Comprehension of Quality by Design in the Development of Oral Solid Dosage Forms

The main goal of pharmaceutical development and regulations is to ensure that each approved drug product keeps the same quality and performance characteristics throughout its commercial life as the lots that were used to prove the product’s safety and effectiveness during the approval process for marketing authorization. In the past, this assurance relied only on product specifications proposed without the support of thorough product and process understanding.¹ Consequently, it is difficult to adequately control the routine product manufacturing process, leading to the failure of established quality control criteria and, equally, ineffectiveness encountered in in vivo product performance due to the lack of defining the critical quality attributes during product development. The pharmaceutical sector has evolved with the implementation of quality guidelines like ICH Q8 “Pharmaceutical Development”, ICH Q9 “Quality Risk Management”, ICH Q10 “Pharmaceutical Quality System” and ICH Q12 “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management”. It has been understood that the quality of pharmaceuticals should be designed during development and built during the manufacturing process. The majority of quality issues are related to the design of pharmaceutical products.¹ No matter how many tests or studies are performed to ensure its quality, a poorly designed pharmaceutical product will exhibit low safety and efficacy. As a result, QbD starts with the understanding that increased testing of pharmaceutical items would not enhance quality. Ultimately, the product must be of high quality.² The new paradigm focuses on the application of modern science and the use of quality risk management tools throughout the product lifecycle.³

Regulatory agencies are looking for pharmaceutical industries to create a standardized quality system that can be used throughout the product’s lifespan, with an emphasis on an integrated approach to quality risk management and science. It is expected to implement the QbD principle in pharmaceutical development. QbD is a systematic approach in pharmaceutical development that starts with predetermined objectives and highlights product and process understanding based on sound science and quality risk management.⁴

The QbD approach starts by identifying the Quality Target Product Profile (QTPP). The QTPP is an important element that forms the basis of the design of the product. Critical Quality Attributes (CQAs) are the properties that should be within a certain range to ensure the desired product quality. The risk assessment identifies CMAs and CPPs that have a potential impact on the CQAs of the product. The design space is a multidimensional combination and interaction of input factors and process parameters that have been shown to provide quality assurance.⁴ The control strategy is intended to ensure that a product with the desired quality is consistently produced.

This article is intended to discuss in-depth the pharmaceutical development of OSDs using QbD principles. OSDs like Immediate-Release (IR) and Extended-Release (ER) tablets and capsules, dispersible tablets, chewable tablets, etc. are considered in the discussion. The USFDA has published examples of pharmaceutical development studies that industries may refer to implementing QbD in their development process.^5,6 There are also other guidances published recently for OSDs that have to be considered during development using QbD. The guidelines are related to the tablet scoring,⁷ size and shape,⁸ elemental impurity,⁹ nitrosamine,¹⁰ chewable tablets,¹¹ drug products administered using an enteral feeding tube,¹² etc.

The QbD elements are outlined in Figure 1 followed by a discussion of each element and their implementation in the pharmaceutical development of OSDs.

Figure 1:
QbD elements.

The QTPP defines the product’s design requirements and should be used to generate CQAs, CMAs, CPPs, and a control strategy. It is concerned with quality, safety, and efficacy, taking into account factors such as route of administration, dosage forms, bioavailability, strength, and stability.⁴ The target should be defined before initiating the development based on the properties of the active substance, the characterization of the reference product, and the intended labeling information and population. Table 1 represents elements to consider while designing the QTPP. After setting QTPP, there is a need to identify CQAs, as discussed below.

CQA is any characteristic (physical, chemical, biological, or microbiological), that should be within a certain range. While identifying CQAs and distinguishing them from the other quality attributes, consider the severity of harm (safety and efficacy) to the patients as described in the QTPP and the basis on which it has been developed (e.g., prior knowledge, scientific principles, and experimentation).¹³

Drug product quality should be achieved through a quality management system and appropriate formulation design and process development. There is a need to investigate only those CQAs that are likely to be impacted by the formulation or process variables. Table 2 indicates CQAs to consider in OSDs.

