Ipqc for parenterals

1. IPQC FOR PARENTERALS 1

2. CONTENTS Introduction to parenterals What is IPQC Importance of IPQC and test performed IPQC tests for parenterals Documentation of parenterals Problems encountered and remedies

3. A parenteral dosage form can be defined as a sterile drug product which is presented in the form of solution, suspension, emulsion, or reconstituted lyophilized powder, suitable for administration by injection through skin or mucous membrane. Para enteron = beside the intestine. PARENTERALS

4. Market survey Projected sales Planning and Scheduling functions personnel Documentation Equipment and control facilities management Material management Preparation of facilities Purchasing Preparation equipment and packaging components Manufacturing of small volume parenterals

5. Manufacturing of products Sterilization of products Aseptic subdivision and sealing Online testing Capping/ outer sealing Inspection Quarantine Finishing, labeling and packaging warehouse Market

6. QC is part of GMP which is concerned with sampling, specification, Testing and with the organization, documentation and release procedures which ensures that the necessary and relevant tests are actually carried out and the materials are not released for sale or supply until their quality has been judged to be satisfactory According to ISO 9000: The operational techniques and activities that are used to fulfil the requirements for quality. QUALITY CONTROL According to WHO Quality itself has been defined as fundamentally relational: 'Quality is the ongoing process of building and sustaining relationships by assessing, anticipating, and fulfilling stated and implied needs.'

7. IPQC means controlling the procedures involved in manufacturing of the dosage forms starting from raw materials purchase to dispatch of the quality product in ideal packaging. It monitors all the features of the product that may effect its quality and prevents errors during processing. It is the activity performed between QA and QC. IN PROCESS QUALITY CONTROL PURPOSE OF IPQC To ensure detectable and significant human errors. Equipment failure and idiosyncrasies. Abnormal interpretation. Adoption of given procedures .

8. To minimize human errors. Provides accurate, specific, and definite description of the procedure to be employed. It is planned system to identify materials and equipment's processed and operated. Used to detect errors if and when it does occur. Is to enforce the flow of manufacturing and packaging operations according to established routes and practice . Importance of IPQC These are the tests performed between QA and QC and provides for the authorization of approved raw materials for manufacturing based on actual laboratory testing generally called as IPQC such as physical, chemical, microbiologic and biologic tests. IPQC TESTS

9. . SCOPE In process quality control are particularly important where a process may vary with time such as tablet weights, fill volume, head space gases etc. TYPES OF IPQC TESTS Physical and chemical. Biologic and microbiologic IPQC Tests Identity tests Quality tests Purity tests Potency tests

10. Identity tests These tests are qualitative chemical methods used to conform the actual presence of compound for example color formation, precipitation. Quality tests These tests a re the physical methods used to measure accurately the characteristic properties of drug . For example: Absorbance, refractive index. Purity tests Purity tests are designed to estimate the level of all known and significant impurities and contaminants in the drug substance under evaluation . For example: Tests for clarity of solutions, Acidity, Alkalinity. Potency tests Potency tests are assays that estimate the quantity of an active ingredient in the drug. Physical and chemical tests

11. Biologic and microbiologic testing It includes macro and micro biologic assays and tests for safety, toxicity, pyrogenicity, sterility, antiseptic activity and antimicrobial preservative effectiveness of tests. Biologic testing of drugs can be Qualitative / Quantitative in nature. It utilizes intact animals , animal preparations, isolated living tissue. When are these tests employed Biologic methods employed in the following situations When adequate chemical assay has not been devised for drug substances although its chemical structure has been established. For example: Insulin When chemical structure of drug substance has not been fully elucidated. For example: Parathyroid hormone. When drug is composed of substances of varying structure and activity For example: Digitalis and posterior pituitary hormone.

12. IPQC for parenteral products Clarity test( for particulate matter ) By visual method Coulter counter method Light obscuration technique Leakage testing( package integrity) Visual methods Bubble test Dye test Vacuum ionization method For fill volume pH Pyrogen testing Rabbit fever response test Limulus amoebocyte lysate test Assay for drug content

13. Sterility test Membrane filtration method Direct inoculation method Test for packing containers For glass containers Water attack test Powder glass test For plastic containers Leakage test, collapsibility test, transparency test, water vapor permeability test. Inspecting for label check Uniformity of contents Uniformity of weight. Passiability of parenteral preparation from needle Conductivity test

14. CLARITY TESTING (DETECTION OF PARTICULATE MATTER) Particulate matter can be detected in parenteral product by two methods, including visual inspection and electronic particulate counting. A) Visual method In visual inspection, each injectable is inspected visually against white and black backgrounds. The white background aids in detection of dark colored particles. The light or reflective particles will appear against the black back ground. Some visual-enhancing aids can increase the efficiency. A magnifying lens at 2.5 × magnification set at the eye level facilitates the inspection. Microscopic examination enhances detection of particulate matter in injectable. Visual inspection gives the qualitative estimation of the particulate matter. Acceptance Standards is that each container checked must not contain any visible particulate matter.

