Strategies
for microbiological contamination control in Api (Active Pharmaceutical Ingredients)
and finished product Manufacturing: Compliance with USFDA guidelines
Som
Prakash Vats1*, Dr. Eshendra Kumar2
Research
Scholar, Sunrise University, Alwar, Rajasthan
Assistant
Professor, School of Basic and Applied Sciences, Sunrise University,
Alwar, Rajasthan
Abstract
In
many cases, the quality of the finished product depends on the microbiological
properties of the medicinal components. Manufacturers are expected by the USFDA
to quantify and describe the bioburden of their goods. This page describes the USFDA's
and compendia's concerns over microbiological contamination. Also covered in
this article are ways to identify microbial contamination, how to get rid of
it, and where it comes from.
Keywords:
Microbial
contamination; source of contamination; control of microbial contamination; USFDA
concern; USP (United States Pharmacopeia) concern; microbial limit test;
INTRODUCTION
As
a supplement to the USP for pharmaceutical microbiology testing which includes
testing for antimicrobial effectiveness, microbial examination of non-sterile
products, sterility, bacterial endotoxin, particulate matter, device bioburden,
and environmental monitoring the Pharmaceutical Microbiology Manual (PMM)
developed from the Sterility Analytical Manual. This manual's stated purpose is
to provide ORS/CDER testing labs with a standardized framework for assessing
the safety and effectiveness of medical goods in accordance with applicable
scientific standards; it will do this by outlining the necessary information,
procedures, and equipment. A new part of the PMM addresses inspectional
guidelines for microbiologists that perform team inspections, and the manual
has grown to include several quick screening methods.
LITREATURE
REVIEW
Roesti
(2019) With reliable microbiological monitoring and trends of
data, the efficacy on the controls may be continually assessed. During the
manufacture of non-sterile drug products, this chapter explains how to
implement high-level multiple microbiological controls. The potential for
product contamination and the various measures to lessen that risk may be
determined by implementing a thorough microbial control program. A facility's
environmental control systems undergo qualification as part of the facility's
life cycle before operations may begin. Particularly when derived from natural
sources, product components pose a high risk of microbial contamination.
Process water, whether used as a solvent in non-sterile product formulations or
to clean surfaces that come into touch with products, has the greatest threat
of microbial contamination of any utility. Cleaning the equipment prevents
non-dedicated equipment from contaminating the product and brings the quantity
of bacteria down to an acceptable level.
Gupta,
Rajesh. (2014). Drug and biologic stability, potency,
purity, and safety may be assured with the use of microbiological approaches.
In order to ensure high-quality pharmaceuticals, it is crucial to use
appropriate microbiological procedures throughout manufacturing. To ensure that
medications are of acceptable microbiological quality, it is necessary to use a
number of overlapping procedures, including validations, monitoring, testing,
and verification. In order to build a strong testing and environmental
monitoring program and guarantee that the techniques are "Suitable for
Intended Purpose," it is crucial to have a good grasp of the science,
regulations, and difficulties associated with the design, qualification, and
validation of microbiological methods. Given the complexity of emerging
alternative microbiological technologies, it is vital to maintain regular
discussions with regulatory bodies in order to adopt them. Improved
microbiological quality assurance of pharmaceuticals and biological products
may result from the simplification of technique, reduction of complexity, and
variety in these procedures made possible by the use of potent contemporary
technology and quick microbiological approaches.
Walsh,
Andrew. (2011). As it relates to Cleaning Validation,
microbiology will be covered in this chapter. Removing chemical residues,
whether from active substances or cleaning agents, is the main emphasis of
Cleaning Validation in practice; microbiological concerns are considered
incidental. The goal of cleaning operations should never be to lower microbial
residues to an acceptable level; that is, it is not their intended aim.
Ratajczak
(2014) There are two categories of pharmaceuticals recognized
by microbiologists: sterile and non-sterile. Pharmacopoeial monographs provide
the relevant microbiological purity requirements that non-sterile medications
must meet. In order to guarantee that the medication is both safe and effective
for therapeutic purposes, pharmacopoeial studies are meticulously planned. The
study included the outcomes of pre-marketing microbiological purity testing.
