Pharmaceutical tablets are one of the most common and popular solid oral dosage forms, with several advantages including their ease of dosing, stability and ability to be manufactured on a large scale. However, the pharmaceutical tablet manufacturing process goes far beyond just pressing powder together to form a tablet.
Formulation development, selection of raw materials, process control, and quality testing during tablet manufacture are key elements in the successful tablet manufacturing process. The main manufacturing route is wet granulation, dry granulation or direct compression, depending on the properties of the API and formulation.
The manufacturing process should also be developed to ensure that the final product is a tablet that meets the required standards for weight, hardness, strength, dissolution, content uniformity and stability. Pharmaceutical firms can use an understanding of these stages when developing a new product, scaling up a formulation, or choosing a manufacturing partner.
What Is Pharmaceutical Tablet Manufacturing?
Pharmaceutical tablet manufacturing is the process of transforming an active pharmaceutical ingredient (API) and selected excipients into a compressed solid dosage form.
The overall process can involve formulation development and raw material preparation, followed by blending, granulation or direct compression, tablet compression, coating, quality testing, and packaging. The individual stages are controlled as changes in the properties of the material or processing conditions can influence the quality and performance of the finished tablets.
Tablet formulation development and commercial tablet manufacturing are similar, but not the same. The formulation development sets up the composition and manufacturing method, while commercial manufacturing involves using the approved formulation and manufacturing process at production scale under controlled manufacturing conditions.
Tablet Formulation Development Before Manufacturing
The formulation must be developed and tested prior to production to determine whether it can be manufactured consistently.
The physical and chemical properties of the API are evaluated during the formulation development. Parameters like solubility, particle size, flowability and compressibility can affect the formulation and manufacturing process.
API and Excipient Selection
API and excipient selection is crucial in the tablet formulation development process. The ingredients are chosen according to the properties of the formulation, tablet requirements, and the manufacturing process.
The Role of Different Excipients in Tablet Formulation
- Binders: They bind the particles together during granulation and compression. They help make tablets with suitable mechanical strength.
- Fillers or diluents: These provide bulk when there is not enough API, and may also contribute to the physical properties required to form tablets.
- Disintegrants: Disintegrants are used to cause the tablet to disintegrate after it has been taken, which may facilitate the release of the active ingredient from the dosage form.
- Glidants: These are substances that are added to enhance the flow of powder and granules. Good powder flow helps to obtain uniform die filling during tablet compression.
- Lubricants: Lubricants are used to minimize the friction between the formulation and punches and dies. They can assist in compression and aid in tablet ejection.
During the formulation development process, it is important to consider the compatibility of the API with the selected excipients. An appropriate combination should result in good flowability, compressibility, stability and dissolution properties as well as good tabletability.
Therefore, the selection of excipients is not based only on their individual functions. The interaction with the API and with other ingredients also needs to be taken into account before finalising the formulation.
Selecting the Manufacturing Route
The manufacturing process should be chosen based on the characteristics of the formulation and not applied in the same way to every product. Depending on the formulation, some may be suitable for direct compression, and others may need to be wet or dry granulated to enhance the powder properties. Formulation optimization can be used to find the most appropriate approach prior to scaling up manufacturing.
Raw Material Dispensing and Quality Verification
After the formulation and manufacturing process are defined and approved, the required APIs and excipients are dispensed based on the respective manufacturing documentation.
Before using raw materials in manufacturing, they should be specified and documented for quality. This may include the supplier’s Certificate of Analysis (CoA) and any applicable identity tests or quality testing. Qualification of suppliers and material traceability is also a critical component of the process.
Weighing and dispensing should be done accurately since the amount of a given API or excipient used in tablet formulation can influence the resulting composition and performance of the tablet. Material status should also be well defined before production.
Supplier qualification and documentation may be a significant component of the pharmaceutical company’s raw material procurement and manufacturing process, especially for companies that outsource this process.
Blending and Powder Preparation
APIs and excipients can be mixed or blended after dispensing to create a uniform powder mixture. Blend uniformity is critical because the active ingredient must be evenly distributed in the formulation.
