IN-PROCESS QUALITY CONTROL TESTS

FOR INJECTABLES

Presented byG.Krishnam RajuM.PharmacyPharmaceutical Analysis & Quality Assurance 1st year 1st semesterHT.NO:-13TK6S0401SVS Group Of InstitutionsSVS school of pharmacy

1

• Definition• Introduction• Various IPQC Tests• Conclusion• Reference

CONTENT:-

2

Definition:-Injections are sterile, pyrogen-free solutions or dispersions (emulsions or suspensions) of one or more active ingredients in a suitable vehicle.

INJECTABLE

3

IPQC is concerned with providing accurate , specific, & definite descriptions of the procedures to be employed, from, the receipt of raw materials to the release of the finished dosage forms.

WHAT DO YOU MEAN BY IPQC?

4

In general, the majority of a manufacturer's time and resources are spent tightening tolerances, ensuring compliance, and/or increasing post-process destructive and non-destructive testing.

While such  efforts are important to a quality-assured and quality-controlled process, there are diminishing returns for higher standards through increased destructive and non-destructive testing.

In most manufacturing environments, the process itself is treated as a black box, where the inputs are tightly controlled and the resulting product is thoroughly tested but the in-process behavior is largely overlooked.

INTRODUCTION

5

1. Environmental control 2.PH 3.Viscosity 4.Osmolality (Occasionally) 5.Condectivity measurements 6.Temperature for heat sterilization 7.Volume filled 8.Lekage test 9.Clarity test 10.Pyrogen test 11.Sterility test

Various IPQC tests for injectable

6

Traffic control:- A carefully designed arrangement to control traffic. Personnel should be permitted into aseptic areas

only after following rigidly prescribed procedures.

Surface disinfection personnel:- Must be inherently neat ,orderly ,reliable and alert. Should be in good health.

Air control:-(HEPA filters) It is composed of glass fibers and filters. It is 99.97% efficient removes particles of 0.3um

size and larger. Velocity is 100+/- 20 ft/min.

1.ENVIRONMENTAL CONTROL

7

2.PH MEASUREMENTTwo different types of methods used in the measurement of PH.

1.Dip a piece of PH paper into the sample.2.PH meter.

8

3.VISCOSITYThese devices also are known as glass capillary viscometers or Ostwald viscometers, named after Wilhelm Ostwald. which consists of a U-shaped glass tube held vertically in a controlled temperature bath. In one arm of the U is a vertical section of precise narrow bore (the capillary). Above this is a bulb, with it is another bulb lower down on the other arm. In use, liquid is drawn into the upper bulb by suction, then allowed to flow down through the capillary into the lower bulb. Two marks (one above and one below the upper bulb) indicate a known volume.

9

The time taken for the level of the liquid to pass between these marks is proportional to the kinematic viscosity.

Most commercial units are provided with a conversion factor, or can be calibrated by a fluid of known properties.

The time required for the test liquid to flow through a capillary of a known diameter of a certain factor between two marked points is measured.

By multiplying the time taken by the factor of the viscometer, the kinematic viscosity is obtained.

10

4.OSMOLALITY (OCCASIONALLY)

Osmolality is a count of the number of particles in a fluid sample.The osmolality of a solution can be measured by osmometer.Freezing point depression osmometer is widely used.

11

Conductivity is measured by conductometerIt is measured the conductivity of vehicle used in sterile preparation.The conductivity of the pure water is 0.55 micro-siemens/cm.

5.Condectivity measurements

12

6.TEMPERATURE FOR HEAT STERILIZATION

It is important to maintain the constant temperature during heat sterilization of product.The temperature changes may causes some undesirable changes like change in potency, change in isotonicity etc. The temperature can be determined by normal thermometer, digital thermometer.

13

Volume in containerAn injection container is filled with a volume in slight

excess of the labeled size

Determination of filled volume: 10 mL or more 1 container3-10 mL 3 containersLess than 3 mL 5 containers

7.VOLUME FILLED

14

Lekage test is employed to test the package integrity.

Package inegrity reflects its ability to keep the product in and to keep potential contamination out.

Which is the flow of matter through the barrier itself.

Lekage tests are 4 types  a) visual inspection b) bubble test  c) dye tests  d) vacuum ionization test

8.LEKAGE TEST

15

A) VISUAL INSPECTION Visual inspection is the easiest leak test method to perform.The method is used for the evalution of large volume parentrals.To increase the sensitivity of the method the visual inspection of the sample container may be coupled with the application of vacuum to make leckage more readily obeservable.This method is simple and inexpensive.Dis-advantage: less sensitive is increased by pressure/vacuum.

16

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.

B)BUBBLE TEST 

• 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.

17

The test container is immersed in a dye bath. Vacuum and pressure is applied for sometime. 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.

C)DYE TESTS 

18

Vacuum ionization test is useful for testing leakage in the vials or bottled 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 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. 

D)VACUUM IONIZATION TEST 

19

Clarity test is carried out to check the particulate matter in the sample.