The research included 1285 samples of non-sterile medications produced by
several Polish pharmaceutical companies. Medications were tested for
microbiological purity using standards laid forth in the European Pharmacopoeia
(EP). The number of samples that did not comply was 1.87 percent, according to
the findings of the tests. Medications comprising raw ingredients of natural
origin accounted for 5.7% of the medication groupings that failed to meet EPs'
standards. Failure to fulfill EP standards was indicated by medicine samples
that included microorganisms whose presence is forbidden and exceeded the
maximum permissible microbiological count limits. Twelve cases of exceeding the
maximum allowed fungal count and ten cases of exceeding the maximum acceptable
aerobic microbial count were the most prevalent forms of non-compliance.
Ahmed
(2022) The GMP requirements are overseen by the US Food and
Drug Administration, which is constituted by the Federal Food, Drug, and
Cosmetic Act. To comply with these rules, pharmaceutical companies must take
reasonable and effective measures to guarantee the quality, purity, and
efficacy of their wares. "cGMP" is another informal way of referring
to GMP. The "current" prefix serves as a reminder to producers that,
in order to comply with rules, they must use modern technology and methods. It
may be insufficient to test only a little portion of a batch to guarantee
quality. Therefore, it is essential that pharmaceuticals be produced in a
controlled environment in order to consistently fulfill the standards mandated
by GMP rules. This will guarantee that quality is included into the design and
production of the medicine. Our primary objective was to examine, from the
perspective of pharmacists, the rationale for the pharmaceutical industry's
adoption of GMP rules.
DETECTION OF MICROBIAL CONTAMINATION
IN BIOLOGICAL/ STERILE PRODUCTS
The presence of microorganisms in
biological products may be detected using a battery of assays. The next
paragraphs detail a few of these tests.
When looking for microbiological
pollutants, differential media is a lifesaver. Some of the particular media,
called rich media, allow for the development of almost all microorganisms. The
existence of colonies with distinct morphologies from the biological products
may be used to identify microbial contamination in rich medium. Additional
testing, such Polymerase Chain Reaction (PCR), may
be conducted on the colonies that are thought to be problematic. Selective
media are different types of media that encourage the development of certain
microbes. The establishment of colonies is a way for se-elective medium to
identify microbial pollutants.
Sometimes, in an effort to make the
detection of microbial contamination more sensitive, the composition of this
medium is changed to restrict or prevent the development of biological
products. This is because there may be just a little amount of microbial
contamination in the biological product, and because the development of these
microbes might be hindered or reduced when exposed to high concentrations of
biological product, leading to inaccurate negative findings. Sometimes, certain
antibiotics, amino acids, or other nutrients are used to restrict or impede the
development of the biological products.
If you suspect microbial
contamination, an immunofluorescence test may help you find out. When the known
microbial pollutants' type, species, and strains are known, this approach is
particularly valuable since it can identify relatively low amounts of microbial
contaminants. Because of this, the sponsor should verify that the test can
identify cross-contaminants and commonly-known contaminants in these
microorganisms before manufacturing begins.
Microbial Contamination in
Nonsterile Products:
In accordance with CFR, the FDA expects
manufacturers to ensure their products are free of harmful microorganisms
(sometimes known as "microbial safety" or the "absence of
objectionable microorganisms"). Regarding the matter of the
microbiological integrity of nonsterile medications, the United States
Pharmacopoeia and the United States Food and Drug Administration concur: the
product need to be fit for consumption. This guarantee is well-grounded in the
chapters that have been harmonized on an international level. Some revalidation
of current procedures is anticipated to be necessary for the adoption of these
three unified chapters. Businesses need to start making preparations for this
task right now and keep proving that they are making progress. From a
microbiological standpoint, the product should not be sold based on the
National Formulary monograph requirement that it be free of certain organisms.
This criterion is limited at best. Chapter 1111, which deals with harmful
creatures, suggests finding out how dangerous "other organisms" are,
which is in line with what the FDA wants—that there be no
"objectionable" organisms. While harmonized microbial limits tests do
look for the "absence of specified microorganisms," it is up to each
company's competent microbiology section to determine whether or not there are
any objectionable bacteria.
Process controls are implemented
using a microbiological viewpoint for nonsterile goods. Producing goods devoid
of "objective organisms" is a clear requirement of the United States
Code of Federal Regulations (21 CFR), even if these controls are not as
stringent as those for aseptic production. It is important to note that the
FDA's concerns on "objectionable organisms" differ from the
compendial tests for "specified" species. Therefore, during the
quarantine period, when the product is not being marketed, it should also be
tested for the presence of "objectionable" organisms.
