International Journal of Trend in Scientific Research and Development (IJTSRD)

Volume 5 Issue 4, May-June 2021 Available Online: www.ijtsrd.com e-ISSN: 2456 – 6470

Some Quality Control Analysis

Parameters for Parenteral Formulations
Shubham Kumar1, Dr. Rajiv K. Tonk2, Dr. Prabodh C. Sharma3
1M.Pharm, 2Professor, 3Associate
Professor,
1, 2, 3Department
of Pharmaceutical Chemistry (Pharmaceutical Analysis),
SPS Delhi Pharmaceutical Sciences and Research University, Saket New Delhi, India

ABSTRACT How to cite this paper: Shubham Kumar |

Parenteral Drugs (Large/small volume parenteral) defined as formulation Dr. Rajiv K. Tonk | Dr. Prabodh C. Sharma
intended for injection into skin, veins, artery muscles or other external "Some Quality Control Analysis
boundary tissue, rather than through the alimentary canal, so that formulation Parameters for Parenteral Formulations"
directly reach to systemic circulation cause the onset action. Intravenous (IV), Published in
subcutaneous (SC), and intramuscular (IM) route are the mostly commonly International Journal
used parenteral routes, but there are also less frequent used routes includes of Trend in Scientific
intradermal, intra-arterial. Generally, are classified into large volume Research and
parenteral and small volume depending on the package size if more than 100 Development (ijtsrd),
ml termed as large volume parenteral and rest small volume parenteral except ISSN: 2456-6470,
biological. In 21st, Century, pharmaceutical manufacturing sector geared up to Volume-5 | Issue-4, IJTSRD42432
deliver the medicine at faster rate with excellence performance. With help of June 2021, pp.944-
automation and sophisticated analytical techniques, thus industries are 948, URL:
capable to achieve significant to quality-controlled formulation. Currently, www.ijtsrd.com/papers/ijtsrd42432.pdf
world-wide efforts have been made to ensure the practice good manufacturing
practice and good laboratory practices for the uplifting of pharmaceuticals. In- Copyright © 2021 by author (s) and
process quality control tests are carried out with a motive to eliminate error International Journal of Trend in Scientific
from each step-in manufacturing and maintain the quality of the finished Research and Development Journal. This
products with the official standards as specified in the pharmacopoeias. is an Open Access article distributed
Present review it is clearly depicted that various pharmacopoeias guides under the terms of
different quality parameters but the major intention is to produce effective the Creative
good quality products and implement the good manufacturing practices. Commons Attribution
License (CC BY 4.0)
KEYWORDS: Parenteral pharmaceuticals, Pharmacopoeia, Specification, In- (http://creativecommons.org/licenses/by/4.0)
process quality control, Finished product quality control

INTRODUCTION:
Parenteral drugs (large/small volume parenteral) are Pharmaceutical are some of the most important players in
described as formulations designed for injection into the parenteral formulation. In the pharmaceutical industry,
skin, veins, artery muscles, or other exterior border tissue quality control is critical to assure the safety and efficacy of
rather than the alimentary canal, such that the formulation the finished product. Formulations must be packaged as safe,
reaches systemic circulation and causes onset effect. The therapeutically active formulations with consistent
most widely used parenteral routes are intravenous (IV), performance and the capacity to pronounce the
subcutaneous (SC), and intramuscular (IM), however there action.[2]The pharmaceutical manufacturing industry in the
are additional less regularly used routes such as intradermal twenty-first century has geared up to offer drugs at a faster
and intra-arterial. Generally, they are categorized as large rate while maintaining high quality. With the use of
volume parenteral or small volume parenteral based on the automation and advanced analytical techniques, enterprises
package size. If the package size is greater than 100 ml, it is are able to achieve substantial quality control in their
considered large volume parenteral; otherwise, it is formulations. Currently, efforts are being made all around
considered small volume parenteral except biological.[1] the globe to guarantee that proper manufacturing and
Automation has become more common in major laboratory techniques are used in the advancement of
pharmaceutical companies as technology has advanced. medicines.[3] Oral, parenteral, and topical pharmaceutical
Furthermore, parenteral medication manufacturers are formulations are the most common. Because oral
focusing their efforts right now on preserving the excellent formulations do not require a sterility test, they have
quality of their products. The single-use technological become more cost effective than parenteral formulations.
technique aided in the preservation of biologic parenteral Parenteral are taken directly into the circulatory system, and
medication quality. Additionally, manufacturers are their commencement of action is achieved with 100 percent
attempting to include quality by design (QbD) into their bioavailability, which necessitates the greatest level of
operations. The parenteral drugs market is expected to reach safety.[4] Any minor change in pH or particle matter might
a stunning value of USD 802 billion by the end of the forecast produce deadly effects on beneficial organisms. Microbial
period based on this assumption (2019-2029). Baxter contamination has a significant impact on the stability of
International Inc., Kelun Pharma B. Braun, Fresenius, Teva parenteral formulations. Pharmacopeias are specific and
Pharmaceutical Industries, Pfizer (Hospira), and Ostuka exact in terms of the norms and criteria that must be