Risk includes the probability of occurrence, the detectability, and the degree of harm. Therefore, using a risk management system, the level of risk can be changed. The following are some principles to keep in mind while adopting quality risk management.^5,6

The assessment of the risk to quality should be based on scientific evidence and ultimately connected to patient safety.

The relative risk of each element can be ranked as high, medium, or low. Further investigation is required for those elements likely to have a high impact on the drug product CQAs. No further investigation is required for the elements having a low impact. A similar relative ranking system can be used throughout product development.

During pharmaceutical development, risk assessment can be carried out in three stages: risk assessment of drug substance attributes, formulation components, and the drug product manufacturing process, as discussed below.

Risk assessment of drug substance attributes on drug product CQAs can be performed based on the physical, chemical and, biological properties of the drug molecule.⁴ Drug substance attributes and drug product CQAs enlisted in Table 3 shall be considered during risk assessment. The rationale for assigning the risk is explained further based on the literature available and the knowledge gained from industrial experience.

The risk of particle size impacting physical attributes can be assigned based on the contribution of the drug substance in the final formulation and the manufacturing process chosen (direct compression or granulation). Drug substances having a significant contribution to the final formulation can play a major role in the physical attributes through their compressibility and flow properties.¹⁴ With a low concentration of drug substance in the formulation, particle size distribution can have a direct impact on drug distribution and, ultimately, on the assay and content uniformity.¹⁵ The risk can be high or moderate, depending on the manufacturing process adopted. Consequently, risk can be assigned. The effect of particle size on dissolution depends essentially on the solubility class of the drug substance as per the Biopharmaceutical Classification System (BCS). The risk of particle size impact dissolution can be higher with poorly soluble drugs.¹⁶ There is no role for particle size if drugs are added in solution form, neither in assay and content uniformity nor in dissolution. The risk of particle size influencing the dissolution of whole tablets is directly related to the dissolution of split tablets. If a drug substance is stable, particle size will not affect degradants or nitrosamine impurities. There is no relationship between particle size and elemental impurities in the drug product.

Drug substances that exhibit polymorphism can impact drug product CQAs. The compressibility and subsequent physical properties of tablets can be influenced by solid-state form.^17,18 Crystal nature can affect flow properties and, later, content uniformity. Different polymorphic forms can have different solubility, dissolution and rate of degradation; risk can be performed based on the polymorphic stability by the drug manufacturer. While performing the risk assessment, USFDA guidance (ANDAs: pharmaceutical solid polymorphism) can be referred.¹⁹

The probability of drug solubility having an impact on drug product CQAs is low, except for dissolution. Depending on the solubility class and pH-dependent solubility behavior of the drug molecule, a risk assessment can be performed.

The flow property of the drug substance matters when the manufacturing process is direct compression to the tablets or direct filling into capsules, and it has a significant contribution to the final blend. It can impact physical attributes like tablet or capsule weight variation, assay, and content uniformity.¹⁵ The flow property of the drug is diminished using the granulation process. The risk of flow property impacting physical attributes, assay, and content uniformity can be assessed depending on the manufacturing process chosen. It plays no role in the generation of degradants or other impurities (elemental and nitrosamine).

The physical attributes of the product are not linked to organic impurities. Impurities usually do not impact a drug product’s assay, content uniformity, and dissolution if their presence and level are controlled in the drug substance specification. The risk to impact degradants in the drug product can be determined if there is evidence of incompatibility or conversion of drug process impurities to the degradants. If the route of drug synthesis or any impurities put any risk of nitrosamine impurity in the drug product, the risk can be assigned and investigated accordingly. Processes using nitrites in the presence of acids, secondary, tertiary, or quaternary amines can create the risk of generating nitrosamine impurities.¹⁰

The physical attributes of the product are not linked to the elemental impurities. The risk assessment must be carried out to evaluate elemental impurities carryover from the drug substance to ensure that the final drug product does not cross Permitted Daily Exposure (PDE) as per United States Pharmacopoeia (USP) general chapter²⁰ <232> and ICH Q3D guidance.⁹ The risk of elemental impurities can be higher in the case of inorganic drug molecules (e.g. potassium chloride, sodium chloride), depending on the risk, the control strategy can be in-placed. The risk of the impact of elemental impurities to impact assay, content uniformity and dissolution is low. Depending on the evidence of element-catalyzed degradation in drug products, the risk of impacting finished product degradants can be assigned.^21,22

