridor* 346

Training Room 148

Open Office 503

Office 104

Freezer Room 88

Record Storage 154

Receiving / De-Box 136

Storage Supply 415

Supply MAL 93

Weigh & Solution Prep 192

Cleaning Supplies 67

Clean Supply 511

Basic Cell Processing #1 264

Basic Cell Processing #2 264

Equipment 389

Gown In-Out* 121

Supply Corridor* 667

Supply MAL 60

Advanced Air Lock In 75

Advanced Cell Processing #1 388

Advanced Cell Processing #2 335

Advanced Air Lock 65

Advanced Air Lock In 75

Advanced Cell Processing #3 374

Advanced Cell Processing #4 329

Advanced Air Lock Out 65

Advanced Air Lock In 75

Advanced Cell Processing #5 368

Advanced Cell Processing #6 338

Advanced Air Lock Out 65

Infectious Air Lock In 90

Infectious Cell Processing 416

Infectious Air Lock Out 86

Return Corridor* 739

Air Lock Out 65

Waste Storage 141

Autoclave 114

East Entry 2 109

Closet 53

Fan Coil Room 49

East Entry 1 185

TOTAL 11,639

*Not incl. in Net Assignable

Additional space saving measures were realized using compact storage where applicable and sliding cleanroom doors at air locks to relieve to congestion of multiple Swing doors in a confined space.

The program space for Level 7

Office Suite

Product Development

PPCR

E. Added Program:

Fairly deep into the design process the decision was made to introduce the promising new technology of rapid decay radioisotope labeling. Initially the attempt was made to provide a dedicated space, but once again to find a minimum of 96 SF for this activity. It was suggested that we discuss a shared space. The very short half-life of Zirconium 89 allows for this potential of housing the labeling process in one of the Low risk rooms.

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and vermin control. Wall finishes shall be cleanroom wall system with seamless welded PVC, PVS or UPVC finish.

• CNC and Unclassified Spaces: Walls will be constructed of microbial growth inhibited fiberglass faced GWB (e.g.

Densarmor) on metal studs. Exterior walls will receive GWB on furring metal studs. Wall finishes shall be gypsum wall board (GWB) with high performance, high build cleanroom coating (epoxy paint with urethane, such as provided by Sika, Life Science Products, Dudick, General Polymers, etc).

4. Ceilings:

• GRADE C Spaces: Suspended Cleanroom Ceiling System, Basis of Design to be Gordon, Inc. “DS Gasket Seal Grid”, model DS-20 2” gasket-seal ceiling grid and suspension.

• GRADE B Spaces: Suspended Cleanroom Ceiling System, Basis of Design to be Gordon, Inc. “FG-55 Flush Grid” ceiling grid and suspension with integral lights.

• Grade D Spaces: GRADE C Spaces: Suspended Cleanroom Ceiling System, Basis of Design to be Gordon, Inc. “DS Gasket Seal Grid”, model DS-20 2” gasket-seal ceiling grid and suspension.

• CNC and Unclassified GMP Spaces: Vinyl faced ceiling panel and grid system, Basis of Design to be Armstrong Clean Room VL Unperforated, 24” x 48”Square Lay-in, model No. 870.

• Office Spaces: Acoustical ceiling panel system, Basis of Design to be Armstrong Ultima, 24” x 48” Square Lay-in, model No. 1913.

5. Doors and Windows:

• Doors and frames shall be suitable for GMP environment.

Frames shall be welded stainless steel (no knock-down frames permitted), or FRP (Fiberglass Reinforced Plastic).

• Doors shall be stainless steel or FRP with flush half glass vision panels in active leaf.

• All door panels shall be fully flush on all sides with no recesses or openings on any side. Top rails must be flat on top, not channel construction.

• Specialty doors such as Horton automatic operating sliding doors are desirable in Tissue Culture Rooms as a space saver; however the door actuator and panel must be carefully selected for clean-ability and low shedding.

• Interior windows are desirable within the cGMP area for safety, visual inspection, aesthetics and providing borrowed light.

• Doors at all airlocks including swinging doors and automatic sliding doors in Cell culture suites will be “soft” interlocked utilizing red/green lights to alert to status of use. Each door of a set will have alarmed status contacts announcing simultaneous or prolonged open door.

