Download Two-Piece Hard Capsules for Pharmaceutical

PHARMACEUTICAL PRO CESSES
Two-Piece Hard Capsules
for Pharmaceutical
Formulations
GLOWIMAGES/GETTY IMAGES
Dennis Murachanian
“Pharmaceutical Processes” discusses scientific and technical principles associated
with pharmaceutical unit operations useful to practitioners in compliance and validation. We intend this column to be a useful resource for daily work applications. The
primary objective for this feature: Useful information.
Reader comments, questions, and suggestions are needed to help us fulfill our
objectives. Case studies submitted by readers are most welcome. Please send your
comments and suggestions to column coordinator Armin Gerhardt at [email protected] or to journal coordinating editor Susan Haigney at [email protected].
KEY POINTS
The following key points are discussed:
•Two-piece hard capsules are a well-established, widely used dosage
form with a long history in the pharmaceutical industry
•Two-piece capsules offer speed of development versus tablets as well as
flexibility of fill materials
•The filling process for two-piece capsules is a robust process and can be
well controlled through the use of proper process monitoring
•Two-piece capsules are an excellent tool for the blinding of
clinical supplies
•Colorants and printing can create a globally accepted dosage form that
can also improve product identification and patient compliance
•Capsule design features include an inward tapered rim, side air vents,
a cap with dimples, and a cap and body with reinforced domes and
matching lock rings
•A wide range of capsule sizes and types for different applications
are available
•Capsule fill materials must be uniformly filled into capsules, have good
bioavailability, and be compatible with the capsule. Fill materials may
be powders, granules, pellets, tablets, and other types of materials
•Two-piece capsules have traditionally been made of gelatin. Hypromellose capsules are now available and may be used in place of
gelatin for improved product stability
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•Compliance personnel must be aware of the
potential problem areas that present high risks
to manufacturing processes, drug properties,
and product quality attributes such as stability, solubility, and dissolution. These include
formulation changes, capsule changes, storage,
handling, processing conditions, product packaging, and other considerations.
INTRODUCTION
Two-piece hard capsules are a well-established dosage form that provides solutions to many of today’s
drug delivery requirements and challenges. Widely
used in the pharmaceutical and nutritional supplement industries for more than a century, they are a
frequently used dosage form for administering both
solid and liquid drugs.
As drug discovery produces ever more complex
drug molecules, the pharmaceutical formulator
is increasingly challenged to develop an orally
available dosage form while meeting demanding
development timelines. Hard capsules typically
offer a quicker and simpler formulation approach
than tablets, making them increasingly relevant in
today’s cost-constrained pharmaceutical environment. While most hard capsule shells are made of
gelatin, alternative shell materials such as hypromellose have emerged in recent years offering further
options to formulation scientists. Additionally,
hard capsules offer flexibility for various fill materials including powders, pellets, granules, mini-tablets, liquids, and semisolid formulations. Special
hard capsules are even available for the blinding of
clinical supplies and rodent administration.
Hard capsules are available in a wide range of
sizes for dosing flexibility and to accommodate
special requirements. Colorants and printing options can further improve product identification
and patient compliance. Hard capsules are often a
preferred dosage form for their visual appeal, ease
of swallowing, and taste and odor masking.
HISTORY OF TWO-PIECE CAPSULES
Capsules are one of the oldest dosage forms in
pharmaceutical history, dating back to the ancient
32 Journal of GXP Compliance
Egyptians. In 1730, de Pauli, a pharmacist from
Vienna, produced oval-shaped capsules to cover
the unpleasant taste of turpentine he prescribed
for people with gout. A century later, patents were
granted to François Achille Barnabé Mothès in Paris
for his invention and the manufacture of gelatin
capsules. By the following year, capsules were being produced in many different parts of the world.
Around the same time, Jules Cèsar Lehuby was
credited for the invention of the two-piece gelatin capsule and granted a French patent for his
“medicine coverings.” Although his principles
for manufacturing two-piece capsules established
the method still used today, technical difficulties stopped further development of this form for
another century. In 1931, Arthur Colton, on behalf
of Parke, Davis & Co., designed a machine that
simultaneously manufactured both capsule bodies
and caps and fitted them together to form a hard
gelatin capsule. His machine still represents the
basic design of machinery used today.
