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
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.
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 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.
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.
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
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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 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.
There are no references from this document.
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