Quality Controlled Environments Manufacturing

Document Issued Department Title
GSOP6.2.001
Rev
For Use Only By Affiliates of Edwards Lifesciences
ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing
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1.0 PURPOSE To define the minimum requirements for classification, operation, design, and construction of environments used for manufacture of sterile devices, which provide the system of product contamination control for air, surfaces, and personnel, to prevent a potential effect to product. 2.0 SCOPE This document applies to facilities for all manufacturing operations and includes minimum gowning standards. If facility limitations affect an operational requirement (section 4 - 5), an implementation plan or exception must be developed and approved by the VP, Quality. 3.0 Table of Contents 4.0 Requirements For Classified Controlled Environments (Ce); For All Facilities .................. 1 5.0 Validation Requirements (All Classified Facilities) ............................................................ 7 6.0 Requirements For New Classified Environments Design / Operation ................................ 8 7.0 Requirements For Unclassified Controlled Environments (Non Clean Room) ................. 13 8.0 References ....................................................................................................................... 13 Revision History ....................................................................................................................... 18
4.0
REQUIREMENTS FOR CLASSIFIED CONTROLLED ENVIRONMENTS (CE); For All Facilities 4.1 4.2 4.2.1 Controlled environments shall meet Table 1 requirements for specific classifications, for manufacturing processes (and exposure after product cleaning) and gowning/ transfer. Operation and Maintenance of Classified manufacturing environmentsFacility specific procedures shall be established for environmental control equipment and practices to assure:
4.2.1.1 Adequate control over airborne particulates, microorganisms, and conditions as required, preventing ingress of lower class air into the CE. 4.2.1.2. Pressure differentials are monitored daily at gown entrances, for verification of proper manufacturing room air pressure. 4.2.1.3 Maintenance of air handling systems, filtration systems 4.2.1.4 Facility cleaning processes, using dedicated janitorial equipment. 4.2.1.5 Stop and re-start of production operations under normal and failure mode (emergency), are controlled to assure re-evaluation of controlled environments 4.2.1.6 Emergency access doors to uncontrolled spaces have tamper-evident seal or alarm so breaches can be detected. 4.2.1.7 Appropriate personnel conduct, and hygiene training per site procedure, including:
Prohibition of health conditions affecting cleanliness of the product; product potentially contaminated by biological material must be segregated for evaluation. No storage, consumption or disposal of food, gum, or tobacco. No cosmetics. Medicated oil or lotion can only be used if covered so as to prevent contact, or if used upon exiting the gowning room. Perfume is acceptable.
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.. IT MUST NOT BE REPRODUCED OR DISCLOSED TO THIRD PARTIES WITHOUT PRIOR WRITTEN PERMISSION OF EDWARDS LIFESCIENCES, LLC. 378 Rev:D Issued:05/12/00 ECN:04536
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Jewelry (if minimally allowed) must be contained so that it cannot fall onto the work surface or expose product to particles. No exposed piercings or personal items. Particle producing material and operations must be minimized and controlled: Corrugate must be prohibited or covered; paper and documents minimized and in sanitized plastic covers wherever possible, not contacting product. Non-production paper (paper not required for manufacturing processes), or non-cleanroom paper, must be minimized, kept in plastic, and non-production items (e.g. decorations, files) not used in the CE. Appropriate cleaning or covering of items before they can be introduced into the CE; sporicidal cleaning (e.g. SporKlenz) prior to entry into tissue product areas. Gowning and entry requirements for classified environments, including the following:
ISO CLASS 5 PRELIMINARY PACKAGING, GLX PKG, TISSUE I.BREP PKG. ISO CLASS 7
OTHER IMPLANT MFG PER TABLE 1.
AREA CLASSIFICATION=>
TYPE OF GOWNING*:
ISO CLASS 8 CLASS 300,000
Hair Cover, (Clean room type, disposable) Foot wear**;

(particle control mats required prior to gown room entry)
x x sterile shoe cover or