• Airlock interlocks shall include a timer which assures recovery time between opening of the outer and inner airlock doors. Airlock status indicators shall be integral with sounder and override button.

• Grade C and D corridor doors do not require interlock to one another, only doors on an airlock need to be interlocked to each other.

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7II. Mechanical Design A. Applicable Codes, Guidelines and Standards

◦ International Mechanical Code (IMC) 2015

◦ International Building Code (IBV) 2015

◦ NIH Design Requirements Manual (DRM), 2015

◦ NFPA 101

◦ 21CFR (Code of Federal Regulations) 211 for cGMP.

◦ ISO14644-1,2,3 - Clean Room standards.

◦ ANSI Z358.1 – American National Standard for Emergency Eyewash and Shower Equipment

◦ ASHRAE – American Society of Heating ,Refrigeration, and Air-Conditioning Engineers

B. Proposed Classification System Environmental Control Requirements sometimes referred to as “General” or “Comfort Controlled” areas within pharmaceutical facilities such as office and technical space. May also be designated “Not Controlled (NC)”

◦ Classified Space - Areas where HVAC systems are specifically designed to reduce airborne contaminants below a specified Level as defined in ISO 14644-1 (tested per ISO14644-2,3), and both temperature and Relative Humidity (RH) are controlled more tightly than in the ambient environment. These areas must be performance verified / qualified. These areas may be tested to meet ISO requirements for airborne 0.5µ particulate and viable organisms in the “in-operation” state to meet US FDA requirements or they may be tested to meet ISO requirements for both airborne 0.5µ and 5.0µ particulate as well as viable organisms in both the “in-operation” state as well as the “at-rest” state to meet EMA and PIC/S requirements. Where EMA and PIC/S requirements are to be satisfied the transition between these two states should take place in 15-20 minutes. This can be verified via the “recovery test” as specified in ISO 14644-3.

◦ MERV- Multiple Efficiency Reporting Value, the ASHRAE 52.2 method of testing filter efficiency by challenging filters with particles of multiple sizes and integrating the efficiency into a single number rating. The higher the MERV number the more efficient the filter. MERV 14/15 is approximately equivalent to a 95% (ASHRAE?) efficient filter.

◦ Air Change Rate (Ventilation Rate)- The volume of air supplied to a room (per hour) divided by the volume of the room. This is a purely numerical evaluation used as a rule of thumb in cleanroom design. Where use of the extract rate would give a higher value, that value should be used.

◦ Particle Generation Rate- The number of particles of a specified size range released into a room (per hour) by processes, people, or in the supply air.

◦ Dilution Ventilation - Reduction in airborne contamination via mixing of clean incoming air with contaminated air within the room and removal of an equivalent amount to exhaust or recirculation via treatment (e.g. filtration).

◦ Displacement Ventilation - Reduction in airborne contamination via “plug flow” of clean incoming air forcing contaminated air within the room to exhaust or recirculation via treatment (e.g. filtration).

◦ Ventilation Efficiency (Effectiveness)- The ability of an HVAC system to dilute contaminants when compared to ideal dilution. A Ventilation Effectiveness of 1.0 indicates that a room is able to dilute contaminants as effectively as is indicated by an ideal dilution calculation.

Displacement ventilation may have effectiveness as high as 3.0-4.0.

◦ Recovery - A test defined in ISO 14644-3 that challenges room environmental performance by measuring the time required for contamination to reduce by two (2) log after the particle generation in the space ceases.

◦ ISO 14644 -This standard classifies spaces following a decimal system according to the concentration of particulate in a series of size ranges, specifically: 0.1, 0.2, 0.3, 0.5, 1.0, and 5.0. An ISO class designation indicates that particulate within the space are within limits as defined by the formula Cn=10N x (0.1/D)2.08 where Cn is the particle count, N is the ISO class, and D is the particle mean diameter in mm.

D. FDA Application of ISO Classifications

◦ ISO 9 - A space that has been classified to meet ISO 14644 requirements (35,200,000 particles/m3) for airborne 0.5µ particulate in the “in-operation” state. This classification does NOT actually appear in FDA guidance but is found in some FDA regulated facilities.

