Romel A. Altamirano


Guidance on Formulating
Semisolid Drugs

The subjects covered here are generally applicable to all
forms of topical drug products, including those that are
intended to be sterile. The topics given below address
several problem areas that may be encountered in the
production of semisolid drug products (including transdermal
products) including their potency, active ingredient
uniformity, physical characteristics, microbial purity, and
chemical purity.


Active ingredient solubility and particle size are generally
important ingredient characteristics that need to be controlled
to ensure potency uniformity in many topical drug
products such as emulsions, creams, and ointments.
Crystalline form is also important where the active ingredient
is dispersed as a solid phase in either the oil or water
phase of an emulsion, cream, or ointment.
It is important that active ingredient solubility in the
carrier vehicle be known and quantified at the manufacturing
step in which the ingredient is added to the liquid
phase. The development data should adequately demonstrate
such solubility and its validation.
Substances that are very soluble, as is frequently the
case with ointments, would be expected to present less of
a problem than if the drug substance were to be suspended,
as is the case with creams. If the drug substance is soluble,
then potency uniformity would be based largely on adequate
distribution of the component throughout the mix.
If the active ingredient is insoluble in the vehicle, then
in addition to ensuring uniformity of distribution in the mix,
potency uniformity depends on control of particle size and
use of a validated mixing process. Particle size can also
affect the activity of the drug substance because the smaller
the particle size, the greater its surface area, which may
influence its activity. Particle size also affects the degree
to which the product may be physically irritating when
applied; in general, smaller particles are less irritating.
Production controls should be implemented that
account for the solubility characteristics of the drug substance;
inadequate controls can adversely affect product
potency, efficacy, and safety. For example, in one instance,
residual water remaining in the manufacturing vessel, used
to produce an ophthalmic ointment, resulted in partial
solubilization and subsequent recrystallization of the drug
substance; the substance recrystallized in a larger particle
size than expected and thereby raised questions about the
product efficacy.
In addition to ingredient solubility and particle size,
other physical characteristics and specifications for both
ingredients and finished products are important.



There are many different kinds of mixers used in the
manufacture of topical products. It is important that the
design of a given mixer is appropriate for the type of
topical product being mixed. One important aspect of
mixer design is how well the internal walls of the mixer
are scraped during the mixing process. This can present
some problems with stainless steel mixers because scraper
blades should be flexible enough to remove interior material,
yet not rigid enough to damage the mixer itself. In
general, good design of a stainless steel mixer includes
blades that are made of some hard plastic, such as Teflon®,
which facilitates scrapping of the mixer walls without
damaging the mixer.
If the internal walls of the mixer are not adequately
scraped during mixing and the residual material becomes
part of the batch, the result may be nonuniformity. Such
nonuniformity may occur, for example, if operators use
handheld spatulas to scrape the walls of the mixer.
Another mixer design concern is the presence of “dead
spots” where quantities of the formula are stationary and
not subject to mixing. Where such dead spots exist, there
should be adequate procedures for recirculation or nonuse
of the cream or ointment removed from the dead spots in
the tank.


Suspension products often require constant mixing of the
bulk suspension during filling to maintain uniformity. When
validating a suspension manufacturing process, determine
how to ensure that the product remains homogeneous during
the filling process and establish the data that support
the adequacy of the firm’s process. When the batch size is
large and the bulk suspension is in large tanks, determine
how the low levels of bulk suspension near the end of the
filling process are handled. If the bulk suspension drops
below a level, can this be adequately mixed? This question
must be answered. If the residual material transferred to a
smaller tank, how is the reliance made on handmixing of
the residual material? The adequacy of the process for dealing
with residual material should be demonstrated.


Typically, heat is applied in the manufacture of topical
products to facilitate mixing or filling operations. Heat
may also be generated by the action of high-energy mixers.
It is important to control the temperature within specified
parameters, not only to facilitate those operations but
also to ensure that product stability is not adversely
affected. Excessive temperatures may cause physical or
chemical degradation of the drug product, vehicle, active
ingredient or ingredients, or preservatives. Furthermore,
excessive temperatures may cause insoluble ingredients to
dissolve, reprecipitate, or change particle size or crystalline
Temperature control is also important where microbial
quality of the product is a concern. The processing of
topical products at higher temperatures can destroy some
of the objectionable microorganisms that may be present.
However, elevated temperatures may also promote incubation
of microorganisms.
Temperature uniformity within a mixer should be
controlled. In addressing temperature uniformity, one
should consider the complex interaction among vat size,
mixer speed, blade design, viscosity of contents, and rate
of heat transfer. Where temperature control is critical, use
of recording thermometers to continuously monitor and
document temperature measurements is preferred to frequent
manual checks. Where temperature control is not
critical, it may be adequate to manually monitor and
document temperatures periodically by use of handheld


