You are on page 1of 7

Quality Control

Quality Control: Microbial Nicole Vu, PhD


Jessica R. Lou, BS

Limit Tests for Nonsterile


Thomas C. Kupiec, PhD

Pharmaceuticals, Part 2 Part 1 of this 2-part article contains


important facts about the topic of microbial
limit tests for nonsterile pharmaceuticals,
including the following statements1:
This article represents
part 2 of a 2-part article Nonsterile pharmaceuticals are not
on the topic of microbial produced by aseptic processes and,
limit tests for nonsterile therefore, are not expected to be
pharmaceuticals. Part 1, totally free from microbial contami-
which was published in nations.
the International Journal The degree of contamination in non-
of Pharmaceutical Com-
sterile products is regulated, and is
poundings May-June
based on the acceptance criteria for
2014 issue (Volume 18,
No. 3), provided an intro-
microbiological quality established in
duction to this topic as Pharmacopeial monographs.
well as a discussion on the The major contaminants of nonsterile
acceptance criteria for pharmaceutical products and ingredi-
microbiological quality ents are bacteria, yeast, and molds.1,2
of nonsterile pharmaceu-
ticals and an overview of Also, the following excerpt from part 1 of
United States Pharmaco-
this topic stated1:
peia Chapter <61>. Part
2 brings us back to this United States Pharmacopeia (USP)
topic with an overview of Chapters <61> Microbiological
United States Pharmaco-
Examination of Non-Sterile Products:
peia Chapter <62>.
Microbial Enumeration Tests and <62>
Microbiological Examination of Non-
Sterile products: Tests for Specified
Microorganisms provide protocols that
allow quantitative enumeration of the
presence of bacteria and fungi. The tests
PHOTO SOURCE:
help determine whether a nonsterile
Analytical Research
Laboratories & product complies with an established
Pickens Photography specification for microbiological qual-
ity. Additionally, these two USP chap-
ters provide guidance on determining
Abstract Cases of contaminated nonsterile products have been the absence of, or the limited occur-
reported in increasing numbers. Often, these contaminated products are rence of, specified microorganisms that
associated with the presence of objectionable microorganisms. The major may be detected under the conditions of
contaminants of nonsterile pharmaceutical products and ingredients are the tests.[3] It is necessary to emphasize
bacteria, yeasts, and molds. The combination of parts 1 and 2 of this series here that the USP provides methodolo-
of articles provides a thorough examination of microbiological quality gies for selected indicator organisms,
but not all objectionable organisms in
testing for nonsterile products.
the FDA opinions.[4]

Nicole Vu and Thomas C. Kupiec are affiliated with Analytical Research Laboratories, Inc., Oklahoma City, Oklahoma; Jessica R. Lou is a PharmD Candidate
at the Oklahoma University Health Science Center, Oklahoma City, Oklahoma.

www.ijpc.com International Journal of Pharmaceutical Compounding


Vol. 18 No. 4 | July | August | 2014 305
Quality Control

Part 1 of this 2-part series of articles


Table 2. Representative Microorganisms for Use in Validation of
provided an overview of USP Chapter <61>,
United States Pharmacopeia Chapters <61> and <62>.3
as well as a discussion on other chapters
within the USP that relate to the microbio- Organism ATCC NCIMB CIP NBRC NCTC NCPF IP
logical quality of nonsterile pharmaceuti- Staphylococcus aureus 6538 9518 4.83 13276 NA NA NA
cals. This article provides an overview of Pseudomonas aeruginosa 9027 8626 82.118 13275 NA NA NA
USP Chapter <62>. Bacillus subtilis 6633 8054 52.62 3134 NA NA NA
Candida albicans 10231 NA NA 1594 NA 3179 48.72
Overview of United Escherichia coli 8739 8545 53.126 3972 NA NA NA
States Pharmacopeia Salmonella enterica

Chapter <62>: Tests for subsp: serovar


typhimurium or 14028 NA NA NA
Specified serovar abony NA NA 80.39 100797 6017 NA NA

