Whitepaper Technical Opinion: Grade A - Air Supply and Local Protection

Whitepaper Technical Opinion: Grade A - Air Supply and Local Protection I N D U S T R Y I N S I G H T S Norman A. Goldschmidt Sr. Principal, President www.geieng.com

I N D U S T R Y I N S I G H T S Genesis periodically publishes white papers and reports about topics of special interest to the industries we serve. As veteran advisors for major corporate infrastructure, energy management, facilities, technology, manufacturing and building systems of every type, our leaders share their perspectives to help both clients and the public at large make high value decisions by having the best available information. All information contained herein is copyrighted and cannot be reproduced without permission. For academic uses, please contact us Copyright Genesis Engineers 2017 - All rights reserved - Do not reproduce without written permission. 2

Whitepaper Technical Opinion: Grade A - Air Supply and Local Protection Introduction The area directly surrounding RABS units has been the subject of discussion since the inception of RABS technology. The essential problem with these units is twofold: 1. Unlike isolators, there is no gaseous decontamination cycle to decontaminate the incoming change parts and doors after the unit is closed. 2. Unlike isolators, RABS are sometimes opened during a run for interventions. Indeed, the perceived ability to open a RABS is the reason that some companies choose this approach rather than the more restrictive isolator. In order to mitigate these risks, it is recommended industry practice to provide a zone of HEPA filtered air flowing down around the RABS unit, to decrease contamination in this zone during setup and when doors are opened for interventions. The problem that results is to determine the appropriate classification and monitoring program for this enhanced environment, to recognize its importance without overstating its abilities. Authors on this topic, such as Agallaco, Akers and Ljysford suggest that the space be classified as ISO 5 meaning ISO 5 for 0.5 micron particles in-operation. However, this gives us no guidance for viable monitoring, nor an EU acceptable approach. To address these shortcomings the authors of the upcoming ISPE Baseline Guide for Sterile products (including this Author) suggest leveraging existing definitions elsewhere within regulation to create a classification for this type of enhanced environment which is less than ISO 5 / Grade A, but is still recognizable to regulators. References PIC/S - GMP Annex 1 Revision 2008, Interpretation of Most Important Changes for the Manufacture of Sterile Medicinal Products, PI 032-2, January 2010 FDA - Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, September 2004 EU EudraLex Volume 4, EU Guidelines to Good Manufacturing Practice - Medicinal Products for Human and Veterinary Use - Manufacture of Sterile Medicinal Products, Annex 1, February 2008 Copyright Genesis Engineers 2017 - All rights reserved - Do not reproduce without written permission. 3

ISPE Information contained in this Technical Opinion was obtained from documents previously published by ISPE. Background In 2004, FDA s Sterile Guideline introduced the terms Local Class 100 (ISO 5) protection and local protection. Similarly, in 2008, the EU Annex 1 document introduced the term Grade A air supply. (For ease of reference, the terms LP and GAAS will be used throughout the remainder of this document.) As noted in the referenced PIC/S document, The new revision of Annex 1 mentions a new term, Grade A air supply, but no definition of this new term is given in the revised Annex. Inspectors and Industry therefore need an interpretation of this new term, especially as a provision of a Grade A air supply is one of the most significant changes in Annex 1. Similarly, the FDA document provides no definition of the term Local Protection. Both terms are widely used in industry today, although the lack of definition creates confusion regarding design requirements and functional limits for these areas. It should be also be noted that neither document makes any recommendation regarding appropriate total and viable particulate limits for these areas, nor do they address unidirectional airflow requirements. The PIC/S document sought to remedy this situation, and provides a definition for the term Grade A air supply. This document also provides recommendations for total (non-viable) particulate limits at the point of supply, and makes recommendations regarding qualification and monitoring of these areas. In order to improve and harmonize understanding of these terms, additional information and recommendations are provided below. For purposes of this document, the focus is on design intent and functional requirements for these controls. Definition The terms Local protection (LP) and Grade A air supply (GAAS) should be considered as equivalent, and are used to indicate any instance where a localized HEPA filtered air supply is used to reduce the risk of total or viable particulate contamination of critical surfaces within a specified working zone. This engineering control can be applied to reduce risk in any background classification, including: ISO 8 (at rest)/eu Grade D, ISO 8/EU Grade C, and ISO 7/EU Grade B cleanroom areas. LP/GAAS are generally configured with terminal HEPA filtration proximate to the work zone (above, or to one side, as appropriate to the risks) in order to ensure ISO 5 particulate levels for 0.5 and 5.0 micron particles, proximate to the work zone, in the at-rest state. Configuration of the extract (return and/or exhaust) to assure a flushing flow of clean air through the area of concern is a key attribute of a well-designed LP/GAAS. In certain cases Copyright Genesis Engineers 2017 - All rights reserved - Do not reproduce without written permission. 4

