IPQC & FPQC Parenteral Formulation
- 1. WWW.SLIDEFOREST.COM 1 ROSHAN H. KHETADE FOR PARENTERALS IPQC & FPQC SKB College of pharmacy
- 2. WWW.SLIDEFOREST.COM 2 CONTENTS Introduction to parenteral Types of parenteral What is IPQC Importance of Quality Control IPQC tests for parenterals 2
- 3. WWW.SLIDEFOREST.COM 3 Introduction to Parenterals Greek para = "beside" and enteron = "intestine", it bypasses the intestines. Parenterals are the sterile dosage form intended for administration other than enteral route and exert their action by directly entering into the systemic circulation. Parenteral are ◦ Sterile ◦ Pyrogen-free & ◦ Free from particulate matter which are injected into the internal body compartment. 3
- 4. WWW.SLIDEFOREST.COM 44 Types of parenterals A} Based on the volume a) Small volume parenterals: volume ≤ 100 ml, b) Large volume parenterals: volume ˃ 100 ml {101ml-1000ml} B} Based on types of packaging a) Single dose units: ampoules, infusions and prefilled disposable syringes. b) b) Multiple dose units: multiple dose vials.
- 5. WWW.SLIDEFOREST.COM 5 Powder for injections Injections Infusions CATEGORIES 5 Implants Concentrated solutions for injections Eg. Enbrel Tegamet Eg. Parazeal IV Afymol Eg. Doxil, Daunasome, Botox Eg. Glidel, Durin, Duros, Eg. Mitoxantrone Inj. USP
- 6. WWW.SLIDEFOREST.COM 66 IPQC means controlling the procedures involved in manufacturing of the dosage forms starting from raw material purchase to dispatch of the quality product in ideal packaging. It monitors all the features of the product that may affect its quality and prevent errors during processing. It is the activity performed between QA and QC. In Process Quality control
- 7. WWW.SLIDEFOREST.COM 77Importance of Quality Control To minimize human errors. Provides accurate, specific and definite description of the procedure to be employed. It is a planned system to identify materials, equipments processed and operations. Is to detect the errors if and when it does occurs. Is to enforce the flow of manufacturing and packing operations according to established routes and practice.
- 8. WWW.SLIDEFOREST.COM 88IPQC tests It provides for the authorization of approved raw materials for manufacturing and these test are generally called as IPQC which includes physical, chemical, microbiologic and biologic tests.
- 9. WWW.SLIDEFOREST.COM 99IPQC and FPQC tests for parenterals Conductivity measurement pH measurement Temperature for heat sterilized product Volume filled QUALITY CONTROL PARAMETERS OF PARENTERAL PHARMACEUTICALS: I. Sterility Test II. Pyrogen test III. Clarity test IV. Leakage Test-non pharmacopoeia test V. Test for Uniformity of Content VI. Uniformity of weight VII.Extractable volume
- 10. WWW.SLIDEFOREST.COM 1010 Conductivity measurement: 1 Conductivity is measured by conductometer. 2 It measures the conductivity of vehicle used in sterile preparation. 3 Conductivity of pure water is 0.55 microsiemens /cm. pH measurement: Two different types of methods used in measurement of pH. 1.Dip a piece of pH paper into the sample. 2.pH meter
- 11. WWW.SLIDEFOREST.COM 1111 Temperature for heat sterilization:- 1. It is important to maintain the constant temperature during heat sterilization of product. 2. The tempraturechanges may cause some undesirable changes like change in potency,change in isotonicity. 3. The temperature can be determined by normal thermometer. Volume filled :– An injection container is filled with a volume in slight excess of the labeled size.
- 12. WWW.SLIDEFOREST.COM 1212 I. Sterility Test: • The tests for sterility are intended for detecting the presence of viable microorganism in pharmaceutical preparation that is designed to be sterile. Method of testing:
- 14. WWW.SLIDEFOREST.COM 14141.Method A (Membrane filtration): • Method A (Membrane filtration) is preferred where the substance under examination is 1. An oil 2. An ointment that can be put into solution. 3. A non bacteriostatic solid not readily soluble in the culture medium, and 4. A soluble powder or a liquid that possesses bacteriostatic and /or fungistatic properties. • For liquid products where the volume in a container is 100 ml or more, method A should be used.
