GMP for laboratory design

GMP for laboratory design
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cGMP for Biotechnology Production Area
Area Design Room Classification (over view) Flow (Personnel, Material, Waste, Product) ~kfk~ 2

General Points Before Designing the Facility
Consider the production process and platform structure Separate access for personnel and raw materials Dedicated HVAC units Dedicated water systems Waste flow and waste management system Put main utilities outside the production area (if possible) The smaller the area, the better for contamination control Smart piping net-work (shorter line, valve system!) ~kfk~ 3

Primary Floor Plan ~kfk~

Room Classification in Biopharmaceuticals production area
EU Class US Class Activities A 100 Aseptic operation during sterile product or microorgsnism is exposed to the environment (Laminar Air Flow Class II conditions) B 1000 Aseptic area surrounding class 100 (A). In case of handling phatogenic MO, Room pressure should be negative. C 10, 000 Fermentation/extraction, non-sterile media preparation, purification steps, storage of sterile materials. D 100, 000 Material wrapping area, Rooms used for sterilization of equipment and materials unclassified Materials Washing room, non-sterile corridor, office, quality assurance laboratory, storage of materials, finished packed product and equipment ~kfk~ 5

Transfer of Material and Personnel flow between Different Area (Classes)
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Air Shower (Air Flow) ~kfk~ 7

General Clean room Design
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Canteen, Toilets and Factory
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Personnel Flow Personnel should access the facility through one general entrance Facility should designed to have separate male/female changing room and Rest Room (Three changing room is usually considered, M/F and visitors) Entrance of the facility should be secured and limited to authorized personnel (entrance of changing room preferred by electronic locks with coded badge entry) Before entering production area, change from city garment to production garment, (1st change) Before entering aseptic room, another change to put sterile gown, sterile boots, sterile hood, sterile gloves and mask or helmet. Personnel should move between areas of a biofacility according to detailed revised . Procedure established according to biological regulatory requirements. ~kfk~ 10

Material Flow All raw materials should be sampled, tested and approved from QA/QC before entering the production area QA/QC released materials should be transferred to production area using a dedicated Material Cardboard Lock External packaging protection (cardboard/plastic film) removed in Air-Lock Cardboard and wood should not be introduced in the production core The production core should have storage facility for raw materials of different temperatures if required Materials that are used in sterile conditions should be prepared and sterilized using validated equipment and procedure (21 CFR ) The effectiveness of the sterilization procedure shall be no less than that achieved. By an attained temperature of C maintained for 20 min. by saturated steam. That is higher than general role of sterile drug products (121.50C for 15 min) ~kfk~ 11

Material Flow (cont.) Sterilized materials/equipments should taken for sterile storage area to core production area via corresponding air lock (Air Lock In) The soiled material/equipment removed from the sterile core production area via air lock (Air Lock Out) Determination air lock is used to decontaminate the external surface of mobile vessels (in case of BL3 lab) After use, the mobile vessel is decontaminated in place (DIP) using clean steam Then the vessel is transferred into the contamination Air lock in which a fumigation cycle is applied (using peracetic acid or hydrogen peroxide generator). ~kfk~ 12

Media and Buffer Flow Limited access to authorized personnel
Two-stage media preparation suite: non-sterile media and sterile media preparation area Specific gowning practices for non-sterile media preparation similar to those for aseptic operations After sterile filtration, validated procedures and container/closure integrity systems should be used to protect media and buffers during storage, transfer to, and distribution into the processing room ~kfk~ 13

Product Flow Dedicated storage equipment for Walking Cell Bank
UNDIRECTIONAL product flow from media and buffer preparation up to product exit Segregation between areas where live organisms are handled and areas where no live organism is manipulated Dedicated product storage room and product exit ~kfk~ 14

Primary Floor Plan UTILITIES ~kfk~

Primary Floor Plan ~kfk~

Process Flow ~kfk~

Personnel Flow ~kfk~

Material Flow ~kfk~

Fermentation Room ~kfk~

Before We Proceed! Where is the most critical area in our plant?
Can I take a sample from the production area to the QC Lab through pass box? Do we need both Gowning Room and Air Shower? Gowning before Air Shower or Air Shower before Gowning? Do we need Air lock between outside and Gowning room? Can you Design the Rest of the Plant? ~kfk~ 25

