Pharmaceutical Development for Historic Dossiers: An Overview

Getting historic dossiers registered in new markets can have its difficulties, especially when the dossier may have been developed prior to a lot of current guidances and requirements. One such difficulty is the concept of Pharmaceutical Development and Quality by Design (QbD).

Quality by Design is the recommended approach to development of new dossiers in the US and EU and involves a systematic approach to development using multivariant analysis and risk analysis to develop a control strategy and reduce the need for lifecycle management. Using the concepts of QbD can be very helpful in avoiding quality questions during assessment of a new application. Where a drug was developed prior to the introduction of QbD, it is still possible to introduce the basic concepts into a Pharmaceutical Development section (3.2.P.2) without carrying out new development studies and Design of Experiments (DoE).

When writing a Pharmaceutical Development section for an older dossier, any information that may be available in the old NtA part 2.A.4 Development Pharmaceutics may still be applicable and used as a starting point, but there is also a wealth of information available from batches that have been in commercial manufacture for years. Without the need for carrying out additional studies the following information can be readily available:

Quality Target Product Profile (QTPP): The target product to be developed is already defined in the original dossier including product description and shelf life.

Critical Quality Attributes (CQAs): The quality attributes required to achieve the target product quality can be found in the finished product specification e.g. description, assay, impurities etc. Batch analysis and stability data can be assessed to see what attributes really are critical, and possibly reduced stability testing can be applied if certain tests are proven not to be stability indicating.

Critical Material Attributes (CMAs): The material attributes of all components which may affect product quality can be found in the specifications of raw materials such as API, excipients, packaging materials and also equipment e.g. API/excipient particle size, impurities etc. It can similarly be shown if certain attributes do not affect finished product quality and thus do not need to be controlled. Some functionality related characteristics of excipients are stated in Ph Eur and should be assessed for risk of impact on quality.

Critical Process Parameters (CPPs): The process parameters which may affect product quality are defined in the manufacturing process and in-process controls e.g. mixing speeds and times, temperatures etc. Any batch analysis or stability data which supported changes in manufacturing process over time can also be used. If data is available to support multiple mixing speeds with no affect on product quality, then ranges can be registered as opposed to a single set speed, this will allow for greater flexibility and reduction in lifecycle management.

By keeping these concepts and terms in mind while writing the 3.2.P.2 and carrying out a risk assessment on each attribute and parameter, and using data to hand, it can greatly reduce questions received from agencies during assessment. By setting a risk-based control strategy it builds a strong justification of specifications and can also lead to the ability to reduce controls that may have been in place historically or allow for greater flexibility by registering ranges rather than set parameters.

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