If the level of solvents is controlled in the drug substance in-line with option 1 of USP general chapter <467> or ICH Q3C guidance and the total daily intake of the drug product is less than 10 g, then the risk is low. If residual solvents exceed the option 1 limit, carryover in drug products must be calculated based on the total daily drug product intake.^23,24 If any solvent is present at a significant level, risk can be evaluated considering its role in the degradation pathways of the drug product.

Depending on the water activity and route of synthesis of the drug substance, it may support microbial growth.²⁵ As per pharmacopoeia and regulatory expectations, there is a need to control total aerobic microbial count, total combined yeast and mould count, and specified micro-organism – Escheria coli in the raw materials going to use in oral solid dosage forms.^26,27 The risk assessment shall be done and control has to be given through raw material specifications.

It is an important element to consider in risk assessment. Hygroscopic drug substances can impact process feasibility, physical attributes, degradants, and microbial count.²⁸ Depending on the manufacturing process, environmental conditions for the operations shall be selected.

After the risk assessment of drug substances, the selection of excipients and their grades, followed by drug-excipient compatibility, is an important step for understanding the role of inactive ingredients in product quality. The selection of raw materials and their grades for the compatibility study should be based on prior knowledge about the drug, its impurities, and degradation pathway, as well as the further manufacturing processing conditions to be used for the drug product. A scientifically sound approach should be used in constructing compatibility studies.

Ideally, product development is divided into two stages: formulation development and process development. At the time of the risk assessment of formulation components, an optimized manufacturing process may not be established, and risks can be analyzed and evaluated using a preliminary manufacturing process. It shall begin with the overall risk assessment of the drug product components to determine which components are likely to have a high risk of impacting the drug product’s CQAs. Depending on the drug product and dosage form, formulation components can be considered in the risk assessment.⁴ The formulation components for guidance enlisted in Table 4 should be considered during risk assessment. The rationale for assigning the risk is explained further.

As discussed under the section risk assessment of drug substance, depending on the contribution of drug substance in the final formulation, selected manufacturing process and solubility class risk of particle size to impact drug product CQA can be assigned.

The diluent can be used alone or in combination. Diluent type and level can significantly impact physical attributes like size, weight, and hardness, including tablet splitability.^29,30 Depending on the dose, particle size of the drug substance, and the manufacturing process, risk assessment can be performed and diluent grades can be selected. The type of dosage form, like dispersible and chewable tablets, shall be given special attention considering palatability due to the use of a particular diluent, and the same shall be considered during risk assessment. Diluent’s particle size and flow properties are important to achieve assay and content uniformity. Lactose incompatibility with drugs having secondary amines,³¹ diluents having high moisture content or peroxides should be considered during risk assessment to impact degradants depending on the drug molecules.

Binder type and level can have a direct impact on compressibility, granule properties, tablet hardness, splitability, disintegration, dispersion time, and dissolution.³² Depending on the solubility class of the drug, the risk of binder to impact dissolution can be assigned. The risk of binders to impact degradants can be assigned based on the drug-excipients compatibility study or any known interactions.

The disintegrant promotes disintegration either by water wicking (crospovidone) or swelling (croscarmelose sodium and sodium starch glycolate).³³ Disintegrant types are important to mimic the disintegration behavior of the generic formulations with the reference product. Level of disintegrant can impact the disintegration time and later dissolution. However, it can affect the stability of the formulation due to its water-loving and absorption tendency (for example, use of crospovidone with diluent dicalcium phosphate dihydrate or trihydrate). Crospovidone rapidly absorbs water. At accelerated stability storage conditions, dicalcium phosphate loses water, which allows it to swell, resulting in tablet/capsule defects, loss of tablet integrity, hardness etc.³⁴

It is preferred to use a minimum effective level of surfactant or wetting agent with poorly soluble drugs. Risk assessment should be conducted depending on the drug molecule and different types of surfactants like cationic, anionic, or nonionic. Surfactants or wetting agents can impact the physical attributes e.g., docusate sodium is used as a wetting agent, which is a waxy material that impacts tablet compressibility significantly. Polysorbates are liquid surfactants that cannot be used in direct compression or direct capsule filling processes; and if used in a granulation process, the risk of affecting physical attributes must be assessed. The risk of surfactants to impact the degradants shall be assessed based on the sensitivity of the drug molecules.