Table 1: List
of some Drugs for APIs (drug substances) containing Endotoxin and their Limit
|
Drug |
Limit |
|
Amoxicillin
sodium |
NMT 0.25 IU/mg |
|
Buserelin |
NMT 1.00 IU/mg |
|
Carbenicillin
sodium |
NMT 55.5 IU/mg |
|
Desmopressin |
NMT 500.0 IU/mg |
|
Fosfomycin |
NMT 0.083IU/mg |
|
Heparin
sodium |
NMT 0.01 IU/mg |
|
Insulin |
NMT 10.0IU/mg |
|
Oxytocin |
NMT 300.0 IU/mg |
|
Somatropin |
NMT 05.0 IU/mg |
|
Tetracyclin
hydrochloride |
NMT 0.50 IU/mg |
|
Vanomycin |
NMT 0.25 IU/mg |
|
Xylitol |
NMT 4.0 IU/mg |
So far, only exceptional
circumstances have necessitated the microbiological examination of nonsterile
medications. To this day, microbiological control of these goods is essential,
since very few nations have laws dictating the maximum allowable concentration
of nonpathogenic microorganisms in non-sterile pharmaceuticals. The viability
of such rules' implementation in GMP and the promotion of hygiene and safety
must be considered in their formulation.
STEPS FOR AVOIDING MICROBIAL
CONTAMINATION
In order to prevent contamination by microbes, several
measures should be implemented. Environmental and cross-contamination control
measures for microorganisms should be included into the facility. Secure
containment of biological goods, an air pressure cascade system, numerous
suites or operations for various products, and separate heating, ventilation,
and air conditioning systems for each suite are all examples. Every step of the
manufacturing process, including washing, formulation, and filling, must be
carried out meticulously under a Class 100 laminar flow hood. It is imperative
that all implements, including centrifuge bottles, glassware, growing media,
and packaging materials, be sanitized before use. To guarantee that there are
no contaminating micro-organisms, it is important to test the growth medium and
other components involved in fermentation and production. This may be done in a
variety of ways, such as using a bioburden test, sterility test, or detecting
bacteria after lengthy incubation. It is important to examine the filters used
to sterilize media both before and after manufacture to ensure their integrity.
To detect and avoid pollutants, it is important to implement in-process
controls. A possible approach to this problem is to test samples taken at
various points in the manufacturing process for the presence of microorganisms
that have no bearing on the biological products. Every production should
conclude with a comprehensive cleaning of the production suite (e.g., using
Steris(R) Corporation's LpH se(R) and Vesphene(R) IIse in a rotational
disinfectant schedule), along with sterilisation of all equipment. Validated
cleaning procedures should be followed to confirm the cleanliness of the rinse
and swab samples. Environmental and staff monitoring of the production sites is
necessary to identify microorganisms that are unrelated to the biological
products. Before, during, and after every production, environmental monitoring
should be carried out.
Starting materials, product-contact packaging components,
production facilities, manufacturing procedures, and equipment are subject to
microbiological and physical requirements and controls to guarantee that drug
products are not contaminated. Controls that shield processes, equipment, and
materials against potential microbiological contaminants are the main means by
which these guarantees are attained. Removal, inactivation, or elimination of
microbiological pollutants is also a common control method, acknowledging the
limitations of preventive measures in all but the most severe cases.
It is essential that all microbiological tests be conducted
in a controlled environment to guarantee that neither the product nor the
material being tested is accidentally contaminated. Under these circumstances,
the examination must take place in a designated space, the laboratory, which
must be geographically and logistically isolated from the production areas by
measures such as limiting access, providing each participant with their own air
supply, and blocking the airflow between the two. Dedicated gowns and other
protective apparel, a wall between the manufacturing and laboratory processes,
and a system for tracking the movement of both people and materials are further
precautions. Disposal of laboratory waste must be done in a way that prevents
contamination of protected areas and production materials. Particular attention
should be given to the design of the sampling technique. There has to be
regular and suitable monitoring of the viable count in the lab. Product testing
in a specific room is not allowed unless the room in question has been used for
tests involving growth promotion or antimicrobial preservation, which cannot be
done without a Laminar-Air-Flow Cabinet. There are a number of tests that need
strict protocols to minimize the possibility of contamination, such as
microbiological monitoring of purified water samples. One such protocol is the
use of a Laminar-Air-Flow Cabinet.