15. B) Automated techniques The automatic systems are also called as the electron particles counter. the electronic particles counter evaluates the particles in injectables automatically. However , this method requires destruction of the ampoule/container for the particle examination. Electronic particles counting may be based on any one of the following principles: a) change in electrical resistance, b) light blockages principle and c) light scattering. Some of the automated systems for visual particle inspection include Autoskan, Eisai Ampoule inspection machine, Schering PDS/A-V system, etc. Autoskan System. The Autoskan system is based on light scattering principle whereby the particle in the path of a light source causes the scattering of light. The scattered light is measured and provides the corresponding information regarding the presence of particulate in the sample. This is a non-destructive test.

16. Coulter counter technique Coulter Counter counts the particles in a sample based on the change in the electrical resistance. Particle size detection limit in this instrument is from 0.1 to 1000 micrometer. The powder sample requires pretreatment such as dispersion in an electrolyte to form a very dilute suspension. The Suspension is usually subjected to ultrasonic agitation to avoid particle agglomerates. Based on change in the electrical resistance A dispersant may also be added to aid particle deagglomeration. Passage of particle causes the change in electrical resistance in between the electrodes which is proportional to the volume of particle. The change in resistance is converted into voltage pulse which is amplified and processed electronically and split into the particle size distribution into many different size-range. This is a destructive test and large errors in measuring flakes and fibers are expected. This test is not recommended by FDA for parenteral.

17. Principle of light obscuration Tungsten lamp produces a constant collimated beam of light that pass through a small rectangular passageway and impinges onto a photodiode. Liquid can flow through the passageway between the light source and photodiode. If a single particle transverses the light beam there results a reduction in normal amount of light received by the photodiode . This reduction of light and the measurable decrease in the output from the photodiode is proportional to the area of the particle interrupting the light flow Thus light obscuration principle measures particle size based on diameter of circle having equivalent area.

18. Test method Use a suitable apparatus based on the principle of light blockage which allows an automatic determination of the size of particles and the number of particles according to size. Method Mix the contents of the sample by slowly inverting the container 20 times successively. If necessary, cautiously remove the sealing closure. Clean the outer surfaces of the container opening using a jet of particle-free water and remove the closure, avoiding any contamination of the contents. Eliminate gas bubbles by appropriate measures such as allowing to stand for 2 min or Sonicate. For large-volume parenterals, single units are tested.

19. the test solution may be prepared by mixing the contents of a suitable number of vials and diluting to 25 ml with particle-free water or with an appropriate particle-free solvent when particle-free water is not suitable. Small volume parenterals having a volume of 25 ml or more may be tested individually. Remove three each of not less than 5 ml, and count the number of particles equal to or greater than 10 μm and 25 μm. Disregard the result obtained for the first portion, and calculate the mean number of particles for the preparation to be examined. For small-volume parenterals less than 25 ml in volume, the contents of 10 or more units is combined in a cleaned container to obtain a volume of not less than 25 ml; Then 3 aliquots are prepared with about 5 ml sample and injected into the sensor.

20. Principle of light scattering When a beam of light strikes a solid object three events occur some of the light is absorbed some is transmitted rest is scattered. Scattered light is composite of diffracted, reflected, refracted light. Particle counters that operate on the basis of light scattering are designed to measure the intensity of light scattered at fixed angles to the direction of the light beam. As the liquid flows into a light sensing zone particles in the fluid scatter light in all directions. The scattered light is directed onto system of elliptical mirrors that then focus the light onto a photo detector. The photo detector converts the signals corresponding area/volume diameter of the particle .

21. Acceptance criteria As per USP LVP : NMT 50 particles/ ml (size 10 or more than 10 micrometer) & 5 particles/ ml (size more than 25 micrometer) SVP : 10,000 particles/ container of size 10 micrometer or greater & NMT 1000 particles/ container greater than 25 micrometer.

22. Leakage test Leakage test is employed to test the package integrity. Package integrity reflects its ability to keep the product in and to keep potential contamination out. It is because leakage occurs when a discontinuity exists in the wall of a package that can allow the passage of gas under pressure or concentration differential existing across the wall. leak test methods. A) VISUAL INSPECTION Visual inspection is the easiest leak test method to perform. But this method is least sensitive.. The method is used for the evaluation of large volume parenteral. To increase the sensitivity of the method, the visual inspection of the sample container may be coupled with the application of vacuum to make leakage more readily observable. This method is simple and inexpensive. However, the method is insensitive, operator dependent, and qualitative. Sometimes, the method is used in combination with pressure and /or temperature cycling to accelerate leakage to improve sensitivity.