With advances made in hard capsule technology,
the use and importance of capsules as a delivery
device has steadily increased, and the market has
seen continuous growth. In the past, capsules were
filled either manually in a labor-intensive process or
by slower machine types. Modern automatic filling
machines can fill as many as 200,000 capsules per
hour. These capsule filling machines are fully automated and instrumented to monitor fill weights and
continuously adjust to maintain target fill weights
making the filling process highly efficient.
HARD-GELATIN CAPSULE MANUFACTURE
While two-piece capsules may be comprised of
various materials, the vast majority are still made
using high-quality gelatin prepared from collagen. Collagen is a fibrillary protein that contains
18 different amino acids. The collagen of bones
and hides is subject to a maceration and purification process with acids and alkalis that split it
hydrolytically into an almost unbranched aminoacid chain of variable length. This end product is
known as gelatin. After physical, chemical, and
microbiological testing, the gelatin is released for
Armin H. Gerhardt, Coordinator
capsule production. Gelatin used in hard capsule
manufacturing must meet the requirements of all
major pharmacopeias.
Capsules are manufactured under strict environmental conditions by a dipping process on high capacity machines. The gelatin is melted with demineralized, filtered, and sterilized water. Entrapped
air is removed by vacuum. The gelatin solution is
then mixed with colorants and transferred to the
capsule manufacturing line.
Standardized steel pins are arranged in rows on
the capsule manufacturing machine. Pins are then
dipped into a temperature-controlled solution to a
precise regulated depth. After dipping, the bars are
rotated to evenly distribute the gelatin around the
pins. Correct gelatin distribution is critical to ensure a homogenous and precise wall thickness. The
pins are then passed through several drying stages
to achieve the optimal water content. After drying,
the capsule halves are stripped from the pins, cut to
the correct length, and the cap and body are joined.
CAPSULE COLORANTS AND PRINTING
Capsule Colorants
Capsule colorants must satisfy the following three
key requirements:
•Regulatory approval in the countries intended
for distribution
•Product protection and marketing
•Patient acceptance.
Regulatory approval considerations. The
capsule colorant must meet the regulatory requirements of all countries designated for distribution.
Because color regulations vary from country to
country, this is an important consideration prior to
capsule approval. Each country or region has a list
of acceptable colorants along with allowable levels
for certain colorants. The term “globally acceptable”
generally refers to the regions of the US, European
Union (EU), and Japan. For a global presentation,
the available palette of colorants is vastly reduced,
consisting mainly of the iron oxides, titanium dioxide, and blue #2.
Iron oxides present a special challenge as they
contain elemental iron that can be toxic at elevated
levels. For patient safety, each country or region
indicates an allowable daily intake of elemental
iron. Guidelines have been established for the daily
intake of iron oxides and elemental iron to assure
patient safety. For example, the World Health Organization has established a limit of 0.5mg/day/kg
of iron oxide, while the US Code of Federal Regulations has an established limit of 5mg/day of elemental iron. It is therefore incumbent on the formulations, quality assurance, and regulatory teams to
be aware of the levels of iron oxide in their capsule
color formulation and calculate the total daily iron
intake based on the daily capsule intake. A reputable capsule supplier can provide assistance and
reformulate to lower iron oxide levels if necessary.
Blue #2 presents another important consideration
as this colorant is known to be light sensitive and
prone to fading. Light protective packaging should
be used to avoid capsule discoloration in capsules
containing blue #2.
A single globally acceptable capsule color can be
applied to both commercial and clinical supplies
and will eliminate the need for multiple capsule
presentations. This strategy will thus reduce stability, testing, and inventory requirements. In the
case of clinical supplies, this approach allows for
maintenance of a readily available inventory of capsules when clinical materials are needed on short
notice regardless of the clinical site. Further, this
approach reduces possible confusion and product
mix-ups at the clinical site and acts as an additional
means of reassurance to the clinician. To avoid
introducing bias into a clinical trial where blinding
by over-encapsulation is required, it is important to
choose a colorant that is sufficiently opaque to fully
hide the contents of the capsule.