bootie per two-stage gowning, Pre.Pkg only.
x
X shoe covers
x
X shoe covers or cleanroom-dedicated shoes.
x
If posted for the operation.
Mask/ Beard cover Hood Frock, Gown, or Coverall Garment
x sterile, Pre.Pkg. (Also per procedure under Class 7) X sterile, Pre.Pkg. x sterile
(gowning sterilization process validated). GLX Pkg: sterilized garb as needed to control bioburden impact.
To cover hair/beard or provide protection, e.g. when working with saline To cover hair/scarf, or for particle control.
Nonsterile (qualified, from supplier or inhouse). Laundry water to be monitored for microbes; laundry environment class to be gown room class.
If required/ posted for operation.
Gloves Non-latex are standard. (Soluble cornstarch powder does not require rinsing off unless for product appearance)
x sterile labeled, individually pkgd. Fresh gloves prior to work on product in Class 5.
X for implant assembly operations; sterile or bulk-sterilized gloves *** (or as required for nonbiol. product; per site procedure, or contact Microbiology lab.)
As needed, for specific product or operator protection, or for radiationsterilized device control. Qualify nonsterile glove bioburden. Non-latex gloves are required for Latex-free claimed product.
* Gowning Instructions must be posted. Preferred sequence: Hair cover; Face cover if nec.; foot wear.; hand wash; hood if nec; garment; gloves if nec. Nonsterile gowns may be reused not more than one week, or until soiled. ** Footwear shall be introduced over a demarcation line, crossover bench/stool, or particle control mat. *** If approved, bulk glove application for tissue valve assembly shall include sanitizing gloves/fingertips with: 70% isopropanol (IPA), or 70% ethanol (may be denatured with methanol or IPA). For tissue valves, bulk glove use must be microbially verified and monitored.
Hand washing with antimicrobial soap. Alcohol sanitizer, gel or foam may be required as a supplement to hand washing, (or sanitizers may be an alternative to hand wash: only for Class 300,000, non-implants, and no contact to final blood-contact surfaces of devices). New hand soap and sanitizers, product- contact wipes, gloves or aids must be approved as specified in GSOP7.2.006 by Edwards Quality Labs evaluation). Hand wash water should meet potable water microbial limits as Action Level. For Preliminary Packaging use purified wash water or hand sanitizer after wash; and two-stage gloves. .Avoid hand rubbing during drying. Hand dryers must be qualified under OPQ protocol for particulates and microbes.
4.2.1.8 Sanitization of manufacturing work surfaces is required at start and between shifts, in rotation with sporicide for tissue process areas weekly, and sanitation for equipment
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and aids required per site procedure. Sterile alcohol should be used at tissue preliminary packaging areas. All disinfectants for work surfaces or product equipment other than the standard list [70% isopropanol, 70% ethanol, and sporicides: 3% hydrogen peroxide, SporKlenz RTU,1%Minncare, 2% Amphyl or Vesphene, 5% chlorine bleach, or equivalent], shall be approved by Quality Labs including residuals (excluding alcohols). 4.2.1.9 The flow of components shall be controlled to prevent contamination. Transition rooms for material transfer require a demarcation line to segregate employees with outside attire, from an area of gowned employees. Components/products stored during janitorial cleaning, must be protected. 4.2.1.10 Biological (tissue) products shall use segregated work tables and gowns, including no crossover of tools, equipment, or personnel without regowning and changing gloves, from other, non-biological product operations in the same cleanroom. 4.2.2 Room Environment Monitoring: Controlled environments shall be monitored per established procedure (e.g. for implants, QCOPM451) and ISO 14644-2.
4.2.2.1 After validation (sec. 5) of an area, a routine monitoring program is required. It must include annual cumulative monitoring of all designated ISO air particulate locations in the CE (sites may be monitored on different months); in Class 5, all ISO sites must be monitored at least every 6 mo. Monitoring of areas outside the demarcation within gowning and transfer areas, is not required For the monitoring plan, periodic Air Particulate/Air Microbial and Work Surfaces may allow for sampling of a reduced number of validation sites at each interval, provided all sites are monitored annually in an operational state, and there is acceptable control based on this general assessment of low risk factors: Risk-evaluation basis for monitoring plan: The use of terminal sterilization, air filtration systems, facility design control, cleaning programs, gowning requirements, preventative maintenance, and historically acceptable bioburden of products, assure environmental controls will be upheld and an extremely low environmental risk to product. In addition, Table 1 provides a risk based classification scheme which is affected by the criticality of product manufactured or process. Based on this risk scheme and risk-reduction factors, the following monitoring plan is defined, for meeting airborne cleanliness specifications per Table 1 and control/action levels:
Class 8 and 300,000 areas shall be monitored quarterly. Classes 5 -7 areas shall be monitored a minimum of monthly.
4.2.2.2 If air cleanliness specifications (Table 1) for particulates are verified to be exceeded, production in impacted areas shall cease until evaluation is documented and corrective action or verification of acceptability in place. Document per site nonconformance procedure or exception record; evaluate impacted product. 4.2.2.3 Pressure differentials are read with doors closed daily. In monitoring, they are read also with door(s) open to simulate manufacturing. Door Open testing for interlocked doors is typically read throughout half to one minute (less if small room). Optional Door Open tests are listed in Table 1, footnote 6. Smoke / vapor test visualization can be used to demonstrate no ingress of lower class air. 4.2.2.4 In addition to specification limits in Table 1, Action Levels/Control Levels shall be established for the following (a documented investigation is required if excursion) :
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Airborne particles and microbes, initially and after trending data are collected. It may be appropriate to evaluate a significant adverse increase in trending count levels (a pattern of six or more average points drifting toward the action level or specification is considered an adverse increase in trending). Pressure differentials for ISO 7/Class 10,000 or cleaner environments. Work surface and tool microbes, and finger/glove microbial levels (typically based on proceduralized Action Levels).
4.2.3
Room HEPAs/ or other room air final filters shall be monitored for the following:
4.2.3.1 Air flow volume or velocity: HEPA face volume or velocity should be monitored annually (reference ISO 14644-2) to verify air exchanges, unless the site justifies dual filter maintenance and general historical experience in the environment to support reduced frequency, which shall be once every two years. Criteria are per Table 1. In addition, HEPA static pressures are recommended to be monitored. If individual filter face results indicate a significant change (e.g. half of previous filter velocity or 2x static pressure) or room conditions are affected, initiate preventive maintenance plan for filters, and document room condition impact. 4.2.3.2 Filter integrity particle scan: Installed HEPA filter face monitoring is recommended optionally to be done periodically (e.g. 2 years), to meet Class 5 based on particle scan of 0.5micron size particles, or pass aerosol leak integrity challenge, or meet minimum aerosol retention of 99.97% (or manufacturer rating if less), as Action Level. 4.2.3.3 Replacement room HEPAs shall be rated for at least 95% retention efficiency (for existing, or legacy facilities) or per Table 3 for newer facilities, and at installation shall pass an aerosol challenge leak test at the rated retention efficiency. Note: For packaged HEPA filter units (i.e. Laminar Flow Hoods/Benches), an aerosol challenge leak test can be omitted provided that the following are ensured:
The supplier of HEPA filters is approved. The supplier has issued a certificate of compliance with the requirements of the applicable standard and proves the integrity of the supplied filters. The risk of damage during transportation, storage and installation is controlled and
filters inspected adequately. 4.2.4. Laminar Flow Work Stations for general use should have Face Velocity at least: 72 108 lfpm (0.36m/s minimum) and must meet particle requirements.
TLS Preliminary Packaging, HEPA Face: an average target value of 90 lfpm (0.46 meter per second) near the HEPA face, at ~ 6-12 (15-30cm) below face is specified. TLS Preliminary Packaging downstream: Only HEPAs with air overspill design (not enclosed in cabinet), are also monitored for downflow laminar velocity, e.g. at height ~30 45 cm above surface or as specified. Biohazard Hoods- A qualified HEPA face velocity for other Biohazard hoods should be determined and monitored.
4.2.5.
Manufacturing equipment in the controlled environment must meet these criteria: cleanable surfaces, resistant to cleaners; non shedding materials, no textile covers; controlled emission into the CE, with emission or exhaust impact qualified.
Shutdown Temperature: Where tissue/tissue valves are stored in the manufacturing facility during shutdown periods, the temperature of a representative location shall be
4.2.6
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monitored or otherwise be known not to exceed 45C, or a Tag-alert placed; in the event the temperature limit was exceeded, QA must be notified and impact evaluated.
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Table 1. Requirements for All Manufacturing Classified Clean Environments