Microorganisms Clostridium sporogenes 11437 or 12343 100651 or


19404 79.3 14293 532 NA NA
USP Chapter <62> provides proce-
dures and test conditions for determin-
ing whether the product under examination meets the acceptance as objectionable (Table 1).3 Alternative methods may be applied if
criteria for the specified microorganisms that have been identified their equivalence to Pharmacopeial procedures has been demon-
strated. As with all microbiological tests, growth properties of the
Table 1. United States Pharmacopeial (Chapter media must be demonstrated, and the method must show to be suit-
<1111>) Acceptance Criteria for Microbiological able for microbial recovery in the presence of a product using the
test strains listed in Table 2. The challenge microbial species must
Quality of Nonsterile Dosage Forms.3
be detected with the same indication reactions described in USP
Absence of Chapter <62> under the Testing of Products section.
TAMC TYMC Specified
Route of (cfu/g, (cfu/g, Microorganism(s)
Testing of Products by United States
Administration cfu/mL ) cfu/mL) (1 g, 1 mL)a
Pharmacopeia Chapter <62>
Oral (non-aqueous) 10 10 Escherichia coli
The procedure for the preparation of test samples follows the
Oral (aqueous) 10 10 Escherichia coli
same principle as previously described for microbial enumeration
Rectal 10 10 None designated
testing (USP <61>). If neutralization of antimicrobial activities
Oromucosal 10 10 Staphylococcus aureus
Pseudomonas aeruginosa
cannot be accomplished, then it may be assumed that the inhib-
ited microorganisms will not be present in the product. In most
Gingival 10 10 Staphylococcus aureus
Pseudomonas aeruginosa instances, the product is diluted 1:10 in a general purpose medium
Cutaneous 10 10 Staphylococcus aureus (e.g., TSB or SCD broth), and then incubated for a defined time
Pseudomonas aeruginosa to resuscitate but not to promote growth of microbial species in
Nasal 10 10 Staphylococcus aureus the product. After the resuscitation step, an aliquot of the sample
Pseudomonas aeruginosa solution equivalent to 1 g (or 1 mL) of the product is transferred
Auricular 10 10 Staphylococcus aureus to an enrichment medium for culturing under conditions optimal
Pseudomonas aeruginosa
for growth of the target species, and then sub-cultured on selec-
Vaginal 10 10 Pseudomonas aeruginosa tive medium for indication tests. The properties of selective media
Staphylococcus aureus
Candida albicans employed in testing by USP <62> are summarized in Table 3.
Transdermal Patch
(drug matrix, adhesive Staphylococcus aureus Test for Absence of Specified Microorganism
layer and backing) 10 10 Pseudomonas aeruginosa
USP Chapter <62> entails procedures to test for absence of Bile-
Inhalation 10 10 Staphylococcus aureus
Pseudomonas aeruginosa
Tolerant Gram-negative Bacteria, Escherichia coli, Samonella,
Bile-tolerant Gram-negative Pseudomonas aeruginosa, Staphylococcus aureus, Clostridia, and
bacteria Candida albicans. While most procedures specify a sample volume
Pharmaceutical equivalent to 1 g (or 1 mL) of the product, the Samonella test is the
substances 10 10 None designated
only case that requires that a sample volume equivalent to 10 g (or
aMinimum amount of product to be used in sample preparation 10 mL) of the product be used. In the test for Clostridia, a portion of
cfu = colony-forming unit; TAMC = total aerobic microbial count; TYMC = total combined yeasts and
molds count the diluted sample is heated to 80C for 10 minutes and then cooled

International Journal of Pharmaceutical Compounding www.ijpc.com


306 Vol. 18 No. 4 | July | August | 2014
Quality Control

Table 3. Properties of Selective Media Used in Table 4. Selective Media and Their Usage in United
Testing by United States Pharmacopeia Chapter States Pharmacopeia Chapter <62>.3
<62>.3 Temperature Time
Growth Growth Indicative Test Medium (C) (Hour)
Medium Promotion Inhibition Reaction Bile Tolerant Mossel Enterobacteria
Gram-negative Enrichment Broth 30 to 35 24 to 48
Mossel Enterobacteria E. coli
Violet Red Bile Glucose
Enrichment Broth P. aeruginosa S. aureus
Agar 30 to 35 18 to 24
Violet Red Bile E. coli E. coli
E. coli MacConkey Broth 42 to 44 24 to 48
Glucose Agar P. aeruginosa P. aeruginosa
MacConkey Agar 30 to 35 18 to 72
MacConkey Broth E. coli S. aureus
Samonella Rappaport Vassiliadis
MacConkey Agar E. coli E. coli Samonella Enrichment
Rappaport Vassiliadis Broth 30 to 35 18 to 24
Samonella Xylose Lysine
Enrichment Broth S. enterica S. aureus Deoxycholate Agar 30 to 35 18 to 48