◦ ISO 8 - A space that has been classified to meet ISO 14644 requirements (3,520,000 particles/m3) for airborne 0.5µ particulate in the “in-operation” state.

◦ ISO 7 - A space that has been classified to meet ISO 14644 requirements (352,000 particles/m3) for airborne 0.5µ particulate in the “in-operation” state.

◦ ISO 6 - A space that has been classified to meet ISO 14644 requirements (35,200 particles/m3) for airborne 0.5µ particulate in the “in-operation” state.

◦ ISO 5 - A space that has been classified to meet ISO 14644 requirements (3,520 particles/m3) for airborne 0.5µ particulate in the “in-operation” state. These spaces are normally constructed with unidirectional flow with an air velocity of .20-.45 m/s

◦ When referring to FDA guidance only the 0.5 micron particle size is measured in the “in-operation” state.

E. Calculation Methodology

◦ All new systems shall be designed with a minimum

20% safety factor (excess capacity).

◦ Airflow, heat load, and equipment sizing information contained herein is schematic only. The design firm is responsible for sizing of all systems, equipment, components, etc., as well as verification of calculations contained herein. No consideration should be granted for changes in sizing or configuration from the information contained herein.

◦ Heat loads and airflows have been calculated using manufacturer’s heat load data and ASHRAE climatic data.

F. Design Description

1. Outdoor Design Conditions:

Outdoor (ambient) conditions used for the design (peak load) of the Mechanical HVAC systems should be based on NIH DRM values

• Summer:

◦ 95°F dry-bulb (> ASHRAE 0.4% annual cumulative frequency of occurrence)

◦ 78°F wet-bulb criteria for outdoor air dehumidification (> ASHRAE 0.4% annual cumulative frequency of occurrence)

• Winter:

◦ 11°F dry-bulb (99.6% annual cumulative frequency of occurrence)

◦ 5 grains per lb moisture

MECHANICAL

M

EC

HA

NI

CA

L

C. Terms, Definitions and Acronyms

◦ Ambient Environment - The environmental conditions where no HVAC systems are present.

◦ Uncontrolled (UC) - Areas where the HVAC systems may be present, but no claim is made or qualified for the specific control of particulate, temperature or humidity. These areas are

ISPE

GRADE

FDA - IN

OPERATION

PIC/S

GRADE

EU AND PIC/S

ACTIVE

AIR

ACTION

LIMITS

(cfu/m3)

IN OPERATION LIMIT

(particles/m3)

AT REST LIMIT (particles/m3)

ISO

USP 0.5

MICRON

PARTICLES/

CU FT

≥0.5µ ≥5.0µ ≥5.0µ ≥5.0µ

Grade5 ISO5 100 A 3,520 20 3,520 20 1

Grade6 ISO6 1,000 N/A 35,200 290 3,520 29 7

Grade7 ISO7 10,000 B 352,000 2900 3,520 29 10

Grade8 ISO8 100,000 C 3,520,000 29,000 352,000 2900 100

CNC+ N/A N/A D N/A N/A 3,520,000 29,000 200

CNC N/A N/A N/A N/A N/A N/A N/A N/A

UC N/A N/A N/A N/A N/A N/A N/A N/A

TABLE 1

Notes:

• Values may be averages; EU and PIC/S require measurement of particles up to and including 0.5 micron and 5 micron; the US require 0.5 micron, hence the table incorporates both to ensure compliance with the most stringent requirement.

• Samples from Grade 5 areas should normally show no viable organisms.

• Recovery from the “In Operation” to the “At Rest” state should be verified to occur within 15-20 minutes for ISPE grades 6, 7 and 8. The recovery test as defined in ISO 14644-3 may be carried out to verify a one or two log reduction test. Recovery testing may also be performed for informational purposes.

• “At Rest” figures are given to support Recovery and “Static” Room Classification testing. Maintenance of these Levels during idle (not in use) periods is not intended.

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2. Indoor Design Conditions 5. Pressurization

• To control the migration of contaminants, the air distribution systems should be designed to attain pressure level within each room relative to all adjacent areas. In general, the design shall provide airflow cascading from clean to less clean areas with a design differential pressure of 0.05 inches water gage between adjacent spaces. Differential pressure transmitters for all rooms should be mounted outside the cGMP area in a central panel.