23. B ) BUBBLE TEST The test package is submerged in liquids. A differential pressure is applied on the container. The container is observed for bubbles. Sometimes , surfactant added liquid is used for immersion of test package. Any leakage is evident after the application of differential pressure as the generation of foaming in immersion liquid. The method is simple and inexpensive. The location of the leaks can be observed in this method. However, it is relatively insensitive and the findings are operator dependent and are qualitative. The optimized conditions can be achieved using a surfactant immersion fluid along with the dark background and High intensity lighting. Generation of a differential positive pressure of 3 psi inside the vial and observation of any leakage using magnifying glass within a maximum test time of 15 minutes.  Positive  leak test  result. Air  bubbles

24. C) DYE TESTS The test container is immersed in a dye bath. Vacuum and pressure is applied for some time. The container is removed from the dye bath and washed. The container is then inspected for the presence of dye either visually or by means of UV spectroscopy. The dye used may be of blue, green, yellowish-green color. The dye test can be optimized by use of a surfactant and or a low viscosity fluid in the dye solution to increase the capillary migration through the pores. The dye test is widely accepted in industry and is approved in drug use. The test is inexpensive and is requires no special equipment required for visual dye detection . However, the test is qualitative, destructive and slow. The test is used for ampoules and vials.

25. D) VACUUM IONIZATION TEST Vacuum ionization test is useful for testing leakage in the vials or bottles sealed under vacuum. This test is used for online testing of the lyophilized products. High voltage, high frequency field is applied to vials which to cause residual gas, if present to glow. Glow intensity is the function of headspace vacuum level. The blue glow is the indicative of vacuum which indicates the absence of leak while the purple glow indicative of no vacuum. The sensitivity of the method is not documented. This test is on-line, rapid and is non destructive test. However , the proteins present in the test sample may be decomposed. This method is used for the lyophilized vials of biopharmaceuticals. 528 × 904 -  Leak Test Vacuum  Systems 

26. Check for fill vol ume After filling the containers they are checked for the correct volume filling. Check for fill volume is by visual inspection. This is important for small volume parenterals where the volume is less . By keeping the container against a bright background we can check for the fill volume. After conforming for the correct fill volume then they are lacked and labelled and sent to the ware house.

27. pH Checking the bulk solution, before filling for drug content , pH, color, clarity and completeness of solution The pH of a formulation must be considered from following standpoint: 1) the effect on the body when the solution is administered 2) the effect on stability of the product 3) the effect on container-closure system pH measurement pH is measured by using a pH meter . pH meter is initially calibrated with respective buffer capsule then the pH of the preparation is measured.

28. What are pyrogens The term pyrogen frequently refers to gram negative bacterial endotoxin. Pyrogen is a general term for any substance that causes fever after IV administration / inhalation . Microbial substances which act as pyrogen includes bacteria , fungi , plasmodia , viruses, staphylococcal endotoxin. The amount of USP reference standard endotoxin needed to initiate pyrogenicity in humans and rabbits is about 1ng/kg. Naturally occurring bacterial endotoxin contain the lipid, carbohydrate and protein makeup of the outer cell membrane of gram negative bacteria.

29. Test for pyrogens can be carried out by in-vitro and in-vivo methods. A ) Rabbit test (in-vivo) B ) LAL test (Limulus amoebocyte lysate) (in-vitro) A)RABBIT TEST : Principle : The test involves measurement of rise in body temperature of the rabbits following the intravenous injection of a sterile solution of the substance to be tested. The body temperature of the rabbits increases if pyrogens are present in the injected test solution. SELECTION OF TEST ANIMALS: Healthy , adult rabbits of either sex, each weighing not less than 1.5kg. Do not use any rabbit for main test if: It shows a temperature variation greater than 0.2 c between two successive readings noted during the determination of initial temperature . 2 ) And it’s temperature is higher than 39.8 c or lower than 38 c

30. EQUIPMENTS REQUIRED FOR THE TEST: All glass ware, syringes, 20 – 30 gauge needle is used and thermometer must be thoroughly washed with water for injection and heated in a hot air oven at 250 c for NLT 30 min. Retaining boxes for rabbits. TEST : The test is carried out on a group of three rabbits. Procedure : Preparation of the sample: Warm the solution to About 37 ± 2 o c before the injection . In the case of lyophilized products dissolve it in normal saline solution. Determination of initial temperature of rabbits : Insert a clinical thermometer into the rectum of each rabbit and normal readings of body temperature are taken prior to the injection of test solution. Two such readings are taken at an interval of 30 minutes and the mean is calculated. This mean reading is taken as the initial temperature of the rabbits or as a control.

31. Temperature recording USP <85> states the following : Use accurate temperature sensing device such as clinical thermometer, or thermistor probes or similar probes that have calibrated to assure an accuracy of ±0.1 c. Insert the temperature sensing probe into the rectum of the test rabbit to a depth of not less than 7.5 cm . Thermocouple contains two dissimilar electric conductor wires joined at one end to form measuring junction that produce thermal EMF. Thermocouples must be calibrated against National institute of standards and technology.