Xylose Lysine P aeruginosa Cetrimide Agar 30 to 35 18 to 72


Deoxycholate Agar S. enterica S. enterica S. aureus Manitol Salt Agar 30 to 35 18 to 72
Cetrimide Agar P. aeruginosa E. coli Clostridia Reinforced Medium for
Manitol Salt Agar S. aureus E. coli Clostridia 30 to 35 (anaerobic) 48
Columbia Agar 30 to 35 (anaerobic) 48 to 72
Reinforced Medium
for Clostridia Cl. Sporogenes C. albicans Sabouraud Dextrose
Broth 30 to 35 3 to 5 days
Columbia Agar Cl. Sporogenes Sabouraud Dextrose
Sabouraud Dextrose Agar 30 to 35 24 to 48
Broth C. albicans
Sabouraud Dextrose
Table 5. Interpretation of Quantitative Test by
Agar C. albicans C. albicans
United States Pharmacopeia Chapter <62>.3
Product Amount (g or mL) MPN
rapidly while another portion is kept at 24 to 48 hrs. The
0.1 0.01 0.001 (per g, mL)
room temperature. The prepared portions enriched samples
+ + + >103
are used separately to inoculate Reinforced are then sub-cul-
Medium for Clostridia, which are then sub- tured to Violet Red + + >102 to <103

cultured on Columbia Agar for an indication Bile Glucose Agar + >10 to <102
test. A list of the selective media and their and incubated at <10
usage in USP Chapter <62> procedures is 30C to 35C for 18
provided in Table 4. In general, the presence to 24 hours. Growth
of any colonies on these selective media of colonies are recorded, and the MPN of with the Japanese Pharmacopeia (JP)
indicates presumptive identification, which bacteria is determined according to Table 5. XVI Chapter 4.05 Microbial Limit Test.
must be confirmed by suitable identifica- USP General Chapter <1111> Acceptance
tion tests. The product complies with the When to Perform United Criteria for Pharmaceutical Preparations
test if no colonies are detected or confirma- States Pharmacopeia and Drug Substances for Pharmaceutical
tory identification tests are negative. Chapters <61> and <62> Use is practically harmonized with the EP
Section 5.1.4, and JP Chapter G4 (12).5
The International Conference on
Quantitative Test for Bile-Tolerant Harmonization (ICH Q4B) recommends
Gram-negative Bacteria that the official pharmacopeial texts con-
Testing Frequency
The quantitation scheme is conducted cerning microbiological tests and accep- In-process and Release Testing
similar to the Most Probable Number tance criteria for nonsterile products According to the Code of Federal
(MPN) method described in USP Chapter be used interchangeably within the ICH Regulations (21 CFR 211), each lot of a com-
<61>. A set of 10-fold serial dilutions of regions. Therefore, both USP Chapters <61>: ponent (e.g., in process or raw materials) or
the product in Mossel Enterobacteria Microbial Enumeration Tests and <62>: drug product that may potentially become
Enrichment Broth containing products Tests for Specified Microorganisms are har- contaminated with objectionable organ-
equivalent to 0.1, 0.01, and 0.001 g is pre- monized with the European Pharmacopeia isms during the manufacturing process or
pared for enrichment at 30C to 35C for (EP) 7.0 Sections 2.6.12 and 2.6.13, also its period of intended use must first pass

www.ijpc.com International Journal of Pharmaceutical Compounding


Vol. 18 No. 4 | July | August | 2014 307
Quality Control

microbiological testing. Written procedures to prevent objectionable organisms in nonster- mation should be included in the testing
ile drug products must be in place, as well as appropriate laboratory testing for each batch. program6:
Additionally, in-process materials must be tested for identity, strength, quality (product
and microbial), and purity, and be approved or rejected during all stages of production.6 1. Sample size and testing intervals based
on statistical criteria
21 CFR 211.84(d): Each lot of a component, drug product container, or closure that is 2. Storage conditions of samples retained
liable to microbiological contamination that is objectionable in view of its intended for testing
use shall be subjected to microbiological tests before use. 3. Reliable and meaningful testing
methods
21 CFR 211.113(a): Appropriate written procedures designed to prevent objection-
4. Carrying out the test in the same con-
able microorganisms in drug products not required to be sterile, shall be established
tainer as the final marketed product
and followed.
5. Testing drug products intended for
21 CFR 211.165(b): There shall be appropriate laboratory testing as necessary of reconstitution both at the time of
each batch of drug product required to be free of objectionable microorganisms. dispensing and during the period of
in-use