It is practically impossible that every unit of lost is perfectly free from visible particulate matter , that is ,from particles that are 30 to 40 micrometer and large in size.

USP limits for large volume infusions

9.CLARITY TEST

Particle size Particle limit

10 mm (or) larger/ml 50

25 mm (or) larger/ml 5

20

1.VISUAL INFECTION BY NAKED EYE:- Each injectable is inspected visually against

White and Black backgrounds. The white background aids in detection of

dark coloured particles. The light or reflective particles will appear

against the black background.

21

2. INSTRUMENTAL METHODS:- This is also called as the particle count

method particle counting may be based on any one of the following principles; change in

Electrical resistance Light absorption Light scattering

22

10.PYROGEN TEST•Pyrogens are products of metabolism in microorganisms Gm-ve bacteria produces most potent pyrogens. •These are lipopolysacchrides chemically and heat stable and are capable of passing through bacteria retentive filter. •When these pyrogens are introduced into a body they produce a mark response of fever with body ache and vasoconstriction within an onset of 1 hour. • Basically there are test performed to detect the presence of pyrogens in sterile parenteral products they are 1) Rabbit Test 2) LAL Test. 23

•This test basically involves the injection Sample solution which is to be tested into a Rabbits Which are use as test animals through ear vein. •The Temperature sensing probe (Clinical Thermometer, Thermosestor or similar probe) into a rectum cavity of Rabbit at the depth of 7.5 cm, the test solution must be warmed at 37 degrees prior to injection.• Then Rectal temperature is recorded at 1,2,3 hr subsequent to injection.• This test is performed in separate area designed solely for this purpose under environmental conditions similar to animal house should be free from disturbances that likely to excite them.

RABBIT TEST

24

No. of Rabbits Individual Temp/Rise (degree Celsius )

Temp rise in group(degree Celsius )

Test

3 rabbits 0.6 1.4 pass

If above not pass3+5=8 rabbits

0.6 3.7 pass

THE RESULTS OF PYROGEN TEST

If above test not passes perform the test again

If above test not passes, the sample is said to be PYROGENIC

• Initially this test is performed on 3 Rabbits but if required results are not obtained this test is repeated on 5 additional Rabbits with same sample solution administer to initial 3 rabbits.• Prior to 1hr of injecting sample solutions the control temperatures of rabbits are determined. •Use only those rabbits whose control temperature is no vary by more than 1 degree Celsius.

25

LAL TEST It is an recently developed in-vitro test method for pyrogen

utilizing gelling property of lysates of amebocytes of limulus polyphemus which is found only at specific locations along the east coast of North America and along southeast Asia.

It is derived from horse shoe crab; the basic procedure is the combination of 0.1 ml of test sample with LAL Reagent after incubation for 1 hr at 37 degree Celsius the mixture is analyzed for the presence of Gel clot.

The LAL Test is positive indicating that the presence of endotoxin. 

Its applications are mainly to Pharmaceutics, Biological, devices, disease states, food, and validation of heat cycles.

This method has several advantages of Rabbit test they are Greater sensitivity andreliability specificity, less variation, wider application, less expensive and simplicity.

26

Sterility is the most important and absolutely Essential characteristics of Parenteral products.

Sterility means complete absence of all viable Micro-organism. It is an absolute term.

The methods which are used to perform sterility test are

a)  Direct  transfer  method. b)  membrane  filtration method.

11)STERILITY  TESTS

27

A)  Direct Transfer method:- it is an traditional sterility test method

which involves a direct inoculation of required volume of a sample in two tests tube containing a culture medium that is FTM, SCDM.

This method is simple in theory but difficult in practice when the demand for repetition in opening  container,  sampling Transferring, and mixing increases causes potential error in operator technique.

28

B)    Membrane Filtration method:- It is official in U.S.P. 1970. This method basically involves filtration of Sample

through membrane filters of porosity 0.22 micron and Diameter 47mm.

The filtration is assisted under Vacuum, after filtration completion the membrane is cut into 2 halves and one halve is placed in two test tubes containing FTM, SCDM medium.

*Interpretation:–If no visible evidence of microbial growth in culture medium in test tube then it is interpreted that the sample representing lot is without intrinsic contamination.

29

CONCLUSION

•Quality control should be a fundamental segment of parenteral products manufacturing. • All of the 4 basic  tests  which are performed are essential and have  its  own  importance  in  parenteral production.• All of these tests ensure that product meet its quality which has been judged to satisfactory also.• Each test is unique and provides detailed assessment of quality control for parenteral products.

30

1)Mehta R.M, Sterilization, pharmaceutics- I.Delhi Vallabh prakashan, 2002. P. 227-228.

2)  Lachman.L,  Liberman  HA,  Kaniz  JL,  Editions,  The  Theory  and  practice  of industrial pharmacy Bombay, Varghese publication House;1986.P.673-675.

3) Akers.MJ, Larrimor DS, Guazzao morton D, Parenteral Quality control, New York, Marcel Deckker; 2006. P. 1-183.

REFERENCE

http://www.nscbip.org/?p=708

31

32