Colloidal silicon dioxide and talc are commonly used glidants in solid oral dosage forms. Its level may or may not have a significant impact on the drug product CQAs; however, risk assessment must be performed to determine the optimum level of the glidant. Significantly low and high concentrations have a negative effect on the flow properties.³⁵

Lubricant can be considered the most significant element of solid oral dosage forms. Magnesium stearate is the choice of lubricant in the pharmaceutical industry due to its effectiveness. Depending on the risk of using magnesium stearate, other lubricants like stearic acid, glyceryl behenate, and sodium stearyl fumarate can be tried. Lubricant type and level can have a significant impact on tablet and capsule physical properties, dissolution, and sometimes degradants (magnesium can act as a catalyst in degradation,³⁶ and sodium stearyl fumarate can form adducts with certain molecules.^37,38 Lubricant levels can have a high risk of impacting the dissolution of poorly soluble drugs from IR dosage forms as compared to ER dosage forms.

In OSDs, stabilizers are added to prevent degradation due to acid, base, peroxides, hydrolysis, or oxidation-reduction reactions. Preservatives can be added to control microbial growth. The selection of stabilizer should be based on the underlying mechanism of degradation in the drug product. The risk assessment shall be performed to finalize and justify the minimum effective level of stabilizers or preservatives to ensure the drug product’s CQA (degradants/microbial count) remains within acceptance criteria during batch release and throughout the shelf life.

Commonly, modified release formulations are designed using matrix or reservoir technology. Release-controlling polymers play important role in achieving the product CQAs. In the matrix technique, the risk of type and level of the polymer to impact physical attributes, assay, content uniformity and dissolution shall be evaluated. In the reservoir technique, the type and level of the polymer have a more direct impact on dissolution than any other drug product CQA, risk shall be assigned accordingly. Performance of delayed-release or timed-release dosage forms largely depends on the polymers having pH-dependent solubility; the risk of polymers levels to resist the drug release in an acidic environment shall be evaluated critically. In all modified release formulations, the risk of the type of polymers to impact alcohol dose dumping shall be also evaluated. Natural-originated cellulosic polymers can contain nitrites which can support the formation of nitrosamine impurities in the drug molecule having secondary to quaternary amine groups.¹⁰

Lot-to-lot or vendor-to-vendor variability signifies the CMAs of the polymer. It is important to perform risk assessment considering the lot-to-lot and or vendor-to-vendor variation which may cause due to the difference in CMAs although it is within the specifications having wider limits. It is also necessary to evaluate the polymer performances vendor-to-vendor due to their different manufacturing process or control strategies. CMAs for the release-controlling polymers are polymer viscosity, particle size, hydroxy – propoxy content which can be thoroughly investigated at their extreme specifications as the risk of impact dissolution is high; if needed tighter in-house control over CMAs can be provided.³⁹

Plasticizers are added to modify the film properties of the release-controlling polymer.⁴⁰ The choice of plasticizer (hydrophilic nature, hydrophobic nature, type) depends on the type of polymer used.⁴¹ The risk of plasticizer to impact dissolution and alcohol dose dumping is higher, investigation shall be done accordingly.

Pore formers are added to hydrophobic polymers to modify and achieve the desired drug release. The level of pore formers in the drug product is critical to maintaining the dissolution; small changes in the pore former can lead to batch-to-batch variation due to its high solubility in aqueous media.

In solid dosage forms, solvents can be used for granulation, tablet coating, and pellet coating. The risk of solvent type to impact dissolution from the modified release dosage forms is always higher; it can be moderate for IR dosage forms. The risk of solvent to impact degradants can be evaluated based on the route of degradation; sometimes it can also lead to the polymorphic conversion of drug molecules.