Product protection and marketing. Capsule
colorants are an important means of creating a
strong brand identity and enhancing brand image.
They can also play an important role in product
identification and can help avoid product confusion,
especially for elderly patients taking multiple medications. Capsule suppliers can even produce customized
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PHARMACEUTICAL PROCESSES
color combinations and may offer exclusivity. Capsule
printing is an additional means of product identification and is even required by the US Food and Drug
Administration for pharmaceutical capsules.
Patient acceptance. Finally, patient acceptance
is the third key consideration in color choice. With
distinct colors, patients can more easily identify their
medications, which may lead to improved patient
compliance and safety. In various studies it has been
consistently demonstrated that the color of the dosage form is the attribute most readily recognizable by
patients followed by other attributes such as product
name, dosage form, shape, and size. Patients are often
immediately aware when their medication or brand is
switched based on a new color. Broadly defined rules
exist for associating colors with certain indications,
studies have also demonstrated the psychological
influence of capsule colors on the therapeutic effect of
a drug. An experienced capsule supplier can help design and select the capsule appearance that maximizes
patient acceptance and utilization.
Capsule Printing
Printing on the dosage form is required for pharmaceutical products to comply with FDA product identification requirements. This is not a requirement for
nutritional supplements. The print must contain some
form of product identification such as the product
name, strength, or code number and is often a means
Figure 1:
The capsule filling process.
34 Journal of GXP Compliance
of improving capsule appearance when a global presentation results in an otherwise dull-looking capsule.
The wide array of printing options provides greater
possibilities in brand protection and identification,
while novel colors and printing also help deter counterfeiting by making drugs harder to copy. Colorants
for printing inks follow the same regulatory approach
as for capsule colorants.
CAPSULE DESIGN
Hard capsules are designed to not only contain
pharmaceutical and nutritional formulations but also
to withstand the rigors of packaging, shipping, and
handling on high-speed filling machines. The filling machine process involves feeding, rectification,
separation of cap and body, filling, closing of cap and
body, and ejection (Figure 1). For high-speed filling
machines, these steps may occur at rates up to 200,000
capsules per hour making the design and integrity of
the capsule of paramount importance.
The typical capsule design involves a body with an
inward tapered rim and side air vents, a cap with dimples, and both a cap and body with reinforced domes
and matching lock rings (Figure 2). Let’s examine each
of these features to fully understand their function.
Lock-Rings And Side Air Vents
Capsules were originally produced as a simple
straight cap and body with no additional features.
Armin H. Gerhardt, Coordinator
With the advent of high-speed filling machines, it
quickly became apparent that this design was inadequate to meet the needs of the industry. One of the
first problems observed was the ease with which the
cap and body would separate after filling and during
shipping. This was often due to air entrapment in the
capsule during the high-speed filling process thus creating sufficient internal pressure to cause separation of
the two parts. To remedy this problem, matching lockrings were introduced onto the cap and body to assure
a tight closure. As capsule filling became ever more
efficient and faster, the lock-rings alone were often
not sufficient to withstand internal forces. To further
improve the capsule design, air vents were introduced
onto the body that allow air to escape during the filling
process and thus eliminate the most common cause of
cap-body separation.
Inward-Tapered Rim
Another important capsule design feature is an inward
tapered rim on the body. As with the side air vents,
the tapered body was introduced in response to the
demands of high-speed filling machines. Prior to
the introduction of the tapered body, even very slight
variances in lateral cap-body alignment would cause
improper closing and result in split and deformed
capsules. The introduction of the tapered body allows
for additional machine tolerance to assure that capsule
rejoining occurs without damage. Of course it is still
critical that the filling machine be properly set-up
by an experienced mechanic prior to a filling run to
ensure a smooth filling operation.