32. Determination of the response of rabbits: The test solution is injected into the ear vein of each rabbit. The volume of injection is 10 ml/kg of the body weight. This volume varies according to the test substance and is prescribed in the individual monograph. Record the temperature of each rabbit at an interval of 30 minutes for 3 hours after the injection. This is the maximum temperature recorded for that rabbit. The difference between maximum temperature and initial temperature is taken as its response. If this difference is negative, it is taken as a zero response .

33. Interpretation of the results Consider any temperature decrease as zero rise. If no rabbit shows an individual rise in temperature of 0.5 c / more above its respective control temperature , the product meets the requirements for absence of pyrogens. If any rabbit shows an individual temperature rise of 0.5 c or more continue test using five other rabbits . If not more than three of eight rabbits show individual rise in temperature of 0.5 c / more if sum of eight individual maximum temperature does not exceed 3.3 c the material under examination meets the requirement for absence of pyrogens.

34. Limitations of rabbit pyrogen test In vivo model A test method that uses a living animal as model will suffer from number of problems offered by biological systems. No two rabbits will possess exactly the same body temperature or respond identically to same pyrogenic sample. Rabbits are sensitive and vulnerable to their environment. Rabbit sensitivity to pyrogens The pyrogenic response in rabbits is dose dependent. The greater the amount of pyrogen injected per kilogram body weight the greater the temperature increase in rabbits. The rabbit test is less sensitive to endotoxin. It reports 50% pass/fail rate with 95% confidence at endotoxin level above 0.098ng/m (9/10ml/kg) dose The greatest rise in temperature for any given dose of endotoxin occurred in the afternoon , while the least raise occurred at midnight.

35. Interferences of the rabbit pyrogen tests Many products administered parenteral cannot be tested for pyrogens with the rabbit test because of the interferences they create in the rabbit response to pyrogens if they are present in the product Any products having a pyretic side effect such as the prostaglandins and the cancer chemotherauptic agents will interfere with rabbit response.

36. Reaction mechanism Endotoxin or a suitably prepared lipid A derivative of endotoxin activates a proenzyme of LAL having a molecular weight of 150,000. Activation also depends on the presence of divalent metal cations such as calcium, manganese or magnesium. It has been shown that the sensitivity of the LAL assay for endotoxin detection can be increased 10 to 30 times by using LAL reagent containing 50mM magnesium. The activated proenzyme related to the serine protease class containing such enzymes as thrombin, trypsin and factor 10a subsequently with a lower molecular weight protein fraction (MW=19000-25000) contained also in the LAL substance. The lower molecular fraction called coagulogen is cleaved into soluble and insoluble subunit .The insoluble subunit appears as a solid clot , or a turbid solution depending on coagulogen. LIMULUS AMOEBOCYTE LYSATE TEST(LAL) In this test the presence of endotoxin is detected by formation of solid gel.

37. Horseshoe crabs are placed in a restraining rack and passively bled for a few minutes. They are promptly returned to the sea unharmed. Amebocyte blood cells are concentrated, washed, and lysed to produce LAL reagent.

38. Gel clot bacterial endotoxin test The gel clot end point is the most commonly used endotoxin test It is simple and requires minimal laboratory equipment Equal volumes of test solution and LAL reagent ( usually 0.1 ml of each) are mixed in glass test tubes . After incubation at 37 degrees c for one hour tubes are observed for clot formation after inverting them. Formation of solid gel clot that withstands inversion of the tube constitutes a positive test. Each lot of gel clot reagent licensed by the FDA must be labeled with sensitivity( lambda) to reference standard endotoxin(RSE).

39. Kinetic turbidimetric assay During LAL endotoxin reaction the solution mixture becomes increasingly turbid The kinetic turbidimetric assay (KTA) requires the incubating micro plate or tube reader driven by an endotoxin specific software. The reaction mixture in a KTA system are continuously monitored for changes in optical density in each sample that are caused by scattering and absorption of light. Generally the KTA measures the onset time needed to reach a predetermined absorbance by each reaction mixture . The onset times for sample are compared with those of endotoxin studies to yield quantitative values for each sample / control that contain endotoxin

40. Kinetic and endpoint chromogenic assay Chromogenic LAL test do not utilize the coagulogen proteins from LAL reagent to produce an endpoint Although endotoxin activates the same enzymatic cascade from the reagent as described above the clotting enzyme reacts with synthetic substrate that has been added to the reaction mixture. The substrate consists of a colorless amino acid chain attached to a chromophore. The activated clotting enzyme cleaves the bond that holds the chromophore to the amino acid. The amount released is proportion to the concentration of endotoxin The chromophore that is released changes the color of the reaction mixture thereby increasing the optical density After reaction is determined the absorbance is read over one log range.

