Qc for sterile pharmaceutical product

QC Of Sterile Pharmaceutical Product


SUBMITTED BYANIKET J.GHOLAP


QUALITY CONTROL TESTS


QUALITY CONTROL

Quality control is define as a set of activities for ensuring quality in product. The activities focus on identifying defects in the actual product produce.


TEST FOR STERILITY

Sterility is defines as freedom from the presence of viable microorganism

Method A: Membrane Filtration

Method B: Direct Inoculation


Fluid Thioglycollate Medium

Soyabean-casein Digest Medium


METHOD A:MEMBRANE FILTRATION

Membrane filter (0.45 μ pore size)

Filter test solution

Remove filter

Cut filter into two halves

First halve second halve (for bacteria) (for fungi) Transfer to 100mL culture media Transfer to 100mL culture media (FTM) (SCDM) Incubate 30-35°C for NLT Incubate 20-25°C for NLT 7days 7days Observe the growth Observe the growth


Aseptically opening each sample container

Using a sterile syringe or needle withdraw the required volume of sample

Aseptically transfer into both culture media

FTM SCDM Incubate 30-35°C for NLT 14 days Incubate 20-25°C for NLT 14 days

METHOD B:DIRECT INOCULATION METHOD


Observation & interpretation of result

No evidences of growth Evidences of growth

Pass sterility testRetesting performed with same no. of sample & volume of media is in original test


Pass sterility test Isolate & identify organism

Second retest with twice no. of sample


Pass sterility test Fail sterility test


TEST FOR PYROGEN

Pyrogen is metabolic by product of living micro-organism/ dead micro-organism themselves.

METOHOD A: RABBIT TEST

OR SHAM TEST

METHOD B: LAL TEST OR BACTERIAL ENDOTOXIN

TEST


The test involves measurement of the rise in body temperature of rabbits in

presence of pyrogen introduced by the IV injection of a sterile solution into

ear vein of rabbit.

Use healthy, adult rabbits of either sex, preferably of the same variety.

•Having temp. variation high than 39.8°C.

•Showing temp. variation >0.2°C between 2 successive reading in the

determination of initial temp.

•Animal show temp. increase over 0.6°C should be remove from pyrogen

testing

METOHOD A: RABBIT TEST OR SHAM TEST

Principle

Test animals

Do not use any rabbit


Carry out the test using a group of 3 rabbits.

•Preparation of the sample Dissolve the substance in or dilute with pyrogen free saline solution. Warm the liquid to approximately 38.5° before injection.

•Volume of injection NLT 0.5 mL/kg & NMT 10 mL/kg of body weight.

•Clinical thermometer inserted into rectum of rabbit to record body temp.

•Two normal reading or rectal temp. taken prior to test injection at an interval of half an hr. & it mean is calculated initial temp.

•Test solution injected into ear vein.

•Record temp. of each rabbit in time interval 30 min for 3 hrs.

•Different between initial & maximum temp. record & take as response.

PROCESS


INTERPRETATION OF RESULT

No. of rabbits Individual temp. rise

( C)⁰

Temp. rise in groups ( C)⁰

Test

3 Rabbits 0.6 1.4 Passes

If above not passes

3+5=8 rabbits

0.6 3.7 Passes


Advantages of Rabbit Test

The human and rabbits are equally responsive to threshold levels of the pyrogens.

Disadvantages of Rabbit test

Based on animal model

Time consuming

Only detect presence of pyrogen not quantify them


Measures the concentration of bacterial endotoxin

Test is using lysate derived from hemolymph cells or amebocytes of

e.g Limulus polyphemus

Endotoxin limit calculated by K/M

K maximum no. of endotoxin which receive the

patient without suffering toxic reaction

M maximum dose administered to a patient/kg/hr

horse shoe crab.


Mechanism of LAL Test

The test is based on the primitive blood-clotting mechanism of the horseshoe crab.


PROCEDURE


Different Techniques

AGel-clot

Technique

B Turbidimetric

Technique

C Chromogenic

Technique


A. GEL CLOT TECHNIQUE

A solid gel is formed in the presence of endotoxins. Technique requires positive and negative controls.

Positive controls

A known concentration of endotoxin added to the lysate solution

Negative controls Water, free from endotoxins, added to the lysate solution

This is based on the measurement of color change which is caused by the release of the chromogenic chemical.

E.g. The quantity of the p-nitroanilide (chromogenic chemical) produced is directly proportional to the endotoxin concentration

B. CHROMOGENIC TECHNIQUE


The development of turbidity after cleavage of an endogenous substrate.

The test is based on the measurement of opacity change due to the formation of insoluble coagulin.

Opacity is directly proportional to the endotoxin concentration.

This technique is used for water systems and simple pharmaceutical

products.

C. TURBIDIMETRIC TECHNIQUE


Advantages of LAL test

Alternative to animal model

Greater sensitivity

Less variability

Less time consuming

Detect the pyrogen and also measure the quantity of pyrogen


PARTICULATE MATTER TEST

Particulate matter refers to the extraneous, mobile, undissolved particles, other than gas bubbles, unintentionally present in the solutions.

METHODS

ALight Obstraction

Particle Count Test

BMicroscopic

Particle Count Test


Particular count is based upon either light scattering, light obstruction/ direct imaging.

Light blockage which allows an automatic determination of the size of particles and the number of particles according to size.

A. LIGHT OBSTRACTION PARTICLE COUNT TEST


TYPE PARTICLE SIZE

LVP Max. 50 Particles/mL ≥ 10 µm

Max 5 Particles/mL ≥ 25 µm

SVP NMT 10,000 Particles/Container ≥ 10 µm

NMT 1,000 Particles/Container ≥ 25 µm

USP LIMIT


LEAKAGE TEST

Test the package integrity.

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

Leakage tests are 4 type

Visual Inspection Bubble Test Dye Tests Vacuum Ionization Test


UNIFORMITY OF WEIGHT

Remove the labels & wash the container & dry

Weigh the container along with content

Empty container completely

Rinse with water & ethanol, dry at 100°C to a constant weight

Cool & weigh

Net weight calculated


All of the tests which are performed are essential and have its own importance in sterile 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.

CONCLUSION


IP 1996 Appendix 2.1 pg. no. A-24 to 26

Appendix 9.5 pg. no. A-117 to 123

Appendix 10 pg.no. A-125 to 126

Remington. The science and Practice of Pharmacy. 21st ed. Page no.

1367 to 1374.

Pharmaceutical Quality assurance by M.A. Potdar second edition

Nirali prakashan pg. no. 13.22, 13.23

www.pharmainfo.net/lal-test

AJPTR article Nithin Chilukuri-4055(1).pdf

Parenteral-preparations-draft-QAS12-479-18072018.pdf

www.pharmaguideline.com

REFRENCES

http://www.pharmainfo.net/lal-test

http://www.pharmaguideline.com/

Qc for sterile pharmaceutical product

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