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 Summer 2010 Volume 14 Number 3

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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 Summer 2010 Volume 14 Number 3

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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.

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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 Summer 2010 Volume 14 Number 3

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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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• 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.

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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.

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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].

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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].