HVAC system for clean room (Design and Practice)
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HVAC system for clean room (Design and Practice)
HVAC system and ISO classes for clean room Characterization of HVAC system Air Filtration and Distribution ~kfk~ 27

Ǿ 211.46 Ventilation, air filtration, air heating and cooling
Adequate ventilation should be provided. Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product Air filtration system, including pre-filters and particulate matter air filters, shall be used when appropriate on air supplies to production areas, measures shall be taken to control recirculation of dust from production. In areas where air contamination occurs during production, there shall be adequate exhaust systems adequate to control contaminants. Air-handling systems for the manufacture, processing and packing of PENICILIN shall be completely separate from those for other drug, products for human use. ~kfk~ 28

Ǿ 211.42 Design and Construction features Part (c) cont
Aseptic processing, which include as appropriate: Floors, walls, and ceilings of smooth, hard surfaces the easily cleanable Temperature and humidity controls An air supply filtered through high-efficiency particular air filters under positive pressure, regardless of whether flow is laminar or non-laminar A system for monitoring environmental conditions A system for cleaning and disinfecting the room and equipment to produce aseptic conditions A system for maintaining any equipment used to control the aseptic conditions. ~kfk~ 29

HVAC system Description
Temperature Pressure RH Air Change Decontamination time Efficacy of air delivery filter Location of air delivery inlets Efficacy of exhaust delivery filter Location of air exhaust delivery outlets Fumigation Partial air recycling HVAC group in standby for the critical cold rooms ~kfk~ 30

Types of HVAC system Reading exercise – text book page 272 ~kfk~

HVAC system (Simple Design)
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HVAC system in detail engineering
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ISO Classification of Clean Room
FED STD 209 0.1 μm 0.2 μm 0.3μm 0.5 μm 5.0 μm Class 3 1 1000/35 35/1 Class 4 10 10, 000/345 75 30 352/10 Class 5 100 100, 000/3450 750 300 3520/100 Class 6 1000 1, 000, 000/34,500 N/A 35,200/1000 7 Class 7 10, 000 345,000 352,000/10,000 70 Class 8 100,000 3,450,000 3,520,000/100,000 700 ISO (Per cubic meter) Fed Std. 209 E. USA (per cubic feet) ISO standard requires results to be shown in cubic meters (1 cubic meter= cubic feet) ~kfk~ 34

540 to more than 600 air changes per hour (98% + ceiling coverage)
CLASS 1 540 to more than 600 air changes per hour (98% + ceiling coverage) ULPA filters ( % on 0.1 microns) Gel/Flush grid ceiling systems raised floors are required Outside/makeup air to be pre-filtered with HEPA filter ~kfk~

540 TO 600 air changes per hour (85-90% ceiling coverage)
CLASS 10 540 TO 600 air changes per hour (85-90% ceiling coverage) ULPA filters (99.999% on 0.3 microns) with a raised floor 90% + coverage with low wall returns Gasketed grids with negative plenums acceptable HEPA filter on make up air ~kfk~

400 to 480 air changes per hour (60-80% ceiling coverage)
CLASS 100 400 to 480 air changes per hour (60-80% ceiling coverage) 99.99% HEPA filters 90%+coverage with low wall returns Raised floor assures optimal performance Gasketed ceiling grid ~kfk~

CLASS 1,000 120 to 150 air changes per hour (40-50% ceiling coverage) 99.99% HEPA filters Raised floor delivers best performance, low wall returns are common Gasketed ceiling grid ~kfk~

CLASS 10,000 45 to 60 air changes per hour (10-20% ceiling coverage) 99.97% HEPA filters Low wall returns acceptable in most applications ~kfk~

20 to 30 air changes per hour (5% ceiling coverage)
CLASS 100,000 20 to 30 air changes per hour (5% ceiling coverage) 95% HEPA filters acceptable Heat load may require more air changes ~kfk~