• Pressure transmitter model/accuracy shall be: Ashcroft DXLdp ±0.25”WC, 114% accuracy and furnished with LED range indicator, SpoolCAL fitting and front access.

• Refer to drawing Appendix B.3 for pressurization plans.

• Pressurization of the rooms should be maintained via primary air delivered to each room via venturi supply and exhaust air valves. Duct mounted hot water reheat coils should be provided downstream of the primary supply air valves for temperature control.

• Pressurization should be monitored via a validated environmental monitoring system which shall be partitioned from the Building Management System.

• Active pressurization control shall be provided by the design firm. One of the following sequences shall be selected:

◦ Direct pressure measurement with variable supply or exhaust

• Note: Recommended for tight room construction due to the small airflow differential required.

◦ Cascade flow tracking control with pressure based reset of offset

• Note: Recommended for tight room construction due to the small airflow differential required.

◦ Constant volume offset tracking

• Note: Additional room leakage may be required to increase the airflow offset.

G. System Description

1. Air Handling System

a. Core and Shell Proposed System

The Core and Shell design indicates providing (6) 100% outside air units, each sized for 10,700 CFM for a total capacity of 64,200 CFM. Each unit is ducted into a common header that feeds Levels 10, 11, and 13. Further evaluation of these units was not considered as part of the POR since they should be divorced from Level 12 East Wing Processing facility. However, their physical dimensions and ductwork/pipe routing were considered in the suggested layout of the Processing Facility HVAC equipment.

b. Proposed System for the Level 12 East Wing Processing Facility

The peak design airflow for the Level 12 processing facility is approximately 45,000 CFM; refer to load calculation in Appendix B.1 for additional information. The NIH Office of Technical Resources (OTR) and NIH-ORF requested the Level 12 air handling units be 100% OA to provide flexibility for future programs. In addition, per the DRM, all air handler components shall be capable of providing 120% of the design capacity and shall be N+1 redundant. Therefore, the base recommendation is to provide three (3) 27,500 CFM 100% OA air handlers to provide a total supply airflow of 55,000 CFM. As an alternative, if floor space is available, then four (4) 18,000 CFM 100 % OA units could be substituted for the larger units.

The air handling systems should operate as constant volume;

however they shall have all of the necessary components to be capable of variable volume operation in the future.

The air handlers should be located on the north side of the Level 13 mechanical room and shall feed into a common duct supply header. Outdoor air may be either routed from the south end of the mechanical room, north end of the mechanical room or the roof as deemed practical by the design engineer and NIH. A wind wake analysis should be performed to verify the final location. Refer to Appendix B.3 for floor plan.

The air handlers shall meet the NIH DRM requirement 6.2.D, except aluminum material can be used in lieu of galvanized steel. In AHU compartments serving cooling coils or steam injection humidifier, 304 stainless steel shall be used. The use of fire rated foamed insulated panels with minimum R-value of 13.6 shall be used instead of “sandwiched” fiberglass insulation between panels. The casing leakage shall be no greater than 1% of rated flow at 150% of design pressure. All AHU sections require drainage capability for wash down. All hardware shall be corrosion resistant (304 or 316 stainless steel is preferred). Due to space constraints in the Level 13 mechanical room, multiple smaller direct drive plug fans arranged in an “array” may be used instead of dual centrifugal fans. Each air handler shall be provided with an airflow monitor and two (2) Variable Frequency Drives (VFDs) per fan array.

The design firm shall review location of the outdoor intake and exhaust based on NIH DRM requirements. The air handlers should be designed to supply 48F Dewpoint supply air directly to controlled spaces as outlined in the airflow diagram. Where chilled water is unable to sufficiently reduce RH Levels, several dehumidification systems such as run-around coil system, heat pipe or dual-path (dual chilled coils in series) systems may be employed. Humidification should be provided at these air handlers via stainless steel atmospheric steam reboilers (1 per AHU) and insulated dispersion manifolds, fed with RO water with city water backup.

Cooling coils shall be located upstream of the fan. The maximum row/fins per inch of the cooling coil shall be 8 RD/10FPI.

