Maintenance of sterile area

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MAINTAINANCE OF STERILE AREA : 

MAINTAINANCE OF STERILE AREA Prepared by: Ravi Rupavatiya Regulatory Affairs Guided by: Mr. Gaurav Sanghvi Dr. Mihir Raval Department Of Pharmaceutical Science

Overview of Presentation : 

Overview of Presentation Brief Introduction of Sterile area lay out Aseptic Filling Sterilization process Maintenance of Personnel Equipments Environment In Process Control Audit & Documentation 2

Slide 3: 

LAY OUT

Sterile Products Are Produced By : 

Sterile Products Are Produced By Aseptic Processing Terminal Sterilization

Aseptic Processing : 

Aseptic Processing Drug Product Container Excipients Closure Sterilization Process Sterile Final Product Aseptic Filling

Terminal Sterilization : 

Terminal Sterilization Drug Product Container Excipients Closure Sterilization Process Sterile Final Product Primary Product (Non - Sterilized)

Overview of Presentation : 

Overview of Presentation Brief Introduction of Sterile area lay out Aseptic Filling Sterilization process Maintenance of Personnel Equipments Environment In Process Control Audit & Documentation 7

Slide 8: 

Maintenance Personnel Training & Monitoring Clean rooms should remain minimum amount of the personnel. It is especially important for an aseptic manufactures. Inspections and controlling should be done, being outside of clean zones. All personnel (including the personnel occupied with clearing and maintenance service), working in such zones, should have regular training concerning manufacture of sterile products, including the bases of hygiene and microbiology.

Continue… : 

Continue… It is necessary to pay special attention to instructing and the control over the workers who have not taken such training but it is necessary for them to enter into a clean room (for example, to the persons occupied in building or maintenance service). Personal hygiene is also important not to be so professional in the terms of work but in the form of employee work satisfaction under safety.

Gowning : 

Gowning Maintenance

Qualifying Personnel After Gowning/Gloving : 

Maintenance Qualifying Personnel After Gowning/Gloving Microbiological surface sampling of several locations Glove fingers Facemask Forearm Chest Periodic requalification is necessary

Surface Monitoring : 

Maintenance Surface Monitoring RODAC Plates: Replicate Organism Detection and Counting Touch Or Contact Plates

Continue… : 

Maintenance Continue… Swabs

MINIMIZE MOVEMENT : Work slowly and purposefully : 

Maintenance MINIMIZE MOVEMENT : Work slowly and purposefully Personnel: Behavior

Overview of Presentation : 

Overview of Presentation Brief Introduction of Sterile area lay out Aseptic Filling Sterilization process Maintenance of Personnel Equipments Environment In Process Control Audit & Documentation 15

Equipment Handling : 

Maintenance Equipment Handling “Surfaces that may come in contact with or directly affect a sterilized product or its containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation, and sterility is maintained throughout processing.” Critical surfaces Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing -Current Good Manufacturing Practice, FDA, September 2004

Some Examples : 

Maintenance Some Examples

Overview of Presentation : 

Overview of Presentation Brief Introduction of Sterile area lay out Aseptic Filling Sterilization process Maintenance of Personnel Equipments Environment In Process Control Audit & Documentation 18

Environmental Monitoring : 

Maintenance Environmental Monitoring “In aseptic processing, one of the most important laboratory controls is the environmental monitoring program” What should an environmental monitoring program cover and how? All production shifts Air, floors, walls, equipment surfaces including critical surfaces. Critical surface sampling should take place at the conclusion of the aseptic processing operation. The location of surfaces to be samples, timing, and frequency of sampling should be specified in writing.

Establishing And Maintaining An Aseptic Environment : 

Maintenance Establishing And Maintaining An Aseptic Environment Use clean-rooms of various classes to establish an aseptic area Clean rooms use combinations of filtration, air exchange, and positive pressure to maintain “clean” environment Lower quality clean areas should not be placed next to high quality areas

Facilities: General Clean room Design : 

Facilities: General Clean room Design HEPA/ULPA filters on ceiling Exhaust vents on floor Drains in aseptic processing areas are inappropriate Airlocks and interlocking doors to control air balance Seamless and rounded floor to wall junctions Readily accessible corners Floors, walls, and ceilings constructed of smooth hard surfaces that can be easily cleaned Limited equipment, fixtures and personnel Layout of equipment to optimize comfort and movement of operators Maintenance

Clean Area Classification : 

Maintenance Clean Area Classification

Examples : 

Maintenance Examples Class 10,000 clean room Class 100 clean room

Control Equipments : 

Maintenance Control Equipments Isolators No direct contact between operator & product Advantage Critical that meticulous aseptic practices be followed including the use of sterile tools for manipulations

Isolators : 

Isolators Maintenance Vertical airflow Horizontal airflow

Open Isolators : 

Open Isolators Require laminar airflow over critical areas Use pressure differential to insure separation of critical area from external environment (17.5-50 Pa 0.07-0.20 water gauge) Local protection of opening to guard against turbulent airflow and pressure waves that could compromise critical area Maintenance

Isolator Decontamination : 

Isolator Decontamination Vaporized agents often used Glutaraldehyde, Formaldehyde, etc Use indicator organisms to demonstrate effectiveness of decontamination Should be able to achieve a 4-6 log reduction in titer Biological indicator should be placed in multiple, justified locations throughout the isolator Hard to reach areas (between fingers on gloves) should be addressed Must show that defined concentration of decontamination agent is uniformly reached in validation studies Maintenance

HEPA Filters : 

