Pharmaceutical Development Annex – Guidance from FDA
The FDA has published an updated version of the Q8 Pharmaceutical Development as discussed earlier on this site (link) the annex to this publication which is of interest, it describes the principles of Quality by Design. This annex is not intended to establish new standards or to introduce new regulatory requirements, however it shows how concepts and tools outlines in the Q8 patent guidance could be put into practice by the applicant for all dosage forms.
This approach defines how your manufacturing process can be developed to be flexible within set parameters in order to deal more effectively with input and process variables, this gives manufactures the power to develop systems that are not ridged, but can be flexed within bounds and ensure consistent final product quality.
Approaches to Pharmaceutical Development
its a detailed document that should relay be read but I will pull out the key points here.
- In all cases the product should be designed to meet patients needs an the intended product performance
- A greater understanding of the product and its manufacturing process can create a basis for more flexible regulatory approaches.
- The degree of flexibility is predicted on the level of relevant scientific knowledge provided in the registration application.
Pharmaceutical development should include, at a minimum, the following elements:
- Defined Quality target product profile – quality, safety, and efficacy, route of administration, dosage form, bioavailability, strength and stability.
- Identifying potential critical quality attributes of the drug product.
- Determining the critical quality attributes (CQAs) of the drug substance, excipients etc
- Selecting the appropriate manufacturing process
- Defining a control strategy
An enhanced, quality be design approach to product development would additionally include the following elements:
- A systematic evaluation, understanding and refining of the formulation and manufacturing process, including:
- Identifying the material attributes and process parameters that can have an effect on product CRAs
- Determining the functional relationships that link material attributes and process parameters to product CQAs
- Using the enhanced product and process understanding in combination with quality risk management to establish appropriate control strategy.
Elements for Pharmaceutical Development
This part of the annex provides guidance on the possible approaches to gaining a more systemic, enhanced understanding of the product and process under development.
- Quality Target Product Profile, including:
- Intended use
- Dosage Strength
- Container closure system
- Therapeutic moiety release or delivery, PK profile
- Quality criteria
- Critical Quality Attributes, defined within appropriate limits, form a guide to product development
- Physical
- Chemical
- Biological
- Microbilogical
- Purity
- Stability
- Risk Assessment, which attributes have the most risk and potential impact.
Design Space
The relationship between the process inputs and the critical quality attributes can be described in the design space
- Select Variable – linkage between and effect of process parameters and material attributes and the identification of variables
- Describing a design space in a submission – a time dependent function, scaling factors, historical data
- Unit Operation Designs – separate design spaces for each function/step can be brought together and relationships established.
- Relationship to scale – what happens to the design space as you scale up
- Design space vs proven acceptable ranges – proven ranges don’t define the design space, although they do influence it
- Design space and edge of failure – defined the ranges where risk of failure increases
Control Strategy
A control strategy is designed to ensure that a product of required quality will be produced consistently. Its important to describe how they are monitored and implemented, they should as a minimum control the critical process parameters, but other functions as well, such as input materials, intermediates, containers systems and process systems. This can lead to less stringent input characteristics, as process systems and control systems can respond through knowledge of the design space parameters, via adaptive processes.
Product Life Cycle Management and Continual Improvement
By monitoring performance and making improvements to the design space the control systems and processes can be adapted and improved.
Summary
the annex describes a step wise approached to defing standard and inputs and how they interact (known as the design space) and then defining how this information can be used to develop control systems that can predict and adapt product characteristics to manage and ensure consistent product development.
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