@ IJTSRD | Unique Paper ID – IJTSRD42432 | Volume – 5 | Issue – 4 | May-June 2021 Page 944
 International Journal of Trend in Scientific Research and Development (IJTSRD) @ www.ijtsrd.com eISSN: 2456-6470
followed when generating monographs for such presented in single dose containers and that contain less
formulations, and they serve as a guide for the industries. than 10 microgram or less than 10 percent of active
According to the International Council for Harmonization, ingredient comply with the monographs for specific test.
pharmacopoeias provide useful instructions for overcoming Suspensions for injection containing more than one active
these flaws by following current good manufacturing ingredient carried out the test for each active ingredient that
practices and harmonizing standard operating procedures corresponds to the specified conditions.[13] In line with IP,
(ICH).[5] unless otherwise stated in the individual monograph,
powders for injection that contain 10 mg or less than 10 mg
QUALITY CONTROL PARAMETERS
or less than 10 percent of active ingredient or that have a
In-process quality control tests are performed with the goal
unit weight equal to or less than 50 mg comply with the test
of eliminating errors from each step of the production
for uniformity of content described under Injections. [14]
process and ensuring that the completed goods meet the
approved pharmacopoeia requirements. [6]In-process Another category contains powders for injection that contain
control tests are important for parenteral quality since they more than one active ingredient. Carry out the test for each
assist to embed excellence into the products. The final active ingredient that corresponds to the pharmacopoeia,
product quality controls tests assess the qualitative and with the exception of multivitamins and trace elements
quantitative aspects of pharmaceutical items. As a result, the powders for injection. Only when the content of active
goal of this research is to give succinct information on the ingredient(s) in a pooled sample of the formulation has been
numerous quality control parameters for parenteral demonstrated to be within acceptable limits of the claimed
formulations as defined by various pharmacopoeias.[7] content should the test for uniformity of content be
performed.[15] Determine the individual amounts of active
General and Universal Tests for Parenteral
substance(s) of 10 dosage units taken at random, according
Formulations:
per British and Indian pharmacopoeias, using an appropriate
Description: Specification and qualitative description of
analytical technique in this analysis. If each individual
the parenteral formulations are significant for physical
content is between 85 - 115 percent of the average content,
inspection. Forexample, the description of parenteral
the parenteral formulation passes the test. If more than one
formulations on a specification may read: transparent
individual content is beyond these limitations, or if one
formulation, category and labeling including ingredients
individual content is beyond the limits of 75 percent to 125
and excipients, imprinted with ‘‘Rx” in some countries as
percent of the average content, the formulation fails the test
per their rules and regulations.[8]
[30,31].Determine the individual contents of additional 20
Identification: Identification or identity test is to dosage units chosen at random if one individual content is
characterize the identity of the active pharmaceutical beyond the ranges of 85 percent to 115 percent but within
ingredient (API) in the formulations. This test is capable the ranges of 75 percent to 125 percent. If no more than one
to differentiate between ingredients of closely related of the individual contents of the 30 units is outside the range
structures that are likely to be present. [9] of 85 percent to 115 percent of the average content, and
none is outside the range of 75 percent to 125 percent of the
Assay: This test determines the strength (purity of
average content, the formulation passes the test. [16]
active ingredients/content of the API) in the parenteral
formulations. [10] Test for Uniformity of Mass: For this test as per BP, remove
any paper labels from a container and wash and dry the
Impurities: This test is aimed quantify the presence of
outside. Open the container and without delay weigh the
any kind of impurities that is not the API or an excipient
container and its contents. Empty the container as
of parenteral formulations. The most common type of
thoroughly as possible by gently tapping, clean it if required
impurities that are measured is related substances,
with purified water and then with ethanol (96%), and dry at
which are processed impurities from the new drug
100-105 °C for 1 hour, or dry at a lower temperature to
substance synthesis, degradation products of the API, or
constant mass if the nature of the container prevents heating
both. [11]
at this temperature. Allow to cool completely in a desiccator
Quality control parameters of parenteral before weighing. The difference between the weighing is the
pharmaceuticals: mass of the contents. Carry on with the procedure for the
Test for Uniformity of Content: As per BP, unless remaining 19 containers.[17] Calculate the average weight. If
otherwise prescribed or justified and authorized, single-dose no more than two of the individual weights deviates from the
suspensions for injection with a content of API less than 2 average weight by more than 10%, and none deviates by
mg or less than 2 % of the total mass, or with a unit mass more than 20%, the results are consistent with IP. According
equal to or less than 40 mg comply with uniformity of to BP, in order to pass this test, no more than two individual
content of single-dose formulations. If the formulation masses of parenteral formulations must differ from the
contains more than one active substance, the requirement average mass by more than the percentage deviation stated
applies only to those substances that correspond to the in Table 1, and none must differ by more than twice that
monographs. [12] As per IP, unless otherwise stated in the percentage.
individual monograph, suspensions for injection that are
Table: Indicating the limits for uniformity of mass as per the British Pharmacopeia
Dosage Form Average Mass Percentage Deviation