Factors Determining the Operation Parameters of Cleanrooms
Air Flow Heating and Cooling Capacities Room Internal Design Differential Pressure and Air Lock ~kfk~ 41

1. Air Flow Sufficient airflow to provide at least 20 to 40 air changes per hour is required to meet Class 10,000 or 100,000 requirements To achieve Class 100 requirements (90 feet per minute air velocity), this carried out only by using vertical unindirectional flow A vertical unindirectional flow for Class 100 requires 20 times more airflow than a class 10,000 clean room of the same size Energy costs just to operate the blowers to provide the airflow make up an important part of clean room cost ~kfk~ 42

2. Heating and Cooling Capacities
This required to maintain air temperature and RH within a specific range: 18 to 220C and 30 to 50 RH% for class 100 and 10000 These above mentioned values are satisfactory for controlling MO growth and resonable worker comfort In spite of room classification, it can be maintained at low temp. between 20C to 80C to meet some requirements. In this case, RH needs to be kept lower than 90% to avoid condensation. Engineering should take into account the variations of external ambient conditions, the number of persons, and the heat and moisture that the process may generate. ~kfk~ 43

3. Room Internal design Adequate positioning of the air delivery inlets and outlets and the air exhaust versus the positioning of the process equipment and personnel within the area will directly impact the capacity to meet the classification requirements This capacity is measured by the recommendation time which represents the time required to recover the room class after contamination with a chemical aerosol The test involves the use of nonviable particle counting devices which are placed at specific locations selected as representative of clean room area. ~kfk~ 44

4. Differential Pressure and Air Lock
This plays a major role in protecting the cleanliness of the room and ensuring the containment of the live organisms within the area The design should be of sufficient flow velocity and self-closing doors to make a real barrier Interlocking system should designed to maintain a minimum time between the closing and opening of the two doors of the air lock Air Shower System, location and design Differential Pressure between adjacent manufacturing areas will be chosen to compensate for the variability of the air pressure and to ensure a unindirectional airflow ~kfk~ 45

Facility Design Overview
BSL1 - basic lab BSL2 - basic lab + aerosol confinement Biosafety cabinet BSL3 - containment laboratory 2 door separation from building occupants BSL4 - maximum containment laboratory separate building from general research population ~kfk~ 46

Biosafety Level 1 Laboratory
Door Sink Easily cleaned work surfaces Impervious bench tops Sturdy furniture Windows fitted with fly screens

Recommended Criteria for Biosafety Levels 2
Agents Practice Safety Requirements (Primary Barriers) Facilities (Secondary Barriers) 2 Associated with human disease. Hazards comes from autoinoculation, ingestion mucous membrane exposure Standard Microbiological Practice plus: -Biohazards sign Sharps precautions Biosafety manual defining any needed waste decontaminating or medical surveillance policies Primary barriers involving Class 1 physical containment devices used for all manipulations of agents cause splashes or aerosols of infectious materials; personnel protection equipment involving protective lab, clothing , gloves, respiratory protection when required Open bench top sink required plus autoclave available ~kfk~ 49

Biohazard warning labels on equipment

Biosafety Level 3 “The laboratory has special engineering and design features.” CDC/NIH BMBL, 5th Ed. 2007

Recommended Criteria for Biosafety Levels 3
Agents Practice Safety Requirements (Primary Barriers) Facilities (Secondary Barriers) 3 Indigenous or exotic agents with potential for aerosol transmission; disease may have serious or lethal consequences Similar to BL-2 BL-2 plus Physical separation from access corridor Self-closing double door access Exhaust air not recirculated Negative airflow into laboratory ~kfk~ 53

Air Pressure and Room Functions (Positive or Negative Pressure?
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Positive air pressure Negative air pressure
Air pressure is higher in the room than outside, so contaminants are kept out Negative air pressure Air pressure in the room is lower than outside, so that contaminant from the room does mot flow out into surrounding areas Used for airborne infection control to protect from very contagious microorganisms ~kfk~