Reinforced Domes
Reinforced domes on the cap and body were another
improvement made to assure that capsules maintain
their integrity during the closing process on the filling
machine. This is achieved by distributing sufficient
gelatin along the dome and transition shoulders during
the dipping and molding process.
Dimples
Dimples are molded into the cap during manufacturing and provide a level of pre-lock force that
prevents the cap and body from separating during
Figure 2:
Coni-Snap capsules.
shipping and handling. The placement and depth
of the dimples also assure that the cap and body are
not difficult to separate during the filling process.
CAPSULE SIZES AND TYPES
Capsule sizes are designated numerically from sizes
000 to 5. Size 000 are the largest size and size 5 is the
smallest. The Table lists the most commonly available
capsule sizes and their respective fill capacities.
Determining the optimal capsule size for a given
product is done by first determining the density of
the formulation using tapped density for powders
and bulk density for pellets and granules. A capsule
volume chart (see Table), generally available from the
capsule supplier, is then referenced. The appropriate capsule size may then be calculated using the
measured density of the formulation, the target fill
weight, and the capsule volume.
There are a variety of capsule types that have been
designed for specific applications such as DBcap designed specifically for double blind clinical studies.
There are two important requirements for blinded
clinical trial materials. The patient should not be able
to see the contents of the capsule, and it should be
difficult for the patient to open the capsule and thus
break the blind. DBcaps meet these requirements
with a cap that covers most of the capsule body
creating a double layer of shell so only the rounded
ends are visible. This dual layer not only ensures
the opacity of capsule contents, but also makes it
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PHARMACEUTICAL PROCESSES
TABLE: Capsule volumes and filling capacities.
Size
000
00el
00
0el
0
1el
1
2el
2
3
4
5
Capsule volume (ml)
1.37
1.02
0.91
0.78
0.68
0.54
0.50
0.41
0.37
0.30
0.21
0.13
Powder tapped density
Capsule capacity (mg)
0.6g/ml
822
612
546
468
408
324
300
246
222
180
126
78
0.8g/ml
1096
816
728
624
544
432
400
308
296
240
168
104
1.0g/ml
1370
1020
910
780
680
540
500
410
370
300
210
130
1.2g/ml
1644
1224
1092
936
816
648
600
492
444
360
252
156
virtually impossible to open, thereby maintaining
the integrity of the blind. As the size and cost of
clinical studies increases, the need to maintain study
integrity becomes ever more critical. The two-piece
capsule can be an invaluable tool in preventing
patient bias by making it difficult for the patient to
break the blind.
Other capsule types include the Licaps Drug
Delivery System. This capsule is designed specifically to contain liquids through a special design
and locking feature. The miniscule size 9 capsule is
useful for rodent and small animal dosing. This is
especially valuable for obtaining early phase pharmacokinetic data.
CAPSULE FILL MATERIALS
Two-piece capsules are an excellent option for containing many different types of fill materials including those that are difficult to compress. Importantly,
capsule formulations typically require less excipient
than tablet formulations and are, therefore, easier to
formulate. Capsule formulations are by far the most
common dosage form for early phase clinical studies where speed to clinic and early proof of safety and
efficacy studies are desired. Cases exist where it was
possible to formulate a new product as a tablet but a
capsule was chosen as the commerical dosage form for
speed to market, usually for competitive reasons.
Regardless of the fill material type, the capsule
formulation must meet the following three important
requirements:
•Capsule filling. The formulation should run
efficiently on the desired filling machine and
36 Journal of GXP Compliance
should maintain content uniformity during the
course of the filling run
•Bioavailability. The contents of the capsule
must release in its entirety in-vivo to guarantee
good bioavailability
•Compatibility. The formulation must be compatible with the capsule.
Capsule filling machines often operate at high
speeds and must accurately and consistently dose
the correct weight of fill material into each capsule.