Stability Testing
The following guidelines are expressed in
Furthermore, a written testing program to assess stability of drug products should be
ICH/FDA guidance documents:
established. Provided that a sufficient number of batches are tested, this information
will determine appropriate storage conditions and expiration dates. The following infor-
ICH Q1A(R2)/FDA: Testing per-
formed during a stability program
should include analyses for product

Whats Under
attributes that are susceptible to
change during storage and that are
likely to influence the products

Your Hood?
quality, safety, or efficacy7

ICH Q6A/FDA: Acceptance criteria
should be set for the total count of
aerobic microorganisms, the total
count of yeasts and molds, and the
absence of specific objectionable
bacteriaThese should be deter-
mined by suitable procedures,
using pharmacopoeial procedures,
and at a sampling frequency or time
point in manufacture which is jus-
IMI offers a complete range of products designed specifically
tified by data and experience.8
for sterile compounding including our renowned line of
Prep-LockTM Tamper Evident Caps for luer lock syringes.
Additional guidance is provided in USP
Easy installation for the pharmacy and easy removal for the Chapter <1163> Quality Assurance in
nurse...no more fumbling with sticky, brittle tape or bulky Pharmaceutical Compounding3 and <1191>
bags. Secure your sterile IV preparations and enhance Stability Consideration in Dispensing
USP <797> compliance! Practice3 where microbiological quality
FREE Sterile Samples for Evaluation! is a condition of sample stability. Thus,
microbial limit is one of the recommended
Innovative Sterile Products tests, and frequency of testing should be
for Compounding Pharmacies sufficient to establish the stability profile
800-344-2554 of nonsterile preparations. For long-term
www.imiweb.com International Medical Industries, Inc. stability study, the test is usually conducted
at 6- to 12-month intervals.
Pharmaceutical Compounding 2014.indd 1 2/17/2014 11:24:49 AM