Powder for parenteral More than 40 mg 10

administration (single dose)

@ IJTSRD | Unique Paper ID – IJTSRD42432 | Volume – 5 | Issue – 4 | May-June 2021 Page 945
 International Journal of Trend in Scientific Research and Development (IJTSRD) @ www.ijtsrd.com eISSN: 2456-6470
Test for Extractable Volume of Parenteral Formulations: with the membrane filter. Apply vacuum to the whole
For Extractable Volume analysis, suspensions and emulsions volume of a solution pool or a single unit as it is transferred
are shaken before application of formulation and before the to the filter funnel. If necessary, add a part of the solution at
determination of the density. Oily and viscous formulations a time until the entire volume is filtered. Begin cleaning the
may subject to temperature dependent change according to inner walls of the filter holder with a jet of particle-free
the instructions on the label, if necessary, and thoroughly filtered water after the last addition of solution has been
shaken immediately before removing the contents. The made. Maintain the vacuum until liquid is no longer visible
contents are then brought to (20-25) °C before measuring on the membrane filter's surface. Place the filter in a Petri
the volume. [18] dish and keep the cover slightly ajar to enable the filter to air
dry. Place the Petri dish on the microscope stage after the
Single-Dose Containers: According to the British
filter has dried, scan the entire membrane filter under the
Pharmacopeia, select 1 container if the nominal volume is 10
reflected light from the illuminating device, and count the
mL or more, 3 containers if the notional volume is greater
number of particles that are equal to or greater than 10 µm
than 3 mL but less than 10 mL, or 5 containers if the notional
and the number of particles that are equal to or greater than
volume is 3 mL or less. Fill a dry syringe with the complete
25 µm. It is also possible to do a partial filter count and
contents of each container selected, not to exceed 3 times the
calculate the overall filter count. Calculate the average
volume to be measured, and equipped with a 21-gauge
number of particles in the formulation under consideration.
needle not less than 2.5 cm in length. Remove any air
bubbles from the syringe and needle, then empty the When performing the microscopic particle count test, do not
contents of the syringe without emptying the needle into a try to size or enumerate amorphous, semi-liquid, or
standardised dry cylinder (graded to contain rather than otherwise morphologically unclear materials on the
deliver the indicated quantities) of sufficient size to contain membrane filter that have the appearance of a stain or
at least 40% of the graduated volume. Alternatively, the discoloration. Surface relief is little or absent, and the
volume of the contents in millilitres may be estimated by materials have a gelatinous or film-like appearance. In such
dividing the mass in grams by the density in millilitres. instances, a sample of the solution can be tested using the
[19]For containers with a nominal volume of 2mL or less, the light obscuration particle count test to help in the
contents of a sufficient number of containers can be pooled interpretation of the enumeration. [24]
to achieve the volume necessary for the measurement, as
Sterility Test
long as each container has its own dry syringe assembly.
One of the most essential quality control parameters is
Open containers with a capacity of 10mL or more and empty
sterility, which aims to completely eliminate any
the contents immediately into the graduated cylinder or
microorganism from the formulation in order to achieve
tared beaker to ascertain the contents. In the event of
safety. According to the BP and USP, the sterility analysis can
containers inspected individually, the volume is not less than
be performed via membrane filtration or direct inoculation
the nominal volume; in the case of containers with a nominal
of the culture media with the product to be tested.[21]For
capacity of 2 mL or less, the volume is not less than the total
the comparison study, appropriate negative controls are
of the nominal volumes of the containers considered
chosen. Fluid thioglycollate is mostly used for the culture of
collectively.[20]
anaerobic bacteria, although it may also be used to identify
Multi-Dose Containers: As per BP and JP, for injections in aerobic microorganisms. For the culture of both fungal and
multi dose containers labelled to deliver a certain number of aerobic bacteria, soya-bean casein digest medium is
doses of a specified volume. Select one container and follow recommended. The most significant and absolutely
the single-dose container instructions, using the same necessary property of parenteral products is sterility. The
number of separate syringe assemblies as the number of absence of all living microorganisms is referred to as
doses given. Each syringe provides not less than the sterility. It is an absolute term.
specified dose due to the large capacity. [21]
Sterility tests are performed using the following methods:
Microscopic Particle Count Test: Single units are tested for A. Direct transfer method /technique.
large-volume parenterals. The contents of 10 or more units B. membrane filtration method /technique.
are combined in a cleaned container for small-volume
A) Direct Transfer method: -It's a traditional sterility test
parenterals less than 25 mL in volume; where justified and
that involves directly inoculating the required volume of a
authorised, the test solution may be prepared by mixing the
sample into two test tubes using FTM, SCDM culture
contents of a suitable number of vials and diluting to 25 mL
medium. When the requirement for repetition in opening
with particle-free purified water or with an appropriate
container, sampling, transferring, and mixing rises, this
solvent without contamination of particles when particle
approach is easy in principle but challenging in practice,
free purified water is not suitable. Individual testing is
resulting in operator fatigue and detoriation in
possible for small-volume parenterals with a volume of 25
technique.[21]
mL or more. [22]Powders for parenteral administration are
constituted with particle-free purified water or with an B) Membrane Filtration method: -It was made official in
appropriate solvent without contamination of particles when 1970 by the U.S.P. It is a more extensively utilized and
particle-free purified water is not suitable. popular approach than direct transfer method. Successful
employment needs a higher level of skill and knowledge than
To offer a statistically reliable assessment, the number of
the approach of direct transfer method. This method
test specimens must be sufficient. Based on an acceptable
involves filtration of the sample via hydrophobic membrane
sample plan, fewer than 10 units of large volume parenterals
filters with a porosity of 0.22 micron and a diameter of
or small-volume parenterals with a volume of 25 mL or more
47mm. After filtration, the membrane is divided into two
may be evaluated. [23] Using several millilitres of particle-
halves and one half is inserted in two test tubes contain FTM,
free filtered water, wet the interior of the filter holder fitted
SCDM media. If there is no apparent indication of microbial