The following is a list of some of the more important
physicochemical parameters to control for a smooth
and efficient filling run:
•Particle size and shape to assure homogeneity
and flow
•Uniformity of particle size to assure constant fill
weights
•Homogeneity of the mixture to assure
content uniformity
•Flow properties to assure accurate fill weights
•Appropriate moisture content; too high may
result in powder caking and poor flow, and
too low can result in a build-up of electrostatic
charge causing poor flow and a potential safety
hazard
•Ability to form compacts under pressure in order
to meet the requirements of filling machine dosing mechanisms.
Some of the more common fill materials for capsules are depicted in Figure 3 and are as follows.
Armin H. Gerhardt, Coordinator
Powders
The most common fill materials for two-piece capsules
are immediate release powders. Powders require fewer
processing steps, reduced excipient requirement, and
overall time savings as compared to tabletting. It is
often possible to go directly from a dry powder blend
to the filling machine with no intermediate steps.
Granules
Granules are useful when a powder formulation
exhibits poor flow or inadequate content uniformity.
Granules may be coated with gastric resistant polymers
in cases where the drug is destroyed by stomach acids.
Other polymer applications can be used to create a
delayed release profile and to improve drug stability.
Granules are often denser than comparable powder
formulations. This usually enables higher fill weights
and thus a smaller capsule size.
Pellets
Pellets are an excellent tool for numerous applications.
Pellets can be coated with sustained release and enteric
film coatings to achieve unique release profiles or
multiple release rates in a single dosage unit by mixing
pellets with different film coatings. Pellets also offer
the ability to mix multiple active ingredients or incompatible active ingredients in a single capsule.
Tablets
A common application is the filling of tablets into
capsules for blinding in clinical trials or filling of minitablets coated to achieve multiple release profiles.
Liquid And Semisolids
As drug discovery continues to yield poorly water
soluble molecules, there is an increasing need for
Figure 3:
Capsule fill materials.
formulation techniques that can improve drug solubility. One such approach is the use of lipid-based
formulations using either liquid-based systems or
semisolids to improve drug solubility and bioavailability. Two-piece hard capsules are an excellent
container for such formulations.
Dosing Of Pure Active Pharmaceutical Ingredient
Capsules may be filled directly with pure active
ingredient as a means of achieving speed to clinic
without the time requirement of preformulation,
formulation, or stability studies. This approach is
becoming increasingly popular as developers face
escalating demands to reduce costs and determine
proof of concept more quickly. Filling machines
designed specifically for this application are available and in some cases can accurately dose weights
as low as 100 mcg.
Dry Powder Inhalers
Two-piece hard capsules, especially those comprised of hypromellose, are used in conjunction
with specially designed inhalation devices for
pulmonary delivery of medication. The benefit of
this approach includes an inexpensive and portable
delivery system that does not require propellants,
as well as the bypassing of hurdles for oral delivery
of peptides such as insulin.
ISSUES RELATED TO FILLING
It is important to establish filling limits and monitor and control each filling run. The basic steps to
do so effectively are as follows:
•Sample 10 capsules at regular intervals of
15-30 minutes. Calculate average weight and
weight range. The results may be plotted
against target values
•If the values are within specification but trending towards the upper or lower limit for six
consecutive measurements, then the weight setting should be adjusted
•If the mean or the range fall outside of the
target values, then the run must be stopped
immediately and an investigation performed to
identify the cause followed by corrective action
Summer 2010 Volume 14 Number 3
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PHARMACEUTICAL PROCESSES
•Isolate all product collected from the previous
satisfactory weight check and either discard or
weight-sort the capsules.
Quality Of Filled Capsules
It is important to perform periodic visual checks of
capsules, usually at the same time as weight checks,
to ensure that filled capsules meet acceptable quality limits. Acceptable quality levels (AQLs) should
be established for visual appearance, and charts are
usually available from the capsule supplier. The
following are examples of quality problems, some of
which are related to filling machine set-up:
•Punched ends—closing force is too high
•Telescoped or split capsules—misalignment of
upper and lower capsule segments, incorrect
setting in the joining station
•Pinholes and cracks that will lead to powder
leakage from capsule—usually due to excessive
vacuum during separation or incorrect setup of
the joining pin
•Grease, which affects visual appearance.