Control of Microbial Contamination:
The main goal of microbial control
of pharmaceuticals is to reduce the likelihood of contamination of medication
products by microbes. Minimizing the growth of any microorganisms that may have
contaminated medicinal items to a point where they pose a threat to the
product's effectiveness is a secondary issue. One minor aspect of this is the
testing of product samples to ensure they meet microbiological requirements. It
is uncommon to find reliable statistical sampling and testing done at batch
release due to the product-destructive nature of microbiological test
procedures. In situations when manufacturing controls guarantee that items are
exceedingly unlikely to become microbiologically contaminated, finished product
testing becomes at most confirmatory, and in the most extreme circumstances, it
may even be unnecessary.
Industries that process food
(including dairy), personal hygiene and beauty goods, and pharmaceuticals have
protocols to prevent microbial contamination. In order to identify possible
sources and pathways of contamination, it is crucial to conduct microbiological
sample of products and raw materials and conduct regular hygiene monitoring of
a facility and equipment. Businesses might lose money and people can get sick
or die from contamination in the food industry.
An outstandingly fundamental aspect
of inspection results is the control of microbial contamination. Failure to
control microbiological contamination (21 CFR 211.113) was the source of eleven
citations in 2005 FDA Warning Letters. These results have been included in the
FDA's Top Ten List of Warning Letters for the last several years. In most
situations, producing pharmaceutical items has included implementing adequate
hygiene programs and practices. Control of microbiological facilities is the
focus of a set of rules. The overarching objective of this system is to
safeguard the pharmaceutical product against microbial contamination.
21CFR Sec. 211.113 Control of
microbiological contamination states that:
Drug items that are not mandated to
be sterile must adhere to certain documented protocols that aim to eliminate
objectionable microorganisms.
Drug goods that claim to be sterile must adhere to certain
protocols that have been devised to avoid microbiological contamination.
Validation of any sterilizing process is an integral part of these processes.
21CFR Sec. 211.165 Testing and
release for distribution states that:
(a) Before each batch of drug product is released, it must
undergo the necessary laboratory testing to ensure it meets all final
standards, including those pertaining to the active ingredient's identification
and potency. Batches of short-lived radiopharmaceuticals that are subject to
sterility and/or pyrogen testing may be released before the testing is
finished, as long as the testing is done promptly.
(b) In order to ensure that each batch of medication product
is free of undesirable microorganisms, it must undergo suitable laboratory
testing, as needed.
(c) A documented protocol outlining the sample technique and
the quantity of units to be tested per batch is required for all testing and
sampling plans.
(d) In order for drug product batches to be approved and
re-released, the quality control unit's sampling and testing acceptance
criteria must be sufficient to ensure that each batch meets all relevant specifications
and statistical quality control requirements. Criteria for statistical quality
control must include suitable acceptance and/or rejection levels.
(e) The firm's test procedures must be proven and verified
to have high accuracy, sensitivity, specificity, and repeatability. Methods for
completing such validation and documentation are available under Section
211.194. (a) Part 2.
(f) Negligible drug items will be rejected if they do not
match the specified standards or any other applicable quality control criteria.
It is possible to reprocess. All processed materials must be completely free of
defects and in accordance with all applicable standards and specifications
before they can be used or accepted.
REGULATORY ASPECTS
There are times when the interests
of USP and FDA align. Sterility, antimicrobial efficiency, antibiotic/vitamin
potency, bacterial endotoxin, microbiological limits, etc., are all important
from a USP perspective. There is zero concern for "Good Manufacturing
Pro-cess" (GMP) that necessitates these testing. Substantiated in the
National Formulary (NF) are the USP monographs that regulate it. To prove that
a product has antimicrobial effectiveness, referees apply the
"Antimicrobial Effectiveness Test" described in chapter 51 of the relevant
monograph.
FDA has its own unique but related
issues. Chapters listed under <1000> in USP, which deal with referees,
are enforced where the requirements are equivalent. On the other hand, USP
referee test methods aren't always enough to address FDA concerns. A good
example of this is the need for pharmaceuticals to be "free of
objectionable microorganisms" as stated in the CFR. "Appropriate
written procedures, designed to prevent objectionable microorganisms on drug
products not required to be sterile shall be established and followed,"
reads 21CFR 211.113, section "Control of microbiological contamination
(a)." "Testing and release for distribution... (b) There shall be
appropriate laboratory testing, as necessary, of each batch of drug product re-quired
to be free of objectionable microorganisms," says 21 CFR 211.165, which
supports this. Clearly, we are facing an issue. According to the current
National Formulary, a product's USP monograph can state, "Absence of
Pseudomonas aeruginosa." In order to prove that Pseudomonas aeruginosa is
not present, you might do the test that is included in the Microbial Limits
chapter. The FDA is concerned that any organisms in the finished product must
be acceptable to both the product and the target population, meaning they must
not be "objectionable". While this test may be necessary to show
compliance with the mono-graph requirements as outlined in NF, it does not
address this issue.
