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Oral Solutions and Suspensions (8/94)
GUIDE TO INSPECTIONS ORAL SOLUTIONS AND SUSPENSIONS
Note: This document is reference material for investigators and other FDA
personnel. The document does not bind FDA, and does no confer any rights,
privileges, benefits, or immunities for or on any person(s).
I. INTRODUCTION
The manufacture and control of oral solutions and oral suspensions has presented some
problems to the industry. While bioequivalency concerns are minimal (except for the antiseptic
products such as phenytoin suspension), there are other issues which have led to recalls. These
include microbiological, potency and stability problems. Additionally, because the population
using these oral dosage forms includes newborns, pediatrics and geriatrics who may not be able
to take oral solid dosage forms and may be compromised, defective dosage forms can pose a
greater risk because of the population being dosed. Thus, this guide will review some of the
significant potential problem areas and provide direction to the investigator when giving
inspectional coverage.
II. FACILITIES
The design of the facilities are largely dependent upon the type of products manufactured and
the potential for cross-contamination and microbiological contamination. For example, the
facilities used for the manufacture of OTC oral products might not require the isolation that a
steroid or sulfa product would require.
Review the products manufactured and the procedures used by the firm for the isolation of
processes to minimize contamination. Observe the addition of drug substance and powdered
excipients to manufacturing vessels to determine if operations generate dust. Observe the
systems and the efficiency of the dust removal system.
The firm's HVAC (Heating Ventilation and Air Conditioning) system may also warrant coverage
particularly where potent or highly sensitizing drugs are processed. Some manufacturers
recirculate air without adequate filtration. Where air is recirculated, review the firm's data
which demonstrates the efficiency of air filtration such should include surface and/or air
sampling.
III. EQUIPMENT
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Equipment should be of sanitary design. This includes sanitary pumps, valves, flow meters and
other equipment which can be easily sanitized. Ball valves, packing in pumps and pockets in
flow meters have been identified as sources of contamination.
In order to facilitate cleaning and sanitization, manufacturing and filling lines should be
identified and detailed in drawings and SOPs. In some cases, long delivery lines between
manufacturing areas and filling areas have been a source of contamination. Also, SOPs,
particularly with regard to time limitations between batches and for cleaning have been found
deficient in many manufacturers. Review cleaning SOPs, including drawings and validation data
with regard to cleaning and sanitization.
Equipment used for batching and mixing of oral solutions and suspensions is relatively basic.
Generally, these products are formulated on a weight basis with the batching tank on load cells
so that a final Q.S. can be made by weight. Volumetric means, such as using a dip stick or line on
a tank, have been found to be inaccurate.
In most cases, manufacturers will assay samples of the bulk solution or suspension prior to
filling. A much greater variability has been found with batches that have been manufactured
volumetrically rather than by weight. For example, one manufacturer had to adjust
approximately 8% of the batches manufactured after the final Q.S. because of failure to comply
with potency specifications. Unfortunately, the manufacturer relied solely on the bulk assay.
After readjustment of the potency based on the assay, batches occasionally were found out of
specification because of analytical errors.
The design of the batching tank with regard to the location of the bottom discharge valve has
also presented problems. Ideally, the bottom discharge valve is flush with the bottom of the
tank. In some cases valves, including undesirable ball valves, have been found to be several
inches to a foot below the bottom of the tank. In others, drug or preservative was not completely
dissolved and was lying in the "dead leg" below the tank with initial samples being found to be
subpotent. For the manufacture of suspensions, valves should be flush. Review and observe the
batching equipment and transfer lines.
With regard to transfer lines, they are generally hard piped and easily cleaned and sanitized. In
some cases manufacturers have used flexible hoses to transfer product. It is not unusual to see
flexible hoses lying on the floor, thus significantly increasing the potential for contamination.
Such contamination can occur by operators picking up or handling hoses, and possibly even
placing them in transfer or batching tanks after they had been lying on the floor. It is also a good
practice to store hoses in a way that allows them to drain rather than be coiled which may allow
moisture to collect and be a potential source of microbial contamination. Observe
manufacturing areas and operator practices, particularly when flexible hose connection are
employed.
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Another common problem occurs when a manifold or common connections are used, especially
in water supply, premix or raw material supply tanks. Such common connections have been
shown to be a source of contamination.
