Romel A. Altamirano

Consideraciones de GMP de liquidos.

The manufacture and control of oral solutions and oral suspensions presents some unusual problems not common to other dosage forms. Although bioequivalency concerns are minimal (except for products in which dissolution is a rate-limiting or absorption-determining step, as in phenytoin suspension), other issues have frequently led to recalls of liquid products. These include microbiological, potency, and stability problems. In addition, 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 who may have compromised drug metabolic or other clearance function, defective dosage forms can pose a greater risk if the absorption profiles are significantly altered from the profiles used in the development of drug safety profiles.

The designs of the facilities are largely dependent on the type of products manufactured and the potential for cross contamination and microbiological contamination. For example, the facilities used for the manufacture of overthe- counter oral products might not require the isolation that a steroid or sulfa product would require. However, the concern for contamination remains, and it is important to isolate processes that generate dust (such as those processes occurring before the addition of solvents). The HVAC (heating, ventilation, and air-conditioning) system should be validated just as required for processing of potent drugs. Should a manufacturer rely mainly on recirculation rather than filtration or fresh air intake, efficiency of air filtration must be validated by surface and air sampling.
It is advisable not to take any shortcuts in the design of HVAC systems, as it is often very difficult to properly
validate a system that is prone to breakdown; in such instances a fully validated protocol would need stress testing — something that may be more expensive than establishing proper HVAC systems in the first place. However, it is also unnecessary to overdo it in designing the facilities, as once the drug is present in a solution form, cross contamination to other products becomes a lesser problem. It is, nevertheless, important to protect the drug fromother powder sources (such as by maintaining appropriate pressure differentials in various cubicles).

Equipment should be of sanitary design. This includes sanitary pumps, valves, flow meters, and other equipment that can be easily sanitized. Ball valves, the packing in pumps, and pockets in flow meters have been identified as sources of contamination. Contamination is an extremely important consideration, particularly for those sourcing manufacturing equipment from less developed countries; manufacturers of equipment often offer two grades of equipment: sanitary equipment, and equipment not qualified as sanitary and offered at substantial savings. All manufacturers intending to ship any product subject  to U.S. Food and Drug Administration (FDA) inspection must insist on certification that the equipment is of sanitary design.

To facilitate cleaning and sanitization, manufacturing and filling lines should be identified and detailed in drawings and standard operating procedures. Long delivery lines between manufacturing areas and filling areas can be a source of contamination. Special attention should be paid to developing standard operating procedures that clearly establish validated limits for this purpose. Equipment used for batching and mixing of oral solutions and suspensions is relatively basic. These products are generally formulated on a weight basis, with the batching tank on load cells so that a final volume can be made by weight; if you have not done so already, consider converting your systems to weight basis. Volumetric means,
such as using a dipstick or a line on a tank, are not generally as accurate and should be avoided where possible. When volumetric means are chosen, make sure they are properly validated at different temperature conditions and other factors that might render this practice faulty. In most cases, manufacturers assay samples of the bulk solution or suspension before filling. A much greater variability is found with those batches that have been manufactured volumetrically rather than those that have been manufactured by weight. Again, the rule of thumb is to avoid any additional validation if possible.

The design of the batching tank with regard to the location of the bottom discharge valve often presents problems. Ideally, the bottom discharge valve is flush with the bottom of the tank. In some cases, valves — including undesirable ball valves — are several inches to a foot below the bottom of the tank. This is not acceptable. It is possible that in this situation the drug or preservative may not completely dissolve and may get trapped in the “dead leg” below the tank, with initial samples turning out subpotent. For the manufacture of suspensions, valves should be flush. Transfer lines are generally hard piped and are easily cleaned and sanitized. In situations where manufacturers use flexible hoses to transfer product, it is not unusual to
see these hoses lying on the floor, thus significantly increasing the potential for contamination. Such contamination can occur through operators picking up or handling hoses, and possibly even through operators placing them in transfer or batching tanks after the hoses had been lying on the floor. It is a good practice to store hoses in a way that allows them to drain, rather than coiling them, which may allow moisture to collect and be a potential source of microbial contamination.

Another common problem occurs when manifold or common connections are used, especially in water supply,
premix, or raw material supply tanks. Such common connections can be a major source of contamination.

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 (to <25 microns). For syrup, 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 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. It is therefore a good idea to indicate particle size in the raw material specification, even though it is meant for dissolving in the processing, to better validate the manufacturing process while avoiding scale-up problems.