It is current good manufacturing practice for a manufacturer
to establish and follow written standard operating
procedures to clean production equipment in a manner
that precludes contamination of current and future
batches. This is especially critical where contamination
may present direct safety concerns, as with a potent drug
such as a steroid (e.g., cortisone, and estrogen), antibiotic,
or sulfa drug, where there are hypersensitivity concerns.
The insolubility of some excipients and active substances
used in the manufacture of topical products makes
some equipment, such as mixing vessels, pipes, and plastic
hoses, difficult to clean. Often piping and transfer lines
are inaccessible to direct physical cleaning. Some firms
address this problem by dedicating lines and hoses to
specific products or product classes.
It is therefore important that the following considerations
be adequately addressed in a cleaning validation
protocol and in the procedures that are established for
production batches.


Cleaning procedures should be detailed and provide specific
understandable instructions. The procedure should
identify equipment, cleaning methods, solvents and
detergents approved for use, inspection and release
mechanisms, and documentation. For some of the more
complex systems, such as clean-in-place systems, it is
usually necessary both to provide a level of detail that
includes drawings and to provide provision to label
valves. The time that may elapse from completion of a
manufacturing operation to initiation of equipment
cleaning should also be stated where excessive delay may
affect the adequacy of the established cleaning procedure.
For example, residual product may dry and become
more difficult to clean.


As part of the validation of the cleaning method, the
cleaned surface is sampled for the presence of residues.
Sampling should be made by an appropriate method,
selected on the basis of factors such as equipment and
solubility of residues. For example, representative swabbing
of surfaces is often used, especially in areas that are
hard to clean or where the residue is relatively insoluble.
Analysis of rinse solutions for residues has also been
shown to be of value where the residue is soluble or
difficult to access for direct swabbing. Both methods are
useful when there is a direct measurement of the residual
substance. However, it is unacceptable to test rinse solutions
(such as purified water) for conformance to the purity
specifications for those solutions instead of testing directly
for the presence of possible residues.


Because of improved technology, analytical methods are
becoming much more sensitive and capable of determining
very low levels of residues. Thus, it is important to
establish appropriate limits on levels of post–equipmentcleaning
residues. Such limits must be safe, practical,
achievable, and verifiable and must ensure that residues
remaining in the equipment will not cause the quality of
subsequent batches to be altered beyond established product
specifications. The rationale for residue limits should
be established. Because surface residues will not be uniform,
it should be recognized that a detected residue level
may not represent the maximum amount that may be
present. This is particularly true when surface sampling
by swabs is performed on equipment.


The extent of microbiological controls needed for a given
topical product will depend on the nature of the product,
the use of the product, and the potential hazard to users
posed by microbial contamination. This concept is
reflected in the current good manufacturing practice regulations
at 21 Code of Federal Regulations (CFR)
211.113(a) (Control of microbiological contamination),
and in the U.S. Pharmacopeia (USP). It is therefore vital
that manufacturers assess the health hazard of all organisms
isolated from the product.