@ IJTSRD | Unique Paper ID – IJTSRD42432 | Volume – 5 | Issue – 4 | May-June 2021 Page 946
 International Journal of Trend in Scientific Research and Development (IJTSRD) @ www.ijtsrd.com eISSN: 2456-6470
growth in the culture medium in the test tube, the sample guides different quality parameters but the major intention
representing the lot is free of intrinsic contamination. If is to produce effective good quality products and implement
visible microbial growth is detected or the test is deemed the good manufacturing practices.
invalid due to inadequate environmental conditions, the
ACKNOWLEDGMENT
sterility test must be repeated. This interpretation must be
I am very thankful to Dr. Rajiv Kumar Tonk and Dr. Prabodh
made by personnel who are familiar with aseptic processing,
Chander Sharma, SPS, Department of pharmaceutics
industrial sterilisation methods, and environmental control
Chemistry, Delhi Pharmaceutical Science and Research
procedures used in the test facility.[22]
University, Saket, New Delhi for providing the guidance and
Pyrogen Test support for publishing this article.
Pyrogens are metabolic products produced by
REFERENCES
microorganisms, with Gm-ve bacteria producing the most
[1] Remington, the Science and Practice of Pharmacy,
powerful pyrogens. These lipo polysaccharides are
Parenteral Preparation, 20th edition. Philadelphia:
chemically and thermally stable, and they can pass through
ISE publication 1 (2000).
bacteria retentive filters. When these pyrogens are injected
into the body, they cause a rapid onset of fever, body aches, [2] Ford JL. “Parenteral products”. In: Aulton ME, (ed.)
and vasoconstriction within 1 hour. The following tests are Pharmaceutics: The Science of Dosage Form Design.
used to determine the presence of pyrogens in sterile New York; Longman (1988).
parenteral products. These are: -
[3] Ansel HC., et al. “Pharmaceutical dosage forms and
C. The Rabbit Test drug delivery system, 7th edition”. Lippincott
D. The LAL Test Williams and Wilkins: Philadelphia (1999)
(C) Rabbit test: - This test includes injecting a sample [4] Colombo G., et al. “Stabilized aqueous suspensions for
solution into rabbits used as test animals through the ear parenteral use”. US6495534 (2002).
vein. The test fluid must be warmed to 37 degrees before
[5] Beecher P. “Encyclopedia of emulsion technology,
injection using a temperature sensor probe (Clinical
basic theory”. Marcel Dekker: New York 1 (1983)
Thermometer, Thermosistor, or equivalent probe) inserted
into a rectum cavity of a rabbit at a depth of 7.5 cm. [6] Collins Gold LC., et al. “Parenteral emulsions for drug
Then temperature of the rectal cavity is measured at 1,2,3 delivery”. Advanced Drug Delivery Reviews 5 (1990):
hours after the injection. This test is conducted in a separate 189-208
location that has been specifically constructed for this
[7] Singh M and Ravin L. “Parenteral emulsions as drug
purpose, in an atmosphere that is comparable to that of an
carrier systems”. Journal of Parenteral Science and
animal house, and is devoid of stimuli that are likely to