ISO 14644-1 CE Class Historical 1 References Examples of Manufacturing 4 Operations
Class 5
100 Fed. Std. 209E (CVG Type I) Tissue Product Preliminary/GLX Packaging,includes unloading Final Brep. (Class 5 area must be within Class7). Laminar Flow Benches used to ensure cleanliness not provided by the surrounding environment
Class 7
10,000 Fed. Std. 209E (CVG Type II) Implant manufacturing/ assembly process exposed to the room 4 environment Gowning for Tissue Product Preliminary /GLX Packaging
Class 8
100,000 Fed. Std. 209E (CVG Type III) Manufacturing of devices intended for blood contact or administration to blood 4 path, exposed to room. Coating, dipping and 4 cleaning operations. Implant operations with only brief (minutes) exposure to the room 4 environment. Preparation of manufacturing 4 solutions , prep of Pre. pkg components, tissue processing.
N/A (300,000)
300,000 Fed. Std. 209E (CVG Type V) Manufacturing of devices intended for contact with only compromised tissue (not significant exposure or surfaces contacting blood path), or component handling Blood contact devices which will undergo 4 subsequent cleaning. Existing Extrusion Operations which are 300,000 Preliminary fresh tissue receiving operations 283,000/ ft 3 (10,000,000/m )
3
Gowning and Transfer (non-mfg)

100,000 Fed. Std. 209E (CVG Type IV) Gowning and Transfer rooms for space after donning apparel or opening materials. Non-manufacturing classified area . Laundry environment class to be at least equal to gown room class
Airborne 2 Particles (AP) 3 3 / ft (/m ) (Spec, see 4.2.2.2) Airborne 3 Microbes (AM) cfu/Kl = 3 cfu/m
100 / ft 3 (3520/m )
10,000 / ft 3 (352,000/m ) (Implant mfg. also requires 5m 70) 100 /m 3 (3 cfu/ft )

3
100,000/ ft 3 (3,520,000/m )
Gowning/Transfer Action Levels: AP: 100,000/ ft 3 (3,520,000/m ) AM: 400 /m 3 (10 cfu/ft )
3 3
cfu / Kl cfu / ft 3 35 .3
(Spec) Air Pressure Differential, P Existing 5 Facilities
(.01H2O = 2.5 Pa)
Tissue Prelim. Packaging Laminar Flow Work 3 Stations:18.75/m 3 (0.47 cfu/ft ) General Laminar Benches: N/A
Implant sites: 200 /m 3 (5 cfu/ft )

3
Nonimplant sites: 400/m 3 (10 cfu/ft ) or per site.

3
600 /m 3 (15 cfu/ft );
Gowning prior to Pre Pkg: final gown stage shall meet Class 7/ 10,000. Legacy Non- HEPA: Meet Class 300,000. Min 0.01H2O / 2.5Pa with doors closed;
Min 0.01H2O/ 2.5Pa doors closed; [Action Level .04

