aseptic processing

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ASEPTIC PROCESSING OPERATION shiva

What is Aseptic Processing?:

What is Aseptic Processing? The production of sterile drug products by bringing together the product, container, and closure that have been subjected to different sterilization methods separately, and assembled them in an extremely high quality environment by skilled personnel using the right tools.

Aseptic Processing: Essential Elements:

Aseptic Processing: Essential Elements

Aseptic Processing: Essential Elements:

Aseptic Processing: Essential Elements Facility Design Zoning, Differential Pressure Temperature Relative Humidity Personnel and Material Flow Air Filtration Equipment Material of Construction Sanitization Component Preparation/Sterilization

Aseptic Processing: Essential Elements:

Aseptic Processing: Essential Elements Process Product Formulation Filtration Filling Lyophilization Capping Personnel Gowning Qualification Aseptic Technique Control and Verification Environmental and Personnel Monitoring Aseptic Filling Simulations (Media Fills)

Aseptic Processing: Essential Elements:

Aseptic Processing: Essential Elements Finished Product Testing Sterility Testing Particulate Testing Container Closure Integrity Testing Other Final Product/Release Testing Stability Testing Documentation Media Fill Records Production Batch Records EM Trend Data Release Testing Batch Records Investigation Response to Excursions Corrective Actions

Environmental Monitoring Components:

Environmental Monitoring Components Airborne nonviable particulate monitoring Airborne viable contaminant monitoring Viable contaminant monitoring of surfaces Viable contaminant monitoring of personnel Temperature and humidity monitoring Pressure differential monitoring

Environmental Monitoring Components:

Environmental Monitoring Components Water monitoring: Total organic carbon Conductivity Microbial Contaminants Endotoxin Air monitoring: Microbial Contaminants.

Regulatory Basis for Environmental Monitoring Program:

Regulatory Basis for Environmental Monitoring Program CFR GMP regulations FDA Guidance Documents USP Informational Chapter

Controlled Area:

Controlled Area Preparation or manufacturing area where nonsterile product, in-process materials and product-contact equipment surfaces, containers and closures are exposed to the environment Control nonviable and viable contaminants to reduce product /process bioburden Class 100,000 or Class 10,000 Capping areas are now considered controlled manufacturing areas Should be supplied with HEPA filtered air Should meet class 100,000 conditions during static conditions

Critical Area:

Critical Area Aseptic processing area where sterile products, components or in-process products are exposed to the environment and no further processing will occur. Air quality must be Class 100 during processing Local Class 100 areas are often utilized during open processing steps during drug substance manufacture. The area just preceding the sterile core should be one classification higher than the core.

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Types of water used in pharmaceutical processes Purified water Water for Injection s – PFW & WFI Softened Water Water for Final Rinse Pure, or clean Steam Water for cooling Autoclaves Microbial testing of air and water

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Why purify raw water ? Although reasonably pure, it is always variable Seasonal variations may occur in water Some regions have very poor quality water Must remove impurities to prevent product contamination. Control microbes to avoid contaminating products

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Contaminants of water (1) There is n o pure water in nature , as it can contain up to 90 possible unacceptable contaminants Contaminant groups: I norganic compounds Or ga n ic compounds Solids Gases Micro-organisms

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Contaminants of water ( 2 ) Micro-organisms : Algae Protozoa Cryptosporidium Giardia Bacteria Pseudomonas Gram negative, non-fermenting bacteria Escherichia coli and coli forms

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Contaminants of water (3) Treatment depends on water’s chemistry and contaminants, influenced by : Rainfall Erosion Pollution Dissolution Evaporation Sedimentation Decomposition

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Contaminants of water (4) Problem m inerals Calcium and magnesium Iron and manganese Silicates Carbon dioxide Hydrogen sulfide Phosphates

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Contaminants of water ( 5 ) Further problem minerals Copper Aluminum Heavy metals Arsenic, lead, cadmium Nitrates

Water For Injection:

Water For Injection Defined by USP Water purified by distillation or reverse osmosis Prepared from water complying with the U.S. EPA National Primary Drinking Water Regulations Contains no added substance

Purified Water:

Purified Water Defined in USP Obtained by a suitable process, usually one of the following: deionization reverse osmosis combination

Potable Water:

Potable Water Meets National Drinking Water Regulations 40 CFR Part 141 Periodic monitoring in-house as well as periodic certificates from municipality (if applicable)

Microbiological Testing:

Microbiological Testing Objectives To review microbiological environmental and quality control testing Microbiological Environmental Monitoring Container integrity testing Pre-sterilization testing. Media fill medium growth promotion testing Sterility Testing Other microbiological laboratory issues

Microbiological testing of water:

Microbiological testing of water Water Water should also be tested for presence of coli forms and/or pseudomonad's if appropriate (may cause biofilm) Water used for parenterals should be tested for pyrogens limit is not more than 0.25 EU/ml Water should be tested using R 2 A agar (low nutrient for the recovery of water borne organisms) incubated for at least 5 days at 30-35°C Sampling procedures should follow those used in production

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Sampling Locations Should be based on risk of microbiological contamination Should be clustered around areas where product or components are exposed e.g. at filling heads on filling lines loading of product into lyophilizers stopper bowls where aseptic connections are made where there are high levels of operator activity (but without impacting on production) Microbiological testing of Air

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Methods Surface monitoring Product contact surfaces, floors, walls, and equipment should be tested on a regular basis Touch plates - used for flat surfaces sample area of 25cm 2 medium protrudes above sides medium contains neutralisers Surface Swabs - used for irregular surfaces area approx 25cm 2 is swabbed qualitative or quantitative

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Active Air Monitoring: impaction, centrifugal and membrane (or gelatin) samplers a certain volume of air is sampled (volume and location should be meaningful) instruments should be calibrated

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Passive Air Monitoring: Settle plates exposed for 30-60 minutes (longer may result in agar drying out) and replaced for duration of filling Media should be capable of growing a range of bacteria and moulds. e.g. Soybean Casein Digest Agar (SCDA) Should consider use of medium specific for moulds if shown to be a problem in the environment Only give qualitative or semi-quantitative results Data generated considered in combination with active air sampling results

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Media used for media fills should be able to support the growth of a wide range of microorganisms (bacteria and moulds) Soybean Casein Digest Medium is usually used. An anaerobic medium may also be substituted occasionally if environmental monitoring indicates presence. Media used for microbiological testing should be tested for its ability to support microbial growth Media

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After the media fill has been completed, it is important to demonstrate that the media would have been able to support the growth of organisms if they had been present . containers with media should be inoculated with 10-100 CFU of organisms such as Bacillus subtilis, Staphylococcus aureus, Candida albicans, Aspergillus niger . Environmental isolates should also be included

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Media types: Soybean Casein Digest medium (SCD), (also knows as Trypticase Soy Broth(TSB)) and Fluid Thioglycollate medium (FTM) is usually used (to detect aerobic and anaerobic organisms) validation studies should demonstrate that the media are capable of supporting growth of a range of low numbers of organisms in the presence of product. May need to incorporate inactivators growth should be evident after 3 days (bacteria), 5 days (moulds) media may be purchased or made in-house using validated sterilization procedures

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Incubation Period At least 14 days incubation 20-25°C for SCD/TSB, 30-35°C for FTM Test containers should be inspected at intervals temperatures should be monitored and temperature monitoring devices should be calibrated if product produces suspension, flocculation or deposit in media, suitable portions (2-5%) should be transferred to fresh media, after 14 days, and incubated for a further 7 days

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