Technology 40 (1986): 34-44.
stimulate them. This test is done on 3 rabbits at first, but if
the desired results are not obtained, the test is repeated on 5 [8] Brazeau GA., et al. “Dosage Forms: Parenterals”. In:
more rabbits using the same sample solution as the first 3 Swarbrick James (Ed.). Encyclopedia of
rabbits [19]. The control temperatures of rabbits are Pharmaceutical Technology. 3rd edition. Informa
established 1 hour before injecting sample solutions. Only Healthcare USA, Inc: New York 1 (2007): 1001-1011.
use rabbits with a control temperature that does not differ
by more than 1 degree Celsius. [9] The United States Pharmacopeia, the National
Formulary. US Pharmacopeial Convention, Rockville,
(D) LAL test: -It is a newly discovered in vitro pyrogen test MD (1995): 1775-1777
technique that makes use of the gelling feature of lysates of
limulus polyphemus amebocytes, which can only be found in [10] Groves MJ. “Parenteral drug delivery system”. In:
a few areas along the east coast of North America and Mathiowitz Edith (Ed.). Encyclopedia of Controlled
southeast Asia. It is derived from horse shoe crab, [18]The Release. John Wiley and Sons, Inc: New York 1-2
basic process involves mixing 0.1 ml of test sample with LAL (1952): 743-777.
Reagent after incubating the mixture for 1 hour at 37 [11] Chien YW. “Parenteral drug delivery and delivery
degrees Celsius before looking for Gel clot. The presence of systems”. In: Novel drug delivery system, 2nd ed. 50.
endotoxin is indicated by a positive LAL Test. Its principal Marcel Dekker: New York (1992): 382-385.
uses are in pharmaceutics, biologicals, gadgets, disease
states, food, and heat cycle validation. This method has [12] Avis KE., et al. “Pharmaceutical dosage forms:
several advantages of Rabbit test they are Greater sensitivity Parenteral medications”. Marcel Dekker: New York
and reliability specificity, less variation, wider application, 1992; 1
less expensive and simplicity. [24] [13] JC Boylan and AL Fites. Parenteral Products, in
CONCLUSION Modern Pharmaceutics, G.L. Banker and C.T. Rhodes,
Quality is an output of continuous intelligent effort. For a Eds. (Marcel Dekker Inc., New York, NY), (1979): 445.
finished product of a maximum quality, quality control tests [14] PP DeLuca and JC Boylan. Formulation of Small-
for pharmaceuticals are utmost requirement for delivering Volume Parenterals in Pharmaceutical Dosage Forms:
the healthier results in patients. The second significant role Parenteral Medications, K.E. Avis et al., Eds. (Marcel
of quality control and assurance is to reduce the any kind Dekker Inc., New York, NY), (1992): 215
contamination that may cause toxicity/adverse event to the
patient. The quality of parenteral preparations is significant [15] RJ Harwood., et al. “The Processing of Small-Volume
and sensitive point, since formulation reached to the Parenterals and Related Sterile Products” in
systemic circulation and produced onset of action. Present Pharmaceutical Dosage Forms: Parenteral
review it is clearly depicted that various pharmacopoeias Medications 2 (1993): 61.