H2O/ 10Pa if Table 3 applies, or as defined.]
6
Min 0.01H2O/ 2.5Pa with doors closed; [Act Level .04 H2O/ 10Pa
if Table 3 applies, or as defined.]
(Spec)
Door Open Option
>0 w/doors open For TLS Pre Pkg / FB Unload, Air Flow to be : 90 lfpm(0.46 m/s) See also 4.2.4. 20/hour
>0 with doors open
>0 with doors closed
>0 with doors open 10/hour
Air Flow/ Exchanges (Action level) See Table 3. for newer CEs.
10/hr non-implant mfg; Implant mfg rooms: 20
10/hour (or alternate justifiable if Legacy facility).
1. ISO Class is primary term. Historical classifications are typically based on the number of particles allowed per cubic foot.. 2. The airborne particle limit is maximum number of particles 0.5m/volume of air, for mean at each location. In the event of known process aerosol interference with 0.5m particle detection, an alternative particle size may be used for Class7-8 certification per ISO 14644-1. 3. Airborne microbe limits are maximum permitted for average of each location. (* Ref.EU Guideline GMP Sterile Medicinal Products Annex 1) 4. Where approved part cleaning processes are used, environmental requirements apply only after cleaning. Major components from uncontrolled environments should be cleaned if appropriate. Environment classifications are minimum requirements; cleaner can be used. 5. Differential is the minimum operating requirement as measured from work areas (totally enclosed); to any adjoining area with lower class; or to less control/same class, or to gowning/transfer: These values may be superseded if a process criteria in site procedure is justified. Note: Janitorial closets of lesser class adjacent to clean room are exception: CE pressure should be >0. Qualify impact if open during mfg. 6. For door open condition, it is required to show prevention of unintended cross-flow of air. As an option to differential pressure >0 (method per section 4.2.2.3), this may be demonstrated by velocity through the door plane at least 0.2 m/s, in each section (top, mid, bottom); or by using smoke / vapor test visualization to demonstrate no ingress of lower class air. Use proper PPE for smoke testing. Pressure shall not remain below zero. If this does not meet criteria, air particulate data must be evaluated and corrective action.
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5.0 VALIDATION REQUIREMENTS (All classified facilities) 5.1 New or significantly modified existing classified environments shall have approved design plans (e.g. a list of specific cleanroom materials and specifications defined or referenced in a protocol, see example in Attachment 2), which comply to section 6, Table 2 and 3. Validations must demonstrate compliance to specifications and design criteria using the methods defined in ISO 14644-1,-2 per site procedure, and 14698-1,2 guidance. CQ - For new building facility construction, verification that construction and facility installation complies with design construction requirements, meeting Table 2, must be documented in a CQ (Construction Qualification or equivalent) protocol and report. Refer to Attachment 1a for CQ minimum content guidelines. The CQ data may have an interim approval prior to beginning OPQ. CQ, OQ reports and preliminary PQ report must be approved prior to release of product produced in the area. Pre-qualification cleaning shall include stages of gross cleaning and sporicidal cleaning. Operational Qualification (OQ) of new classified environment rooms requires a series of tests and measurements to determine that all parts of the installation operate together to achieve the required conditions in Table 3 and Table 1(airborne levels), in an at-rest mode, without personnel, one time. Design airflow and pressure shall also be verified. Physical test data, with preliminary microbial as applicable, must be approved to initiate manned PQ operation. Provisions for the operational aspects per section 4.2 must be readied. Performance Qualification (PQ) is required to demonstrate that the complete installation achieves the required performance conditions as specified in Table 3 and Table 1 in a production/simulation mode, with the process functioning, to qualify the environmental control system with the specified maximum number of personnel present (within 10%). The goals of PQ are to establish confidence that environmental controls are effective and reproducible. Also perform testing to characterize work surfaces, equipment, fingertips affecting product. 5.5.1 For new facilities, PQ is performed during three production days over two or more weeks, covering all or worst-case shifts, breaks, and representing start-up of production. The number of air particulate sites sampled in the PQ must conform to ISO14644-1 and be uniformly spaced.
5.2
5.3 5.4
5.5
Bioburden testing is required during the validation of new areas or new processes (PQ or PPQ). For tissue areas, solution and product contact surfaces must be monitored during validation. Liquid sterilization requires evaluation of bioburden and environmental microorganisms. Product may be released following completion of environmental results from its PQ test interval and product bioburden evaluation as appropriate. The protocol should define specific product release requirements. Reports should describe controls which assure no environmental risk to product (e.g. 4.2.2.1 description). To re-validate existing facilities for addition of processes, exhausts/air, or increased personnel manning (e.g. >10 %), a PQ study during one production shift is required. For a cabinet hood to be operated within a controlled environment (with exhausts), the OQ must evaluate the classification of the hood environment, requirements herein, and impact on the surrounding controlled environment. For a process performed in a certified HEPA hood outside the controlled environment, a minimum of one qualification of a process in the hood is done.
5.5.2 5.5.3
5.5.4
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5.6
Format for CQ is defined in Attachment 1a. The format of controlled environment OQ/PQ protocols and reports should contain the minimum elements (see Attachment 1b,c), and for approval refer to GSOP7.2.004 (plus Regulatory Affairs for PQ for PMA products).
Note: Controlled environment qualification is not under scope of manufacturing process /equipment validation, which refers to GSOP6.2.001 for controlled environment validation; Attachments herein apply for format and content of environmental/system documents.
5.7 5.8 5.9
Sites must qualify gown laundry processes, or verify contractor gown cleanliness. Ergonomic stretch activities must be evaluated initially to determine any impact on meeting the controlled environment conditions required. Operation of printers or other equipment with moving parts shall be evaluated by Microbiology, and preferably located away from any tissue handling areas. For tissue areas, paper and label material shall be evaluated for microbiological content and control needed. Sanitization shall be applied for use of computer equipment in controlled environments. Sites must qualify effectiveness of changes in facility janitorial cleaning agents, with corporate Microbiology concurrence (unless equivalent to a previously qualified cleaner). For work surface cleaners, see section 4.2.
5.10
6.0
REQUIREMENTS FOR NEW CLASSIFIED ENVIRONMENTS DESIGN / OPERATION
6.1
All new classified environments (since 3/2000) shall comply with the requirements of this procedure. Definition: New classified environments are defined as those areas in which a new or completely modified air handling systems have been installed for long term use. Design Plans (specific room design criteria) shall be defined for new or modified environments and filed with the CQ or Master Validation Plan. Refer to example in Attachment 2.
6.2
The design of new classified environments shall ensure that the following criteria are met: 6.2.1 Construction material shall facilitate adequate cleaning and resist shedding and have:

Materials shall have a smooth surface, be impervious to cleaning agents per 4.2.1.8, easily cleanable, non-porous, free of crevices , and minimize shedding. Minimized recesses, horizontal surfaces and ledges where dust or other debris could accumulate. Coved floor corners (radiused) for ease of cleaning and eliminate of dust accumulation. Suitable materials for effective cleaning, including resistance to the chemicals and cleaning agents which will be used. Enclosed storage area for janitorial supplies is preferred on the clean side of the room (supplies remain in CE).
6.2.2
The design plan shall include means for entry/exit of personnel and materials, and facilitate appropriate gowning practices as defined in section 4.2:
There shall be a physically separate gowning room for Class 100,000 and cleaner environments.
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Gowns shall be stored on the clean side of the gowning area for all classifications except Class 300,000. If reused, segregation of gowns, hair covers and footwear during storage is required. Adequate storage space for personal outer clothing and personal items shall be provided outside of the gowning room. Material pass-through chambers, airlock rooms, or material transfer rooms, shall be provided for transfer of production materials into and out of all controlled environments except for Class 300,000, to avoid exposing the controlled environment directly to uncontrolled areas. Pass-throughs must have signage, indicators, or interlocks to avoid opening two sides simultaneously.
6.2.3
To facilitate appropriate hand washing:
Hand washing facilities for personnel shall be within the gowning room for all classifications of new facilities, except Class 300,000 areas where there is no handling of direct blood- contact-product surfaces and hand sanitizer is used. All operational requirements per section 4.2 to be met. The hand washing water supply shall be designed to facilitate routine flushing or sanitation, e.g. with hot water, chemicals, or ozone. Hot water shall be maintained at approximately 45 C or higher prior to the mixing valve. Note: It is recommended to design capability of boiler heat capacity to a temperature of >60C. Sinks shall not have plugs or overflows. Sinks and hand dryers shall allow hands-free use. Hand dryer output and other equipment shall meet room standards in operation, and should be designed to use controlled air and to minimize particulates.
6.2.4
A cascading flow of positive pressure air shall be maintained with filtered air, to the uncontrolled space at the lowest pressure. Refer to Table 3.
Leakage of air out of the room shall be minimized with well-sealed doors. windows and wall joints (unless room vents are necessary to achieve pressure differentials per Table 3). Anti-backdraft dampeners should be considered if beneficial to assure positive pressure where production cleanrooms open directly to an uncontrolled environment. Gowning and transfer rooms in new facilities shall meet the standard of design with interlocks or equivalent, to avoid opening both inside and outside doors at once. Interlocks should consider emergency release mechanisms, e.g. buttons, trigger from fire alarm, etc. Uniform flow out of open doors (high, medium, low), is desired.
6.2.5
Pressure differential gauges must be installed to provide readings between two adjoining rooms of different classification; the sensing point should be located away from the door, intakes or vents to minimize air turbulence.
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6.2.6
The facility shall be constructed to maintain integrity and minimize sources of contamination:
Penetration points for utilities, sprinklers, equipment, etc. shall be sealed or covered with escutcheon plates or similar devices. The sprinkler heads should be situated and shaped for minimum intrusion into the cleanroom, insofar as this is compatible with their primary safety function; pendant sprinkler heads are acceptable or flush, with rubber outer seal where local codes allow. Asbestos, lead, other heavy metals, and fiberglass-containing materials are not be used Pipes or other utilities not flush mounted to the ceiling, shall not be placed above product work areas. Utilities should be labeled. The entrance to the controlled environment gowning and transfer rooms should not be located near a building entrance where ever possible, unless appropriate pest controls are in place to minimize potential insect entry and controls are in place to minimize air flow into these rooms. Doors should not be left open. Processes that may emit any problem substances like silicone or glycerin and the like, particularly in oil or liquid states, should be isolated within the controlled environment. Proper chemical storage rooms should be included in the Design plan, and grounding wires incorporated for storage cabinets. A floor plan of the new controlled environment (CE) with demarcation between zones for contamination control (e.g. gown and transfer demarcation lines for shoe cover), personnel and material movement, should be documented.
6.3
Approved construction materials are listed in Table 2. Materials listed are the minimum standards to be met. Materials specified for areas of higher control can be used in less controlled areas.
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Table 2. Construction Materials for New Classified Room Environments

