QUALITY CONTROL OF BIOLOGOCALS

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QUALITY CONTROL OF BIOLOGOCALS:

QUALITY CONTROL OF BIOLOGOCALS Guided by Dr.. S.S.Patil Principal-AMCP, Peth Wadgaon Presented by, Rani M. Mhetre M.pharm first yr

CONTENTS :

CONTENTS INTRODUCTION TO QUALITY CONTROL INTRODUCTION TO BIOLOGICALS INTRODUCTION TO ANTIBIOTICS EVALUATION OF ANTIBIOTICS PYROGEN TEST BACTERIAL ENDOTOXIN TEST BIOLOGICAL REACTIVITY TEST IN VIVO BIOLOGICAL REACTIVITY TEST IN VITRO INTRACUTANEOUS TEST IMPLANTATION TEST SAFTY TEST BIOLOGICALS INTRODUCTION TO IMMUNITY TYPES OF IMMUNITY VACCINES QUALITY CONTROL OF VACCINES ANTISERUM ALLERGENIC EXTRACTS QUALITY CONTROL OF ALLERGENIC EXTRACTS

What is quality control:

What is quality control Quality control (QC) is a procedure or set of procedures intended to ensure that a manufactured product or performed service adheres to a defined set of quality criteria or meets the requirements of the client or customer.

BIOLOGICALS:

BIOLOGICALS Immunizing agents and allergenic extracts are two of main groups of drugs classified as biological by FDA. As biological are derived from microorganisms it also includes antibiotics. Biologics are the natural products: virtually all of the drugs from this group are derived from once living organisms including man, higher animals , plants and microorganisms. Although there are some exceptions to this rule, even the so called synthetic proteins today are produced in living systems.

ANTIBIOTICS:

ANTIBIOTICS The word antibiotic comes from the Greek anti meaning 'against' and bios meaning 'life' (a bacterium . These are substances produced by microorganisms, which selectively suppress the growth of or kill other microorganisms at very low concentrations. is a life form).

Antibiotic susceptibility test:

Antibiotic susceptibility test DIFFUSION METHOD Kirby-Bauer disc diffusion method Stokes disc diffusion method DILUTION METHOD Broth dilution method Agar dilution method

PRINCIPLE:

PRINCIPLE Evaluation is done by using antibiotic discs i.e. about 6mm in size Paper discs saturated with chemicals are used to determine sensitivity or resistance to antibiotics Discs are placed on the surface of agar medium Due to this antibiotic will diffuse into medium and inhibit the the organism around the disc Then it is incubated after incubation the zone is produced around the disc where no growth has occured this zone is called as zone of inhibition

INTERPRETATION:

INTERPRETATION SENSITIVE - zone size is equal to or larger than or not more than 3mm smaller than control INTERMEDIATE - zone size is atleast 2mm but smaller than control strain RESISANANT- zone size of test strain is smaller than 2mm

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Factor Influence Inoculum density Larger zones with light inoculum and vice versa Timing of disc application If after application of disc, the plate is kept for longer time at room temperature, small zones may form Temperature of incubation Larger zones are seen with temperatures < 35 o C Incubation time Ideal 16-18 hours; less time does not give reliable results Size of the plate Smaller plates accommodate less number of discs Depth of the agar medium Thin media yield excessively large inhibition zones and vice versa Proper spacing of the discs Avoids overlapping of zones Potency of antibiotic discs Deterioration in contents leads to reduced size Composition of medium Affects rate of growth, diffusion of antibiotics and activity of antibiotics Acidic pH of medium Tetracycline, novobiocin, methicillin zones are larger Alkaline pH of medium Aminoglycosides, erythromycin zones are larger Incubation in the presence of CO 2 Increases zone size of tetracycline and methicillin Addition of thymidine to medium Decreases activity of trimethoprim Addition of defibrinated blood Decreases activity of sulfonamides On chocolate agar, decreased activity of Sulfonamides, trimethoprim, aminoglycosides Reading of zones Subjective errors in determining the clear edge Chelating agents such as cal-cium, magnesium and iron Decreases diffusion of tetracycline and gentamicin Factors influencing zone size in antibiotic susceptibility testing

RECENT ADVANCES IN SUSCEPTIBILITY TESTING:

RECENT ADVANCES IN SUSCEPTIBILITY TESTING Antibiotic Disk QC Testing Workflow Input test information via LIS/ bar code reader or manually Insert antibiotic disk test plate or ID panel Select "Read QC Test" for instant color digital reading Productivity Enhancement Features: 2-Way LIS Interface Touch Screen Monitor Bar Code Reader Review QC antibiotic disk plates or ID panels on-screen Select "View QC Results" Options: Adjust zone diameters or ID panel well results Images can be saved and archived Review QC test results All QC results are based on current CLSI/BSAC guidelines Print and transfer test results via LIS.