@ IJTSRD | Unique Paper ID – IJTSRD42432 | Volume – 5 | Issue – 4 | May-June 2021 Page 947
 International Journal of Trend in Scientific Research and Development (IJTSRD) @ www.ijtsrd.com eISSN: 2456-6470
[16] Gadzag M., et al. “Stable parenteral compositions of [21] The United States Pharmacopeia, the National
vinblastine or vincristine”. US5397784 (1995). Formulary. US Pharmacopoeial Convention, Rockville,
MD, 1995; 1775-7. Encyclopedia of Controlled
[17] Brahmankar DM and Jaiswal SB. “Absorption of
Release. John Wiley and Sons, Inc: New York 1-2
drugs”. In: Biopharmaceutics and pharmacokinetics a
(1952): 743-77.
treatise. Vallabh Prakashan: Delhi (2006).
[22] Singh M and Ravin L. “Parenteral emulsions as drug
[18] Patel RM. “Parenteral suspension: An overview”.
carrier systems”. Journal of Parenteral Science and
International Journal of Current Pharmaceutical
technology 40 (1986): 34-44.
Research 2.3 (2010): 4-13.
[23] Date AA., et al. “Parenteral microemulsions: An
[19] Chang HC., et al. “Parenteral sustained release dosage
overview”. International Journal of Pharmaceutics
forms of butorphanol for dogs”. International Journal
355 (2008): 19-30
of Current Pharmaceutical Research 176 (1999): 147-
56. [24] JK Haleblian. “Characterization of Habits and
Crystalline Modifications of Solids and Their
[20] KE Avis., et al. Forms: Parenteral Medications. Eds.
Pharmaceutical Applications”. Journal of
(Marcel Dekker Inc., New York, NY) (1993): 61.
Pharmaceutical Sciences 64.8 (1975): 1269-1288.

@ IJTSRD | Unique Paper ID – IJTSRD42432 | Volume – 5 | Issue – 4 | May-June 2021 Page 948