IV. RAW MATERIALS
The physical characteristics, particularly the particle size of the drug substance, are very
important for suspensions. As with topical products in which the drug is suspended, particles
are usually very fine to micronized (less than 25 microns). For syrups, elixir or solution dosage
forms in which there is nothing suspended, particle size and physical characteristics of raw
materials are not that important. However, they can affect the rate of dissolution of such raw
materials in the manufacturing process. Raw materials of a finer particle size may dissolve faster
than those of a larger particle size when the product is compounded.
Examples of a few of the oral suspensions in which a specific and well defined particle size
specification for the drug substance is important include phenytoin suspension, carbamazepine
suspension, trimethoprim and sulfamethoxazole suspension, and hydrocortisone suspension.
Review the physical specifications for any drug substance which is suspended in the dosage
form.
V. COMPOUNDING
In addition to a determination of the final volume (Q.S.) as previously discussed, there are
microbiological concerns. For oral suspensions, there is the additional concern with uniformity,
particularly because of the potential for segregation during manufacture and storage of the bulk
suspension, during transfer to the filling line and during filling. Review the firm's data that
support storage times and transfer operations. There should be established procedures and time
limits for such operations to address the potential for segregation or settling as well as other
unexpected effects that may be caused by extended holding or stirring.
For oral solutions and suspensions, the amount and control of temperature is important from a
microbiological as well as a potency aspect. For those products in which temperature is
identified as a critical part of the operation, the firm's documentation of temperature, such as by
control charts, should be reviewed.
There are some manufacturers that rely on heat during compounding to control the
microbiological levels in product. For such products, the addition of purified water to final Q.S.,
the batch, and the temperatures during processing should be reviewed.
In addition to drug substances, some additives, such as the parabens are difficult to dissolve and
require heat. The control and assurance of their dissolution during the compounding stage
should be reviewed. From a potency aspect, the storage of product at high temperatures may
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increase the level of degradants. Storage limitations (time and temperature) should be justified
by the firm and evaluated during your inspection.
There are also some oral liquids which are sensitive to oxygen and have been known to undergo
degradation. This is particularly true of the phenothiazine class of drugs, such as perphenazine
and chlorpromazine. The manufacture of such products might require the removal of oxygen
such as by nitrogen purging. Additionally, such products might also require storage in sealed
tanks, rather than those with loose lids. Manufacturing directions for these products should be
reviewed.
VI. MICROBIOLOGICAL QUALITY
There are some oral liquids in which microbiological contamination can present significant
health hazards. For example, some oral liquids, such as nystatin suspension are used in infants
and immuno-compromised patients, and microbiological contamination with organisms, such
as Gram-negative organisms, is objectionable. There are other oral liquid preparations such as
antacids in which Pseudomonas sp. contamination is also objectionable. For other oral liquids
such as cough preparations, the contamination with Pseudomonas sp. might not present the
same health hazard. Obviously, the contamination of any preparation with Gram-negative
organisms is not desirable.
In addition to the specific contaminant being objectionable, such contamination would be
indicative of a deficient process as well as an inadequate preservative system. The presence of a
specific Pseudomonas sp. may also indicate that other plant or raw material contaminants could
survive the process. For example, the fact that a Pseudomonas putida contaminant is present
could also indicate that Pseudomonas aeruginosa, a similar source organism, could also be
present.
Both the topical and microbiological inspection guides discuss the methods and limitations of
microbiological testing. Similar microbiological testing concepts discussed apply to the testing
of oral liquids for microbiological contamination. Review the microbiological testing of raw
materials, including purified water, as well as the microbiological testing of finished products.
Since FDA laboratories typically utilize more sensitive test methods than industry, consider
sampling any oral liquids in which manufacturers have found microbiological counts, no matter
how low. Submit samples for testing for objectionable microorganisms.
VII. ORAL SUSPENSIONS UNIFORMITY
Those liquid products in which the drug is suspended (and not in solution) present
manufacturer and control problems.
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Those liquid products in which the drug is suspended (and not in solution) present manufacture
and control problems. Depending upon the viscosity, many suspensions require continuous or
periodic agitation during the filling process. If delivery lines are used between the bulk storage
tank and the filling equipment, some segregation may occur, particularly if the product is not
viscous. Review the firm's procedures for filling and diagrams for line set-up prior to the filling
equipment.