HEPA Filters High Efficiency Particulate Air Minimum particle collection efficiency: 99.97% for 0.3µm diameter particles. Disposable Filter made of pleated borosilicate glass Maintenance

Pressure Differentials : 

Pressure Differentials Used to maintain airflow in the direction of higher cleanliness to adjacent less clean areas. A minimum of 10-15 Pascal should be maintained between the aseptic area and an adjacent rooms with differing clean room classifications (doors open). Maintenance

Air Lock : 

Air Lock Permits the passage of objects and people into a clean room. Consists of two Airtight Doors in series which do not open simultaneously. Spray down materials with 70% IPA before placing in the airlock. Maintenance

Materials NOT permitted in a Clean room : 

Materials NOT permitted in a Clean room Fiber-shedding materials such as cardboard and paper Cardboard packaging must be removed and items placed into non-cardboard containers. Wood (i.e. wooden pallets) Undesignated charts Maintenance

Cleaning : 

Cleaning Maintenance 1. Vacuum all accessible surfaces 3. Mop floors using a lint free polyester mops attached to stainless steel handles 2. Wipe surfaces with a cleaning solution

Disinfectants & Antiseptics : 

Disinfectants & Antiseptics Antiseptic : Agent applied to living tissue Disinfectant : Agent applied to inanimate surface Examples : Glutaraldehyde Formaldehyde Other aldehydes Chlorine-releasing agents Iodine and iodophors Peroxygens Ethylene oxide Maintenance

Continue… : 

Continue… Chlorhexidine Gluconate, 4% wv (HibitaneR, SolvahexTM, Clenz 4 Chlorhexidine) Acetate and Diacetate, 2% (NolvasanR) Broadest spectrum Better residual activity than iodophors Occasional skin sensitivity (mucous membranes) Iodophors (BetadineR, DuraprepR) Excellent Spectrum, contains iodine Less residual activity than Chlorhexidine Partially inactivated by organic debris Occasional skin sensitivity Maintenance

Slide 35: 

Isopropyl Alcohol 70% (or Ethyl Alcohol 90%) Protein coagulant Degreases skin Ineffective against spores Hexachlorophene PhisohexR (no longer recommended) Very potent against Gram positive bacteria (e.g., Staphylococcus) Poor effect against enteric bacteria (Gram negative) Inactivated by organic debris and alcohol Long residual action Maintenance Continue…

Overview of Presentation : 

Overview of Presentation Brief Introduction of Sterile area lay out Aseptic Filling Sterilization process Maintenance of Personnel Equipments Environment In Process Control Audit & Documentation 36

In Process Controls : 

In Process Controls Sterilizing grade filters (0.22μm pore size or smaller) Use of redundant sterilizing filters should be considered Filters should be validated including the use of microbial challenge Maintenance Sterile Filtration

To be used in the Filtration : 

To be used in the Filtration Poly-vinyli-denedi-fluoride (PVDF) Poly-tetra-fluoro-ethylene (PTFE) Poly-ether-sulfone (PES) Nylon 6,6 (N66) Choice depends on properties (i.e. hydrophobic or hydrophilic, and compatibility with process materials) Maintenance Materials

Filter Validation : 

Filter Validation Factors that affect filter performance Filtration microbial challenge Challenge should be at least 107 organisms / cm2 of filtration area Number of uses Filtration time limit Integrity Testing Forward Flow Bubble point Maintenance

Slide 40: 

Used to validate the aseptic process. Use microbial growth media instead of drug product-any contamination will result in microbial growth. Maintenance Media Fills

Media Fill Study design : 

Media Fill Study design The design of a media fill study should address the following factors: Any factors associated with longest run that can pose contamination risk. Lyophilization (if applicable). Aseptic assembly of equipment. Number of personnel and their activities. A representative number of aseptic additions. Shift change, breaks, gown changes. Aseptic equipment connections/disconnection. Aseptic sample collection. Container closure system. Maintenance

Sterility Testing : 

Sterility Testing 21 CFR 211.167“ For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements.” Sterility can be defined as the freedom from the presence of viable microorganisms. However, the conditions that guarantee absolute sterility are usually too harsh for active ingredients, and the definition of sterility for a medicinal product must be defined in functional terms. http://www.who.int/biologicals/vaccines/sterility_testing/en/index.html Maintenance

There are TWO alternative methods available when conducting sterility tests. : 

There are TWO alternative methods available when conducting sterility tests. The direct inoculation Membrane filtration Maintenance

Slide 44: 

The Direct Inoculation Maintenance

Slide 45: 

Maintenance Continue…

Membrane Filtration : 

Membrane Filtration membrane filter (pore size 0.45 μm); any microorganism present being retained on the surface of the filter. After washing in situ, the filter is divided aseptically and portions are transferred to suitable culture media which are then incubated at the appropriate temperature for the required period of time. Water-soluble solids can be dissolved in a suitable diluent and processed in this Way oil-soluble products may be dissolved in a suitable solvent, e.g. isopropyl myristate. Maintenance Recommended by most pharmacopoeias, the method by which the great majority of products are examined.

Overview of Presentation : 

Overview of Presentation Brief Introduction of Sterile area lay out Aseptic Filling Sterilization process Maintenance of Personnel Equipments Environment In Process Control Audit & Documentation 47

Slide 48: 

Audit & Documentation General Audit Documentation

Slide 49: 

Documentation Continue…

Slide 50: 

Documentation Continue…

Slide 51: 

Documentation Documentation

POSITIVE INTERACTION : 

POSITIVE INTERACTION ?

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