The selection of core pellet size is important during generic product development to mimic the drug release profile of the reference product. It also impacts the friability during operation, which can impact the assay and sometimes the content uniformity of the low-dose molecules during capsule filling. The risk of core pellet size to impact assay and content uniformity is also high where polymer-coated pellets are compressed to the tablets using cushioning agents; a significant difference in the pellet size distribution and density can lead to segregation. The risk of pellet size to impact assay, content uniformity, and dissolution can be assessed accordingly.

Cushioning agents are added to the dispersible or micro- dispersible tablets containing multiparticulate. After dispersion, the drug release is controlled by the polymeric film of multiparticulate. Cushioning agents provide cushion to the multiparticulate during compression, preventing rupturing of the polymeric film. The risk of cushioning agents impact on physical attributes (tablet size, compressibility, and splitability), content uniformity, and dissolution shall be evaluated.⁴²

After completion of the initial risk assessment of the formulation variables, high-risk factors should be considered for further investigation; in some cases, variables considered medium-risk can also be investigated. Experiments can be designed to study One Factor at A Time (OFAT) or use a multifactorial design. The factors shall be the formulation variables and the responses shall be the CQAs or intermediate CQAs. The formulation risk assessment identifies potential high-risk CMAs which can impact product CQAs and should be part of the control strategy. Depending on the function of input materials in the drug product, CMAs can be as follows: as shown in Table 5.

To identify the high-risk steps that are likely to impact the final drug product CQAs, a risk assessment of the manufacturing process should be performed while developing and optimizing the manufacturing process. Following that, identify the intermediate CQAs that are directly connected to the final drug product CQAs. The risk assessment should focus on the process variables that potentially affect the selected intermediate CQAs to identify which process factors have the highest probability of causing CQA failure. To improve the manufacturing process and decrease the chance of failure, those variables should be evaluated.⁴ Refer Table 6 for different manufacturing steps depending on the type of formulation which can impact intermediate CQAs and later impact final drug product CQAs. The rationale for assigning the stepwise risk is explained further.

The particle size and cohesiveness of the drug substance can adversely impact its flowability, which can affect intermediate CQAs like blend uniformity and blend assay, which later results in the failure of drug product CQAs like assay and content uniformity.^14,15 The risk of the blending process to impacting these CQAs is less if drug substance is added in the granulation step and the concentration of extra granular components is insignificant. The risk of the pre-lubrication/blending step impacting other attributes like physical attributes, dissolution, and degradation is low. Holding the blend can also lead to segregation and impact the blend uniformity.

The lubrication time can impact the compressibility and hardness of the tablet.⁴³ The lubricant type, concentration, lubrication time, and specific surface area are the key elements in a successful compression process. Poor lubrication results in sticking/picking/ ejection problems, and over-lubrication results in capping/ lamination issues during compression. Poor lubrication can also impact capsule filling due to sticking to the tamping pins. Depending on the solubility class of the drug, lubrication time can impact dissolution.⁴⁴ The probability of drugs with high aqueous solubility being impacted by lubrication is lower; it can be high in the case of poorly soluble drugs.

Granulation is performed to improve flow, compressibility, and uniformity.⁴⁵ Depending on the type of diluent and drug concentration, poor or over-granulation can affect intermediate CQAs like particle size distribution, which later impact compression parameters like weight variation, hardness, tablet splitability, content uniformity, and dissolution. Loss on drying after the granulation stage is critical for controlling blend compressibility, residual solvents (if organic solvents are used for granulation), microbial load, and degradation of sensitive molecules (by hydrolysis).⁴⁶

Milling is performed to achieve uniform granules and size distribution. Particle size distribution can be considered an intermediate CQA as it affects blend uniformity, weight variation, hardness, tablet splitability, content uniformity, and dissolution. The probability of a milling step impacting degradants is lower unless the drug is heat sensitive or has a low melting point affected by the heat generated during milling.