ISO Class Area
Ceilings
Class 5
Class 6/7
Class 8 Class 300,000
Stainless Steel Polymer Panel Gypsum board or similar materials impervious to damage with epoxy, enamel/ acrylic paint . HEPAs covered with perforated stainless steel.
Plastic faced, Cleanroom tile. Gypsum board or similar materials impervious to damage with epoxy, enamel or acrylic paint. Polymer Panel Coated metal.
Plastic-faced Cleanroom tile. Gypsum board or similar materials impervious to damage with acrylic, enamel or epoxy paint or vinyl coated. Polymer Panel Coated metal
No standard
Sealed/secured in place. Walls (Doorframes should incorporate hospital stops at bottoms, for ease of cleaning.) Doors and window frames should be flush mounted into wall for ease of cleaning. Window glazing should also be flush mounted on the clean room side Floors
Secure in place or sealed. Gypsum board or similar materials impervious to damage with epoxy, enamel or acrylic paint. Polymer-surface clean room panels. Certified Prefab Modular Clean room Coated Metal or Stainless Steel
Secure in place to minimize leakage. Gypsum board or similar materials impervious to damage with epoxy, enamel , or acrylic paint/vinyl coated. Soft wall of vinyl or equivalent. Plastic Panels
Stainless Steel Gypsum board or similar materials impervious to damage l with epoxy, enamel/ acrylic paint Polymer panel
Painted
Monolithic vinyl seamless Monolithic epoxy Floor drains are not allowed
Welded seamless vinyl Floor drains are not allowed unless air break and diked
Reinforced vinyl tile Terrazzo Sealed concrete if epoxy coated. Floor drains are not allowed unless air break and diked Clean room designated light fixtures
Sealed concrete
Lighting Fixtures (Serviceable without impacting room integrity) Pipes and Electrical
Clean room designated light fixtures
Clean room designated light fixtures
No standard
Standard construction except for points of entry into clean room: must be acceptable for clean room usage
No standard
Note: Table lists minimum requirements. Materials from cleaner classifications can be used. If no material is listed, only materials from cleaner classifications are appropriate. In addition, refer to other design criteria per section 6.2.
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6.4
Air handling and filtration design shall ensure that the following criteria are met, in addition to Table 1 criteria, for new systems installed since GP1114 Rev.E (3/2000) :
Table 3. New Classified Environments (CE): Air Handling and Filtration Qualification Requirements
ISO Class Area Air Filtration and Filter Integrity. (Action Level) Class 5 Prefilter, 30% Intermediate filter, 80-85%.* Final filter, 99.97% HEPA Laminar air flow @ work surface 0.04H2O (10 Pa) Class 6/7 Prefilter, 30% Intermediate filter, 80-85%.* Final filter, 99.97% HEPA Class 8 Prefilter, 30% Intermediate filter, 80-85%.* Final filter, 99.97% HEPA Gowning/ Transfer Prefilter, 30% Intermediate filter, 80-85%.* Final filter, 95% HEPA. Final filter, 8085% Class 300,000 Prefilter, 12%
Pressure Differential from enclosed cleanroom To adjoining room of less clean class or less control.
To uncontrolled Environment.
0.04H2O (10 Pa). To room of lower class. ( less is Action Level; see Table 1 for op.spec.) >0 door open, Spec.(see 6.4.2) 0.06H2O (15Pa), Less is Action Level.
0.04H2O (10 Pa) To room of lower class. ( less is Action Level; see Table 1 op.spec.) >0 door open, Spec. .(see 6.4.2) 0.06H2O (15Pa), Less is Action Level. >0 door open, Spec. .(see 6.4.2) 0.01H2O (2.5 Pa), Action Level. >0 door open, Spec. .(see 6.4.2) >0 H2O
>0 H2O door open 0.06H2O (15Pa) Tissue Packaging Velocity 90 lfpm (.46 m/s) See also Table 1.
Air Flow / Filter Volume/ Face Velocity / Air Exchanges

Note: Design Air Changes apply only during initial qualification. Action Level.
The design shall assure that the airflow to the controlled space is maintained such that air cleanliness requirements, pressure differentials, and calculated room air changes are readily met during manufacturing.
Room Air Changes 20/hr (Design for 30 minimum) Room Air Changes: 10-20/hr; Design 20. Mfg rooms serving Implant mfg: 20/hr Room Air Changes: Main CE Entrance Gown room: 20/hr; Room Air Changes 10/hr
Other rooms: 10/hr. * Intermediate filter may not be possible in small installations or self-contained HEPA units. Single pre-filters require more frequent change out .
6.4.1 6.4.2
Filter efficiency to be per ASHRAE (American Society of Heating, Refrigeration, and Air Conditioning Engineer) or equivalent rating method. Pressure Differential gradient must allow doors to open while avoiding unintended cross flows. Refer to Table 1 Footnote 6 for optional methods to demonstrate outward flow and minimizing ingress of contamination when doors are opened. Flow visualization can be used to demonstrate the effectiveness of both concepts. Humidity controls shall be implemented if required by product / process requirements or per site design requirements. Humidifiers if used shall be non-condensing near product and shall not contribute to air-borne contamination (no standing water) of clean area. Generally, relative humidity (RH) is For Information Only, and for personnel comfort. Typical CE desired parameters (e.g. on average are 30 70%RH in cooling/operating mode or as defined in dew point) are determined. Temperature specifications shall be based on any requirements of process, equipment or materials if applicable. If not applicable, environmental control design criteria shall reference a general personnel comfort range (e.g. 62-76F/17-24C) to be qualified for new CE facilities.
6.4.3
6.4.4
GSOP6.2.001
Rev
Page 13 of 18
7.0
REQUIREMENTS FOR UNCLASSIFIED CONTROLLED ENVIRONMENTS (Non Clean Room)
7.1
Unclassified controlled environments are utilized for manufacturing operations which require minimization of visible particles but do not require a classified environment and are, therefore, unmonitored. Examples include: 7.1.1 Manufacturing of devices with no blood-path or compromised tissue contact. 7.1.2 Compounding raw material resin to be re-melted for extrusion or molding in a classified environment. 7.1.3 Components or processes which have subsequent cleaning operations. 7.1.4 An area in which exterior of a closed final heart valve primary package is exposed. 7.1.5 Areas where final packaging labeling of sterile, sealed product is performed
7.2
To minimize particles, the following materials shall be used: 7.2.1 Cleanable, non-porous flooring 7.2.2 Drop ceiling 7.2.3 Air filtration that is equivalent to a retention efficiency of 30% (air conditioning filtration)
7.3 7.4
General cleaning procedures are used, and if appropriate, hand cleansing or gloves. Garb requirements shall be posted (e.g. haircover and lab coat/frock requirements where applicable, posted at a designated location for donning) or defined in procedure. Coats/smocks that are used for work on product at the work station must be controlled (i.e. if worn outdoors, they must not be subsequently returned to work on clean product applications at the work station). For electronics areas, ElectroStatic Discharge (ESD) controls should be defined in the area procedure where applicable.
8.0
REFERENCES
8.1 ISO 14644-1 Cleanrooms and associated controlled environmentsPart 1: Classification of air cleanliness 8.2 ISO 14644-2 Cleanrooms and associated controlled environmentsPart 2: Specification for testing and monitoring to prove continued compliance with ISO14644-1. 8.3 ISO 14644-4 Cleanrooms and associated controlled environmentsPart 4: Design, construction and start-up. Guideline only. 8.4 ISO14698-1 Cleanrooms and associated controlled environmentsBiocontamination controlPart 1: General principles and methods. Guideline. 8.5 ISO 14698-2 Cleanrooms and associated controlled environmentsBiocontamination controlPart 2: Evaluation and interpretation of biocontamination data. Guideline
GSOP6.2.001
Rev
Page 14 of 18
Attachment 1a CQ Section
Approval Page Purpose Scope/ System Description
CQ Minimum Suggested Information /Instructions Follow Template 22298 with applicable content.
Approval requirements for CQ protocol documented in Template #22298. Include controlled environment name Include any background information as to why the validation is required. Provide description of where controlled environment area is located. Room number, classification, product lines. Design Plan, reference to location. Responsibilities may be addressed. Include a listing of document numbers, revision level, and document name of any reference documents used in the development of the protocol. Attach or summarize Room Design Criteria and/or Master Validation Plan if applicable. Includes a listing of all test cases required to complete the qualification. CQ Minimum Test Cases are: 1. Facility Major Components & Equipment/Instrument Verification (AHU, Filters) and Installation Qualification 2. Facilities Utility Verification (new buildings/as needed) 3. Preventive Maintenance Verification, calibration of gauges 4. Facility drawings verification & Vendor Documentation Verification (e.g.HEPA Filter supplier retention certification, manuals) 5. Control documentation (refer to SWV and verification of alarms, configuration settings, if applicable.) 6. Controlled Environment Construction Checklist Cross-reference to the Attachments or forms where data will be collected for the test case. If individual equipment requires IQ, cross reference. Construction shall meet requirements (GSOP6.2.001). . As-built drawings must be verified or notated. Final construction drawings are archived. Initiate HEPA filter room drawing within Edwards system. Complete Document any test instruments used in execution. Document verification that all requirements are met. Document a listing of all deviations and status of each deviation encountered during the execution of the protocol. Document any Deviations using a Protocol Deviation Report or equivalent explanation. Interim approval is documented use of section 10 of the template. as approval page, accompanied with relevant attachments. Complete Final report form with Interim approval page included as one attachment. Develop an addendum report to document additional major components installed or changes to the air handling system or other items defined in Design Plan parameters.
References
Procedure/ Test Summary
Acceptance Criteria
Appendices
CQ Report Form Addendums
GSOP6.2.001
Rev
Page 15 of 18
Attachment 1b OPQ Protocol Section

