PHCT 401 Aseptic Processes & Techniques

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1 PHCT 401 Aseptic Processes & Techniques Principles of Aseptic Techniques Aseptic Processing Sterility Testing Laminar flow air cleaning Quality Control Tests Personnel

2 Principles of Aseptic Techniques Overview Certain pharmaceutical products must be sterile Parenteral preparation o Injections o Intravenous infusions o Non-injectable sterile fluids Urological (bladder) irrigation solutions Peritoneal dialysis & Haemodialysis solutions Ophthalmic preparations o Eye drops/oint o Eye lotions o Contact lens solution

3 Dressings Implants Two categories of sterile products Terminally Sterilized (TS) can be sterilized in their final containers Non-Terminally Sterilized (NTS) cannot / will not be sterilized in their final containers. Principle Starting with sterile materials and equipments, it is possible to produce a sterile product if strict precautions are taken to avoid microbial contamination

4 Methods used, collectively described as Aseptic Technique Aseptic manufacturing procedures available for different types of products. Awareness of aseptic handling procedures to be adopted to minimize risk of product contamination. Those who have cause to open, use or dispense sterile products e.g Hospital Pcy Manufacturing under conditions that do not permit entry of contaminating µorganisms Aseptic Manufacturing Processing

5 Asepsis A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product Aseptic Processing the processing of drug components (drug, containers, excipients etc.) in a manner that precludes microbiological contamination of the final sealed product

6 Aseptic processing: A method of producing sterile products in which sterile bulk product or sterile raw materials are compounded and filled into sterile containers in a controlled environment, in which the air supply, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels Objective is to maintain the sterility of a product, assembled from sterile components Operating conditions so as to prevent microbial contamination. Combination of various simple techniques and processes.

7 Spoilage of medicines due to microbial contamination is undesirable Various consequences Financial loss main Risk of initiating infection (though uncommon)? More important in terms of o Risk to the patient o Possible loss of life Financial implications of product-related infections Additional treatment costs Product recalls Possible litigation & damage to reputation

8 Understanding Aseptic processes & techniques Understand various sources of contaminating microorganisms in the production or work area Personnel o Skin and respiratory tract flora o Microbial transfer from operators Atmosphere - air Water Raw materials Packaging materials Equipment Buildings o Walls & ceilings o Floors &drains o Doors, windows & fittings

9 Quality of pharmaceutical products refers to fitness for purpose Product should not only have the desired therapeutic properties Safe for administration by intended route Sterile products free from microbes Others like oral preparations, need not be sterile Free from indicator pathogens that can be contracted through the oral route Greater attention paid to quality of sterile product Reflects additional Quality assurance required

10 In demonstrating quality, tests carried out to detect the absence of quality Sterility Test o Sampling products at random o Testing for presence of microorganisms o Samples taken should be representative of the whole population Sampling Technique o Absence of microorganisms will only allow you to estimate the statistical probability that the batch sampled is sterile. o All products should therefore be manufactured in a suitable environment By procedure that minimizes the possibility of microbial contamination occurring Building quality into the product At the end of the manufacturing process, tests can be performed as additional measure, since Quality is not inspected into the product

11 Application of Aseptic Techniques & Processes Techniques designed to prevent accidental contamination of sterile materials & pure cultures from the environment during handling Pharmaceutical manufacturing Foods & cosmetics Pure cultures of microorganisms used in Pharmaceutical biotechnology Recombinant human insulin Production of immunological products- vaccines Production of antibiotics Careful handling to prevent accidental contamination of pure stock

12 Aseptic technique involve procedures such as: Use of sterile apparatus & materials at all times Use of proper closures & containers Wrapping of apparatus for sterilization Flaming of necks of containers in Bunsen burner flame Minimal exposure of materials during handling Spraying & swabbing of benches & work area with a suitable disinfectant Washing & scrubbing of hands

13 Use of protective clothing-to keep all clothing parts together Automated Hand-Washing System Keeping the operator s dirt and germs out of the sterile cleanroom environment and away from sensitive products and processes is the main objective of the sterile cleanroom suit

14 Carrying out operations within/under special handling cabinets equipped with filtered air.

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16 Wearing of protective clothing Clothing worn must be made from nonshedding materials: terylene a suitable fabric Proper head gears/wears Rubber or plastic gloves Face masks to prevent the release of droplets must be worn by operators in the aseptic areas for production of especially NTSP Prevents airborne contamination of both microbial and particulate matter. Clothing that are close fitting at the neck, wrist and ankles more suitable

17 Clothing should be used once a day Fresh headwear, overshoes and powder-free gloves should be provided for each working session. Four Pillars of a robust Aseptic Processing Personnel Training &Monitoring Environmental Monitoring Facility Design HVAC Validation Process Simulation (Media Fills)

18 Sterility Testing Required for all sterile products Not overriding control to cover all shortcomings Adequate attention must be paid to every stage in the production process Adequate premises Sterilizing equipment and process Skilled and trained personnel etc Building quality into the product ST is actually the detection of the absence of quality!