- 15. WWW.SLIDEFOREST.COM 1515 1. Sterilization of filtration system and membrane filtration of examined solution under aseptic conditions. 2. Filtration of the sample through a membrane filter having the nominal size of 0.45µ and a diameter of 47mm. 3. After filtration the membrane is removed aseptically from the metallic holder and divided into two halves. 4. 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. 5. The other half is transferred into 100ml of fluid thioglycolate medium and incubated at 30 to 35 ˚c for not less than 7 days. The procedure of membrane filtration
- 16. WWW.SLIDEFOREST.COM 16162.Method B: Direct inoculation method • This method is only used when membrane filtration is not possible the sample is inoculated directly into the media or the device is placed directly into the media • Process: 1Aseptically opening each sample container from a recently sterilized batch of product. 2. Using a sterile syringe and needle to withdraw the required volume of sample for both media from the container 3. Injecting one-half of the required volume sample into a test tube containing the required volume of FTM and the other half volume of sample into a second test tube containing the required volume of SCD.
- 18. WWW.SLIDEFOREST.COM 1818Interpretation of Results 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 the material being tested renders the medium turbid so that the presence or absence of microbial growth cannot be easily determined by visual inspection,14 days after incubation , transfer portion (< 1 ml) of the medium to fresh vessels of the same medium and then incubate original and transfer vessel for not less than 4 days. • If No evidence of microbial growth is found- complies with test for sterility.
- 19. WWW.SLIDEFOREST.COM 1919II. Pyrogen test 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)
- 20. WWW.SLIDEFOREST.COM 2020 A) Rabbit test (in-vivo) a) Preliminary Test (Sham Test):- Injecting intravenously 10 ml per kg body weight of a pyrogen-free saline solution warmed to about 38.5° C. Record the temperatures of the animals, beginning at least 90 minutes before injection and continuing for 3 hours after injection of the test solution. Any animal showing a temperature variation of 0.6°C or more must not be used in the main test. Selection of animals is done in it. b) Main Test: Carry out the test using a group of three rabbits.
- 21. WWW.SLIDEFOREST.COM 2121 • Procedure:- 1. Inject the solution under examination slowly into the marginal veins of the ear of each rabbit over a period not exceeding 4 mins. 2. Record the temperature of each animal at half hour intervals for 3 hours after injection. 3. The difference between the initial temperature and the maximum temperature which is the highest temperature recorded for a rabbit is taken to be its response. • Preparation of the sample:- Dissolve the substance in or dilute with pyrogen free saline solution . Warm the liquid to approximately 38.5° before injection.
- 23. WWW.SLIDEFOREST.COM 2323B) LAL test (Limulus amoebocyte lysate) (in-vitro) • The LAL (limulus amebocyte lysate) Assay is an in vitro assay used to detect the presence and concentration of bacterial endotoxins in drugs and biological products. Procedure:- ◦ Equal volume of LAL reagent and test solution (usually 0.1 ml of each) are mixed in a depyrogenated test-tube ◦ Incubation at 37°C, for1 hour ◦ Remove the tube and invert in smooth motion at 180° angle ◦ Observe the result
- 24. WWW.SLIDEFOREST.COM 2424Interpretation of Result • The tubes are incubated at 37±1°C FOR 60 ±2 minutes. • When the tubes are inverted at 180ºC angle, formation of firm gel confirms positive reaction. • While formation of a viscous gel that doesn't maintain its integrity or absence of a firm gel confirms negative reaction.
- 25. WWW.SLIDEFOREST.COM 2525III. Clarity test: 1. VISUAL INSPECTION BY NAKED EYE: ◦ Each injectable is inspected visually against White and Black Backgrounds. ◦ The White background aids in detection of dark colored particles. ◦ The light reflective particles will appear against the Black background. Medical-Pharmaceutical-Drug-Clarity- Tester
- 26. WWW.SLIDEFOREST.COM 26262. Coulter Counter method: • The sample solution is added to an electrolyte solution which is drawn through a small orifice. • As particle passes through the orifice it displaces its own volume of electrolyte. • Particle detected by the increase in electrical resistance. • Voltage pulses are proportional to the particle size. • Particles below 0.2µm can also be detected.