In addition to a determination of the final volume (on
weight or volume basis) as previously discussed, there are
microbiological concerns, and these are well covered in
other chapters in this book.

For oral suspensions there is the additional concern
of 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. It is necessary to establish 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 batch records must demonstrate compliance using control
charts. There are some processes in manufacturing in
which heat is used during compounding to control the
microbiological levels in the product. For such products,
the addition of purified water to make up to final volume,
the batch, and the temperatures during processing should
be properly documented.

In addition to drug substances, some additives
- such as the most commonly used preservatives, parabens
- are difficult to dissolve, and require heat (often to 80°C). The
control and verification of their dissolution during the
compounding stage should be established in the method
validation. 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.
There are also some oral liquids that are sensitive to
oxygen and that 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, as by nitrogen purging. In addition, such products
might also require storage in sealed tanks, rather than
in those with loose lids. Manufacturing directions provided
in this book are particularly detailed about the purging
steps, and these should be closely observed.

Microbiological contamination can present significant
health hazards in some oral liquids. For example, some
oral liquids, such as nystatin suspension, are used in
infants and immunocompromised patients, and microbiological
contamination with organisms (such as Gram-negative
organisms) is not acceptable. 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, contamination with
Pseudomonas sp. might not present the same health hazard.
However, the presence of a specific Pseudomonas sp. may also
indicate other plant or raw material contamination
and often points to defects in the water systems and
environmental breaches; extensive investigations are often
required to trace the source of contamination. 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. For example, the presence of a
Pseudomonas putida contaminant could also indicate that
P. aeruginosa, a similar source organism, is also present.
Because FDA laboratories typically use more sensitive
test methods than industry, samples of oral liquids in
which manufacturers report microbiological counts well
within limits may be found unacceptable by the federal
laboratories. This result requires upgrading the sensitivity
of testing procedures.

Liquid products in which the drug is suspended (not in
solution) present some unique manufacturing and control
problems. Depending on 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. Procedures
must therefore be established for filling and diagrams
established for line setup prior to the filling equipment.

Good manufacturing practice would warrant testing
bottles from the beginning, middle, and end of a batch to
ensure that segregation has not occurred. Such samples
should not be combined for the purpose of analysis. Inprocess
testing for suspensions might also include an
assay of a sample from the bulk tank. More important at
this stage, however, may be testing for viscosity.

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. In addition, 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 that 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 established.

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

For example, for solutions, the key aspects that should
be addressed during validation include ensuring that the
drug substance and preservatives are dissolved. Parameters
such as heat and time should be measured. In-process
assay of the bulk solution during or after compounding
according to predetermined limits is also an important
aspect of process validation. For solutions that are sensitive
to oxygen or light, dissolved oxygen levels would also
be an important test. Again, the development data and the
protocol should provide limits.

As discussed, the manufacture of suspensions presents
additional problems, particularly in the area of uniformity.
The development data should address the key compounding
and filling steps that ensure 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 over-the-counter antacids, usually require a
bioequivalency or clinical study to demonstrate their effectiveness.
Comparison of product batches with the biobatch
is an important part of the validation process. Make sure
there are properly written protocol and process validation
reports and, if appropriate, data for comparing full-scale
batches with biobatch available during FDA inspection.

One area that has presented a number of problems is
ensuring the stability of oral liquid products throughout
their expiry period. The presence of water or other solvents
enhances all reaction rates: Because fluids can contain a
certain amount of oxygen, the oxidation reactions are also
enhanced, as in the case of vitamins and the phenothiazine
class of drugs. Good practice for these classes of drug
products should include quantitation of both the active and
primary degradant. There should be well-established specifications
for the primary degradant, including methods of
quantitation of 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
to determine whether contact of the drug product with
the closure system affects product integrity.
Other problems associated with inadequate closure
systems are moisture losses that can cause the remaining
contents to become superpotent and microbiological contamination.

Problems in the packaging of oral liquids have included
potency (fill) of unit dose products and accurate calibration
of measuring devices such as droppers, which are
often provided. For unit dose solution products the label
claim quantity within the limits described should be

Another problem in the packaging of oral liquids is
lack of cleanliness of the containers before filling. Fibers
and even insects often appear as debris in containers,
particularly in the plastic containers used for many of
these products. Many manufacturers receive containers
shrink-wrapped in plastic to minimize contamination from
fiberboard cartons, and many manufacturers use compressed
air to clean the containers. Vapors, such as oil
vapors, from the compressed air have occasionally been
found to present problems, and it is a good practice to use
compressed gas from oil-free compressors.
Romel A. Altamirano