International Journal of Pharmaceutical Compounding www.ijpc.com


308 Vol. 18 No. 4 | July | August | 2014
Quality Control

Repeat Testing Table 6 lists microorganisms that are pri- can adversely impact the quality and safety
A procedure for investigating test results marily foodborne, but some of these species of the finished product.10
that fail to meet given microbial limit can persist in pharmaceutical or healthcare
specifications should be established by the products. One such example includes the Water Activity of
manufacturers, and this procedure should many cases of contaminated alcohol wipes Non-Sterile Products
containing Bacillus cereus species, which
allow for confirmatory testing. However, and Relationship to
contributed to one fatality in a child and
the logic and rationale for conducting the
eight other deaths that have not yet been
Microbiological Quality
retest should be based on sound scientific (United States
judgement.4 In the event that a root cause positively linked. Of note, no yeast or mold
species are officially included in the FDAs Pharmacopeia Chapter
cannot be determined, all values obtained
(original and re-test) must be reported and list. The information in Table 6 may poten- <1112>)
taken into consideration when evaluating tially be of interest in determining which Traditionally, low-water activity has
the microbial quality of the product. The organisms should be added to an objection- been used to control microbial deterioration
FDA expressed the following opinions4: able list. Additionally, any organisms that of food. Reduced water activity (aW) greatly
persist in high level within any manufactur- assists in the prevention of microbial
Data review must evaluate the ing process should be strongly considered proliferation in pharmaceutical products.
relationship between the organ- an objectionable candidate because they Additionally, low-water activity promotes
isms found in test samples, and the self-preservation and thereby prevents
potential for the existence of other microbial growth within pharmaceutical
objectionable conditions. drug products. However, it should be noted
Table 6. The U.S. Food and that resistant microorganisms, including
The importance of identifying all Drug Administration List of spore-forming Clostridium spp., Bacillus
isolates from either or both total Objectionable Foodborne spp., Salmonella spp., and filamentous fungi,
plate count testing and enrichment Organisms.11 may persist within the product although
testing will depend upon the prod- they may not proliferate. Non-aqueous liq-
Gram-negative Organisms
uct and its intended use. Obviously, uids or dry solid dosage forms will not sup-
Aeromonas hydrophila and other species
if an oral solid dosage form such as port spore germination or microbial growth
Brucella species
tablet is tested, it may be accept- due to their low-water activity.
Campylobacter jejuni
able to identify isolates when test- When formulating an aqueous oral or
ing show high levels. However, for Coxiella burnetii topical dosage form, candidate formulations
other products such as topicals, Cronobacter species should be evaluated for aW so that the drug
inhalants or nasal solutions where Francisella tularensis product may be self-preserving, if possible.
there is a major concern for micro- Miscellaneous bacterial enterics: For example, small changes in sodium
biological contamination, isolates Plesiomonas shigelloides chloride, sucrose, alcohol, propylene glycol,
from plate counts, as well as enrich- Salmonella species or glycerin in a formulation may result in
ment testing should be identified. Shigella species the creation of a drug product with a lower
Vibrio cholerae Non-O1 Non-O139
aW that can discourage the proliferation
So, the first consideration should be the of microorganisms in the product. This is
Vibrio cholerae Serogroups O1 and O139
total numbers of microorganisms present. particularly valuable with a multiple-use
Vibrio parahaemolyticus
High levels of bioburden may indicate a product that may be contaminated by the
Vibrio vulnificus
manufacturing process is out of control, or end-user.
Yersinia enterocolitica
that a spoilage organism is proliferating in Water activity is the ratio of water vapor
the product. If the numbers of organisms Gram-positive Organisms pressure in the product (P) to vapor pres-
in the product are not large, the next con- Bacillus cereus and other Bacillus species sure of pure water (Po) at the same tem-
sideration is whether those organisms are Clostridium botulism perature. Water activity can be determined
objectionable. One approach is to transfer Clostridium perfringens directly from the partial vapor pressure or
the enrichments prepared in the compen- Enterococcus species dew point, or indirectly by determination
dial test to non-selective media in addi- Listeria monocytogenes
of equilibrium relative humidity (ERH%).
tion to the required selective media. Any Pharmaceutical drug products with water
Mycobacterium bovis
colonies recovered and identified should be activities well below 0.75 are excellent can-
Staphylococcus aureus
evaluated using a risk-based approach sug- didates for reduced microbial limit testing.
Streptococcus species
gested in USP Chapter <1111>.9 Table 7 contains suggested microbial limit

www.ijpc.com International Journal of Pharmaceutical Compounding


Vol. 18 No. 4 | July | August | 2014 309
Quality Control

testing strategies for typical pharmaceuti-


Table 7. Recommended Tests Based on Representative Water Activity
cal and OTC drug products based on esti-
mated aW. Manufacturers are urged to test
of Pharmaceuticals and Over-the-counter Products.3
their products for aW before developing Water Greatest Potential Recommended
reduced test strategy. Products Activity Contaminants Testing
Nasal inhalant 0.99 Gram-negative bacteria TAMC, TYMC, absence of S. aureus
and P. aeruginosa
Conclusion
Hair shampoo 0.99 Gram-negative bacteria TAMC, TYMC, absence of S. aureus
The microbial limit for nonsterile and P. aeruginosa
products must be within an acceptable Antacid 0.99 Gram-negative bacteria TAMC, TYMC, absence of E. coli and
range that does not pose health hazards to Salmonella spp.
intended patient groups or diminish prod- Topical cream 0.97 Gram-positive bacteria TAMC, TYMC, absence of S. aureus
and P. aeruginosa
uct stability. Objectionable organisms can
be detected using procedures prescribed Oral liquid 0.9 Gram-positive bacteria, fungi TAMC, TYMC