The quality of the blend may be affected by the sequence in which materials are introduced, particle-size characteristics, equipment conditions, and mixing time. Where necessary, materials can also be sieved or milled to provide desirable particle characteristics prior to additional processing.
After the blending step, the formulation may undergo various processing routes depending on its properties and manufacturing needs. Wet granulation involves granulation, drying, sizing, lubrication and compression of the blended material. In dry granulation, the powder is compacted prior to sizing, lubrication and compression without needing to use a liquid. If the formulation properties are suitable for flow and tablet compression, the blended material can proceed directly to compression by direct compression.
The manufacturing route will depend on the formulation, API properties, excipient properties, and finished-tablet requirements.
Granulation and Direct Compression Methods
Granulation and direct compression are among the most important routes used in the pharmaceutical tablet manufacturing process. Wet granulation, dry granulation, and direct compression are the major techniques used.
Wet Granulation
Wet granulation is the process of mixing and forming a wet mass from powders with the help of a liquid, usually a binder. The wet material is then granulated, dried and sized prior to tablet compression.
The initial steps generally include weighing and mixing the API and excipients, and preparing and adding the binder solution. The powders are formed into a wet mass, granulated and dried. After the granules are sufficiently conditioned, they can be sized or milled to the desired particle size and/or particle shape. Final excipients such as lubricants can then be added prior to compression.
When the formulation needs to be improved in terms of flowability, compressibility or other powder properties, the wet granulation process can be considered. The exact process and conditions vary depending on the formulation and desired properties of the finished tablet.
Dry Granulation
Dry granulation is a process where granules are formed by mechanical compaction without the use of liquid. Powders may be compacted into larger masses or ribbons and then milled or sized to the desired granule size for further processing.
When the liquid or drying process is undesirable and the powder characteristics need to be improved, dry granulation may be useful. It can also be used for moisture- or heat-sensitive materials.
Direct Compression
Direct compression is a tablet manufacturing method that involves compressing a properly prepared powder blend without an intermediate wet or dry granulation step.
In this process, factors like flowability, compressibility, particle size distribution and uniformity of the blend take on greater significance. Direct compression may not be suitable if the powder does not flow consistently or cannot form a good tablet.
One benefit of direct compression is that fewer processing steps are required than with granulation. But not all formulations can be used with direct compression. The choice is based on the API, excipient system, formulation design and manufacturing needs.
When a formulation requires good flow and compression properties suitable for tablet manufacturing, directly compressible granules (DC granules) may be used.
Tablet Compression Process
The compression of the prepared powder blend or granules into tablet form on a tablet press is known as tablet compression. The material must flow consistently into the die cavity so that the correct amount of formulation is available for each tablet before compression. The material is then compressed between the top and bottom punches to create the tablet’s shape and size. Once compressed, the final tablet is released from the die and transferred for additional processing, such as coating and/or packaging.
There are a number of process parameters that should be monitored during compression, as they may affect important tablet properties. Some of these can include tablet weight, thickness, hardness, compression force, and overall tablet consistency. Controlling these parameters helps ensure uniformity within the batch and minimizes variation between tablets.
At this stage, the flow and compression properties of the blend or granules are also significant. Poor powder flow can result in improper die filling which in turn can cause tablet weight variation, and poor compressibility can give rise to tablets with insufficient mechanical strength. However, over-compressing can have a negative impact on the properties of the tablet and could impact disintegration and/or dissolution.
Tablet compression is not simply a mechanical process. The formulation characteristics, material properties, equipment settings and process controls must all work together to ensure that the tablets consistently meet the required quality standards.
Tablet Coating Process
Not all pharmaceutical tablets need to be coated. The need for coating will depend on the formulation, product requirements, and the function of the finished dosage form.
Film Coating
Film coating involves applying a fine layer to the tablet surface. This can enhance the physical appearance, offer protection and help to mask an undesirable taste.
Enteric Coating
If the formulation is intended to delay the release of the contents of the tablet, then enteric coating can be used. The coating is designed around the planned release properties of the product.
Functional or Modified-Release Coatings
Special coating formulations are used to manipulate drug release based on the design of the product. The coating process should be controlled in order to get the desired performance in a consistent manner.
Tablet coating can help to protect the tablet, enhance its appearance, mask its taste and ensure that the drug is released at the required time.