A good operator training program and a detailed
machine set-up checklist are invaluable in reducing the amount of waste from a capsule filling run.
Problems such as content uniformity and weight
variation can often be traced back to issues that
began during capsule filling.
Stability And Storage
Two-piece hard gelatin capsules
have a water content of 12%-15%.
When moisture levels are below
12%, capsule brittleness becomes
a problem. When moisture levels
are above this range, deformation
becomes apparent. Empty hard
gelatin capsules should be stored
in closed containers at 15°-25°C
and 35%-55% relative humidity
(RH). Capsule filling should also
be conducted under controlled
temperature and humidity conditions. Filled capsules should
38 Journal of GXP Compliance
Figure 4:
Mechanical properties.
be stored in a controlled environment based on the
product stability profile, and the storage area should
have a monitoring system. Figure 4 demonstrates
the effect of moisture content on capsule shell brittleness for both gelatin and hypromellose capsules
(discussed in a later section).
It is always a good practice to ensure that all
fill materials are compatible with the hard gelatin
capsule. For example, moisture sensitive drugs
may degrade in the presence of capsule moisture.
Also, some excipients may be hygroscopic causing the capsule shell to lose moisture and become
brittle or discolored.
Packaging for hard gelatin capsules should protect the capsules from both mechanical effects and
high atmospheric humidity. High-density polyethylene bottles are usually an acceptable container for
bulk capsules, though a desiccant may be required
for water sensitive drugs. For blister packaging,
PVC alone may be acceptable but is known to have
a high moisture vapor transmission rate. A combination blister film of PVC/PVDC may be necessary
to minimize brittleness problems. Aluminum films,
while expensive, provide an excellent moisture
barrier and may be the advisable choice for capsules
containing water-sensitive drugs.
Gelatin crosslinking is a phenomenon wherein
amino acids from adjacent protein strands or within
a protein strand bind together. Crosslinking causes
the formation of a swollen, rubbery, water-insoluble
membrane (pellicle) during dissolution testing in
Armin H. Gerhardt, Coordinator
distilled water. Figures 5 and 6
demonstrate a dissolution media of distilled water containing
acceptable dissolving gelatin
capsules and cross-linked capsules. The insoluble film acts
as a barrier to drug release and
usually causes out-of-specification dissolution results. Common causes of gelatin crosslinking include aldehydes (in the
active ingredient or excipients),
high heat and humidity, and
rayon coilers. FDA recognizes the limitations of distilled
water dissolution media and
has approved an enzyme test
method to remedy the problem
of cross-linked gelatin capsules.
The enzyme dissolution test
method is official in the United
States Pharmacopeia, National
Formulary (USP33-NF28).
Figure 5:
CAPSULE MATERIALS
Gelatin and hypromellose are
materials used to make twopiece hard capsules.
Cross-linked capsules.
Passing capsules.
Figure 6:
Gelatin
Gelatin is by far the most
common and well-known
material used to produce twopiece hard capsules. Its origin
has already been described in
this article. Gelatin has a long
history of safety and outstanding performance characteristics
making it an excellent polymer
for producing capsules. It is
nontoxic, widely used in foods,
acceptable for use worldwide,
and recognized in all pharmaceutical pharmacopeia.
Summer 2010 Volume 14 Number 3
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PHARMACEUTICAL PROCESSES
Hypromellose
In recent years gelatin alternatives have been investigated for reasons of stability and also because of
objections to animal-derived materials. Hypromellose
has been extensively and successfully developed into
two-piece capsules for use in the pharmaceutical and
nutritional industries and is available from numerous
suppliers. Hypromellose is a plant-derived material
and, therefore, answers the need for certain religious,
cultural, and dietary restrictions.
Important benefits of hypromellose include a moisture content of approximately 4%-6% making it an
excellent container for moisture-sensitive drugs. Hypromellose capsules are also less prone to brittleness.
Additionally, hypromellose does not bind to itself;
therefore, dissolution delays due to crosslinking are not
an issue. However, capsules made with hypromellose
have a higher oxygen transmission rate than those
made from gelatin, which may be a consideration for
oxygen-sensitive compounds.