Good manufacturing practice would warrant testing bottles from the beginning, middle and end
to assure that segregation has not occurred. Such samples should not be composited.
In-process testing for suspensions might also include an assay of a sample from the bulk tank.
More important, however, may be testing for viscosity.
VIII. PRODUCT SPECIFICATIONS
Important specifications for the manufacture of all solutions include assay and microbial limits.
Additional important specifications for suspensions include particle size of the suspended drug,
viscosity, pH, and in some cases dissolution. Viscosity can be important from a processing
aspect to minimize segregation. Additionally, viscosity has also been shown to be associated
with bioequivalency. pH may also have some meaning regarding effectiveness of preservative
systems and may even have an effect on the amount of drug in solution. With regard to
dissolution, there are at least three products which have dissolution specifications. These
products include phenytoin suspension, carbamazepine suspension, and sulfamethoxazole and
trimethoprim suspension. Particle size is also important and at this point it would seem that any
suspension should have some type of particle size specification. As with other dosage forms, the
underlying data to support specifications should be reviewed.
IX. PROCESS VALIDATION
As with other products, the amount of data needed to support the manufacturing process will
vary from product to product. Development (data) should have identified critical phases of the
operation, including the predetermined specifications, that should be monitored during process
validation.
For example, for solutions the key aspects that should be addressed during validation include
assurance that the drug substance and preservatives are dissolved. Parameters, such as heat and
time should be measured. Also, in-process assay of the bulk solution during and/or after
compounding according to predetermined limits are also an important aspects of process
validation. For solutions that are sensitive to oxygen and/or light, dissolved oxygen levels would
also be an important test. Again, the development data and the protocol should provide limits.
Review firm's development data and/or documentation for their justification of the process.
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As discussed, the manufacture of suspensions presents additional problems, particularly in the
area of uniformity. Again, development data should have addressed the key compounding and
filling steps that assure uniformity. The protocol should provide for the key in-process and
finished product tests, along with their specifications. For oral solutions, bioequivalency studies
may not always be needed. However, oral suspensions, with the possible exception of some of
the antacids, OTC products, usually require a bioequivalency or clinical study to demonstrate
effectiveness. As with oral solid dosage forms, comparison to the biobatch is an important part
of validation of the process.
Review the firm's protocol and process validation report and, if appropriate, compare data for
full scale batches to biobatch, data and manufacturing processes.
X. STABILITY
One area that has presented a number of problems includes the assurance of stability of oral
liquid products throughout their expiry period. For example, there have been a number of
recalls of the vitamins with fluoride oral liquid products because of vitamin degradation. Drugs
in the phenothiazine class, such as perphenazine, chlorpromazine and promethazine have also
shown evidence of instability. Good practice for this class of drug products would include
quantitation of both the active and primary degradant. Dosage form manufacturers should
know and have specifications for the primary degradant. Review the firm's data and validation
data for methods used to quantitate both the active drug and degradant.
Because interactions of products with closure systems are possible, liquids and suspensions
undergoing stability studies should be stored on their side or inverted in order to determine
whether contact of the drug product with the closure system affects product integrity.
Moisture loss which can cause the remaining contents to become superpotent and
microbiological contamination are other problems associated with inadequate closure systems.
XI. PACKAGING
Problems in the packaging of oral liquids have included potency (fill) of unit dose products,
accurate calibration of measuring devices such as droppers that are often provided. The USP
does not provide for dose uniformity testing for oral solutions. Thus, for unit dose solution
products, they should deliver the label claim within the limits described in the USP. Review the
firm's data to assure uniformity of fill and test procedures to assure that unit dose samples are
being tested.
Another problem in the packaging of Oral Liquids is the lack of cleanliness of containers prior to
filling. Fibers and even insects have been identified as debris in containers, and particularly
plastic containers used for these products. Many manufacturers receive containers shrink-
wrapped in plastic to minimize contamination from fiberboard cartons. Many manufacturers
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utilize compressed air to clean containers. Vapors, such as oil vapors, from the compressed air
have occasionally been found to present problems. Review the firm's systems for the cleaning of
containers.
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