CGMP에 적합한 시설 설계

박철환, 이영철, 이종대, 이용석, 김상용

한국생산기술연구원

Facility Design Based on the CGMP Concepts

Chulhwan Park, Youngchul Lee, Jongdae Lee, Yong-Seok Lee, Sangyong Kim

Korea Institute of Industrial Technology (KITECH)

Introduction

The Korea Biotechnology Industrialization Center (KBIC) of the Korea Institute of Industrial Technology (KITECH) will build a manufacturing facility to meet the CGMP (Current Good Manufacturing Practices) regulations and other national and international standards by 2003. Business scope of the KBIC will include manufacturing of clinical and commercial biotechnology products for global distribution. The KBIC manufacturing facility will be operated under the CGMP and other applicable regulations, policies, and laws. To facilitate this purpose, appropriate quality system and infrastructure will be established. This document includes a facility design features, functional areas, description of each flow, HVAC distribution, critical systems description, clean room classification, room pressurization.

Facility Description

The facility is designed for manufacturing, processing, packaging and holding of multiple clinical and commercial biotechnology products, including bulk proteins and finished products, according to the CGMP regulations.

(1)	Facility Design Features

The facility was designed based on the following CGMP concepts (21CFR211 Subpart C - Buildings and Facilities). ① Adequate space for manufacturing and laboratory activities (211.42 (a) and (c)): approximately 3,000 m2 of manufacturing area, 600 m2 of QC (Quality Control) lab and 4,760 m2 of entire area  ② Environmental control using HEPA filters and differential air pressure in manufacturing and lab areas (211.42 (c)): positive pressure in purification, fill, cell bank lab and bioassay lab areas to negative pressure in fermentation and other QC lab areas  ③ Cleaning and maintenance (211.42 (a), 211.56 and 211.58)  ④ HVAC control system (i.e. Monitoring System) and effective operation (211.46)  ⑤ Utilities (211.44, 211.48, 211.50, 211.52 and 211.58)  ⑥ Securities et al. Access to the manufacturing and QC lab areas is controlled by a double security system, consisting of building access security and room or lab access security. Only approved and registered personnel can access the manufacturing and QC lab areas. Access to restricted areas in the facility such as sample storage and document archiving rooms are limited to authorized personnel. The access to these areas is monitored through a monitoring system.

(2)	Functional Areas

The facility consists of 7 functional areas (Figure 1). Administration, QC lab and the mechanical areas are located at the two extreme wings of the building while the production suite is located at the center of the complex. The production suite consists of four major areas comprised of fermentation area, purification area, formulation/fill/finish/packaging area and warehouse. Those are physically and environmentally separated from each other while satisfying the adjacency requirement as demanded by the production process. The production suite is arranged in the continuous order with respect to the logical process flow. The formulation/fill/finish/packaging area protrudes from the buildings main axis in order to reduce the travel distance of personnel and goods within the building and to form a dedicated delivery area for the warehouse.

(3)	Description of Each Flow

General Flow: All raw materials and equipments will enter through the service entrance and will go to the warehouse. After QC inspections materials and equipments will be distributed to appropriate bioprocess areas. In-process materials will move in the order of fermentation, purification, formulation/fill/finish, packaging/labeling areas and warehouse. After QC inspection, finished product will be shipped out through the warehouse. All personnel and visitors will enter the facility through the main gate and then through the main entry door of the administration wing to enter the building. A separate entry point into the building is provided for personnel entering the utility wing.

Personnel Flow: The main point of entry (#1901) is located at the administration wing. Upon entry, various personnel would separate into the four work zones of production, warehouse, QC lab/QA, administration. This single point entry system allows effective security supervision and contamination control between the controlled areas of production suites and the uncontrolled environment of the administration and the QC lab area. The personnel of QC lab and administration will enter directly into their respective work areas whereas entry into the production area is through a first stage gowning room. The process personnel will enter the Lockers (#1003 & 1007) - first stage gowning rooms - to remove street clothing and shoes and to change into plant uniforms. The lockers include isolated Lavatories (#1002 & 1008) and Shower Facilities (#1004 & 1006) from the operation spaces. Upon entry into the production suite, each personnel will proceed towards respective work areas of fermentation, purification, formulation/fill/finish, packaging/labeling and warehouse. Personnel entering the fermentation, purification and formulation/fill/finish areas are required to put on clean room outfit and/or aseptic outfit respective of clean room classification of each suite at each entry point (#1101, 1201, 1502 & 1525). Personnel exiting the fermentation and purification suites will enter dedicated Degowning Rooms (#1125 & 1225) to take off clean room outfit and exit through a Return Corridor (#1224). Personnel exiting the Formulation Room (#1510) will track back and re-enter the two stage Gowning/Degowning Rooms (#1502 & 1503) to take off aseptic and clean room outfits and exit into a Corridor (#1501). Personnel leaving the Filling Room (#1515) will exit via Lyophilization Room (#1523) and Powder Handling Room (#1520) and the Degowning Room (#1521) to take off aseptic and clean room outfits and exit into a Clean Room Corridor (#1501).