1- Class A and B (Kept at positive air pressure)
Room Function Filtration of inactivated product, filling, formulation, sterile storage if included in a neutral aseptic production room, cellular culture, and nonpathogenic virus replication if aseptic processing, purification, if required by the process, aseptic media preparation. This room is equipped with a class 100 (Class A) laminar airflow hood. Room Access: - Personnel Air lock three doors: two parts - Materials Air Lock IN - Materials Air Lock OUT with fumigation for live organism handling area ~kfk~ 57

2- Class B (Kept at negative air Pressure)
Room Function: Culture of pathogenic virus and inactivation of pathogenic virus if aseptic Operations, purification if requested by the process. Room is equipped with class A laminar airflow cabinet Room Access: - Personnel Air lock four doors: two parts - Materials Air Lock IN - Materials Air Lock OUT (with fumigation) ~kfk~ 58

3- Class C (Kept at positive air pressure)
Room Function: Bioreactor culture and purification of non-pathogenic products, clean material Storage, media preparation Room Access: - Personnel Air Lock two doors - The access to media preparation production rooms proceeds via an Air lock\ if the facility is designed for cell culture and viral replication ~kfk~ 59

4- Class C (Kept at negative air pressure)
Room Function: Bioreactor culture and purification of pathogenic products (production room classified as BL3) Room Access: - Personnel Air lock four doors - Materials Air Lock IN - Materials Air Lock OUT (with fumigation) ~kfk~ 60

HVAC Technical Design Example
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Operating parameters for Class B kept at positive air pressure
Area Production room Material AL IN OUT Personnel AL 1 Personnel AL 2 Pressure (Pa) +45 (a) (b) +30 (e) Min Change (AC/h) 40 200 20 600 Decontamination time (min) 15 3 12 1 Partial Air Recycling Yes 100% (c) YES Temperature (oC) 18-22 NA (d) RH (%) 30-50 40-60 Air Delivery Filter (% DoP Retention) 99, 950 99, 995 Air Exhaust Filter G 85 Location of Delivery Inlet Ceiling Location of Exhaust Outlet Bottom of Wall Fumigation NO Notes, Between sterile storage and production room Between production room and corridor as balancing Delivery and exhaust separated for the fumigation cycle The parameter must be controlled during the fumigation cycle Between, PAL and production room by balancing ~kfk~ 63

Air Shower (Air Flow) ~kfk~ 64

Air Shower (Details) ~kfk~ 65

Production Room Class B
Class B kept at Negative air pressure Sterile Storage Material AL IN Production Room Class B (Negative Pressure) Personnel AL 1 Personnel AL 2 Personnel AL 3 Material AL OUT Corridor ~kfk~

What is Pressure Cascade?
A process whereby air flows from the cleanest area, which is maintained at the highest pressure to a less clean area at lower pressure. ~kfk~ 67

Pressure Cascade Dirty Environment (Ambient Pressure)
15 Pa pressure Difference More Clean Environment (Higher Pressure) 15 Pa pressure Difference Cleanest Environment (Higher Room Pressure) ~kfk~ 68

Measuring Pressure Cascade
The pressure cascade differential over the doorway is measured with a portable magnahelic gauge or micro manometer ~kfk~ 69

Operating Parameters for Class B kept at negative air pressure
Area Production room Material AL IN OUT Personnel AL 1 Personnel AL 2 Personnel AL 3 Pressure (Pa) -30 (a) (b) +30 -15 Min Change (AC/h) 40 200 20 600 Decontamination time (min) 15 3 12 1 Partial Air Recycling Yes 100% (c) YES NO Temperature (oC) 18-22 NA (d) RH (%) 30-50 40-60 Air Delivery Filter (% DoP Retention) 99, 950 99, 995 Air Exhaust Filter G 85 Location of Delivery Inlet Ceiling Location of Exhaust Outlet Bottom of Wall Fumigation Notes, Between sterile storage and production room Between production room and corridor as balancing Delivery and exhaust separated for the fumigation cycle The parameter must be controlled during the fumigation cycle Between, PAL and production room by balancing ~kfk~ 71