1. Deionized Water Systems for Purified Water

The microbiological control of deionized water systems
used to produce purified water is important. Deionizers
are usually excellent breeding areas for microorganisms.
The microbial population tends to increase as the length
of time between deionizer service periods increases. Other
factors that influence microbial growth include flow rates,
temperature, surface area of resin beds, and, of course, the
microbial quality of the feed water. These factors should
be considered in assessing the suitability of deionizing
systems where microbial integrity of the product incorporating
the purified water is significant. There should be a
suitable routine water monitoring program and a program
of other controls as necessary.
It is not necessary to assess and monitor the suitability
of a deionizer by relying solely on representations of the
deionizer manufacturer. Specifically, product quality
could be compromised if a deionizer is serviced at intervals
based not on validation studies but, rather, on the
“recharge” indicator built into the unit. Unfortunately,
such indicators are not triggered by microbial population
but, rather, are typically triggered by measures of electrical
conductivity or resistance. If a unit is infrequently used,
sufficient time could elapse between recharging and sanitizing
to allow the microbial population to increase significantly.
Preuse validation of deionizing systems used to produce
purified water should include consideration of such
factors as microbial quality of feed water (and residual
chlorine levels of feed water where applicable), surface
area of ion-exchange resin beds, temperature range of
water during processing, operational range of flow rates,
recirculation systems to minimize intermittent use and low
flow, frequency of use, quality of regenerant chemicals,
and frequency and method of sanitization.
A monitoring program used to control deionizing systems
should include established water quality and conductivity
monitoring intervals, measurement of conditions and
quality at significant stages through the deionizer (influent,
postcation, postanion, post–mixed bed, etc.), microbial
conditions of the bed, and specific methods of microbial
testing. Frequency of monitoring should be based on the
firm’s experience with the systems.
Other methods of controlling deionizing systems
include establishment of water-quality specifications and
corresponding action levels, remedial action when microbial
levels are exceeded, documentation of regeneration,
and a description of sanitization and sterilization procedures
for piping, filters, and so forth.

2. Microbiological Specifications and Test Methods

Microbiological specifications and microbial test methods
for each topical product should be well-established to
ensure that they are consistent with any described in the
relevant application or USP. In general, product specifications
should cover the total number of organisms permitted,
as well as specific organisms that must not be present.
These specifications must be based on use of specified
sampling and analytical procedures. Where appropriate,
the specifications should describe action levels where additional
sampling or speciation of organisms is necessary.
Manufacturers must demonstrate that the test methods
and specifications are appropriate for their intended purpose.
Where possible, firms should use methods that isolate
and identify organisms that may present a hazard to
the user under the intended use. It should be noted that
the USP does not state methods that are specific for waterinsoluble
topical products.
One test deficiency to be aware of is inadequate dispersement
of a cream or ointment on microbial test plates.
Firms may claim to follow USP procedures, yet in actual
practice they may not disperse product over the test plate,
resulting in inhibited growth as a result of concentrated
preservative in the nondispersed inoculate. The spread
technique is critical, and the firm should document that the
personnel performing the technique have been adequately
trained and are capable of performing the task. Validation
of the spread-plate technique is particularly important
when the product has a potential antimicrobial affect.
In assessing the significance of microbial contamination
of a topical product, both the identification of the
isolated organisms and the number of organisms found
are significant. For example, the presence of a high number
of organisms may indicate that the manufacturing
process, component quality, or container integrity may be
deficient. Although high numbers of nonpathogenic organisms
may not pose a health hazard, they may affect product
efficacy and physical/chemical stability. Inconsistent
batch-to-batch microbial levels may indicate some process
or control failure in the batch. The batch release evaluation
should extend to both organism identification and numbers
and, if limits are exceeded, there should be an investigation
into the cause.


Manufacturing controls necessary to maintain the antimicrobiological
effectiveness of preservatives should be
evaluated. For example, for those products that separate
on standing, there should be data available that show the
continued effectiveness of the preservative throughout the
product’s shelf life.
For preservative-containing products, finished product
testing must ensure that the specified level of preservative
is present before release. In addition, preservative effectiveness
must be monitored as part of the final ongoing
stability program. This can be accomplished through analysis
for the level of preservative previously shown to be
effective or through appropriate microbiological challenge
at testing intervals.
For concepts relating to sterility assurance and bioburden
controls on the manufacture of sterile topicals, see the
Guideline on Sterile Drug Products Produced by Aseptic


As with other dosage forms, it is important to carefully
control how changes are made in the production of topical
products. The procedures should be able to support
changes that represent departures from approved and validated
manufacturing processes. There should be written
change control procedures that have been reviewed and
approved by the quality-control unit. The procedures
should provide for full description of the proposed change,
the purpose of the change, and controls to ensure that the
change will not adversely alter product safety and efficacy.
Factors to consider include potency or bioactivity, uniformity,
particle size (if the active ingredient is suspended),
viscosity, chemical and physical stability, and microbiological
Of particular concern are the effects that formulation and
process changes may have on the therapeutic activity and
uniformity of the product. For example, changes in vehicle
can affect absorption, and processing changes can alter the
solubility and microbiological quality of the product.


