QUALITY BY DESIGN || definition of qbd, main goal, elements of qbd, QTPP AND CQA

 

QUALITY BY DESIGN(QbD)

¨    DEFINATION

OVERVIEW

MAIN GOAL

ELEMENTS

TOOLS 

DEFINITION

The ICH guideline Q8 (R2) Pharmaceutical Development defines the term Quality by Design (QbD) as “a systematic approach to development that begins with predefined objectives emphasizes product process understanding and process control, based on sound science and quality risk management (QRM).”

OVERVIEW

QbD main goals:

• Obtaining meaningful quality requirements for the product based on clinical effectiveness.
• By increasing the process and product design and control, we may increase process capability while lowering product issues and variability.
• To encourage root cause investigation and control any modifications made to a medicine after it has received approval.
• To increase the effectiveness of the production and product development processes.

As a result, the first step in the pharmaceutical QbD method is to identify the crucial quality attributes from the perspective of the patient. 

ELEMENTS OF QbD

The elements of QbD include:

• The CQAs for a drug product are identified by the Quality Target Product Profile (QTPP).
• Critical Material Attributes (CMAs) and product design.
• Designing the process and determining the Critical Process Parameters (CPPs). Links between CMAs and CPPs and COAs are part of this.
• Developing specifications for active pharmaceutical ingredients (APIs), excipients, and the finished drug product as well as controls for each stage of production is part of the control’s strategy.
• Capabilities for processes and ongoing development.

Quality Target Product Profile (QTPP):

The QTPP is a list of the quality criteria that a pharma product must meet in order to be of the intended quality. On this foundation, product design will start.

The following factors should be taken into account when developing the QTPP:

• The product's intended use, administration method, preferred dose form, and medication delivery mechanism.
• Efficacy of the dosage.
• To be used is a container-closure mechanism.
• Pharmacokinetic properties (such drug dissolution) and the release of the therapeutic component in the suggested dosage form.
• Stability, purity, sterility, medication release, and other quality standards for the finished product.

Critical Quality Attributes (CQAs):

• The CQAS of the drug product can be determined after the QTPP is complete. CQAs are characteristics of the final product that must fall within a specific range, limit, or distribution in order to maintain the aimed level of product quality.
• These characteristics might be physical, chemical, biological, or microbiological.
• The identity of the prescription drugs, assay results, content uniformity, drug release profile, degradation products, microbiological levels, moisture content, and physical characteristics including size, color, shape, and friability are a few examples of quality aspects of drug products.
• Some of them might not be essential qualities.
• The severity of the harm that may result from a product breaking from that attribute's approved range determines whether or not that attribute is critical.

Product Design:

• A well-designed product is one that satisfies patient needs, and clinical trials might attest to this.
• Stability studies provide evidence to the performance of such a product over the course of its shelf life.
• Therefore, product design must be focused on creating a sturdy product that provides the target QTPP for the duration of the product's shelf life.

The following topics need to be thoroughly studied for excellent product design:

Particle size, polymorphism, solubility, melting point, pKa, oxidative stability, partition coefficient, bioavailability, membrane permeability, and other physical, chemical, and biological properties of the medication are a few examples.

Details on intrinsic excipient variability, excipient kind, and grade (common excipients including binders, diluents, disintegrants, glidants, coloring agents, sweeteners, suspending agents, film coatings, preservatives, flavors, etc.).

Testing for drug-excipient compatibility to determine where drug compounds interact with excipients.

The CMAs of both the medicine and the excipients to guarantee the creation of a reliable formulation.

CMA vs CQA

CMA	CQA
Raw materials must have certain physical, chemical, biological, or microbiological properties that must fall within a limitation or a range in order to be of the desired quality.	Limits or ranges that intermediates or finished drug products must fall within are determined by the physical, chemical, biological, or microbiological characteristics of the drug product in order to maintain the intended quality.

Process Design:

• A collection of unit operations is carried out in a certain order during the manufacturing process of a drug product to produce the finished good.
• Any activity that causes a substance to change physically or chemically is referred to as a unit operation.
• Unit activities used in the production of tablets include milling, mixing, granulating, drying, compressing tablets, and coating.
• To produce the required product, processes must be designed so that each unit activity is carried out as expected. 
• To do this, it is crucial to:

Identify the critical causes of variations.

Manage these variations during the process.

Predict quality attributes of the product with accuracy and reliability.

Any parameter that is necessary to the process and is referred to as an important Process Parameter (CPP) is one whose Changes could negatively affect a CQA.

Prior to monitoring and regulation, all CPPs for a particular process must be accepted in order to ensure the production of products of the desired quality.

To determine whether a process can withstand changes in the input materials and processing parameters and still produce a result of an acceptable quality, process robustness studies must be carried out.

This research will help to find CPPs that affect the efficacy of medicines.

Evaluation of CMAs, CPPs and CQAs for unit operation of tablet compression

CMAs	CPPs	CQAs
Particle size distribution Proportion of oversize/fines Shape of granules Cohesive properties Hardness Density values/bulk/tapped/true Electrostatic properties Brittleness Moisture content Polymorphism	Type of press Design of hopper, vibration, height Feed mechanism zero force feed/gravity, rotational direction Tool design-metal quality, score configuration Maximum punch load Pressing speed Compression force (pre, main) Penetration depth of punch Dwell time Ejection force	Appearance of tablet Tablet weight and uniformity Hardness Friability Content uniformity Thickness Tablet density/ porosity Defects Disintegration time Moisture content Dissolution profile

Control Strategy:

The data generated during developmental studies must be used to set up a control strategy. It is common to have controls at three levels as follows:

Level 1: 

• Real-time CQAs monitoring of the output materials is done using automated engineering controls. 
• The system's monitoring of the input material characteristics and automatic process parameter adjustments are intended to ensure that CQAs always meets the established acceptance requirements. 
• Systems using Process Analytical Technology (PAT) are an instance of such a type of control.

Level 2: 

• In this case, control over the pharmaceutical process is emphasized together with an understanding of the process and product. 
• This is QbD, which permits the control of variables and so ensures the quality of the drug product.

Level 3: 

• This tactic is based on extensive product testing, just like in the production of conventional pharmaceuticals. 
• The possibility of product issues is high since the sources of variability have not been identified and because CMAs and CPPs studies on the quality of drug products have not been conducted.
• In practical settings, it is preferable to combine level 1 and level 2 control tactics to create a hybrid strategy that includes:

1. Controlling input material qualities based on research into their effects on product quality and processability.

2. Creating up product requirements.

3. Having the most significant unit operations that affect product quality under control.

4. Rather of depending just on end-product testing, test while in-process, in real-time.

5. Implementing a monitoring program to confirm that the procedure and output are under control.