41. Advantages compared to the rabbit test Proponents of the LAL test claim that the test offers at least seven advantages over the rabbit test for detecting pyrogens . Greater sensitivity Greater reliability Better specificity Less variation Wider application Use as a problem solving tool Less expense. Researchers summarized the superiority of LAL test over the rabbit test by following: After tens of thousands of tests an unexplained negative LAL test result –rabbit positive test result was never recorded. Sometimes the rabbit test initially fails to detect pyrogens that were sometimes confirmed by initial LAL tests.

42. Limitations of the LAL tests The greatest limitation of the LAL test is the problem of interference of the lysate –endotoxin interaction that is caused by a variety of drugs and other substances The reaction is mediated by clotting enzyme that is heat labile, pH sensitive and chemically related to Trypsin . Inhibition caused by any material known to denature protein or to inhibit enzyme action . Inhibition can be overcome by dilution or pH adjustment. Dilution reduces the concentration of endotoxin and places greater demand on the sensitivity of the LAL regent to detect diluted amounts of endotoxin. LAL test applications Used in atleast six different areas pharmaceuticals, biologics, devices, disease states, food, validation of dry heat cycles.

43. Assay Assay is performed according to method given In the monograph of that parental preparation in the pharmacopeia Assay is done to check the quantity of medicament present in the parenteral preparation. So we can know the exact amount of medicament present such that it can perform its action. We should follow the official monograph IP/BP/USP for performing the assay.

44. Sterility test It is done for detecting the presence of viable forms of bacteria, fungi and yeast in parenteral products. The test for Sterility must be carried out under strict aseptic conditions in order to avoid accidental contamination of the product during test. All glassware's required for the test must be Sterile. Sterility testing attempts to reveal the presence or absence of viable micro-organisms in a sample number of containers taken from batch of product. Based on results obtained from testing the sample a decision is made as to the sterility of the batch. Sterility can be defined as the freedom from the presence of viable microorganisms.

45. Major factors of importance in sterility testing : The environment in which the test is conducted The quality of the culture conditions provided The test method The sample size The sampling procedure Environmental conditions : Environmental conditions avoid accidental contamination of the product during the test. The test is carried out under aseptic conditions regular microbiological monitoring should be carried out . Culture conditions : Appropriate conditions for the growth of any surviving organism should be provided by the culture media selection.

46. Factors affecting growth of bacteria : Nutrition Moisture Air Temperature pH Light Osmotic pressure Growth inhibitors   Culture media used for sterility testing: Fluid thioglycolate medium Soybean casein digest medium

47. Fluid thioglycolate medium(FTM): FTM provides both aerobic and anaerobic environments within the same medium.FTM is an excellent medium for the detection of bacterial contamination. Thioglycolate has the advantage of neutralizing the bacteriostatic properties of mercurial preservatives. COMPOSITION : L-cysteine , trypticase peptone, dextrose , yeast extract, sodium chloride, sodium thioglycolate,resazurin,agar,purified water ,final pH 7.1 specific role of some ingredients primarily intended for the culture of anaerobic bacteria. incubation of the media: 14 days at 30 -35°C

48. Soybean casein digest medium: Soya-bean casein digest medium primarily intended for the culture of both fungi and aerobic bacteria specific role of some ingredients. incubation of the media: 14 days at 20 -25°C   COMPOSITION Trypticase soya broth, trypticase peptone, phytone peptone, sodium chloride , dipotassium phosphate, dextrose, purified water , final pH 7.3 Sterility test methods Direct inoculation method Membrane filtration method. Membrane filtration methods Selection of filters for membrane filtration : pore size of 0.45µ effectiveness established in the retention of micro-organisms appropriate composition the size of filter discs is about 50 mm in diameter  

49. The procedure of membrane filtration sterilization of filtration system and membrane filtration of examined solution under aseptic conditions. Filtration of the sample through a membrane filter having the nominal size of 0.45µ and a diameter of 47mm. After filtration the membrane is removed aseptically from the metallic holder and divided into two halves. The first half is transferred into 100 ml of culture media meant for fungi and incubated at 20˚ to 25 ˚c for not less than seven days. The other half is transferred into 100ml of fluid thioglycolate medium and incubated at 30 to 35 ˚c for not less than 7 days.

50. Advantages of membrane filtration over direct inoculation method Greater sensitivity The entire contents can be tested providing an advantage in the sterility testing of LVP and increasing the ability to detect contamination. The antimicrobial agent and antimicrobial solutes in the product sample can be eliminated by rinsing prior transferring the filter into test tubes of media thereby minimizing the incidence of false-negative test results. Organisms present in an oleaginous product can be separated from the product during filtration and cultured in a more desirable aqueous medium. Disadvantages This method cannot differentiate the extent of contamination between units if present because all product contents are combined and filtered through a single filter and cultured in single test tube. There exists a higher probability of inadvertent contamination in manual operations .