The FDA Concern
If your product permission to market
application said that you will test the completed product by the Microbial
Limits Tests, then you must actually do so; otherwise, the FDA will enforce the
GMP requirement. As far as GMP is concerned, this is the only issue. Although
testing according to the USP chapter may be required, it is insufficient to
prove microbiological quality, and the Agency has made it quite clear that they
are worried about unpleasant microorganisms in the product. The Food and Drug
Administration really says this in its instructional handbook for QC microbiology
lab inspections from 1993:
Topical medication treatments, nasal
solutions, and inhalation products have been linked to a multitude of issues
due to microbial contamination. Chapter 1111 of the USP Microbiological
Attributes offers limited particular instructions, other from the following:
"The importance of microorganisms in nonsterile pharmaceutical products
should be assessed considering the product's use, its nature, and the possible
danger to the user." Total counts and designated indicator microbiological
pollutants should be regularly tested for in specific categories, according to
the USP. For instance, Salmo-nella-specific natural plant, animal, and mineral
items; E. coli oral liquids; P. aeruginosa and Staphylococcus aureus topicals;
and yeast and mold administration articles for rectal, urethral, or vaginal
use. Definitive microbiological limits are also included in a number of
particular monographs. According to Dr. Dunnigan of the FDA's Bureau of
Medicine, there is a health risk, and there is an acceptable degree and kind of
microbial contamination in products. He warned in 1970 that gram-negative
microbes in topical treatments provide a moderate to major risk to human
health. Multiple illnesses have been linked to gram-negative contamination of
topical treatments, according to both the literature and our own
investigations. A Massachusetts hospital reported Pseudomonas cepacia infection
of Povidone Iodine products a few years ago, which is the typical case.
Hence, it is anticipated that all
companies would create microbiological standards for their nonsterile goods.
The technique for chosen indicator species is provided in the USP Microbial
Limits Chapter <61>, just as for other undesirable organisms, but not all
of them. Take Pseudomonas cepacia as an example. It's common knowledge that
large concentrations of this microbe in topical products or nasal solutions are
unpleasant. However, the USP does not give any test procedures to detect its
presence.
The recall of the inhalation
solution containing metaproterenol sulfate is an important illustration of this
issue. This product does not need microbiological testing according to the USP
XXII mono-graph. The presence of Pseudomonas gladioli/cepacia in the product
led the FDA to classify it as a Class I recall. According to the health hazard
assessment, individuals with immunocompromised conditions, cystic fibrosis, or
chronic obstructive airway disease are at an exceptionally high risk of
developing a lung infection, which might be fatal. The testing methods outlined
in the Compendia's general Microbial Limits section would not have been able to
detect these species either.
Colony identification is one
possible outcome of microbial testing using the Total Aerobic Plate Count
assay. It bears repeating that the USP indicator organisms should not be the
only ones used for identification. The product and its intended application
will determine the significance of detecting all isolates via either Total
Plate Count testing or enrichment testing. Testing a solid oral dose form, as a
tablet, may obviously allow for the acceptable identification of isolates when
levels are high. Isolates from plate counts and enrichment tests should be
identified for additional products where there is a considerable risk for
microbiological contamination, such as topicals, inhalants, or nasal solutions.
The USP Concern
Proving the "absence of
objectionable microorganisms" was never the goal of this chapter,
according to the USP's 1982 report. "The tests described in the Microbial
Limits Tests <61> were not intended to be all-inclusive, i.e., to detect
all potential pathogens," the microbiology committee mentioned in a
one-page Stimuli to the Revision Process stated today. This could only be
achieved with a comprehensive guide on microbiological detection in the lab.