- 27. WWW.SLIDEFOREST.COM 2727 IV. Leakage Test (visual inspection, bubble test, dye tests ) • The test is used for ampoules and vials. • 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. • 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. Leakage test can be done by dye bath test( using methylene blue solution)
- 28. WWW.SLIDEFOREST.COM 2828 • It is detected by producing negative pressure within an incompletely sealed ampule, usually in a vacuum chamber, while the ampule is entirely submerged in a deeply colored dye solution. • The pressure inside chamber causes penetration of dye in and it is being visible after the ampule has been washed externally clear it of dye.
- 29. WWW.SLIDEFOREST.COM 2929 V. Test for Uniformity of Content As per IP&BP : - Determine the content of active ingredient(s) of each of 10 containers taken at random, using the method given in the monograph. • The preparation under examination complies with the test if the individual values thus obtained are all between 85 and 115 per cent of the average value. • The preparation under examination fails to comply with the test if more than one individual value is outside the limit 85 to 115 per cent of the average value • or if any one individual value is outside the limits 75 to 125 per cent of the average value. • If one individual value is outside the limits 85 to 115 per cent but within the limits 75 to 125 per cent of the average value, repeat the determination using another 20 containers taken at random.
- 30. WWW.SLIDEFOREST.COM 3030 • 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 per cent and none is outside the limits 75 to 125 per cent of the average value. As per USP:- Stage1: Take 10 units randomly and perform the assay. It passes the test if the relative standard deviation (RSD) is less than 6% and no value is outside 85-115%. Fails the test if one or more values are outside 75-125%. Stage2: Take 20 more units and perform the assay procedure. Passes the test if RSD of all the 30 tablets is less than 7.8%, not more than one value is outside 85-115%, and no value is outside75-125%. Or else the batch fails the test.
- 31. WWW.SLIDEFOREST.COM 3131VI. Uniformity of weight: • Uniformity of weight: Remove labels and wash the container and dry. • Weigh the container along with its contents. • Empty the containers as completely as possible. • Rinse with water and with ethanol and dry at 100°C to a constant weight. • Allow to cool in desiccators and weigh. • The difference between the weights represents the weight of the contents. • Repeat the procedure with 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 deviates by more than 20%.
- 33. WWW.SLIDEFOREST.COM 3333VII. Extractable volume : Extractable volume (IP):- • Where the nominal volume does not exceed 5 ml, the containers comply with the requirements of Method 1 and where the nominal volume is greater than 5 ml, the containers comply with the requirements of Method 2. Suspensions should be shaken before the contents are withdrawn; oily injections may be warmed but should be cooled to 25º C before carrying out the test • Method 1- Use 6 containers, 5 for the test and 1 for rinsing the syringe used. • Inspect the 5 containers to be used in the test visually and ensure that each contains approximately the same volume of the preparation. • Using a syringe with a capacity not exceeding twice the volume to be measured and fitted with a suitable needle, take up a small quantity of the liquid under examination from the container reserved for rinsing the syringe, and discharge it from the syringe whilst the needle is pointing upwards so as to expel any air.
- 34. WWW.SLIDEFOREST.COM 3434 Withdraw as much as possible the contents of one of the containers reserved for the test and transfer, without emptying the needle, to a dry graduated cylinder of such capacity that the total combined volume to be measured occupies not less than 40 per cent of the nominal volume of the cylinder. Repeat the procedure until the contents of the 5 containers have been transferred and measure the volume. The average content of the 5 containers is not less than the nominal volume and not more than 115 per cent of the nominal volume. Method 2 — Transfer the contents of not less than 3 containers separately to dry graduated cylinders such that the volume to be measured occupies not less than 40 per cent of the nominal volume of the cylinder and measure the volume transferred.
- 35. WWW.SLIDEFOREST.COM 3535 • The contents of each container are not less than the nominal volume and not more than 110 per cent of the nominal volume • Multiple dose containers labelled to yield a specific number of doses shall contain a sufficient excess to permit the withdrawal of the designated number of doses. Extractable volume (BP) • Single dose container: Select 1 container if the nominal volume is 10 ml or more, 3 containers if the nominal volume is more than 3 ml and less than 10 ml, 5 containers if the nominal volume is 3 ml or less Take up individually the total contents of each container selected into a dry syringe of a capacity not exceeding 3 times the volume to be measured, and fitted with a 21-gauge needle not less than 2.5 cm in length
- 36. WWW.SLIDEFOREST.COM 3636 Take up individually the total contents of each container selected into a dry syringe of a capacity not exceeding 3 times the volume to be measured, and fitted with a 21-gauge needle not less than 2.5 cm in length. Expel any air bubbles from the syringe and needle, then discharge the contents of the syringe without emptying the needle into a standardized dry cylinder (graduated to contain rather than to deliver the designated volumes) of such size that the volume to be measured occupies at least 40 per cent of its graduated volume. Alternatively, the volume of the contents in millilitres may be calculated as the mass in grams divided by the density. For containers with a nominal volume of 2 ml or less, the contents of a sufficient number of containers may be pooled to obtain the volume required for the measurement provided that a separate, dry syringe assembly is used for each container. The contents of containers holding 10 mL or more may be determined by opening them and emptying the contents directly into the graduated cylinder or tared beaker.