51. Samples size to be taken Number of articles in batch (injectables) Number of articles to be tested Not more than 100 articles 10%/ 4 articles whichever is greater More than 100 but not more than 500 10 articles For more than 500 2%/ 20 articles whichever is less For large volume parenterals 2%/10 containers whichever is less.

52. Direct inoculation method Required quantities of liquid is removed from the test containers with a sterile pipette / sterile syringe. Aseptically transfer the specified volume of the material from each container to vessel of culture medium Mix the liquid with medium but not aerate excessively Incubate the inoculated media for not less than 14 days , unless otherwise specified in the monograph at 30 c - 35 c in the case of fluid thioglycolate medium and 20 c - 25 c for soybean casein digest medium. When materials examined renders the medium turbid so presence / absence of microbial growth cannot be determined readily by visual examination transfer suitable portions of medium to fresh vessels of the same medium between 3 rd. and 7 th day after test is started. Continue incubation of the transfer vessel for not less than 7 additional days after transfer and total of NLT 14 days.

53. Interpretation of results At the end of the incubation period the following observations are possible: No evidence of growth; hence the preparation being examined passes the test for sterility. If there is evidence of growth, retesting is performed using the same number of samples, volumes to be tested and the media as in the original test. If no evidence of microbial growth is then found, the preparation being examined passes the test for sterility. If There is again evidence of the microbial growth then isolate and identify the organisms. If they are not readily distinguishable from those growing in the containers of the first test then the preparation being examined fails the test for sterility. If they are distinguishable from the organisms of the first test then again do the test using twice the number of samples. The preparation being examined passes the test for sterility in case there is no evidence of microbial growth. In case there is evidence of growth of any micro organisms in second re –test, the preparation being examined fails the tests for sterility.

54. Powdered glass Test: Use crushed glass containers in 250-ml conical flask, add 50 ml high purity water, cap the flask with borosilicate glass beaker Place the containers in the autoclave and close it securely hold temperature at 121 c±2 c for 30 min., counting from the time this temperature is reached. cool the flask, decant the water from the flask into a clean vessel, and wash the residual powdered glass with high purity water, add 5 drops methyl red solution, titrate immediately with 0.02 N sulfuric acid . Record the volume of 0.02N Sulfuric acid used to neutralize the extract from 10 g of the prepared specimen of glass.   Test for packaging containers Type Type of test Size (ml) ml of 0.02N H 2 SO 4 ˡ Powder glass All 1.0 ˡˡ Water attack 100/less Over 100 0.7 0.2 ˡˡˡ Powder glass All 8.5 Non parenteral Powder glass All 15.0 Water attack at 121°C Rinse 3 or more containers with high purity water. Fill each container to 90% of its capacity with high purity water. Cap all the flasks with borosilicate glass beaker, place in the autoclave at 121 C for 60 min

55. Test for plastics Leakage test 10 containers are filled with the parenteral fluid and inverted for 24 hrs. and checked for any leakage. Transparency Dilute the preparations and compare the cloudiness with the control that is water. Water vapor permeability Containers stored at 20-25 o c at 60±5% Rh for 14 days and check for water vapor permeability. Rubber closure tests Sterilization Fragmentation Self sealability Clarity and color

56. Labels and labeling The label states the name of the preparation (in case of a liquid preparation) The percentage content of drug in a specified volume (in case of dry preparation) The route of administration Storage condition Expiration date Name of the manufacturer The lot number Containers for injection that are intended for use as dialysis, or irrigation solution are labeled to indicate that the contents are not intended for use by iv infusion Injection intended for veterinary use are labeled to that effect The containers are so labeled that a sufficient area of the container remains uncovered for its full length to permit inspection of the contents

57. UNIFORMITY OF CONTENTS: Unless otherwise stated in the individual monograph, suspensions for injection that are presented in single dose containers and that contain less than 10mg or less than 10 % of active ingredient comply with the following test. For suspensions for injection containing more than one active ingredient carry out the test for each active ingredient that corresponds to above conditions. The test for uniformity of contents should be carried out only after the content of active ingredient in a pooled sample of the preparation has been shown to be within accepted limits of the stated content. Determine the content of active ingredient of each of 10 containers taken at random, using the suitable analytical method of equivalent accuracy and precision.

58. The preparation under examination complies with the test if the individual values thus obtained are all between 85 and 115 % of the average value . The preparation under examination fails to comply with the test if more than one individual value is outside the limits 85 to 115% of the average value or if any one individual value is outside the limits 75 to 125% of the average value . If one individual value is outside the limits 85 to 115% but with in the limits 75 to 125% of average value, repeat the determination using another 20 containers taken at random . The preparation under examination complies with the test if in the total sample of 30 containers not more than one individual value is outside the limits 85 to 115% and none is out side the limits 75 to 125% of the average value.