Approval Page Purpose
OPQ Controlled Environment Minimum Information / Instructions

Approval requirements for protocol (GSOP7.2.004). Include controlled environment name and location Include any background information as to why the validation is required. Provide description of controlled environment, Room number, classification, product lines. Reference facility Master Validation Plan if applicable. Describe if any impact on product risk management, controls, rationale why not. Responsibilities may be addressed. Include a listing of document numbers, revision level, and document name of any reference documents used in development of the protocol. Environmental samples are based on ISO14644-1 methods and site procedure. If PQ includes product bioburden/pyrogen samples, the following information: Part Number/Model of product to be sampled (nonsterile). Sample size per run monitored e.g. five bioburden is based on the ISO11737-1 which indicates that this is within the range of common bioburden sample sizes, and pyrogen sample size of minimum three is based on USP. Identify any calibrated test instrument (may be on data forms) manufacturer and/or description, and MET#. Includes a listing of all tests required for the qualification. Where applicable, standard test procedures shall be referenced. If any of the minimum required tests are not applicable, a rationale must be provided. OQ Functional Verification Testing (Unmanned, At-rest) requires the following: Pre-Cleaning and Post-Final Cleaning (sporicide/ 5% bleach) evaluation if new facility 1.Air Flow Volume/Velocity and Air Exchange Rate 2. HEPA Filter Aerosol Challenge Integrity test (Prerequisite verification) 3. Pressure Differentials/ Cascade 4. Airborne Particulate and Microbial Testing 5. Surface Microbial Testing PQ shall verify the following: 1. Pressure Differentials 2. Airborne Particulate and Microbial Testing 3. Surface Microbial Testing 4. Personnel Finger and Tool Testing 5. Temperature / Humidity reading 6. Process/ Bioburden and Pyrogen Testing Acceptance limits based on GSOP6.2.001 and site procedure must be defined. The location of data and sample traceability shall be referenced. Document a listing of all deviations and status of each deviation encountered during the execution of the protocol. Document any Deviations using a Protocol Deviation Report or equivalent memo. When the services of a supplier are involved in the testing to be completed, the protocol will refer to the suppliers name and address and number of the SQR or other site reference to the supplier approval. The Data Collection Forms will be defined in the protocol to be used to document the execution of the Tests.
Scope
References
Test Articles and Controls Equipment and Materials
Procedure/ Test Summary
Acceptance Criteria Records to be maintained Supplier Qualification Protocol Attachments
GSOP6.2.001
Rev
Page 16 of 18
Attachment 1c OPQ Report Section

Approval Page Purpose Scope Test Articles Deviations and Failures
OPQ Controlled Environment Minimum Information / Instructions