Quality Control Throughout Tablet Manufacturing
Testing of tablets is not the only part of quality control. Quality control is integrated throughout the pharmaceutical tablet manufacturing process to help ensure that the product meets the required specifications, from raw material preparation to final release.
In-Process Quality Checks
Various in-process checks can be performed during manufacturing based on the formulation and manufacturing process. The checks are designed to detect variations in the process while the batch is being produced and enable corrective action to be taken before completion of the batch.
- Tablet weight: Measured to ensure uniformity in tablet production and to detect die filling or powder flow differences.
- Thickness: Measured to ensure tablet consistency and to detect any changes in tablet thickness or the compression process.
- Hardness: Checks are used to monitor the physical strength of the tablets during the compression process.
- Compression parameters: Monitored to ensure uniformity of tablet formation across the batch.
- Appearance: Tablets can be visually inspected for defects, surface irregularities, colour uniformity and other visual changes.
This way, testing is done throughout the production process and not just at the end of the batch.
Finished Product Testing
After tablets are completed, they can be subjected to various quality checks depending on the product and applicable specifications.
- Weight variation: This test determines if there is variation in weight throughout the batch.
- Hardness: Assesses the resistance of the tablet to mechanical stress when being handled, packaged and transported.
- Friability: Measures the resistance of tablets to abrasion and loss of substance when they are handled.
- Disintegration: Measures the ability of a tablet to disintegrate under certain test conditions.
- Dissolution: Assesses the dissolution of the API from the tablet under controlled test conditions.
- Assay: Measures the level of active ingredient in the final product.
- Content uniformity: If applicable, determines if there is a uniform amount of active ingredient in each dosage unit.
Quality Assurance
Quality assurance is not just about lab testing. Consistent product quality is achieved through batch documentation, manufacturing records, traceability, handling of deviations, process controls and batch release.
A controlled quality system can help ensure that the manufacturing process is correctly documented and deviations or unexpected variations in the process are evaluated prior to batch release.
Common Tablet Manufacturing Defects and Their Causes
Despite the correct formulation and equipment choice, issues can occur during tablet manufacturing. Common defects are capping, chipping, sticking, picking, lamination, weight variation and hardness variation.
The causes of these issues may vary depending on the formulation and the manufacturing process.
Capping and Lamination
Capping occurs when the tablet breaks off the main body, while lamination occurs when it is split into different layers. These defects can be related to formulation properties, trapped air, poor compression conditions or inappropriate granule properties.
Sticking and Picking
Sticking occurs when the material sticks to the tablet tooling, while picking occurs when material comes off the surface of the tablet and sticks to a punch.
Moisture content, formulation properties, lubrication and tooling conditions can all be factors in these problems.
Chipping
Chipping is the breaking or loss of material from the sides of a tablet. This can happen if the mechanical strength of the tablets is not sufficient, or if there is too much stress from manufacturing or handling.
Weight and Hardness Variation
The flowability of the powder, the amount of material in the die, the compression force, or the properties of the granules can cause weight or hardness variation in the tablet.
The defects illustrate the importance of considering formulation, material properties, equipment conditions, and process controls as a whole rather than separately in the tablet manufacturing process.
Pharmaceutical Tablet Packaging and Storage
Packaging is an essential part of the pharmaceutical tablet manufacturing process as it helps protect the product after production.
Typical packaging formats are:
- Blister packs
- Strip packs
- Containers or bottles
The choice of packaging is dependent on the formulation and the level of protection needed. Packaging can be used to protect tablets from moisture, light, contamination and physical damage.
Packaging and labeling also aid traceability of the product. Batch details, manufacturing information, expiry information, and storage information can be included according to the product and regulatory requirements.
Storage conditions should be determined based on the needs of the specific formulation and finished product. It is therefore not possible to assume that the same temperature or humidity conditions are appropriate for all pharmaceutical tablets.
Key Equipment Used in Tablet Manufacturing
Pharmaceutical tablet manufacturing involves a variety of equipment to prepare, process, compress, coat and package the formulation at different stages.
Milling and Size-Reduction Equipment
Milling equipment is used as required to reduce the particle size, break agglomerates or obtain the desired particle characteristics before blending or subsequent processing.
