Oral Solid Dosage Manufacturing

by Dave DiProspero, Director of Pharmaceutical Process Technology

SOURCE: CRB

SUMMARY:

Oral solid dosage products can take several different shapes, and with those different forms comes different production techniques and facility designs. Here’s what is involved with manufacturing an orally-ingested drug product.

DESCRIPTION:

Small molecules, tablets, capsules, soft gels, effervescence, gummies, and pills. These are all oral solid dosage (OSD) forms, a term that refers to a final drug product therapy that is ingested through the mouth, dissolved in the digestive system, and delivered to the body through absorption into the bloodstream.

This widely used and well-proven drug delivery system originated in 1842 when Englishman William Brockedon patented tablets of compressed sodium and potassium carbonate. This product was used as a calcium supplement and antacid. Today, OSD drug products are the most common dose form physicians prescribe for a variety of indications.

OSD is such a dominant delivery form for three main reasons. It’s relatively easy to administer, it’s easy to distinguish one OSD product from another, and OSD manufacturing methods are well understood and well-developed.

Understanding OSD forms

The most common OSD forms are tablets and capsules. Both forms are comprised of an active pharmaceutical ingredient (API), which can also be called a drug substance, and dry powder ingredients. Tablet forms are made through compression and can either be coated, meaning they have an extra layer to create a smooth surface, or uncoated. Capsules are created through a coating process, where the drug substance and dry ingredients layer around a seed material.

Each of these forms can have variable bioavailability and rate of release. Depending on the therapeutic use of the OSD product, it will have an immediate, sustained, controlled, or extended-release. These factors influence drug manufacturing platforms and the equipment and technology used in the manufacturing process.

The overall goal for OSD processing regardless of the type of product is to create a formulation that ensures each dose–a single tablet or capsule–is consistent. Each one has a repeatable distribution of ingredients, and there is a consistency of dissolution and bioavailability to ensure that the drug product is safe and effective.

This guide provides a comprehensive explanation of the OSD manufacturing process and addresses many key factors and production considerations. For additional information on OSD manufacturing, see other industry guidance, including the ISPE OSD Baseline Guide Volume 2 – Third Edition.

Primary OSD Processing Platforms

OSD drug products typically consist of a dry powder formulation that includes the drug substance or API, various excipients, and intermediates and fillers. Where they differ is the final form and the individual characteristics of the ingredients, such as particle size, bulk density, flowability, among other factors. As such, different products require different processing methods and platforms. The final dose form requirements also dictate which processing platform is used.

Given the number of processing platforms and some very specialized methods, in the interest of providing a basic overview, this guide focuses on the four most commonly used in the industry today.

1. Wet granulation

A platform and process that involves a combination of liquids and solids, via a variable intensity motive force (typically high shear or low shear mixing in a granulator) working the powders and creating a dense granule that can be compressed or encapsulated.

Wet granulation is the process of joining powder particles together to create a larger particle, known as a granule. The granules can be composed of particles that are either the same or dissimilar materials depending upon the formulation ingredients. In the wet granulation process, granules are joined together using a binder solution, often aqueous, that is sprayed into the process.

The two primary types of wet granulation are high shear and low shear.

In the case of high shear, the binding solution is introduced to the dry particles in a vessel that has a motor-driven blade or impeller system that creates a variable intensity (or high shear force) interaction. The most common piece of equipment for this process is a vertical or horizontal (top drive or bottom drive) high shear granulator.

In the case of low shear, the binding solution is introduced to the dry particles in a vessel, via a spray atomization configuration that creates a softer (or low shear force) interaction. The most common piece of equipment for this process is a fluid bed granulator.

2. Dry granulation

A platform and process that involves a combination of solids only, via a variable intensity motive force (typically high force compaction in a roller compactor) working the powders and creating a dense granule that can be compressed or encapsulated.

Dry granulation is the process of joining powder particles together to create a very dense larger particle or granule. In the dry granulation process, a high-motive force joins the granules and compacts the powders without the use of an additional binder.

A dry granulator system incorporates press rolls and milling to compact the particles. Adjusting the distance between the rolls creates a variable intensity (or high shearing force compaction) interaction. A roller compactor is the most common piece of equipment.

3. Direct compression

A platform and process that involves a combination of solids only, via a low-intensity motive force (typically gentle tumbling in a blender) to homogeneously combine the powders capable of being compressed or encapsulated.

The direct compression process homogeneously combines ingredients, without directly changing or impacting the starting granules. It is a mixing process that uniformly blends the powders through particle movement and rotation. The most common piece of equipment is a tumble blender, which can be configured in various ways.

4. Particle coating

A platform and process that involves a combination of liquids and solids, via low-intensity motive force (typically atomized liquid to powder coating in a fluid bed processor) to coat the powder granules for encapsulation.

The particle coating process applies an active drug and/or sealer onto an individual granule or bead (like grain sugar) to create a capsule dosage form. A liquid and solid suspension is sprayed onto the face of the bead material to achieve the proper coating characteristics. A spray atomization configuration creates a soft and consistent interaction between the solution and dry particles in a vessel. The most common piece of equipment is a fluid bed coater.

