Quality by Design (QbD) - Quality as mainstay for the development of a medicated plaster.

José Maria Altinier – Galenic Development Supervisor

The use of Quality by Design (QbD) concept to medicated plasters (patches) development gives us the certainty to obtain safety and reliable products for patients with verifiable efficacy, long before they enter their production stage.

When medicated plaster development is considered, we normally focus on the clinical or pharmacological advantages that this pharmaceutical form has over others, such as providing a sustained release of the drug substance for several days, helping the patient to comply prolonged treatments or avoid the effect of first-pass hepatic metabolism, suffered by orally administered drugs. But we could ask ourselves, what place do we assign to quality in the development of these products.

Let’s talk about history. Quality management concept appears in pharmaceutical production from 1980s, with the first publications of a Good Manufacturing Practice (GMP) guidance, firstly in the United States and later in Europe. The objective in this first stage was to ensure that the products were manufactured in such a way that they meet the specifications and requirements for their use, also known as Quality Target Product Profile (QTTP), using the manufacturing steps monitoring and manufactured product attributes analysis as tools.

Already in the 1990s, the International Conference on Harmonization (ICH) was born as a result of the need to define common rules between good manufacturing practices developed by different countries. This institution was in charge of publishing the so-called ICH Guidelines, which focused on the different aspects of quality management. Three of these guides refer to good practices for the development of new products (ICH 8, 9 and 10), generating the term Quality by Design. The concept of Designing with quality refers to the fact that it is no longer enough for us to taking into control the manufacture of the products, avoiding errors occurrence that harm the product itself or the patients safety, it becomes necessary that the development focus on reducing the possibility of such errors emergence, studying and defining the attributes of the materials used, as well as the manufacturing parameters as starting points and using the analysis of the risks involved in each case as a fundamental tool.

Finally, at the beginning of the 2000s, this development strategy began to be considered and required by regulatory entities for the registration of new products, with the United States Food and Drug Administration (FDA) as a pioneer.

But, what do we mean by attributes and parameters, and most importantly, how can we analyze the risks in a product that does not yet exist and whose development we have just considered?

Before answering this question, let’s talk a little about Risk Analysis. These analyzes are normally carried out by experts in the different development aspects, who seek to identify and evaluate the factors that could have a negative effect on our product, both in its composition and in the processes to which it is subjected during its manufacture. Once identified and evaluated, actions can be taken to control, mitigate or eliminate them, in the best case.

Going back to our question, an experienced pharmaceutical developer can define a set of raw materials that could be used in the development of a new product, based on developer’s previous experience and availability of raw materials on the market. These materials would be composed of a drug substance, responsible for the therapeutic action and a set of excipients which would accompany the drug substance in the formula. Both drug substance and excipients have physical and chemical characteristics that we call attributes, which can have an impact on the product properties or on the way in which it is processed. Those attributes that produce a significant impact on the product must be identified and studied to define an acceptable value or range of variation for it, called specification. Once the specification is defined, only raw materials that comply with it may be used in manufacturing, mitigating the risk of a negative impact on the product properties or on the way in which it is manufactured.

The same concept is applied to the manufacturing process development. The speed, time, temperature, or any other variable that can be modified during the process, we call them parameters and like the attributes, parameters that can have a significant impact on the properties of the product will be identified and studied to define a value or acceptable range of variation, thus reducing the risk of a negative impact on the properties of the product.

With the definition of process parameters and raw materials attributes, we can generate what we call a design space, which is nothing more than a safe variation margin that guarantees that the product meets the requirements for which it was designed, providing to the patient, quality and safety.

In this way, through the risk analysis and the definition of a design space, we can generate a product that meets the requirements for which it was designed even before it enters in the commercial manufacturing stage, providing quality from its design.

Currently, this development concept for new products has become a working standard for the world industry and is applied by the most recognized pharmaceutical companies.

Developing medicinal patches under this work concept guarantees us to be able to provide patients with safety and reliable products with verifiable efficacy throughout their useful life.

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