additional engineering controls, such as enclosures or RABS with glove ports can be reasonably employed to enhance the air quality within the work zone. Due to the variations in background classifications, particulate limits (total and viable) and critical design parameters must be determined on a case by case basis. Examples of application of LP/GAAS are provided in Table 1, LP/GAAS Examples. Environmental Monitoring (EM) Application of LP/GAAS is straightforward from a HVAC design perspective (i.e. location and number of HEPA filters, location of returns, design airflow rates, etc.). However, establishing target At-rest or In- operation limits for these areas is often overlooked during facility design, which can cause considerable difficulty and delays during qualification of these areas. Furthermore, care must be taken to clearly differentiate LP/GAAS zones from ISO5/Grade A zones or conditions, as these limits may not be applicable. The similarity in nomenclature can cause confusion if precise definitions and terminologies are not established and followed. We suggest the following principles for establishing LP/GAAS EM limits: 1. Monitoring/testing of LP/GAAS zones should include measurement of total and viable particulates proximate to the work zone for the process. 2. At-rest monitoring/testing is primarily useful as a pre-check of overall system performance and to establish limits for recovery, during qualification testing. 3. LP/GAAS air supply will generally meet ISO 5 requirements for 0.5 micron and 5.0 micron particles, when measured 100-150mm below the filter face or grille, under all conditions. 4. While particulate levels in the work zone are a function of the LP/GAAS configuration, airflow rates, sanitization and rate(s) of particulate generation (which is heavily influenced by gowning); a well-designed LP/GAAS, should be should be capable of achieving a one log reduction in total particulates, below the in-operation background limit. 5. Care must be taken to establish appropriate viable limits where LP/GAAS is used in classified areas below ISO7/Grade B. Viable particulate limits should be consistent with the less rigorous gowning and sanitization requirements for these areas. A careful review of the specific manipulations required to expose and collect EM plates should also be performed. 6. For initial qualification purposes, viable particulate limits 1/2 to 1/3 of the background environment limits are recommended. At the completion of qualification testing, historical EM data should be reviewed and limits adjusted, as appropriate, using statistical analysis. Recommended initial qualification EM limits are shown in Table 2. Copyright Genesis Engineers 2017 - All rights reserved - Do not reproduce without written permission. 5

Table 1 Examples of LP/GAAS Applications PROCESS LP/GAAS APPLICATION BACKGROUND CLASSIFICATION DESIGN INTENT Transfer of presterilized Syringe Tubs (double bagged) from Grade D to Grade C LP/GAAS provided over outer bag removal station ISO 8 (at rest)/ Grade D Protect the inner bag or syringe tub from external contamination during de-bagging and transfer to the inner bag removal station. For installations with automated tub decontamination, protection of the inner bag is not considered to be critical. Process Tank Protection LP/GAAS provided over tank manway or other open material addition ports ISO 8 / Grade C LP/GAAS is provided to protect clean exposed product contact surfaces from external contamination during material additions. Capping LP/GAAS is provided over fully stoppered vials, from exiting Grade A conditions to closure of the crimp seal. ISO 8 / Grade C or ISO 8 (at rest only)/ Grade D This application is consistent with EU Annex 1 requirements and FDA recommendations for capping operations. Isolator Mousehole LP/GAAS is provided on the outside of the isolator mousehole, to minimize risk of isolator contamination due to induction. ISO 8 / Grade C Reduce risk of induction of air into the isolator due to turbulence. This application is cited as an example in Appendix 1 of the FDA Guidance. RABS Door swings LP/GAAS is provided along perimeter of RABS enclosure over door swings. ISO 7 / Grade B RABS door swings, to protect gloves (gauntlet) and interior door surfaces during open door interventions. This application is an oft-cited requirement during FDA inspection of RABS based facilities.

Autoclave/Oven Unloading LP/GAAS is provided over, or near, the autoclave/oven unload area. ISO 7 / Grade B or ISO 8 / Grade C Minimize risk of contamination of sterilized articles during cooling. This application (or lack thereof) has become a common regulatory audit observation, though the scientific basis has not been proved. Parts Prep (wrapping/preparation for autoclaving) LP/GAAS is provided in the parts prep area, to protect clean articles during wrapping and preparation for autoclave sterilization. LF benches (workstations) are commonly used to meet this requirement. ISO 8 / Grade C Maintain cleanliness of clean product contact surfaces during assembly and autoclave prep. This application commonly involves use of laminar flow benches for parts wrapping Parts Washer Unloading LP/GAAS is provided over the parts washer unloading area. ISO 8 / Grade C Reduce risk of particulate contamination of clean product contact surfaces during unloading & transfer operations.