Combination preheat/energy recovery coils with 40% propylene glycol should pre-condition the supply air. The inlet air to this air handler shall be filtered high-capacity deep pleat MERV 7/8 bags (MERV 11 alternate should be considered). Discharge air from these air handlers shall be MERV 14/15 filtered using a “V-bank” mini-pleated filter with a pressure drop of not more than 0.4 inches W.C. at 2000 CFM for a 24 inch x 24 inch unit.

Supply air should be distributed to each zone via a venturi style quick acting tight shutoff Terminal Unit Supply (TUS) air valves with duct mounted hot water Reheat (RH) coils downstream.

Supply air should be hard ducted to Terminal Air Filter (TAF) units located in each space. The TUSs and associated RH coils should be located on Level 13 and ducted down to the TAFs.

Each duct penetration through the Level 13 floor shall have a water-tight penetration through a 6” high epoxy coated curb to prevent any water damage to the space below.

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4. Ventilation Criteria

Outdoor air supply rates should be based on minimum dilution ventilation requirements for occupant comfort, occupant density, pressurization criteria and/or exhaust requirements.

Outdoor air shall be provided to all areas in conformance with ASHRAE 62.1 and shall be greater than or equal to 6 ACH.

The following room air change rates (ACH; air changes per hour) should be applied to conceptual design in order to maintain the desired room cleanliness classification.

• ISO 7 - 40 ACH minimum

• ISO 8 – 20 ACH minimum

• CNC – 20 ACH minimum

• AIR LOCKS – ACH rate of classification above plus 10 ACH or designed for <5 minute 2 log recovery.

The final design should employ computational fluid dynamic modeling (with 0.5 micron 4g/cm3 particle tracking or multi-dimensional dilution calculation) in the design of the cleanrooms to achieve cleanroom classification.

INDOOR DESIGN CONDITIONS

AREA SUMMER (DB/RH) WINTER (DB/RH)

Grade B; ISO 7 Spaces 65°F ± 2° 55% RH max.

65°F ± 2° 35% RH min.

Grade C & D; ISO 8 Spaces 68°F ± 2° 55% RH max.

68° ± 2° 35% RH min.

CNC Spaces 70°F ± 2° 55% RH max.

68°F ± 2° 35% RH min.

Uncontrolled Spaces 72°F ± 2° 55% RH max.

68°F ± 2° 35% RH min.

Mechanical Space Not in Scope Not in Scope

3. Internal Heat Gains

INTERNAL HEAT GAINS

AREA PEOPLE SENSIBLE/

LATENT (BTU/Hr)

LIGHTING

(Watts/SF)

EQUIPMENT

(Watts/SF)

Basic, Staging, Cryo Freezer, Log-in Office and QC Lab

500/500 2 Notes 1,2

Uncontrolled areas such as Office, Storage Small Equip and Jan. Closet

250/250 1 Note 2

Gowning and Degowning 500/500 2 -

Infectious, Basic, and Advanced Cell Processing

750/750 2 Notes 1,2

Mechanical Rooms N/A N/A N/A

TABLE 2

TABLE 3

Note 1: 8 Watts or actual, whichever is higher Note 2: Refer to equipment list for information on equipment.

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Unclassified rooms may use standard butterfly damper air valves with integral hot water reheat coils. The TUSs and RH coils can be located above the Level 12 ceiling or within the Level 13 mechanical room similar to the classified spaces.

The TAFs filters in the room should be accessible from room side.

HEPA filter velocities shall not exceed 90 FPM when positioned as terminal supply air filters. The filters shall have silicone gel seal on the downstream side of the filter to form a positive seal. The terminal filter module should be complete with insulated module, filter, filter aerosol and pressure test ports, damper adjustment, grill, trim and hardware. The module shall be constructed of stainless steel or aluminum with exposed trim being stainless steel.