19 Sterility does not detect all known living forms Official tests for sterility detects gross contamination with most common organisms (including pathogens) Most probable contaminants limited to bacteria and fungi. No test for viruses Difficulty in culturing viruses

20 Design of Sterility Tests Critical considerations Sampling method should give the greatest probability of picking up an infected unit within the batch. Batch Container Unit Volume of medium Inhibitory substances in the product Product should not affect the ability of the medium to support growth. Added product not > 10% of the volume of medium. B.P Details from U.S.P.

21 Media appropriate to support likely contaminant Bacteria Fungi modified Inactivation Of preservatives Any constituent with AMA activity Inactivation aids recovery of contaminants Inactivators Not inhibitory to growth promoting property of medium Should not interfere with nutritive quality of the medium

22 Methods of inactivation Dilution Inactivation by constituents Destruction or inactivation / antagonization by addition of sterile inactivators. Physical removal by filtration. Other critical consideration Controls Incubation conditions Interpretation of results

23 Controls Two major controls against which to check conclusion from the test series. Negative Control Sterility of the media used Checked by including un-innoculated bottles from the same batch as that used in the test Positive Control Growth promoting properties of the batch Inactivation of inhibitory substances in the product Demonstrated by including an exact set with same quantities of test substance (sample) in the same volumes of the batch of test media

24 Reporting Sterility Testing Results CODE SAMPLE NUTRIENT MEDIUM CONTROL OREGANISM EXPECTED RESULT AET Sample Thioglycolate No Organism - ve ANT Sample Thioglycolate No Organism -ve FGT Sample SDM No Organism - ve AET PC No Sample Thioglycolate S. aureus + ve ANT PC No Sample Thioglycolate Clostridium + ve FGT PC No Sample SDM Candida + ve AET NC No Sample Thioglycolate No Organism - ve ANT NC No Sample Thioglycolate No Organism -ve FGT NC No Sample SDM No Organism - ve ACTUAL RESULT KEY AET = Aerobic Test ANT = Anaerobic Test FGT = Fungal Test PC = Positive Control NC = Negative Control

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28 Laminar Flow Air Cleaning Providing the environment for aseptic manufacturing Cleanrooms with specific requirements Two major types Differentiated by their method of ventilation. Turbulently ventilated cleanrooms ( nonunidirectional ) Unidirectional flow cleanrooms (originally known as laminar flow The unidirectional type of cleanroom uses very much more air than the turbulently ventilated type, Gives a superior cleanliness. w.

29 Figure shows a turbulently ventilated room receiving clean filtered air through air diffuses in the ceiling. This air mixes with the room air and removes airborne contamination through air extracts at the bottom of the walls. The air changes are normally equal to, or greater than, 20 per hour, this being much greater than that used in ordinary rooms, such as in offices. In this style of cleanroom, the contamination generated by people and machinery is mixed and diluted with the supply air and then removed. Non-unidirectional Airflow

30 Unidirectional Airflow The horizontal flow cleanroom uses the same filtration airflow technique as the downflow, except the air flows across the room from the supply wall to the return wall. One major limitation of the horizontal flow design is that the downstream contamination in the direction of airflow increases.

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32 Steps in Aseptic Room Air Filter Air intake Pre-filtration Temperature regulation Humidification HEPA filtration HEPA - High Efficiency Particulate Air filters Can remove 99.97% of airborne

33 Air intake From environment high up Away from polluted area of town & chimneys Pre-filtration Through a pre-filter Set of coarse filters next to the air intake Removes large particles ( 5µm) Temperature regulating/adjustment Regulates air temperature to ambient If too cold, heats up

34 Humidification Prepare air of required humidity Incoming air passed through system of fine atomized spray of de-mineralized water HEPA filtration Final filtration step Air forced through high efficiency air filters Removes 99.97% of airborne particles of 0.3µm size Particles 0.3µm size most difficult to filter Considered MPPS (Most Penetrating Particle Size)

35 Airflow Control Vertical laminar flow

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38 Personnel High standards of personal hygiene Most common source of contaminants in sterile drug products. Large numbers of microbes Healthy population known as reservoir of many microbes.(pathogens) Shed numerous viable & non-viable particles into environment Free from communicable diseases & open lesions on exposed body surfaces.

39 Organisms carried on (larger) skin particles. Adherence to high standards of cleanliness ensured by Adequate hand-washing facilities Protective garments head gears, gloves

40 Appropriate training of all staff before being permitted to enter the Aseptic Manufacturing area Fundamental Training Topics Principles of cgmp Practice & theory of assigned task Aseptic technique Microbiology Gowning proficiency training, observation. Specific SOPs covering aseptic manufacturing area operations.

41 Laminar Flow Air Cleaning

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