The manufacturing of topical transdermal products
(patches) has many problems in scale-up and validation.
Problems analogous to production of topical creams or
ointments include uniformity of the drug substance and
particle size in the bulk gel or ointment. Uniformity and
particle size are particularly significant when the drug
substance is suspended or partially suspended in the vehicle.
Viscosity also needs control because it can affect the
absorption of the drug; the dissolution test is important in
this regard. Other areas that need special inspectional
attention are assembly and packaging of the patch, including
adhesion, package integrity (regarding pinholes), and
controls to ensure that a dose is present in each unit.
Because of the many quality parameters that must be
considered in the manufacture and control of a transdermal
dosage form, scale-up may be considerably more difficult
than for many other dosage forms. Therefore, special attention
should be given to evaluating the adequacy of the
process validation efforts. As with other dosage forms,
process validation must be based on multiple lots, typically
at least three consecutive successful batches. Summary
data should be augmented by comparison with selected data
contained in supporting batch records, particularly where
the data appear unusually uniform or disparate. Given the
complexities associated with this dosage form, the tolerances
or variances may be broader than for other dosage
forms. In addition, batches may not be entirely problem
free. Nevertheless, there should be adequate rationale for
the tolerances and production experiences, based on appropriate
developmental efforts and investigation of problems.


In general, semisolid dosage forms are complex formulations
having complex structural elements. Often they are
composed of two phases (oil and water), one of which is
a continuous (external) phase, and the other of which is a
dispersed (internal) phase. The active ingredient is often
dissolved in one phase, although occasionally the drug is
not fully soluble in the system and is dispersed in one or
both phases, thus creating a three-phase system. The physical
properties of the dosage form depend on various factors,
including the size of the dispersed particles, the interfacial
tension between the phases, the partition coefficient
of the active ingredient between the phases, and the product
rheology. These factors combine to determine the
release characteristics of the drug as well as other characteristics,
such as viscosity.
For a true solution, the order in which solutes are added
to the solvent is usually unimportant. The same cannot be
said for dispersed formulations, however, because depending
on at which phase a particulate substance is added,
dispersed matter can distribute differently. In a typical
manufacturing process, the critical points are generally the
initial separation of a one-phase system into two phases
and the point at which the active ingredient is added.
Because the solubility of each added ingredient is important
for determining whether a mixture is visually a single
homogeneous phase, such data, possibly supported by optical
microscopy, should usually be available for review. This
is particularly important for solutes added to the formulation
at a concentration near or exceeding that of their solubility
at any temperature to which the product may be
exposed. Variations in the manufacturing procedure that
occur after either of these events are likely to be critical to
the characteristics of the finished product. This is especially
true of any process intended to increase the degree of
dispersion through reducing droplet or particle size (e.g.,
homogenization). Aging of the finished bulk formulation
before packaging is critical and should be specifically
addressed in process validation studies.


The key parameter for any drug product is its efficacy as
demonstrated in controlled clinical trials. The time and
expense associated with such trials make them unsuitable
as routine quality control methods. Therefore,
in vitro surrogate tests are often used to ensure that product quality
and performance are maintained over time and in the presence
of change. A variety of physical and chemical tests
commonly performed on semisolid products and their components
(e.g., solubility, particle size and crystalline form
of the active component, viscosity, and homogeneity of the
product) have historically provided reasonable evidence of
consistent performance. More recently, in vitro release testing
has shown promise as a means to comprehensively
ensure consistent delivery of the active component or components
from semisolid products. An in vitro release rate
can reflect the combined effect of several physical and
chemical parameters, including solubility and particle size
of the active ingredient and rheological properties of the
dosage form. In most cases, in vitro release rate is a useful
test to assess product sameness between prechange and
postchange products. However, there may be instances in
which it is not suitable for this purpose. In such cases,
other physical and chemical tests to be used as measures
of sameness should be proposed and discussed with the
agency. With any test, the metrics and statistical approaches
to documentation of “sameness” in quality attributes
should be considered. The evidence available at this time
for the in vitro – in vivo correlation of release tests for semisolid
dosage forms is not as convincing as that for in vitro
dissolution as a surrogate for in vivo bioavailability of solid
oral dosage forms. Therefore, the FDA’s current position
concerning in vitro release testing is as follows:

a. In vitro
release testing is a useful test to assess
product sameness under certain scale-up and
postapproval changes for semisolid products.

b. The development and validation of an
in vitro release test are not required for approval of an
NDA, ANDA, or AADA, nor is the in vitro
release test required as a routine batch-to-batch
quality control test.

c. In vitro release testing alone is not a surrogate
test for in vivo bioavailability or bioequivalence.

d. The in vitro release rate should not be used for
comparing different formulations across manufacturers.