Class C kept at Positive air pressure
Material AL IN Production Room Class C (Positive Pressure) Personnel AL Material AL OUT Corridor ~kfk~

Operating parameters for Class C kept at positive air pressure
Production Room Air lock (a) Pressure (Pa) +30 (b) Min Change (AC/h) 20 Decontamination time (min) 12 3 Partial Air Recycling YES Temperature (oC) 18-22 RH (%) 40-60 NA Air Delivery Filter (% DoP Retention) 99, 995 95 Air Exhaust Filter G 85 Location of Delivery Inlet Ceiling Location of Exhaust Outlet Bottom of wall Bottom of Wall Fumigation Occasional Notes, Value should be justified if the corridor is not classified as Class D or if the room is a production room for cell culture media preparation and viral production Adjusted between production room and corridor ~kfk~ 73

Operating Parameters for Class C kept at negative air pressure
Production Room Air lock (a) Pressure (Pa) -15 -30 Min Change (AC/h) 20 Decontamination time (min) 12 3 Partial Air Recycling NO Temperature (oC) 18-22 RH (%) 40-60 NA Air Delivery Filter (% DOP Retention) 99, 995 95 Air Exhaust Filter G 85 Location of Delivery Inlet Ceiling Location of Exhaust Outlet Bottom of wall Fumigation YES Notes Air Lock independent HVAC group ~kfk~ 74

Operating Parameters for Class D
Production Room Pressure (Pa) Steps of 15 pa Min Change (AC/h) 20 Decontamination time (min) 3 Partial Air Recycling YES Temperature (oC) 18-22 RH (%) 40-60 Air Delivery Filter (% DOP Retention) 95 Air Exhaust Filter G 85 Location of Delivery Inlet Ceiling Location of Exhaust Outlet Bottom of wall Fumigation Occasional ~kfk~ 75

Operational consideration: Fumehood
Reading exercise – text book page 313 ~kfk~

Special Guidelines for Multiuse and Multistream Facilities
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Multiuse Facility designed for successive production of different strains. Detailed and validated change Over procedures should be followed to prepare the area for the next product. Removal of the working culture, working cell line Decontamination of all materials and equipment Room cleaning and sanitazation Room fumigation (if environmental safety codes permit) using paraformaldehyde, peracetic acid, or other validated method. Sublimation time for over a period of 6 h. HVAC unit should shut down during this time and this phase is followed by neutralization step involving sublimation of ammonium acetate. The efficiency of fumigation increase at 25oC and RH 80%. ~kfk~

Multi-strain Facility
Facility designed to allow producing different starins concurrently in the different manufacturing area within the limits defined by regulatory requirements. The following points should be considered when designing such facilities: Separate HVAC systems: Each room with its attached AL’s should be served by at least one HVAC which prevents air recirculation between rooms where different strains are handled Dedicated AL’s for personnel and material Dedicated system for material decontamination and effluent treatment Dedicated personnel: movement of personnel within the production core should be restricted to ensure segregation between the different areas. Validated cleaning procedures, especially for multiuse equipment ~kfk~

Dispensary Layout ~kfk~

Dispensary Layout Is this a good layout? ~kfk~

Improve dispensary Layout
WEIGH What should the room pressured be? ~kfk~

Common mistake in the design
Production Plant Toilet staff Change Room staff ~kfk~

Improve Design Production Plant Change Room Toilet staff ~kfk~

Make Area Classification and Suggest Type of Airlock!!
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cGMP and GLP requirements
Cell Bank (MCB and WCB) Cell Propagation Area R&D Facility QC and QA laboratories

What is GLP ? GLP is a regulation covering the quality management of non-clinical safety studies Good Laboratory Practice (GLP) embodies a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and achieved. These studies are undertaken to generate data by which the hazards and risks to users, consumers and third parties, including the environment, can be assessed for pharmaceuticals, agrochemicals, cosmetics, food and feed additives and contaminants, novel foods and biocides. GLP helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessment.