Table 2 Recommended Initial Qualification Limits for Total and Viable Particulates IN OPERATION LIMITS INSTALLATION LP/GAAS in ISO 7/Grade B Background LP/GAAS in ISO 8/Grade C Background w/rabs EXAMPLES LP/GAAS is provided along perimeter of ISO 5/Grade A RABS enclosure, to protect interior door surfaces and gloves from contamination during open door activities (sanitization, set-up, controlled open door interventions) Active RABS installation over capper, from cap infeed from isolator/aseptic area to completion of capping. BACKGROUND CLASSIFICATION Total Particulates (p/m3) Active Air Viable (cfu/m3) Settle Plates (90 mm plate, cfu/4 hours) Contact Plates (55 mm plate, cfu/plate) EU Grade B 35,200 5 3 3 EU Grade C 352,000 33 17 8 Gloveports provided for routine interventions prior to application of crimp seal. Interventions include manipulation of EM plates

LP/GAAS in ISO 8/Grade C Background w/o RABS LP/GAAS provided over tank manway or material addition ports LP/GAAS provided over autoclave/oven unloading area LP/GAAS provided at parts washer unload, or for parts wrapping and prep ISO 8 / EU Grade C 352,000 50 25 12 LP/GAAS in ISO 8 (at rest)/grade D Background Syringe tub outer bag removal station ISO 8 (at rest)/eu Grade D 3,520,000 100 50 25

Industry and Regulatory Citations ISPE RABS Definition 2005 Advanced Aseptic Processing Technology (textbook) Copyright Genesis Engineers 2017 - All rights reserved - Do not reproduce without written permission. 10

FDA - Guidance for Industry Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice: Multiple material transfers are generally made during the processing of a batch. Frequently, transfers are performed via direct interface with manufacturing equipment. Properly maintained and operated rapid transfer ports (RTPs) are an effective transfer mechanism for aseptic transfer of materials into and out of isolators. Some transfer ports might have significant limitations, including marginal decontaminating capability (e.g., ultraviolet) or a design that has the potential to compromise isolation by allowing ingress of air from the surrounding room. In the latter case, localized HEPA-filtered unidirectional airflow cover in the area of such a port should be implemented. Isolators often include a mousehole or other exit port through which product is discharged, opening the isolator to the outside environment. Sufficient overpressure should be supplied and monitored on a continuous basis at this location to ensure that isolation is maintained. If stoppered vials exit an aseptic processing zone or room prior to capping, appropriate assurances should be in place to safeguard the product, such as local protection until completion of the crimping step. Use of devices for on-line detection of improperly seated stoppers can provide additional assurance. EudraLex Volume 4, Annex 1: 120. Vial capping can be undertaken as an aseptic process using sterilized caps or as a clean process outside the aseptic core. Where this latter approach is adopted, vials should be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped. PIC/S - GMP annex 1 revision 2008, Interpretation of most Important changes for the Manufacture of sterile Medicinal products: The new revision of Annex 1 mentions a new term, Grade A air supply, but no definition of this new term is given in the revised Annex. Inspectors and Industry therefore need an interpretation of this term, especially as a provision of a grade A air supply is one of the most significant changes in Annex 1. The term grade A air supply is specifically used to describe a supply of air which is HEPA filtered, and at the point of supply meets when tested, the non-viable particulate requirements of a grade A area, as defined in paragraph 4 of the revised Annex 1. It is important to differentiate between the terms grade A air supply and grade A area. A grade A air supply should be qualified and monitored as follows: Qualification requirements: Qualification is done only under at rest conditions: For the crimp-capping machine the atrest state is achieved when the air supply is switched on, the crimp-capping machine is operating (feeding of vials and crimp caps is not considered necessary) and there is no interference by operators. For the conveyor tunnel for liquid products the at-rest state is Copyright Genesis Engineers 2017 - All rights reserved - Do not reproduce without written permission. 11

achieved when the air supply is switched on, the conveyor belt is switched on and there is no interference by operators. Non-viable particles should be measured and are expected to meet grade A requirements. The probe should be located at the point of supply of the filtered air. Smoke studies should be performed. Whilst unidirectional air flow is not required, efficient protection of the vials should be demonstrated and the absence of air entrainment from the surrounding room should be demonstrated. Limits for air velocity should be in place and justified. Monitoring requirements: Monitoring requirements for non-viable particles and microbiological contamination should be defined by the company following a risk assessment. Copyright Genesis Engineers 2017 - All rights reserved - Do not reproduce without written permission. 12