2. Exhaust

a. Core and Shell Proposed System

(14) 18,200 CFM exhaust fans provide general exhaust for the entire building, for a total building general exhaust of 254,800 CFM. To provide redundancy, all general exhaust fans are on emergency power and are ducted into a common header with (1) redundant fan on standby. Each exhaust fan has a dedicated heat recovery unit associated with it that is piped into a central heat recovery loop. The exhaust fans and associated heat recovery units are located on Level 14 and the exhaust stacks are ducted up through to the roof. There are (9) other exhaust fans of various sizes and locations that provide specialty exhaust for the building. Further evaluation of these units was not considered as part of the POR since they should be divorced from the Level 12 East Wing Processing facility.

b. Proposed System for Level 12 East Wing Processing Facility

The peak design airflow for the Level 12 processing facility is approximately 42,000 CFM of general exhaust and 3,500 CFM of specialty exhaust for the Infectious Cell processing; refer to load calculation in Appendix B.1 for additional information. Due to concerns about cross contamination, it was decided by the team to provide dedicated exhaust fans for Level 12 and not tie into the building’s primary system. In addition, per the DRM, all exhaust fans shall be capable of providing 120% of the design capacity and shall be N+1 redundant. Therefore, four (4) 16,800 CFM exhaust fans are required for a total general exhaust of 50,400 CFM. Two

(2) 4,200 CFM exhaust fans should be dedicated to the Infectious Cell processing for a total specialty exhaust of 4,200 CFM.

The exhaust fans should operate as constant volume; however each fan shall have all of the necessary components to be capable of variable volume operation in the future. As a result, each exhaust fan stack should be equipped with a Variable Geometry Nozzle (VGE) to allow the exhaust fans to modulate airflow in the future and still maintain a discharge velocity of 3,000 FPM. (As an alternative, an outdoor air intake hood and bypass damper could be installed or “strobic” style high induction exhaust fans may be employed.)

The core and shell system should utilize a pumped glycol heat recovery loop for the remainder of the building. The Level 12 general exhaust fans should each be furnished with its own custom dedicated Energy Recovery Units (ERUs) and piped into the building heat recovery loop. This should add approximately an additional 120 GPM to the building heat recovery loop.

ERUs should not be provided on the specialty exhaust fans.

Similar to the AHU construction, the ERUs shall be constructed of either Aluminum or Stainless steel and use fire rated foamed insulated panels with a minimum R-value of 13.5.

The casing leakage shall be no greater than 1% of rated flow at 150% of design pressure. The energy recovery coils shall be located downstream of MERV 8 filters and shall be no greater than 8 rows deep at a density of 10 FPI.

Due to limited available floor space on Level 13 and 14, the EFs and associated ERUs cannot be located within the building adjacent the core and shell ERUs. Therefore, they should be mounted on the roof, refer to Appendix B.3 for roof plan.

A CFD analysis of the re-entrainment of the general and infectious exhaust discharge air with the intake air should be required to confirm the location of the exhaust discharge.

The design-build contractor shall evaluate both mixed-flow impeller and centrifugal fans for exhaust service. All motors shall be located outside the air stream and shall be NEMA MG1 rated.

3. Chilled Water

a. Core and Shell Proposed System

20” chilled water supply/return mains provided under the “E-Wing Enabling Infrastructure” project deliver 44-46ºF chilled water to Building 10 with an average 15ºF temperature differential. Chilled water is routed up the exterior of the building and enters the building on Level 14 mezzanine. A 6” supply/return header feeds the AHUs on Level 13. The core and shell AHUs require a peak flowrate of 719 GPM; excluding the redundant AHU. Assuming a maximum velocity through the chilled water mains of 10 ft/sec, the chilled water mains have approximately 181 GPM of spare capacity which is equivalent to 113 tons of cooling at a 15ºF differential.

b. Proposed System for Level 12 East Wing Processing Facility

The chilled water demand for the new AHUs is approximate 752 GPM at a 15ºF temperature differential. The 20” piping mains, plant chilled water pumps and chillers appear to have sufficient capacity to satisfy the increase demand according to the engineer of record (AEI). However, the core and shell design for 6” mains only has approximately 181 GPM of spare capacity.

Therefore, either the 6” mains should need to be increased to 8” or dedicated 6” mains provided to the new AHUs.