There are other processing platforms that include, but are not limited to, single pot processing (vacuum), extrusion and spheronization, hot-melt extrusion (HME), spray drying; however, the four main processing platforms are the most common in manufacturing facilities.

Primary OSD Manufacturing Unit Operations

One of the unique aspects of OSD manufacturing is that the typical unit operations (steps in the process) are very well defined and relatively unchanged over the past century. Although the unit operations may involve various equipment and technologies, there is a well-defined progression from raw materials into the final product.

The ingredient dispensing and formulation unit operation

The first unit operation is the introduction of the various ingredients and raw materials into the manufacturing process. This starts with accurately weighing the APIs, excipients, fillers, and miscellaneous materials, and then dispensing them into the process vessel.

Handling powders typically produces dust, so ingredient dispensing must occur in a controlled and contained environment. This may include local exhaust ventilation (LEV) enclosures, downflow booths, isolators, or other containment and process control devices.

Primary process equipment for ingredient dispensing and formulation:

• Dust control/operator/environment protection system (LEV, downflow booth, isolation)
• Sifting size reduction and/or milling systems
• Process feed and receipt material handling technology (lifts/manipulators/etc)
• Scales and weigh devices
• Wash-in-place or clean-in-place systems

One key challenge of ingredient dispensing and formulation is the fact that ingredients and materials come from raw material suppliers in a wide range of containers and packaging types. For example, materials can arrive in various sized bags, drums, boxes, and supersacks, among other options. This means material handling equipment like lifts, inverters, and manipulators will be required in this operation, which also requires consideration for safety and ergonomics.

The granulation and drying unit operation

The granulation and drying unit operation begins to combine the various ingredients and raw materials to create the appropriate granule characteristics for a compressible or encapsulated drug product. This includes dispensing ingredients into the granulation train (wet or dry) and working the materials to achieve the desired results.

Primary process equipment for granulation and drying:

• Granulator
• Dryer
• Solution preparation and delivery systems (for the wet granulation process)
• Size reduction and/or milling systems
• Process feed and receipt material handling technology
• Scales
• Wash-in-place or clean-in-place systems

Space can be one key challenge during this unit operation. Granulation and drying processes generally require tall spaces, especially when using gravity to feed and receive. If manufacturers want to fit this process into an existing facility, it will often require renovations and upgrades. It is also possible to separate the two operations into different rooms, but integrated granulation and drying is more efficient.

NOTE: Occasionally, materials are pre-blended (via a blending operation) prior to the granulation and drying step.

The blending unit operation

The blending unit operation combines the active ingredients and excipients and/or lubricants to achieve a homogenous distribution of ingredients. This process may occur more than once in the overall operation. For example, a manufacturer might pre-blend materials prior to granulation and post-blend (or final blend) prior to compression.

Primary process equipment for blending:

• Blender (fixed station, portable, or intermediate bulk container type)
• Containment and dust collection solutions
• Process feed and receipt material handling technology
• Scales
• Wash-in-place or clean-in-place systems

One of the biggest blending challenges is loading and unloading the blender. If done improperly, this step can be inefficient. Furthermore, it can introduce contaminants into the formulation, generate dust, and separate the blend. With fixed station blenders (i.e., twin shells, slants, double cones, and ribbons) do a complete evaluation of the upstream and downstream process to determine optimal solutions.

One solution is to use an intermediate bulk container (IBC) or an in-bin blending system. The blend happens in the same transfer container that is used upstream and downstream of the blending process. Discharge only occurs once, which reduces the chance for material segregation and improves containment control.

Another consideration for blending is designing the process with a through-the-wall configuration. In this instance, the drive mechanism for the blender is outside the GMP blending space, and only the product container portion of the system is in the process room. This allows for smaller rooms and quicker cleaning and turn over.

The compression and/or encapsulation unit operation

The compression and/or encapsulation unit operation creates the final dosage form that patients receive. This step compresses or encapsulates the formulation into the end product: a tablet or capsule.

Primary process equipment for compression or encapsulation:

• Tablet press or encapsulator
• Metal check, deduster, polisher
• Tablet tester (to check weight, thickness, and hardness)
• Containment and dust collection solutions
• Process feed and receipt material handling technology
• Scales
• Wash-in-place or clean-in-place systems

As is the case with the granulation unit operation, the compression and encapsulation process generally requires tall spaces, especially to use gravity to feed and receive. Again, if this unit operation is going into an existing facility, thoroughly review and evaluate the layout and configuration to achieve a safe and efficient compression/encapsulation operation.

A high hat around the tablet press or encapsulator, with a lower ceiling for the rest of the room, can solve this problem, too. This allows for the desired gravity feed from the IBC or transfer bin, but also avoids a high ceiling for the whole room, which minimizes air and cleaning requirements.