Particular "index" or "indicator" or-ganisms were the
intended target of the USP processes. Although Ps. Cepacia cannot be detected
in this chapter, further differentiation of the organism is necessary. This and
the detection of thousands of additional potentially harmful species are also
left out of the chapter's detailed instructions. Every single monograph has its
own set of standards, such as maximum allowable total aerobic counts or the
lack of any one of four chosen "indicator" species. To guarantee that
one may test for those microbiological criteria in the specific monographs, the
chapter on Microbiological Limits Tests offers techniques.
CONCLUSION
There has long been worry about the
presence of unwanted and possibly harmful microbial contaminants in
pharmaceutical products. The active medicinal ingredient's effectiveness, or
lack thereof, might be affected by these impurities, which can have
pharmaco-logical consequences that are difficult to anticipate. More
worryingly, they might be poisonous. Manufacturers are compelled to use several
technological and scientific procedures throughout the production cycle by the
FDA's Current Good production Practices (cGMP) standards due to the grave risks
posed by these contaminants to patient safety. The final purpose of these
methods is to guarantee, with a high degree of certainty, that the
pharmacological products fulfill all of the specified requirements. To aid in
their control, compendia also provide standardized microbiological limit
testing.
Abbreviation
API: Active pharmaceutical
ingredient
CDER: Center for Drug Evaluation and
Research
CFR: Code of
federal Regulations
EP: European
Pharmacopoeia
FDA: Food and Drug Administration
GMP: Good Manufacturing Practice
NF: National Formulary
ORS: Office of Regulatory Science
PCR: Polymerase Chain Reaction
PMM: Pharmaceutical
Microbiology Manual
QC: Quality Control
USFDA: United States Food and Drug
Administration
USP: United States
Pharmacopeia
Reference
1.
Ahmed, Md & Sultana, (2022). Good
Manufacturing Practice (GMP) Guideline in Pharmaceutical Industries:
Implementation and Its Significance from the view of Pharmacists. International
Journal of Modern Pharmaceutical Research, ISSN: 2319-5878, 6(1), 46-60,
2.
Ratajczak, Magdalena & Jaworska,
Marcelina Maria & Kamińska, D. & Pecyna, Paulina &
Dlugaszewska, Jolanta. (2014). Microbiological quality of non – sterile
pharmaceutical products. Saudi Pharmaceutical Journal. 47. 10.1016/j.jsps.2014.11.015.
3.
Walsh, A., “Microbial Aspects in Cleaning
Validation,” in Microbiology and Sterility Assurance in Pharmaceuticals and
Medical Devices, Madhu Raju Saghee, Tim Sandle, and Edward C. Tidswell, eds.,
Business Horizons, 2011, ISBN: 978-8-190646-74-1.
4.
Gupta, Rajesh. (2014). Validation of
Microbiological Methods – Expectations for Regulatory Compliance. Webinar - BioPharma
Asia. 3. 24.
5.
Roesti, David & Goverde, Marcel.
(2019). Microbiological Control Strategy. In book: Pharmaceutical
Microbiological Quality Assurance and Control, WILEY, ISBN: 978-1-119-35607-3.
(pp.1-21).
6.
Halls, N. A. (2002). Microbial control
of pharmaceuticals. In J. Swarbrick (Ed.), Encyclopedia of Pharmaceutical
Technology (Vol. 1, pp. 1753–1764). Taylor & Francis/CRC Press
7.
Fowler, J. (2005). Monitoring your
production environment. In Troubleshooting Microbial Contamination in an
Industrial Environment (Mould & Bacteria Reviews, Issue 11). Retrieved
from https://www.researchgate.net/publication/40999115_Microbial_Contamination_A_Regulatory_Perspective
8.
Baird, R. M., Hodges, N. A., & Denyer,
S. P. (2000). Handbook of Microbiological Quality Control in Pharmaceuticals
and Medical Devices. CRC Press. ISBN: 978-0203305195.
9.
Nighat Razvi, R. A.(2014). Estimation of
microbial contamination in various API and Excipients. World journal of
Pharmacy and Pharmaceutical sciences,1771-1777.
10.
Chatwal, G. R., and M. Arora. Pharmaceutical
Chemistry – Inorganic (Vol. I): Impurities and Pharmaceutical Substances and
Their Limit Tests. Himalaya Publishing House, 2010, pp. 28–71.
11.
Saba Sultana and Shahid Mohammed (2018). A
Review on Stability Studies of Pharmaceutical Products. International Journal
for Pharmaceutical Research Scholars (IJPRS), ISSN: 2277 – 7873, V-7, I-1, 2018