Approval requirements for protocol are per GSOP7.4.001. Provide an objective statement for the qualification. Provide Scope (content same as protocol). Reference sample traceability for samples tested. Any deviations from the established protocol steps and requirements shall be described and justified. Summarize the corrective action, and provide status of the deviation (open of closed). If no deviations were encountered, utilize appropriate statement. Summarize the Qualification Results. Analyze data in a manner that it can be compared directly to the acceptance criteria. If acceptance criteria was not met, reference the deviation section and determination if acceptance criteria was met after the implementation of corrective action resulting from the deviation. Detail the Conclusion of the qualification. Provide a clearly stated summary of passed or failed acceptance criteria, along with any required corrective action with a disposition of the controlled environment. If product is to be released, a disposition for product should be stated. Reference to the site procedure for environmental monitoring. Include data, executed data collection forms and any raw data generated during the execution or reference to their location if filed with routine environmental monitoring program. Include the Deviation Report Summary and approved Deviation Report Form or equivalent. Interim reports may be used to document partially completed testing in order to allow limited decision making. Form E0441 - Environmental Control / Evaluation Report or a full report format may be used. An Addendum is used to document additional test results generated or provide clarification on information collected, after the initial test report has been signed off.
Results / Summary and Analysis
Conclusion
Attachments
Interim Reports Addenda
GSOP6.2.001
Rev
Page 17 of 18
Attachment 2. Example of Room Pre-Construction Design Criteria

(Other formats may be used provided that the same required information is included).
ROOM DESIGN CRITERIA SHEET, Building_____________ Room_____

Ref to GSOP6.2.001 rev.____
ROOM Class: OCCUPANCY: SQUARE FEET: ROOM DESCRIPTION: CEILINGS: WALLS: DOORS: FLOOR: COVE BASE: LIGHTING: HVAC: (approx targets) List material type, if Recessed flush to ceiling, how held in place, if back sealed. Temp F/C Rel Hum. % Air chg per hr * Recirc Pre Filters 30% Intermed Filters __% HEPA Filters _____% Product processing operations including (List material) (List material & Sealed joints). Door seals (list type around perimeter of doors. Self closing. Interlocked etc) (List Material) Class (ISO ) ROOM NUMBER: NOISE LEVEL: DATE: < 90 dB
Yes ATMOSPHERE/ Air Design: ROOM PRESSURE:
(Describe) Air-conditioned space with positive airflow with respect to outside of room. Highlevel supply and low level return.
Example: Positive room pressure 0.04 Water in relation to connecting rooms (Door Open > 0; define maximum duration simulating worst case production ingress/egress). Positive Pressure to Base Building Uncontrolled = 0.06 Water.
UTILITIES: PIPES/ ELECTRICAL: SERVICES: Pass Through/Transfer Rm: GOWNING:
Electricity, Processed H2O, Processed Compressed Air, Penetration Points Sealed. Standard construction per GSOP6.2.001 Telephone, and Network hookups. Exhaust vent for Material flow to be described. Gowning room, describe features per per GSOP6.2.001. Hand Washing and Drying facilities. Personnel and material flow chart to be included with PVP or Design Plan. Work with the EHS department to determine specific safety design criteria for the building or room which will be verified through the permit process. This may include chemical storage. Recesses, horizontal surface/ledges minimized.
EHS
ADDITIONAL NOTES:
Prepared by/Date:_________________________
Quality Approved /Date ________________________________

* Design target approximate(not >10% less)
References________________________.To be filed with CQ or MVP.
GSOP6.2.001
Rev
Page 18 of 18
Revision History Rev Subject A New document release. Document number changed from GP1114 to GSOP6.2.001. B C Reworded and consolidated text to reworded to clarify global requirement status. Clarifications in scope and throughout. Defined ISO # as primary class, and updates to Table 1 including pressure criteria door open test options; section 4 clarifications for use and testing of controlled env. Changed MBC to lab name. New facilities to have standard interlocks, construction materials updated, facility floor plans and safety in design plans added. CQs to use form# 22298 template. Eliminated document title references.
ECR 79513 81783 90581
Date 1/04/2010 4/2/2010 4/26/2011
ECN 66299 68248 76336

Quality Controlled Environments Manufacturing

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Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

ISO CLASS 8 CLASS 300,000

Hair Cover, (Clean room type, disposable) Foot wear**;

x x sterile shoe cover or

Mask/ Beard cover Hood Frock, Gown, or Coverall Garment

If required/ posted for operation.

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

Table 1. Requirements for All Manufacturing Classified Clean Environments

Gowning and Transfer (non-mfg)

10,000 / ft 3 (352,000/m ) (Implant mfg. also requires 5m 70) 100 /m 3 (3 cfu/ft )

Implant sites: 200 /m 3 (5 cfu/ft )

Nonimplant sites: 400/m 3 (10 cfu/ft ) or per site.

600 /m 3 (15 cfu/ft );

Min 0.01H2O/ 2.5Pa doors closed; [Action Level .04

Door Open Option

>0 with doors open

>0 with doors closed

>0 with doors open 10/hour

10/hr non-implant mfg; Implant mfg rooms: 20

10/hour (or alternate justifiable if Legacy facility).

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

5.7 5.8 5.9

REQUIREMENTS FOR NEW CLASSIFIED ENVIRONMENTS DESIGN / OPERATION

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

To facilitate appropriate hand washing:

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

Table 2. Construction Materials for New Classified Room Environments

Class 8 Class 300,000

Clean room designated light fixtures

Clean room designated light fixtures

Document Issued Department Title

For Use Only By Affiliates of Edwards Lifesciences

ECN 4/26/2011 76336 Quality Controlled Environments for Manufacturing

Air Flow / Filter Volume/ Face Velocity / Air Exchanges

ROOM DESIGN CRITERIA SHEET, Building_________ Room_