To help mitigate discharge air temperature and dew point fluctuations of the Level 12 AHUs due to varying chilled water temperatures from the site chilled water plant, an air cooled chiller with remote evaporator barrel should be provided. The air cooled chiller should be sized to provide trim cooling of the Level 12 AHUs and should reduce the supply air temperature from approximately 55ºF saturated down to 48ºF saturated. Since the site chilled water system should be sized to provide full cooling, N+1 redundancy is not required and only one (1) 50 nominal ton air cooled trim chiller should be provided. The chiller should be located on the roof and the remote barrel hung from the ceiling in the Level 14 mechanical room to avoid requiring glycol and heat exchanger. The chiller should be furnished with dual refrigerant circuits and have a maximum chilled water supply temperature of 42ºF at a 10ºF temperature differential. Two (2) 125 GPM 5 HP inline pumps should be hung from the ceiling in close proximity to the evaporator barrel and piped to the downstream cooling coils of AHU 12-1, 2, and 3. The AHU trim coils should also be piped to the site chilled water loop, but should be isolated closed during normal operation when the trim chiller is operational.

4. Steam System

a. Core and Shell Proposed System

A 12” High Pressure Steam (HPS) main provided under the “E-Wing Enabling Infrastructure” project delivers 125 PSIG steam to Building 10. HPS is routed up the exterior of the building and enters the building on Level 14. The Core and Shell design proposes installation a two stage PRV station that produces medium pressure (80 PSIG) for various autoclaves and low pressure (15 PSIG) steam for preheat, reheat, and humidification.

There are three (3) preheat hot water converters that require a total peak LPS load of 17,925 MBH; excluding one

(1) converter which is on standby. There are also three (3) reheat hot water converters that require a total peak LPS load of 12,000 MBH; excluding one (1) converter which is on standby. Therefore, the total core and shell low pressure steam capacity for preheat and reheat is approximately 30,000 MBH.

Humidification load of core and shell equipment is unknown.

All low pressure and medium pressure condensate is collected on the B2 floor via (6) condensate recovery units and pumped back to the campus steam plant.

b. Proposed System for Level 12 East Wing Processing Facility

The AHU 12-1, 2, and 3 systems should require approximately 3,000 MBH of preheat and 114 MBH of reheat, excluding any heat gain from the heat recovery coils. Therefore, the Level 12 preheat and reheat systems should have a total steam demand of 3,100 lbs/hr of 15 psig steam. In addition, the Level 12 humidification system should require approximately 1,500 lbs/hr of 15 psig steam.

Therefore, the core and shell steam PRV station should need to be sized for a minimum of 4,600 lbs/hr of capacity for the Level 12 systems or two (2) new dedicated PRV stations are required.

All low pressure condensate should be piped to the core and shell condensate receivers and then pumped back to the campus steam plant.

Since high pressure steam is generated by an existing plant, an evaluation of the system should be performed during detailed design to identify and single points of failure that may compromise the new systems.

5. Humidification System

a. Core and Shell Proposed System

The core and shell AHUs all use low pressure (15 PSIG) plant steam for humidification.

b. Proposed System for Level 12 East Wing Processing Facility

Each AHU should have a dedicated chemical-free steam-to-steam atmospheric steam generator with RO water for make-up and potable water for backup. The chemical free-steam should be piped to a short absorption distance dispersion manifold assembly installed in each AHU upstream of the cooling coils.

Locating the humidifier in this position within the AHU should allow the cooling coil to double as a moisture eliminator, mitigating nuisance smoke detection alarms and reducing the risk of water damage to the fans and cell processing suite.

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The steam-to-steam generators will serve a total humidification load of approximately 1,400 lbs/hr of atmospheric steam to maintain a minimum set point of 40% RH at a space temperature of 68ºF, assuming these conditions for the entire 55,000 CFM of supply air. Due to efficiency losses and line loses, approximately 1,500 lbs/hr of 15 PSIG plant steam is required. Three (3) 700 lbs/hr steam-to-steam generators are required to provide N+1 redundancy; 1 per AHU. The generators can be located where currently indicated on the AEI 15% schematic design drawings along the east wall of the Level 13 mechanical room or in-between each AHU to minimize humidifier pipe lengths. Refer to Appendix B.3 for floor plan.

6. Hot Water Preheat/Reheat

a. Core and Shell Proposed System

There are three (3) 8,962 MBH preheat hot water converters that have a total capacity of 17,925 MBH; excluding one (1) converter which is on standby. The preheat hot water converters add heat to the 40% propylene glycol heat recovery loop that is piped to all AHUs. Four (4) 750 GPM 125 ft head 40 hp pumps circulate the water.

There are also three (3) 6,000 MBH reheat hot water converters that have a…