Biological tests for antibiotics includes mainly following tests:

Biological tests for antibiotics includes mainly following tests PYROGEN TEST BACTERIAL ENDOTOXIN TEST INTRACUTANEOUS TEST IMPLANTATION TEST SAFETY TESTS BIOLOGICALS BIOLOGICAL REACTIVITY TEST IN VIVO AND IN VITRO AGAR DIFFUSION TEST DIRECT CONTACT TEST ELUTION TEST SYSTEMIC INJECTION TEST DEPRESSOR SUBSTANCES

PYROGEN TEST:

PYROGEN TEST The pyrogen test is designed to limit to an acceptable level the risks of febrile reaction in the patient to the administration, by injection, of the product concerned. The test involves measuring the rise in temperature of rabbits following the intravenous injection of a test solution and is designed for products that can be tolerated by the test rabbit in a dose not to exceed 10 mL per kg injected intravenously within a period of not more than 10 minutes.

INTERPRITATION:

INTERPRITATION If the sum of the responses of group of 8 rabbits doesn’t exceeds 1.4 and if response of any individual rabbit is less than 0.6 the preparation being examined passes the test, if response of any rabbit is0.6 or any or if sum of responses of 3 rabbits exceeds 1.4 continue the test using 5 other rabbits . If not more than 3 of 8 rabbits show individual responses of 0.6 or more and if sum of the group of 8 rabbits doesn’t exceed 3.7. The preparation being examined passes the test.

BACTERIAL ENDOTOXINE TEST:

BACTERIAL ENDOTOXINE TEST Limulus Amebocyte Lysate (LAL) tests detect and quantify bacterial endotoxins extracted from the outer membrane of gram negative bacteria. The critical component of the LAL reagents used in endotoxin tests is derived from blood cells (amebocytes) of the horseshoe crab, Limulus polyphemus . It contains the proteins of the blood clotting mechanism, which is triggered by endotoxins. LAL reagents are primarily used to test for endotoxins in injectable pharmaceuticals, biological products, and medical devices. They are also used in renal dialysis centers and a wide range of other applications.

METHODS OF LAL TEST:

METHODS OF LAL TEST CHROMOGENIC METHODS TURBIDIMETRIC METHODS GEL-CLOT METHODS

BIOLOGICAL REACTIVITY TEST IN VIVO:

BIOLOGICAL REACTIVITY TEST IN VIVO SYSTEMIC INJECTION TEST INTRACUTANEOUS TEST IMPLATAION TEST

Evaluation of Skin Reactions :

Evaluation of Skin Reactions Erythema and Eschar Formation No erythema Very slight erythema (barely perceptible) Well-defined erythema Moderate to severe erythema Severe erythema (beet-redness)to slight eschar formation (injuries in depth) Edema Formation * No edema Very slight edema (barely perceptible) Slight edema (edges of area well defined by definite raising) Moderate edema (raised approximately 1mm) Severe edema (raised more than 1mm and extending beyond the area of exposure) * Excludes noninflammatory (mechanical)edema from the blank or extraction fluid.

Intracutaneous Test :

Intracutaneous Test This test is designed to evaluate local responses to the extracts of materials under test following intracutaneous injection into rabbits. Examine injection sites for evidence of any tissue reaction such as erythema,edema,and necrosis.Swab the skin lightly,if necessary,with diluted alcohol to facilitate reading of injection sites.Observe all animals at 24,48,and 72hours after injection.

Implantation Test :

Implantation Test The implantation test is designed for the evaluation of plastic materials and other polymeric materials in direct contact with living tissue of importance are the proper preparation of the implant strips and their proper implantation under aseptic condition. EVALUATION Calculate the differences between average scores for the Sample and Control sites.The requirements of the test are met if the difference does not exceed 1.0,or if the difference between the Sample and Control mean scores for more than one of the four implant sites does not exceed 1for any implanted animal.

BIOLOGICAL REACTIVITY TEST IN VITRO:

BIOLOGICAL REACTIVITY TEST IN VITRO AGAR DIFFUSION TEST DIRECT CONTACT TEST ELUTION TEST

AGAR DIFFUSION TEST:

AGAR DIFFUSION TEST This test is designed for elastomeric closures in a variety of shapes. The agar layer acts as a cushion to protect the cells from mechanical damage while allowing the diffusion of leachable chemicals from the polymeric specimens. Extracts of materials that are to be tested are applied to a piece of filter paper. INTERPRETATION The biological reactivity (cellular degeneration and malformation) is described and rated on a scale of 0 to 4 .Measure the responses of the cell cultures to the Sample Preparation, the Negative Control Preparation, and the Positive Control Preparation. The cell culture test system is suitable if the observed responses to the Negative Control Preparation is grade 0 (no reactivity) and to the Positive Control Preparation is at least grade 3 (moderate). The Sample meets the requirements of the test if the response to the Sample Preparation is not greater than grade 2 (mildly reactive). Repeat the procedure if the suitability of the system is not confirmed.