Tablet coating

One of the final steps in the OSD manufacturing process is tablet coating. After a core tablet has been compressed, a film or functional coat is applied to the tablet. This improves the taste and makes the tablet easier to swallow. A functional coating is also common. This is an additional active ingredient applied to the outside of the tablet.

Primary process equipment for tablet coating:

• Tablet coater with a process air handler
• Solution preparation and delivery system
• In-process testing devices
• Process feed and receipt material handling technology
• Scales
• Wash-in-place or clean-in-place systems

Tablets must be safely and efficiently loaded into and discharged from the equipment without damaging them. Ergonomic assist devices or using gravity to assist with movement are both effective solutions for discharging tablets to and from bins.

Other OSD manufacturing processes

Beyond these primary and most typical OSD manufacturing unit operations, there are other processes. Some are relatively standard and traditional, while others are more specialized. A few worth noting are:

• Ingredient and raw material sampling of incoming goods
• Extrusion and spheronization
• Spray drying
• Hot-melt extrusion (HME)
• Vacuum/microwave and single pot processing
• Tablet printing and sorting
• Capsule banding
• Tablet in capsule filling
• Capsule in medical device delivery
• Packaging and serialization

Continuous OSD Manufacturing

So far, I’ve discussed the process and platforms in terms of a traditional batch processing operation. However, increasingly, OSD manufacturers are moving toward a modern continuous processing operation. This approach integrates the individual batch unit operations and processing steps into a single continuous process, which can reduce cost and time, as well as produce higher quality products.

Rather than manually transferring in-process work from process to process and unit operation to unit operation, continuous manufacturing (CM) feeds material through all the operations in a single equipment train that is also a closed process. This eliminates many of the ergonomic issues associated with moving the product and ingredients, the contamination risks associated with an open process, testing and quality control errors that human operators make, and production delays that come from all these aspects. Not only does this shorten production time and improve quality, but the processing capacity is more readily adjustable to accommodate changing demands.

Continuous manufacturing uses the same processing platforms as traditional batch processing for wet and dry granulation, as well as direct compression.

Fully integrated continuous manufacturing systems

A fully integrated CM system begins at bulk powder handling and ends at tablet coating. There is full integration and process control from “powders in” to final dose form coated “tablets out.” The system encompasses:

• Upstream bulk powder material handling and feed of excipients and APIs
• Processing platforms that include direct compression, wet granulation or dry granulation
• Conventional tablet compression with fully automated tablet testing
• Post tablet compression/pre-coating tablet relaxation
• Continuous coating
• Final dose form collection and handling

Partially integrated and hybrid continuous systems

A partially integrated and hybrid CM system typically begins at powder feed and ends at tablet compression. The bulk powder handling and tablet coating operations are separated, using more traditional batch operations for these unit ops. The system encompasses:

• Feed of excipients and APIs
• Processing platforms that include direct compression, wet granulation or dry granulation
• Conventional tablet compression with fully automated tablet testing

Advanced end-to-end (API to final dose form) continuous systems

Even more exciting and innovative, advanced end-to-end CM systems combine drug substance manufacturing with drug product manufacturing for a truly continuous operation. In this configuration, there is full integration and process control from “chemical synthesis” to final dose form coated tablets. The system encompasses:

• Upstream bulk raw material storage and feed of chemical entities
• Continuous integrated drug substance processing platforms that include dissolution, crystallization/filtration, drying, and sizing
• Continuous integrated drug product processing platforms that include direct compression, wet granulation, or dry granulation
• Conventional tablet compression with fully automated tablet testing
• Post tablet compression/pre-coating tablet relaxation
• Continuous coating
• Final dose form collection and handling

Continuous manufacturing for OSD is not a one-size-fits-all approach, and there are many options and configurations to first enter the arena. Fully integrated systems are among the most complex to implement; however, they also represent a growing number of installations around the world, allowing for the widest range of capabilities. Partially integrated and hybrid CM systems offer a great launchpad and entry into CM. Direct compression systems are among the most popular and easiest to implement. Advanced end-to-end CM systems are truly transformational and offer exciting potential but have the greatest complexity of all.

Final owner/engineer/vendor considerations

Regardless of the process or processes, there are a few universal considerations for any OSD manufacturing operation. Keep these things in mind:

• A successful OSD facility upgrade and/or new build project benefits the most when it includes close communication and full collaboration among the owner, engineers, constructors, and equipment and technology vendors.
• The owner and engineers should plan, align, and strategize on the various operational capabilities of the facility, the technologies, the unit operations, and the vendor options.
• Involve the operators early and often in the decision-making process. They know the operations better than the engineers, and their buy-in is critical in the success of the effort.
• Consider a focused pre-qual strategy which involves compiling vendor profiles, establishing budgets, soliciting bids and presentations, and shortlisting.
• Address the process, equipment, and facility integration aspects early to determine what impact those factors have on the design and selected vendors.
• Consider sole-sourcing equipment.

Looking for more information? Download additional process flow diagrams.

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