in USP <61> and <62>, but practitioners Oral suspension 0.87 Fungi TAMC, TYMC
and manufacturers should be aware of the Topical ointment 0.55 None Reduced testing
possibility for contamination by organ- Lip balm 0.36 None Reduced testing
isms not included in the USP list. Similarly, Suppositories
products with low-water activity may resist (vaginal, rectal) 0.3 None Reduced testing
microbial proliferation, but contaminating Compressed tablets 0.36 None Reduced testing
microorganisms may remain viable and Liquid-filled capsule 0.3 None Reduced testing
potentially be pathogenic. Therefore, aW TAMC = total aerobic microbial count; TYMC = total combined yeasts and molds count
measurements cannot solely be used to
justify the elimination of microbial testing
For Use in the ICH Regions. Microbiological [ICH Website.] October 1999. Available at:
for product release. Contamination con-
Examination of Non-Sterile Products; www.ich.org. Accessed April 7, 2014.
trol is a preventive activity that demands Annex 4AMicrobial Enumeration Tests 9. Roundtable: 15 Years in Pharmaceutical
conscientious adherence to GMP and good General Chapter; Annex 4B(R1)Test for Microbiology [American Pharmaceutical
compounding practice. Specified Micro-organisms General Chapter; Review Website]. October 30,
Annex 4C(R1)-Acceptance Criteria For 2013. Available at: www.ameri-
Pharmaceutical Preparations and Substances canpharmaceuticalreview.com/
References For Pharmaceutical Use. [ISPE Website.] Featured-Articles/148857-Roundtable-
1. Vu N, Lou JR, Kupiec TC. Quality control Available at: www.ispe.org. Accessed April 7, 15-Years-in-Pharmaceutical-Microbiology/.
analytical methods: Microbial limit tests for 2014. Accessed January 16, 2014.
nonsterile pharmaceuticals, part 1. IJPC 2014; 6. U.S. Department of Health & Human 10. Sutton S. What is an Objectionable
18(3): 213220. Services. U.S. Food and Drug Administration. Organism? [American Pharmaceutical
2. Clontz L. Microbial Limit and Bioburden Code of Federal Regulations Title 21, Part Review Website]. October 12, 2012. Available
Tests: Validation Approaches and Global 211. Available at www.accessdata.fda.gov/ at: www.americanpharmaceuticalreview.
Requirements. 2nd ed. Boca Raton, FL: CRC scripts/cdrh/cfdocs/cfcfr/CFRSearch. com/Featured-Articles/122201-What-is-
Press 2009. cfm?CFRPart=211. Accessed April 7, 2014. an-Objectionable-Organism-Objectionable-
3. United States Pharmacopeia Convention, 7. International Conference on Harmonisation. Organisms-The-Shifting-Perspective/.
Inc. United States Pharmacopeia 36 International Conference on Harmonisation Accessed January 16, 2014.
National Formulary 31. Rockville, MD: US of Technical Requirements for Registration 11. U.S. Food and Drug Administration. 2012a.
Pharmacopeial Convention, Inc.; 2013: of Pharmaceuticals for Human Use. ICH Bad Bug Book: Handbook of Foodborne
Chapters <61>, <62>, <1111>, <1112>, <1163>, Harmonised Tripartite Guideline. Stability Pathogenic Microorganisms and Natural
<1191>. Testing of New Drug Substances and Products Toxins, 2nd Edition. [FDA Website.]
4. U.S. Department of Health and Human Q1A (R2). [ICH Website.] February 6, 2003. Available at: www.fda.gov/downloads/
Services. U.S. Food and Drug Administration. Available at: www.ich.org. Accessed April 7, Food/FoodSafety/FoodborneIllness/
Guide To Inspections of Microbiological 2014. FoodborneIllnessFoodborne
Pharmaceutical Quality Control Laboratories. 8. International Conference on Harmonisation. PathogensNaturalToxins/ BadBugBook/
Available at: www.fda.gov/ICECI/ International Conference on Harmonisation UCM297627.pdf. Accessed February 21, 2014.
Inspections/InspectionGuides/ucm074914. of Technical Requirements For Registration
htm. Accessed February 18, 2014. of Pharmaceuticals For Human Use.
5. ISPE Glossary of Pharmaceutical ICH Harmonised Tripartite Guideline. Address correspondence to Nicole Vu, PhD,
Biotechnology Terminology. Guidance Specifications: Test Procedures and Acceptance Analytical Research Laboratories, Inc., 840
for Industry. Q4B Evaluation and Criteria for New Drug Substances and New Research Parkway, Suite 546, Oklahoma
Recommendation of Pharmacopeial Texts Drug Products: Chemical Substances Q6A (4). City, OK 73104. E-mail: nvu@arlok.com

International Journal of Pharmaceutical Compounding www.ijpc.com


310 Vol. 18 No. 4 | July | August | 2014