GLP Promotes Quality and Validity of test data
To make the incidence of False Negative more obvious To make the incidence of False Positive more obvious

The Fundamentals Points of GLP
Resources: organization, personnel, facilities and equipment. Rules: Protocols and written procedures Characterization: test items and test systems Documentation: raw data, final report and archieves Quality assurance unit.

1- Resources 1.1 Organization and Personnel
GLP regulations require that the structure of the research organization and the responsibilities of the research personnel be clearly defined. GLP also stresses that staffing levels must be sufficient to perform the tasks required. The qualifications and the training of staff must be defined and documented. 1.2 Facilities and Equipments The regulations emphasize the need for sufficient facilities and equipment in order to perform the studies. All equipment must be in working order: A strict program of qualification, calibration and maintenance attains this.

Protocols and Written Procedures
2- Rules Protocols and Written Procedures The main steps of research studies are described in the study plan or protocol. The routine procedures are described in written standard operating procedures (SOPs) Laboratories may also need to standardize certain techniques to facilitate comparison of results (Inter and Intra-laboratories result validation)

Test Items and Test Systems
3- Characterization Test Items and Test Systems To perform a study correctly, it is essential to know as much as possible about the materials used during the study

4- Documentation 4.1 Raw data The raw data collection method is important. The raw data must also reflect the procedures and condition of the study. 4.2 Final Report The study report is the responsibility of study director. He must ensure that the content of the report describe the study accurately. The study director is also responsible for the scientific interpretation of the results. 4.3 Archieves Storage of records must ensure safekeeping for many years, coupled with logical and prompt retrieval.

5- Quality Assurance As Defined by GLP
Is a team of persons changed with assuring management that GLP compliance has been attained within the laboratory. They are organized independently of the operational and study program, and function as witnesses to the whole pre-clinical research process.

GLP ≠ cGMP

What is Cell Bank ? A cell bank system is a system whereby successive batches of a product are manufactured by culture in cells derived from the same master cell bank. A number of containers from the master cell banks are used to prepare a working cell bank. The cell bank system is validated for a passage level or number of population doublings beyond that achieved during routine production.

Cell Bank in Biotechnology Factory
Master Cell Bank*: A culture of (fully characterized) cell distributed into containers in a single operation, processes together in such a manner as to ensure uniformity and stored in such a manner as to ensure stability. A master cell bank is usually stored at -700C or lower. Working Cell Bank: A culture of cells derived from the master cell bank and intended for use in the preparation of production cultures. The working cell bank is usually stored at -700C or lower. * a copy of master cells is usually deposited in culture collection for more safety.

External tip recommended

MCB and WCB MCB WCB Preserve the mother culture (original strain) to ensure the maintenance of the original strain in safe place and stored under proper condition. Preserve the early generation culture to ensure the reproducibilty of results with minimal variation in strain efficiency Should be Outside the Production area Inside the Production area. Long term preservation Shorter term of preservation Should be under high strict control policy Under the normal biological material control policy

Cell Propagation Area (Laboratory Level)
Part of the Production area (i.e cGMP should applied) Usually contained the WCB Contains the first part of the production chain (Laminar airflow-Incubator-Shaker) for small volume inoculum Few analytical equipment for evaluation of microbial activities and growth efficiency (Inoculum Quality) ALL EQUIPMENT SHOULD COMPLY TO cGMP REQUIREMENTS

Research and Development Facilities
R&D is NOT PART OF production area (NO complete cGMP Requirements), i.e MUST BE LOCATED OUTSIDE THE PRODUCTION AREA NO Biomaterials is allowed to be transferred to the Production area. R&D laboratories are controlled under the GLP systems. All Equipment used should be Calibrated, Validated based on the GLP requirements. Its preferable to have equipment equivalent in technology with those in the production area! (i.e supplier company, work under the same methodd, same design) The obtained product is for Research only.

QC and QA Laboratories QC and QA IS PART OF the PRODUCTION SYSTEM But Preferably located outside the PRODUCTION AREA. These Laboratories work under GLP more than cGMP Equipment used should be completely calibrated, validated High class analytical Equipment. QC unit is completely independent units and carry all responsibilities of drug release.

Thank You

GMP for laboratory design

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