DIRECT CONTACT TEST:

DIRECT CONTACT TEST This test is designed for materials in a variety of shapes. The procedure allows for simultaneous extraction and testing of leachable chemicals from the specimen with a serum-supplemented medium. The procedure is not appropriate for very low- or high-density materials that could cause mechanical damage to the cells. INTERPRETATION The Sample meets the requirements of the test if the response to the Sample Preparation is not greater than grade 2 (mildly reactive). Repeat the procedure if the suitability of the system is not confirmed.

ELUSION TEST:

ELUSION TEST This test is designed for the evaluation of extracts of polymeric materials. The procedure allows for extraction of the specimens at physiological or nonphysiological temperatures for varying time intervals. It is appropriate for high-density materials and for dose-response evaluations. INTERPRETATION The Sample meets the requirements of the test if the response to the Sample Preparation is not greater than grade 2 (mildly reactive). Repeat the procedure if the suitability of the system is not confirmed. For dose-response evaluations, repeat the procedure, using quantitative dilutions of the sample extract.

SAFTY TESTS BIOLOGICALS:

SAFTY TESTS BIOLOGICALS The safety test set forth here is intended to detect in an article any unexpected , unacceptable biological reactivity . This in vivo test is provided for the safety assessment of biologics and biotechnology-derived products.

IMMUNITY:

IMMUNITY Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection , , or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide range of pathogens irrespective of antigenic specificity. Other components of the immune system adapt themselves to each new disease encountered and are able to generate pathogen-specific immunity.

TYPES OF IMMUNITY:

TYPES OF IMMUNITY

VACCINE:

VACCINE Vaccine may be defined as pharmaceutical suspensions or solutions of an immunogenic substance or compound that is intended to inuce active immunity.

Types of vaccines:

Types of vaccines Inactivated vaccines are composed of micro-organisms that have been killed with chemicals and/or heat and are no longer infectious. Examples are vaccines against flu, cholera, plague, and hepatitis A. Most vaccines of this type are likely to require booster shots. Live attenuated vaccines are composed of micro-organisms that have been cultivated under conditions which disable their ability to induce disease. These responses are more durable and do not generally require booster shots. Examples include yellow fever, measles, rubella, and mumps. Toxoids are inactivated toxic compounds from micro-organisms in cases where these (rather than the micro-organism itself) cause illness, used prior to an encounter with the toxin of the micro-organism. Examples of toxoid-based vaccines include tetanus and diphtheria. Subunit -vaccines are composed of small fragments of disease causing organisms. A characteristic example is the subunit vaccine against Hepatitis B virus.

QUALITY CONTROL OF VACINES:

QUALITY CONTROL OF VACINES Testing for bacterial contamination Testing for aerobic contamination Testing for anaerobic contamination Testing for extraneous viruses Testing for salmonella species Testing for mycoplasma species Testing for contamination with fungi Testing virus content of vaccine

Testing for aerobic contaminants :

Testing for aerobic contaminants Use a general purpose broth culture medium that supports the growth of most likely contaminants for example Tryptic soy broth or nutrient broth. 1. Inoculate 1 mL of the wet vaccine or reconstituted freeze dried vaccine into 9 mL of broth. 2. Incubate at 30°C to 37°C for 24 hours. 3. Record results Interpretation Gross contamination after 24 hours, retest in twice the number of cultures. If contamination is evident after the second culture, discard the vaccine

Testing for Salmonella species :

Testing for Salmonella species Materials Liquid media: Selenite broth Tetrathionate broth Solid Media MacConkey agar Salmonella-Shigella agar Brilliant Green agar Desoxycholate citrate agar XLD agar Method 1. Inoculate 9 mL of one of the liquid media with 1 mL of vaccine 2. Incubate at 37°C for 18 to 24 hours 3. Inoculate a loopful of incubated broth onto one of the solid media. 4. Incubate 18 to 24 hours. Observe . If no Salmonella growth is detected, incubate again for 18 to 24 hours. 5. Discard the vaccine, if Salmonella are detected.

Testing for contamination with fungi :

Testing for contamination with fungi Sabouraud dextrose agar is used to cultivate fungi. Chloramphenicol at 0.05 g/L can be added to inhibit bacteria. Inoculate the agar with 100 mL of vaccine and spread over the plate. Inoculate a control plate with diluent only. Incubate at 25°C to 30°C for one week. Observe daily and record results. Growth on the control plate invalidates the test, which should then be repeated. Vaccine should be free of fungal contamination.