Blenders and Mixers
APIs and excipients are blended to obtain a uniform powder/granule mixture. Consistent mixing is important, especially to ensure blend uniformity.
Wet Granulation Equipment
If the formulation requires wet granulation, a wet granulator is used. The equipment mixes powders with a binder solution to create wet granules, which are then dried and sized.
Fluid-Bed Dryers
Wet granules can be dried after the granulation process using a fluid-bed dryer. Drying conditions must be well controlled as per the formulation requirements.
Dry Granulation Equipment or Roller Compaction Equipment
Dry granulation equipment is employed to form the powder into larger masses or ribbons, which are then milled and sieved into granules.
Rotary Tablet Presses
The rotary tablet presses are used to make tablets by filling the prepared blends or granules into the die, compressing the material, and ejecting the tablet. Compression parameters must be controlled to ensure consistent tablet quality.
Tablet Coating Equipment
Tablets are coated with film or functional coatings, if necessary, by coating equipment.
Packaging Equipment
The packaging equipment includes blister packs, strips and suitable container formats according to the product protection and packaging requirements.
Equipment for a pharmaceutical tablet manufacturing process should be selected according to the formulation, manufacturing route, scale and product requirements.
How Manufacturers Select the Right Tablet Manufacturing Process
Not all tablet formulations can be made using the same manufacturing process. The manufacturing method used will depend on the nature of the API, excipients, formulation and the properties of the finished product.
Direct Compression
If the formulation is suitable in terms of flowability, compressibility, particle-size distribution and blend uniformity, direct compression may be feasible.
The primary benefit of direct compression is that it can reduce processing steps because the powder blend can be compressed directly without any separate granulation process.
Dry Granulation
If compaction of the powder has no adverse effect on the properties of the material, dry granulation may be used. It can be beneficial if the formulation is moisture or heat sensitive, or if the processing properties required for direct compression are not appropriate.
Wet Granulation
When granulation can enhance the flow or compressibility of the formulation or improve other formulation properties, wet granulation may be used. It adds more steps to the process, including the addition of binder, granulation, drying, and sizing.
Factors That Influence Process Selection
The manufacturing process for a tablet depends on the properties of the API, excipients, formulation, and desired properties of the finished tablet. Manufacturers may need to consider a number of factors before determining the most suitable manufacturing method: direct compression, dry granulation, or wet granulation.
- Flowability and compressibility of the API: The flow and compression properties of the API may affect how easily it can be processed and its ability to be converted into tablets.
- Moisture and heat sensitivity: Some materials may be sensitive to moisture or heat, and this can impact the suitability of a particular manufacturing process.
- Dose level: The dosage level of the API can affect the formulation approach and excipients used.
- Particle-size distribution: Particle size can influence flow characteristics, blending, and compression behaviour, and therefore particle size may need to be controlled.
- Homogeneity of the blend: The formulation should be able to provide uniform distribution of the active ingredient and other ingredients prior to compression.
- Desired tablet performance: The final performance of the tablet with regard to physical characteristics and dissolution rate also affects process selection.
- Available equipment and production scale: The manufacturing process needs to be suitable for the available equipment and the scale at which the product will be manufactured.
The goal is to identify a process that can produce tablets with consistent quality and performance.
Choosing a Reliable Pharmaceutical Tablet Manufacturing Partner
When selecting a pharmaceutical manufacturing partner, there are more factors to consider than production capacity. Businesses need to consider the manufacturer’s formulation and manufacturing skills, quality systems, and regulatory capabilities for the product they plan to manufacture.
- Tablet formulation experience: Tablet formulation and optimization experience will be beneficial when transitioning a product from development to manufacture.
- Oral solid dosage experience: Manufacturers should have experience in tablet manufacturing and other relevant oral solid dosage products.
- Appropriate process selection: The manufacturer should be able to choose and fine-tune the manufacturing process based on the formulation and material characteristics.
- Quality systems: Quality systems and WHO-GMP practices are critical to ensure the consistent quality of products and manufacturing processes.
- Testing capabilities: In-process and finished product testing should be performed during manufacturing to monitor critical quality attributes.