- 37. WWW.SLIDEFOREST.COM 3737 The volume is not less than the nominal volume in case of containers examined individually, or, in case of containers with a nominal volume of 2 ml or less, is not less than the sum of the nominal volumes of the containers taken collectively. Multi-dose container: (BP) • For injections in multi-dose containers labelled to yield a specific number of doses of a stated volume, select one container and proceed as directed for single-dose containers using the same number of separate syringe assemblies as the number of doses specified. • The volume is such that each syringe delivers not less than the stated dose
- 39. WWW.SLIDEFOREST.COM 3939 1UNIVERSAL TESTS FOR PARENTERAL PREPARATIONS: a Description b Identification c Assay d Impurities a Description:- This test is often called appearance on a specification and is a qualitative description of the parenteral preparations. For example, the description of parenteral preparations .
- 40. WWW.SLIDEFOREST.COM 4040 B Identification:- The purpose of the identification or identity test is to verify the identity of the active pharmaceutical ingredient (API) in the parenteral preparations. This test should be able to discriminate between compounds of closely related structures that are likely to be present. C Assay :- This test determines the strength or content of the API in the parenteral preparations and is sometimes called a content test D Impurities This test determines the presence of any component that is not the API or an excipient of parenteral preparations. The most common type of impurities that are measured is related substances, which are processed impurities from the new drug substance synthesis, degradation products of the API, or both.
- 41. WWW.SLIDEFOREST.COM 4142 • United states pharmacopeia (2000) volume 2. • Indian pharmacopeia (1996) volume 2. • Lachman.L, Liberman HA, Kaniz JL, The Theory and practice of industrial pharmacy Bombay, Varghese publication House. • Md. Sahab Uddin et al., 2017 - Quality control parameters of parenteral pharmaceuticals based on pharmacopoeias. • Amrutha et al., 2017- In-Process and Finished Products Quality Control Tests for Sterile and Non Sterile Dosage Form. • Powerpoint presentations from slideshare. References
Editor's Notes
- #6: Injections:-interpreted as relating to injecting directly into the body, bypassing the skin and mucous membranes Infuse: In medicine, to introduce a solution into the body through a vein. An infusion is the therapeutic introduction of a fluid other than blood into a vein. The infused fluid might, for example, be a saline (salt) solution. Concentrates for injections or intravenous infusions are sterile, pyrogen-free solutions intended for injection or infusion after dilution. Enbrel is svp and tegamet is a lvp Implants are introduced inside the body cavity or beneth the skin
- #9: 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 are 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.
- #30: GENERAL PROCEDURE : Determine the content of the active ingredient of each of 10 containers taken at random. The preparation under examination complies with the test if the individual values thus obtained are all between 85 and 115 percent of the average value. The preparation under the examination fails to comply with the test if more than one individual value is outside the limits 85 to 115 percent of the average value or if any one individual value is outside the limits 75 to 125 percent of the average value. If one individual value is outside the limits 85 to 115 percent but within the limits 75 to 125 percent of the 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 percent and none is outside the limits 75 to 125 percent of the average value.
- #31: GENERAL PROCEDURE : Determine the content of the active ingredient of each of 10 containers taken at random. The preparation under examination complies with the test if the individual values thus obtained are all between 85 and 115 percent of the average value. The preparation under the examination fails to comply with the test if more than one individual value is outside the limits 85 to 115 percent of the average value or if any one individual value is outside the limits 75 to 125 percent of the average value. If one individual value is outside the limits 85 to 115 percent but within the limits 75 to 125 percent of the 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 percent and none is outside the limits 75 to 125 percent of the average value.