In vitro release is one of several standard methods that
can be used to characterize performance characteristics of
a finished topical dosage form; that is, semisolids such as
creams, gels, and 20 ointments. Important changes in the
characteristics of a drug product formula or the thermodynamic
properties of the drug or drugs it contains should
show up as a difference in drug release. Release is theoretically
proportional to the square root of time when the
formulation in question is in control of the release process
because the release is from a receding boundary.
In vitro
release method for topical dosage forms is based on an
open chamber diffusion cell system such as a Franz cell
system, fitted usually with a synthetic membrane. The test
product is placed on the upper side of the membrane in
the open donor chamber of the diffusion cell, and a sampling
fluid is placed on the other side of the membrane in
a receptor cell. Diffusion of drug from the topical product
to and across the membrane is monitored by assay of
sequentially collected samples of the receptor fluid. The
in vitro
release methodology should be appropriately validated.
Sample collection can be automated. Aliquots
removed from the receptor phase can be analyzed for
drug content by high-pressure liquid chromatography or
other analytical methodology. A plot of the amount of
drug released per unit area (mcg/cm) against the square
root of time yields a straight line, the slope of which
represents the release rate. This release rate measure is
formulation specific and can be used to monitor product
quality. The release rate of the biobatch or currently
manufactured batch should be compared with the release
rate of the product prepared after a change, as defined
in this guidance.


The design of in vivo bioequivalence studies for semisolid
dosage forms varies depending on the pharmacological
activity of the drug and dosage form. A brief general
discussion of such tests follows. The objective is to document
the bioequivalence of the drug product for which
the manufacture has been changed, as defined in this guidance,
compared with the drug product manufactured
before the change or with the reference-listed drug. The
study design is dependent on the nature of the active drug.
The bioequivalence study can be a comparative skinblanching
study as in glucocorticoids (FDA, 1995) or a
comparative clinical trial or any other appropriate validated
bioequivalence study (e.g., dermatopharmacokinetic
study) for the topical dermatological drug product. The
assay methodology selected should ensure specificity,
accuracy, interday and intraday precision, linearity of standard
curves, and adequate sensitivity, recovery, and stability
of the samples under the storage and handling conditions
associated with the analytical method. (See Van Buskirk
et al., 1994.)

FDA, Topical Dermatological Corticosteroids:
In Vivo Bioequivalence, June 2, 1995. Van Buskirk, G.A., Shah, V.P.,
Adair, D., et al., Workshop report: scale-up of liquid and semi-solids disperse systems, Pharm. Res.,11, 1216–1220, 1994.


Approved Target Composition —Components and amount of each ingredient for a drug product used in an
approved pivotal clinical study or bioequivalence study

Batch—Specific quantity of a drug or other material produced
according to a single manufacturing order during
the same cycle of manufacture and intended to have uniform
character and quality, within specified limits (21 CFR

Contiguous Campus—Contiguous or unbroken site or a
set of buildings in adjacent city blocks

Creams/Lotions—Semisolid emulsions that contain fully
dissolved or suspended drug substances for external application.
Lotions are generally of lower viscosity

Diluent—Vehicle in a pharmaceutical formulation commonly
used for making up volume or weight (e.g., water,
paraffin base)

Drug Product—Finished dosage form (e.g., cream, gel,
or ointment) in its marketed package. It also can be a
finished dosage form (e.g., tablet, capsule, or solution)
that contains a drug substance, generally, but not necessarily,
in association with one or more other ingredients
(21 CFR 314.3(b))

Drug Release—Disassociation of a drug from its formulation,
thereby allowing the drug to be distributed into the
skin or be absorbed into the body, where it may exert its
pharmacological effect

Drug Substance—Active ingredient that is intended to
furnish pharmacological activity or other direct effect in
the diagnosis, cure, mitigation, treatment, or prevention of
a disease or to affect the structure or any function of the
human body, but that does not include intermediates used
in the synthesis of such ingredient (21 CFR 314.3(b))