Process Flow: Working cell bank is prepared in a Cell Bank Room (#1107) and brought into the Inoculum Room (#1113) through a pass box. Cell is incubated in the Inoculum Room and transferred into the Fermentation Room (#1111) to begin the fermentation process. After fermentation, in-process material is transferred into the Purification Room-1 (#1114) either through a transfer line or by personnel to begin the downstream process. In-process material is passed into the adjacent purification area through a pass box. Upon final purification, in-process material will be stored in Bulk Material Storage (#1206 & 1207) for QC inspection and released for next stage of production. In-process material will enter the formulation/fill/finish/packaging area through a pass box in Material Storage (#1504) and enter the Formulation Room (#1510). Formulated product is transferred into the Filling Room (#1515) through a pass box. The formulated product is filled into vials and freeze-dried in the lyophilizer (#1523). Freeze-dried product is stoppered and transferred through a pass box into the Capping Room (#1517). Capped product is transferred through a pass box into the Inspection Room (#1516) and then sent out for packaging in the Packaging & Labeling Room (#1601). Packaged material is stored in the Quarantined Material Storages (#1702 & 1703) until QC inspection. QC passed product is sent to Product Storages (#1704, 1705, 1706 & 1707) in the warehouse to be shipped out.

Material Flow: All raw materials are delivered to the warehouse and segregated into pre-QC and post-QC materials. To avoid introducing bulky containers into the clean corridors of the controlled areas, QC approved raw materials enter the Decasing Room (#1719) to be decased and wiped down and delivered to Material Storages (#1121, 1203 & 1504) of each production suite via air locks or pass boxes for small items. Materials from the storage rooms are weighed in each respective Weighing Room (#1120, 1204 & 1505) and entered into production areas.

Equipment Flow: All equipment used for production is delivered to the warehouse (#1710). Upon QC inspection, equipment to be used are delivered to Washing Rooms (#1118, 1223 &, 1512) of each respective production area to be washed, assembled and sterilized (#1119 & 1222) for use in production. Used equipment from the fermentation and purification areas will leave through the exit Air Locks (#1115, 1116, 1211 & 1218) of each production room and delivered to each respective washing rooms via Return Corridor (#1224). Used equipment from Formulation Room (#1510) and the Filling Room (#1515) will pass through a dedicated pass box and air lock respectively to enter the Vial Washing & Preparation Room (#1512) for washing and sterilization. Unloaded (#1511) sterilized equipment will be delivered directly into the Filling Room (#1515) through a dedicated doorway and into the Formulation Room (#1510) through a dedicated pass box.

Waste Flow: All waste from processing rooms are sent either to the kill tank and neutralization tank systems located in the service pit of the building or sent out through exit Air Locks (#1115, 1116, 1211 & 1218) along Return Corridor (#1224) to Waste Staging Room (#1715) located in warehouse. Waste from the fermentation suite will be autoclaved in the Vestibule (#1115) before release.

(4)	HVAC Distribution and Critical Systems Description

The entire GMP facility is supplied by 13 separate air handling units, nine of which are dedicated for the production suite alone. All air handling units are weather proof and are placed on top of the roof exposed to the weather as a result of building area limitation.

The critical utilities and their delivery conditions are given below. USP Purified Water(>4bar, 25℃), WFI(>4bar, 80℃), Pure Steam(4bar, Sat.), Plant Air(7bar, 30℃), Chilled Glycol(4bar, -10℃).

(5)	Clean Room Classification and Room Pressurization

The clean rooms in this facility are classified into class 100,000, class 10,000, class 1,000 and class 100. Fermentation and Purification Room-1 will maintain class 100,000 status except the Inoculum Room, Cell Bank, and Purification Rooms 2 and 3 which will maintain class of 10,000. The fill/finish area will maintain class 100 for the Filling Room and the AC-Unload Room and class of 10,000 for the rest of the area. The Sterility Test Room located in QC lab will maintain a class of 10,000 and will be equipped with and isolator inside. The rest of the controlled area will maintain as non-classified areas.

In general, the relative pressure of each production area is greater than that of the surrounding corridors in order to prevent contaminants from entering these areas. For Purification Room-2, Purification Room-3 and Filling Room, relatively positive pressure is maintained. On the other hand, relatively negative pressure will be maintained Fermentation Room (#1111) and Purification Room (#1114) for containment in fermentation area. The pressure differential among the rooms will be monitored and controlled through an active pressure control system.

Acknowledgments

The authors would like to thank Prof. Chanwha Kim (Korea University), Prof. Eun Kyu Lee (Hanyang University), Prof. Whan-Koo Kang (Hannam University) for helpful advice and discussions.

References

1. FDA.: "Guidance for industry, Manufacture, processing or holding active pharmaceutical ingredients" (1998).

2. http://www.fda.gov (1999).