Like any granulation, roller compaction or slugging is performed to improve flow, compressibility, and uniformity, and, additionally, prevent degradation due to solvents. The particle size distribution is a critical in-process factor to control during the dry granulation process as it later plays a role in achieving finished product CQAs like physical attributes, tablet splitability, content uniformity, and dissolution.⁵

The shape, size, and score configuration of the tablets are defined by the tooling design selected during development. Compression force can impact the tablet hardness, splitability of the scored tablets, friability, disintegration time, and dissolution. Press speed and feeder speed can impact tablet weight variation and content uniformity. Sometimes, tablet weight variability can lead to Out-of-Specification (OOS) assay results. The compression is unlikely to impact degradation.^5,6

Coating defects can impact the elegancy of the finished dosage form. Assay and content uniformity are mainly determined up to the compression step and are unaffected by the film coating process variables. The risk of the film coating process impacting tablet assay and content uniformity is low. The film coating composition can sometimes moderately impact the disintegration time of the coated tablets and later dissolution. The hold time of aqueous film coating dispersion can impact the microbial count in the drug product. Depending on the type of solvent used in the coating process, and the sensitivity of the drug to the particular solvent, it can impact degradants.

Drug layering over multiparticulate is done using a wurstor fluid bed processor, and over tablets is done using conventional coating pans. In both cases, the risk of this step to impact the assay is high.⁶ In the case of multiparticulate risk to impact, content uniformity can be lower than in the tablet pan coating. The hold time of a drug coating solution can impact the degradants and microbial count.

Controlled-release polymer coating, either performed on multiparticulate or tablets, directly impacts dissolution and alcohol-induced dose dumping. The risk of affecting other products’ CQAs is less.⁶

The risk of the capsule filling step to impact weight variation and later content uniformity is high. Sometimes improper setting can lead to capsule defects, but the risk of impacting other product CQAs is lower.

The drug product manufacturing process risk assessment identifies potentially high-risk attributes and/or process parameters. Depending on the risk assigned, design and conduct experiments to determine which process parameter is critical. Depending on the manufacturing process and the type of drug product, CPPs can be established (Table 7).

The study of any individual unit operation or parameter while keeping other parameters constant, will give a Proven Acceptable Range (PAR). By changing more than one factor at a time, multidimensional combinations and interactions of input variables and process parameters can be evaluated. If it demonstrates its ability to provide assurance of quality, it generates design space.⁴ Accordingly, develop a control strategy by controlling CMAs, fixing the processing equipment, and defining acceptable ranges for the CPPs.

A control strategy is a planned set of controls (Figure 2) derived from formulation and process understanding to ensure that the desired quality is consistently produced.⁴ The elements of the control strategy can include the critical attributes related to the input materials (drug substances and excipients), intermediates (in-process semi-finished goods), container closure systems, product specifications, and testing or monitoring frequencies that contribute to the final product quality. The control strategy can be further reviewed and revised based on additional experience gained or as part of continuous improvement during the commercial lifecycle of the product. Working within the design space is not considered a change; moving out of the design space is considered a change and requires regulatory approval as per post-approval change procedures.

Figure 2:
Outline of control strategy.

As a part of continuous improvement, it is expected of pharmaceutical companies to evaluate innovative methods to improve product quality throughout the commercial life of the product. Product performance can be monitored and verified for its robustness or anticipated quality through trend data analysis from product annual reports. Recently, ICH also published guidance Q12- “Technical and regulatory considerations for pharmaceutical product lifecycle management”; which provides a context for simplifying the management of post-approval changes in a more efficient manner using technical and risk-based approaches. This guideline also demonstrates how increased product and process understanding can be helpful in managing post-approval changes.⁴⁷ Risk-based categorization of post-approval changes, including the identification of established conditions, will enable to making decisions regarding whether the proposed changes require notification to the regulatory agency or not, or require prior approval.

Based on existing guidance and references, QbD is an essential part of pharmaceutical quality. It is intended to provide a better understanding of the product, process, risk, and mitigation. The QbD approach leads to the development of robust products, more efficient technology transfers, and minimizes batch failures. The QbD approach allows for even more regulatory flexibility in the future. Ease of dealing with Chemistry, Manufacturing, and Controls (CMC) within a pre-existing design space, reduction in post-approval changes, time savings, and cost-effective commercialization.