Hypromellose capsules are manufactured by a dipping and curing process somewhat similar to that of
gelatin capsules. Though numerous manufacturers
now produce such capsules, it is important to be aware
that unlike gelatin capsules, there may be important
differences in the composition of hypromellose capsules. Depending on the capsule manufacturing process, a gelling agent may be necessary. These gelling
agents vary by supplier. For example, some capsules
may be produced using gellan gum while others are
produced with various types of carrageenan. Each
of these gelling agents imparts different performance
characteristics to the capsules. For certain manufacturing processes a gelling agent may not be required
and these are reported to have dissolution benefits over
those made with gelling agents. It is important to be
aware of the complete composition of the hypromellose
capsules being used when developing a new product.
IMPLICATIONS FOR COMPLIANCE
The information discussed previously is fundamental to the use and handling of two-piece
capsules in pharmaceutical manufacturing.
Compliance personnel should have a general
understanding of the properties of the active
40 Journal of GXP Compliance
drugs, products, and processes for which they
are responsible. This includes knowledge about
the inactive ingredients including the two-piece
capsules used in product formulations. Quality
personnel should be aware of the potential problem areas that present high risk to manufacturing processes. This includes situations that may
potentially impact drug properties and product
quality attributes such as stability, solubility, and
dissolution. These risks should be appropriately
evaluated and addressed with proactive responses.
The following are hard capsule considerations
on which compliance personnel should be especially vigilant:
•Formulation changes. When changing capsule formulations, a stability study should be
conducted to assure that drug stability and dosage forms visual appearance remains intact. A
particular consideration for gelatin capsules is a
stability study to ensure that dissolution performance potentially affecting bioavailability is not
adversely impacted by the formulation change.
A formulation change might also cause capsules
to become brittle or deformed due to a hydrodynamic effect. A filling machine trial should
be conducted on equipment representative of
a commercial filling machine to verify that the
formulation continues to meet specifications for
content uniformity and uniformity of fill weight
•Capsule changes. When changing suppliers
for gelatin capsules it is necessary to perform
stability and dissolution testing to verify that
the product meets established product performance criteria. In most cases an abbreviated
stability study will be acceptable, though a full
stability protocol may be required as a matter
of company policy or for products with known
stability challenges. The need for a bioequivalence study when changing capsule suppliers
is a question that often arises. In most cases,
especially for immediate release powder formulations, bioequivalence studies are not
conducted when changing gelatin capsule suppliers. However, this issue is usually taken on
a case-by-case basis and needs to be addressed
Armin H. Gerhardt, Coordinator
by the formulations, quality control, and regulatory affairs teams.
Due to potential variations in composition
amongst suppliers of hypromellose capsules
a supplier change will usually prompt a full
stability study and potentially a bioequivalence
study.
A change in capsule polymers (e.g., from gelatin
to hypromellose) will most likely be viewed as
a significant change requiring full stability and
bioequivalence studies
•Capsule storage and handling. To maintain
capsule integrity, empty capsules should be
stored in closed containers under controlled
conditions of 15°-25°C and 35%-55% RH.
•Capsule processing conditions. It is best to
avoid temperature extremes and maintain a relative humidity of 40-60% when handling empty
capsules and storing filled capsules. If possible,
finished product should be stored in an environment monitored for temperature and humidity
•Capsule manufacturing. Capsule filling
machines may vary in operating principle,
machine set-up, and operation depending on
the machine supplier. Thorough and ongoing training of filling machine technicians is
imperative to ensure efficient capsule filling
that meets product specifications with a minimum of rejected product
•Capsule product packaging. Because moisture is critical to the physical property of the
capsule shell, product packaging should be
sufficiently moisture resistant. Bulk high-density polyethylene bottles are usually acceptable
with or without a desiccant. Blister materials
can be designed to provide adequate resistance
to moisture vapor transmission. Changes to
blister films for cost reduction purposes should
also be carefully evaluated to avoid stability
problems with the final dosage form.