Safety test in young chicks :

Safety test in young chicks This test involves giving susceptible chickens ten doses of vaccine. The formal test described by OIE uses one-day-old SPF chicks. In many circumstances, it will be necessary to use commercial chickens and they may be older than one day old. In this case collect serum and test for HI titres to make sure they do not have maternal antibodies to Newcastle disease virus. Use two groups of chickens, a minimum of ten chickens per group. Take a serum sample from the chickens. Use the HI test to test for antibodies to determine susceptibility. Use only chickens that test negative for Newcastle disease antibodies, preferably SPF chickens. Administer ten doses (10 7.0 EID 50 ) by eye-drop of the I-2 vaccine to each chick in the treatment group. Administer diluent only by eye-drop to each chick in the control group. Observe daily for 21 days for clinical signs. Interpretation If any serious clinical signs or deaths attributable to the vaccine are observed, discard the vaccine.

ALLERGENIC EXTRACTS:

ALLERGENIC EXTRACTS Allergenic extracts are concentrated solutions or suspensions of allergens used for diagnosis and treatment of allergic diseases. TYPES Pollen extracts Dust extracts Food extracts Inhalant extracts

QUALITY CONTROL OF ALLERGENIC EXTRACTS:

QUALITY CONTROL OF ALLERGENIC EXTRACTS Isoelectric focusing SDS-PAGE Immunoblotting Rocket immunoelectrophoresis CIE & CRIE Radial immunodiffusion ELISA inhibition Double-Bind ELISA Protein & carbohydrate determination

REFERANCES:

REFERANCES A . 1. Lindquester, Gary J. (2006) Introduction to the History OF Disease and Immunity, Rhodes College. Silverstein, Arthur M. (1989) History of Immunology (Hardcover) Aca disease . demic Press. Note: The first six pages of this text are available online at: ( Amazon.com easy reader ) Gherardi E. the Concept of Immunity. History and Applications. Immunology Course Medical School, University of Pavia. The Columbia Electronic Encyclopedia, Sixth Edition. Columbia University Press (from Answers.com, 2006.) Maleissye J (1991). Histoire Du Poison. Paris: Francois Bourin, ISBN 2876860821 (in French. Translated in Japanese: Hashimoto I, Katagiri T, translators (1996). [History of Poison]. Tokyo: Shin-Hyoron, Ltd., ISBN 4-7948-0315-X C0020). This article incorporates content from the 1728 Cyclopaedia , a publication in the public domain . " Mithridate ". Microbiology and Immunology On-Line Textbook : USC School of Medicine Janeway, Charles ; Paul Travers, Mark Walport, and Mark Shlomchik (2001). Immunobiology; Fifth Edition . New York and London: Garland Science. ISBN 0-8153-4101-6 .. 8. Coico, R., Sunshine, G., and Benjamin, E. (2003). “Immunology: A Short Course.” Pg. 48. Keller, Margaret A. and E. Richard Stiehm (Oct 2000). "Passive Immunity in Prevention and Treatment of Infectious Diseases" . Clinical Microbiology Reviews 13 (4): 602–614. Doi : 10.1128/CMR.13.4.602-614.2000 . ISSN 0893-8512 . PMC 88952 . PMID 11023960 . National Institutes of Health "Smallpox - A Great and Terrible Scourge" Variolation ^ Immunization: You call the shots. The National Immunization Program at the Centers for Disease Control and Prevention B . UNITED STATE PHARMACOPIEA AND NATIONAL FORMULARY C. Giles scientific inc.santa Barbara, California USA D. Allan, W.H. and R.E. Gough, 1974b E. Remington THE SCIENCE AND PRACTICE OF PHARMACY F. ASEAN (1998) Manual of ASEAN Standards for Animal Vaccines , Livestock Publication Series No 2A. Allan, W.H. and J.E. Lancaster (1978) Newcastle Disease Vaccines, Their Production and Use , FAO Animal Production and Health Series No 10, 1978. Office International des Epizooties (OIE) Manual of Standards for Diagnostic Tests and Vaccines, 2000 . Website http://www.oie.int/eng/normes/mmanual/A_summry.htm Mowat, N. and M. Rweyemamu (1997) Vaccine Manual : The Production and Quality Control of Veterinary Vaccines for Use in Developing Countries, FAO Animal Health and Production Series No 35. E . .Allergen Extract Analysis 111 Clinical Reviews in Allergy and Immunology Volume 21, 2001 Laboratory Methods for Allergen Extract Analysis and Quality Control Thomas J. Grier Laboratories, Inc., PO Box 800, 639 Nuway Circle, Lenoir, NC 28645Greer

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