Emulsion—Two-phase systems in which an immiscible
liquid (dispersed phase) is dispersed throughout another
liquid (continuous phase or external phase) as small droplets.
Where oil is the dispersed phase and an aqueous
solution is the continuous phase, the system is designated
as an oil-in-water emulsion. Conversely, where water or an
aqueous solution is the dispersed phase and oil or oleaginous
material is the continuous phase, the system is designated
as a water-in-oil emulsion. Emulsions are stabilized
by emulsifying agents that prevent coalescence, the
merging of small droplets into larger droplets and, ultimately,
into a single separated phase. Emulsifying agents
(surfactants) do this by concentration in the interface
between the droplet and external phase and by providing
a physical barrier around the particle to coalesce. Surfactants
also reduce the interfacial tension between the phases,
thus increasing the ease of emulsification on mixing.
Emulsifying agents substantially prevent or delay the time
needed for 27 emulsion droplets to coalesce. Emulsification
is the act of forming an emulsion. Emulsification can
involve the incorporation of a liquid within another liquid
to form an emulsion or a gas in a liquid to form a foam.

Formulation—Listing of the ingredients and quantitative
composition of the dosage form

Gel—Semisolid system in which a liquid phase is constrained
within a three-dimensional, cross-linked matrix.
The drug substance may be either dissolved or suspended
within the liquid phase.

Homogenization—Method of atomization and thereby
emulsification of one liquid in another in which the liquids
are pressed between a finely ground valve and seat under
high pressure (e.g., up to 5,000 psi)

Internal Phase—Internal phase or dispersed phase of an
emulsion that comprises the droplets that are found in the

In Vitro Release Rate—Rate of release of the active drug
from its formulation, generally expressed as amount/unit

Ointment—Unctuous semisolid for topical application.
Typical ointments are based on petrolatum. An ointment
does not contain sufficient water to separate into a second
phase at room temperature. Water-soluble ointments may
be formulated with polyethylene glycol.
Pilot-Scale Batch
—Manufacture of drug product by a
procedure fully representative of and simulating that
intended to be used for full manufacturing scale

Preservative—Agent that prevents or inhibits microbial
growth in a formulation to which it has been added

Process—Series of operations, actions, and controls used
to manufacture a drug product

Scale-down—Process of decreasing the batch size

Scale-up—Process of increasing the batch size

Shear—Strain resulting from applied forces that cause or
tend to cause contiguous parts of a body to slide relative
to one another in direction parallel to their plane of contact.
In emulsification and suspensions, it is the strain
produced on passing a system through a homogenizer or
other milling device. Low shear: Processing in which the
strain produced through mixing or emulsifying shear is
modest. High shear: Forceful processes that, at point of
mixing or emulsification, place a great strain on the product.
Homogenization, by its very nature, is a high-shear
process that leads to a small and relatively uniform emulsion
droplet size. Depending on their operation, mills and
mixers are categorized as either high-shear or low-shear

Significant Body of Information—A significant body of
information on the stability of the product is likely to exist
after 5 years of commercial experience for new molecular
entities or 3 years of commercial experience for new dosage

Strength—Strength is the concentration of the drug substance
(e.g., weight/weight, weight/volume, or unit
dose/volume basis) or the potency, that is, the therapeutic
activity of the drug product as indicated by appropriate
laboratory tests or by adequately developed and controlled
clinical data (e.g., expressed in terms of units by reference
to a standard) (21 CFR 210.3(b)(16)). For semisolid dosage
forms the strength is usually stated as a weight/weight
or weight/volume percentage.

Structure-Forming Excipient—Excipient that participates
in the formation of the structural matrix that gives an
ointment, cream, gel, etc., its semisolid character. Examples
are gel-forming polymers, petrolatum, certain colloidal inorganic
solids (e.g., bentonite), waxy solids (e.g., cetyl alcohol,
stearic acid), and emulsifiers used in creams.

Suspending Agent—Excipient added to a suspension to
control the rate of sedimentation of the active ingredients

Technical Grade—Technical grades of excipients differ
in their specifications and intended use. Technical grades
may differ in specifications or functionality, impurities,
and impurity profiles.

Validation—Procedure to establish documented evidence
that provides a high degree of assurance that a specific
process or test will consistently produce a product or test
outcome meeting its predetermined specifications and
quality attributes. A validated manufacturing process or
test is one that has been proven to do what it purports to
or is represented to do. The proof of process validation is
obtained through collection and evaluation of data, preferably
beginning with the process development phase and
continuing through the production phase. Process validation
necessarily includes process qualification (the qualification
of materials, equipment, systems, building, and
personnel), but it also includes the control of the entire
processes for repeated batches or runs.

Romel A. Altamirano