SUMMARY
This article has addressed the basics of two-piece
hard capsule preparation as it relates to formulation development, stability, manufacturing, and
patient compliance. Hard capsules are one of the
most widely used dosage forms. Their formulation and processing have been well documented
for many years. Over time, the expanded selection
of polymers has made the capsule dosage form
advantageous for a broad range of uses. Continuous technological innovations have considerably
increased the speed of production with continuous
monitoring and adjustment capabilities.
Compliance personnel should be aware of the
factors affecting two-piece capsules and capsule filling to ensure that finished product meets all specifications. Changes to the capsule supplier, polymer, fill formulation, or even capsule colorant can
impact product performance and must, therefore,
be thoroughly evaluated before implementation.
Capsule moisture content is especially important to capsule performance. Capsule storage and
handling should be conducted under controlled
conditions. Product packaging and stability must
take capsule moisture into consideration.
Capsule colorants and printing are useful means
of product identification. When evaluating a capsule color formulation and print ink, the compliance professional should confirm that all dyes and
colorants meet the regulatory requirements for the
intended countries of distribution. Iron content
and daily iron intake limits must also be considered
when using capsules containing iron oxides.
Monitoring and continuous checks of the capsule
filling operation are important to ensure that the
finished product is in compliance. High reject
rates, frequent stoppages to the filling operation,
and difficulty maintaining target fill weights are all
indicators of a problematic process requiring investigation and corrective action.
Two-piece hard capsules are a well-known and
characterized dosage form and are recognized in
all of the major pharmacopeia. Two-piece capsules
will perform reliably when used in conjunction
with a well understood formulation and validated
manufacturing process. The use of colorants makes
the capsule an appealing and acceptable dosage
form to the final user, the patient.
Summer 2010 Volume 14 Number 3
41
PHARMACEUTICAL PROCESSES
GENERAL REFERENCES
ABOUT THE AUTHOR
Augsburger, L.L., “Hard and Soft Shell Capsules,” Modern Pharmaceutics, Third Edition, Gilbert S. Banker, Christopher T.
Rhodes, Editors, Marcel Dekker, 1996.
Capsugel Division of Pfizer, Technical Reference File, February 2009.
Capsugel Library, “All About The Hard Gelatin Capsule,” 1997.
Cole, G.C., “Capsule Types, Filling Tests, And Formulation,”
Hard Capsules, K.Ridgway Editor, The Pharmaceutical
Press, 1987.
Digenis, G.A., Gold, T.B., Shah,V.P., “Crosslinking Of Gelatin
Capsules And Its Relevance To Their In Vitro-In Vivo Performance,” J.Pharm.Sci. 83, 7, 1994.
Lightfoot, D.K., “Capsule Filling, Answers to 10 Common Questions
About Capsule Filling,” Tablets and Capsules, January 2007.
Overgaard, A.B.A., Højsted, J., Hansen, R., Møleer-Sonnergaard, J., Christrup, L.L., “Patients Evaluation Of Shape,
Size And Colour Of Solid Dosage Forms,” Pharmacy World
& Science, Volume 23, Number 5, 2001.
Stegemann,S., “Colored Capsules-A Contribution to Drug
Safety,” Pharm.Ind. 67, No.5, pp 1088-1095, 2005. GXP
Dennis Murachanian, R.Ph., M.S. is Senior Manager of Business
Development at Capsugel Division of Pfizer. Dennis has been in
the pharmaceutical industry for over 20 years with experience
in formulations and technical operations. Dennis has been a
course instructor at numerous short courses and holds a patent
for novel drug delivery. He may be reached by e-mail at dennis.
[email protected].
42 Journal of GXP Compliance
ABOUT THE COLUMN COORDINATOR
Armin H. Gerhardt, Ph.D., is an industry consultant who spent
more than 16 years at Abbott split between formulation services in
R&D and project management for new drug product development
teams. Armin retired from Abbott in 2007. He has taught various
courses in pharmaceutical processing for many years. Armin has
also authored book chapters on pharmaceutical unit operations.
He can be reached by e-mail at [email protected].