59. UNIFORMITY OF WEIGHT: For powders for injection that are required to comply with the test for uniformity of content of all active ingredients ,the test for uniformity of weight is not required. Remove any adherent labels from a container and immediately weigh the container and its contents. Empty the container as completely as possible by gentle tapping, rinse if necessary with water and then with Ethanol (95%) and dry at 1000 c to 1050 c for 1hr. If the nature of the container precludes such treatment, dry at a lower temperature to constant weight.Allow to cool in a desiccator and weigh. The difference between the weights represents the weight of the contents. Repeat the procedure with a further 19 containers and determine the average weight. Not more than two of the individual weights deviate from the average weight by more than 10% and none deviate more than 20%.

60. Document is a paper that provides information especially of an official or legal nature, written report or record. Documentation is a method of preparing a written material, which describes the process in terms of specifications, instructions etc. Documentation and records are essential for obtaining accreditation, certification of ISOs and approvals by Federal Bodies. Documentation

61. Provide working details necessary for manufacturing, packaging and QC. Reduce the risk of mistakes inherent in verbal communication. Help in tracing the deviation from the expected yields. Help in decreasing the batch to batch variations so that the quality of product kept within the limit of acceptability. Considered as history of batch operations. Self inspection of procedures in order to achieve better control of operations and improvement of product design Importance Of Documentation of Records

62. Particulars with respect to their storage, stability & handling . Instructions of all manufacturing & packaging procedures, preferably batch wise are documented so that no further calculations are required at the work of floor level. Instructions for non product related operations such as cleaning & disinfections, maintenance of equipment, monitoring of working conditions use of specific conditions. Records such as batch manufacturing record, batch packaging record, test record for no product related operations as indicate. Procedures for testing for e.g. physical, chemical, microbiological. Etc. to be followed. Specifications of starting material packaging materials and product for the compliance by the quality control department. Important areas of documentation

63. In FDA-speak: “If it is not documented . . . it did not happen!” or, it’s a rumor!” Document, Document , Document!!!

64. OBSERVATION PAREMETERS OBSERVATIONS / ACCEPTANCE CRITERIA Date - Time Observation should be recorded at an interval of one hour a)Manufacturing area General cleanliness Floor, walls, ceiling ,fans, window panels and ledges should be visibly free from dirt, dust foreign matter. RH/temperature Note the RH and temperature on the hygrometers Insect trap/ air curtain-ON Should be in operation. Status label for All tanks Jacketed vessels Other accessories All manufacturing and storage tanks , jacketed vessels, filter press, pipes, colloidal mills & other accessories should be labeled with CLEANED or TO BE CLEANED or product label with details of product name, mfg. date stage and date of processing.

65. Raw materials other than the current batch removed Raw materials only for batch under process should be required for present and others should be removed from process area. All tanks properly covered All manufacturing & storage tanks should be covered with lids Status label for Balance Sifter Multi-mill Blender Tray drier Other accessories All in-process materials Packaging Labeling Segregation quarantine RM quality during sifting Sugar quality after milling Blend quality

66. Packaging area General cleanliness Floors, walls, ceiling, fans and ledges should be visibly free from dust and foreign matter. Insect trap/air curtains-ON Should be in operation Status label present for Packaging/filling area Filling machine ROPP cap sealing machine Packaging / filling area, filling machine ,sealing machine should be labelled with CLEANED or TO BE CLEANED or product label with details of product name , batch name, mfg. date stage & date of processing. Packaging materials other than that required for current batch removed Packaging materials only of the batch under packaging should be present and others should be removed Bottle washing Water sprinkler Check all the water jets of the bottle washing machine are in working condition Washing bottles –check The glass bottles should be free from physical defects. Pour filtered water into bottles close and check the bottles again ,should be free from particles, fibres.

67. Filling tanks Labelled Cover present/ absent Solution level NLT 1/4 of tank height Product label with product details must be present Tanks should be covered during filling process Solution level should be NLT ¼ of tank height. ROPP cap No visual defects cleanliness Sealing/threading Ease of cap opening /re-sealing Should be free from damages and monogram should be uniform and should be in Centre. Caps should be free from dust and metallic particles Sealing should be complete threading should be without cuts. Should open properly with good bridge cutting and should reseal properly without over turning. Leak test Before seal opening After re-sealing Invert the filled ,sealed bottles &keep for 30min .it should not leak. Open the cap and reseal ,invert the bottle again and check for leakage. Check on filled bottles Sealing Volume Foreign matters and defects Sealing should be proper without cuts Check as per BPR Should be free from foreign matter and glass.