- Scale up and commercial manufacturing: The manufacturer should have equipment, capacity, and process controls capable of supporting scale-up to commercial manufacture.
- Technology transfer: When it is necessary to transfer a formulation or manufacturing process from one site to another or into commercial production, technology transfer capability can be helpful.
- Regulatory and technical documentation: Regulatory and technical documentation is significant for a product’s development, production, and market.
- Supply continuity: The manufacturer must be able to support ongoing production requirements, and ensure that the products produced are consistent.
The right manufacturing partner should be able to support formulation and process development through scale-up and commercial production, not just with the last step of compression. This greater capability can enable pharmaceutical companies to better address manufacturing, quality and supply needs.
How Octavius Pharma Supports Tablet Manufacturing
Octavius Pharma provides formulation development, directly compressible (DC) granules, finished formulations, contract manufacturing, technology transfer, pharmaceutical raw material outsourcing and commercial pharmaceutical manufacturing.
Octavius Pharma’s DC Granules are directly compressible materials for formulations suitable for direct compression, depending on the formulation and manufacturing requirements. This may be especially relevant for pharmaceutical companies considering a tablet manufacturing strategy that includes direct compression.
Pharmaceutical tablet formulation development, process selection, use of DC granules, quality controls, technology transfer and commercial production can support pharmaceutical tablet development and production.
Conclusion
The pharmaceutical tablet manufacturing process is divided into a number of controlled steps, including formulation development, raw material preparation, blending, granulation or direct compression, tablet compression, coating, and quality testing, as well as packaging. These stages must be accurately managed in order to ensure that the tablet product is consistent in quality and complies with specifications.
The manufacturing method (direct compression, dry granulation, or wet granulation) depends on the characteristics of the API, excipients, formulation, and desired properties of the finished product. Good formulation development and selection of a suitable process can help support consistent manufacturing from the development stage to commercial production.
Using an experienced manufacturing partner with a combination of formulation development, quality systems, scale-up, technology transfer and commercial manufacturing capabilities can facilitate the transition from formulation to reliable and large-scale tablet manufacturing for pharmaceutical companies. Octavius Pharma offers solutions in these areas, including DC Granules and finished pharmaceutical formulations.
Frequently Asked Questions
What is the pharmaceutical tablet manufacturing process?
The pharmaceutical tablet manufacturing process involves several controlled stages, including formulation development, raw material preparation, blending, granulation or direct compression, tablet compression, coating where required, quality testing, and packaging.
What are the main methods used to manufacture pharmaceutical tablets?
The three main approaches are direct compression, wet granulation, and dry granulation. The most appropriate method depends on the formulation and material properties.
Is granulation always required for tablet manufacturing?
No. Some formulations can be manufactured using direct compression when the powder blend has suitable flow, compressibility, and other required properties.
What is direct compression in tablet manufacturing?
Direct compression is a manufacturing process in which a suitably prepared powder blend is compressed directly into tablets without a separate wet or dry granulation step.
What is the difference between wet granulation and dry granulation?
Wet granulation uses a liquid or binder solution to form granules, followed by drying and sizing. Dry granulation uses mechanical compaction without liquid and is followed by milling or sizing.
What quality tests are performed on pharmaceutical tablets?
Depending on the product and applicable specifications, testing can include weight variation, hardness, friability, disintegration, dissolution, assay, and content uniformity.
Why are pharmaceutical tablets coated?
Tablet coating can be used to improve appearance, protect the tablet, mask taste, and provide specific drug-release characteristics where required.
What causes common tablet manufacturing defects?
Defects such as capping, lamination, sticking, picking, chipping, weight variation, and hardness variation can be related to formulation characteristics, powder or granule properties, moisture, compression parameters, tooling, or other process conditions.
How does formulation development affect tablet manufacturing?
Formulation development helps determine whether the API and excipient combination has suitable properties for manufacturing and helps identify the appropriate manufacturing route, process parameters, and quality requirements.
How do pharmaceutical companies choose a tablet manufacturing partner?
Companies should evaluate formulation expertise, manufacturing capabilities, quality systems, testing facilities, scale-up experience, technology transfer support, regulatory documentation, and the ability to maintain consistent commercial production.