68. Coding details B.No/Mfd./Exp./price Clarity Positioning Check all coding details on labels and cartons and compare with BPR and signed specimens Clarity of printing should be free from ink smudges. Position of coding details should be proper against each detail. Labelling Soiling/smudging Print clarity Positioning Gumming Labels should be free from soiling and printed matter should be free from smudging Printed matter & colors should be uniform shades & clear Pasting of labels should be proper without cross labelling or wrinkles. Should be proper without excess gum Carton Printing clarity Coding details/clarity Carton erection & closing Should be of uniform shades and clear Coding details should be compared with BPR and signed specimens and be clear & properly positioned Should be neat and definite with proper bottom. Sides locking. Closing should seal properly & shouldn't open out Leaflet Presence of proper literature should be properly checked printing matter and folding should be proper.

69. Measure cup/ dropper Cleanliness Free from visual defects Fixation of cup/dropper assembly Should be clean and visually free from any foreign matter Should be free from dents, scratches, breakage. Cups should fix to the bottle neck with slight push and should not fall out when lifted. Corrugated box –external Address/position/clarity Handling cautions/ position Pack slip Stapling Stacking Should be printed on left bottom side printing should be without smudges Should be printed on another length wise portion opp to printing of address in middle of panel. Should be pasted with details properly stamped , for trade name products, with monogram& generics monogram Good quality rust proof should be used & should be used at 45 deg angle NT 60 mm b/w two stapling. Should be properly stacked & lower box should withstand the weight. Corrugated box internal Liners & partitions contents Liners should be placed properly & formation of partition should be uniform. Should comply as per the instructions & quantities to be pkd

70. Master formula records Name of the product ________________________________________ Name and Weight of API ____________________________________ Name and Weight of Ingredient _______________________________ Description of equipment ____________________________________ Statement of theoretical yield _________________________________ Process and packaging procedure _____________________________ A description of container ____________________________________ closure and packaging material _______________________________ In process control during processing ___________________________ In process control during packaging____________________________ Precaution to be taken______________________________________

71. Date Time Incubation temperature Humidity in case of hygroscopic substances’ Plate no duration Location No of colonies           Product_______________________________ lot no._______________ Room____________________ date exposed_____________________ Media__________________________ Environmental control

72. Description of containers ___________________________________ Q/C report of container ____________________________________ Date ________________________ Equipment used ______________ Cleaning agent used ________________________________________ Cycle of washing: __________________________________________ Sign . Of officer ____________________________________________   Preparation of equipment's and containers Articles Date Time when oven started Desired temp attained Temperature Time when oven switched off           If sterilized by dry heat or autoclave

73. Equipment's used for filtration ___________________________________ Date__________________________ Time_________________________ Result of test or analysis of solution_______________________________ Equipment used for filling_______________________________________ Date________________________________________________________ Sign. Of officer____________________________________________ Time Filling started Filling completed       Filtration and filling

74. Ampoule filling on industrial scale followed by terminal autoclaving Ampoule filling on small scale Steps of filling and sealing Powder filling machine in vials and ampoules

75. Visual inspection: Description ___________________ Total no of filled, sealed & sterilized containers rejected ___________ Nature of defects ___________________________________   Name of worker who examined   (i). ________________________________________________ (ii). _______________________________________________ (ii). _______________________________________________   IPQC RECORDS

76. Product name_______________________ Batch no_______________________ Strength___________________________ batch size ______________________ Category___________________________ mfg. date _______________________ MFG no _________________________ exp date _______________________ Description of packaging ______________ Pre-coding of labels & printed packaging materials Examined verified by_____ No . of pre-coded __________________________ Printed packaging material received _____________________ Result of bulk finished products ______________________ Sign. Of officer ___________________________________________ Batch packaging and labeling records

77. Problems encountered and their remedies Problem encountered Remedy Leakage of ampoules Discard the ampoule Use new ampoule with proper sealing Perforation in filter leading to defective filtration Changing the filter Foreign particles/dust Membrane filtration Fibres Optical and visual inspection pH Use of buffers Leaching Internal coating of glass containers.

78. Encyclopedia of pharmaceutical technology third edition edited by James Swabrick volume 5. Indian pharmacopeia (1996) volume 2 United states pharmacopeia (2000) volume 2 Pharmaceutical dosage forms : parenteral medications volume 3 by Kenneth E Avis; Herbert A Lieberman; Leon Lachman. The Theory and Practice of Industrial Pharmacy by Leon Lachman ; Herbert A. Lieberman ; Joseph L. Kanig. Parenteral Quality Control: Sterility, Pyrogen, Particulate and Package Integrity Testing By (author) Michael J. Aker; Revised by Dana Morton Guazzo. By Daniel S. Larrimore. References

79. IPQC PowerPoint presentation from author stream by Govind Bhandari from Mahakal institute of pharmaceutical studies. Sterile Dosage Forms I. Parenteral Products by Professor Dr. Nagia Nagib Afifi by German university in Cairo ( GUC). Pharmaceutical practical guide. Some PowerPoint presentations from slideshare. Product management and Documentation by professor of East west college of pharmacy Bangalore.

80. THANK YOU