Careful management of specifications makes pharmaceutical products safe - Part 3

The "Careful handling of specifications in pharmaceutical quality systems“ theme is dealt with as a four part BLOG article. The article describes which cardinal errors occur when dealing with specifications, salient incorrect assumptions regarding them and how errors in managing specifications can be avoided.

Specifications: Process control tool

Parameters of the manufacturing process that influence critical quality attributes of the pharmaceutical product are referred to as Critical Process Parameters (CPP). Due to their particular relevance, specifications must be chosen so that they correspond closely enough to meet the quality specifications for the product with sufficient certainty. At the same time, the specifications must be broad enough to allow the manufacturing process to operate in a manner that eliminates repeatedly exceeding specification limits and allows consistent production of quality conforming products.

Pharmaceutical operators are legally required to verify the ability of the process to manufacture products in accordance with the defined quality criteria. The CPP and its specifications are essential elements of process control. The process capability check, or the process validation, therefore includes at least a check for compliance with the specifications of critical process parameters.

The following aspects must be taken into account for subsequent routine production:

If the results of validation runs are too close to the specification or process limits, it must be assessed whether the process is still safe, i.e. whether it will also run within the specified process limits in routine production. No later than the time of process validation, it must be assessed whether the process specifications have been selected too narrowly. If this is the case, suitable measures must be put in place so that the product can be produced in accordance with the specifications set out for the routine process.

These measures may need to include a change in process specifications. This is usually associated with invalidating validation runs that have already been performed, repeating them, or redoing the entire process validation again. In any case, all negative or out-of-specification (OOS) results, must also be documented and evaluated in corresponding quality management processes (OOS procedures, discrepancy procedures). This includes a summary assessment of the impact of OOS results on the result of the validation and explaining why validation runs can be repeated.

Does Quality by Design protect against violating defined specification limits?

Quality by Design (QbD) and Design of Experiment (DoE) are established terms of modern pharmaceutical development, manufacturing and quality control and are described in the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (Guidelines Q8 - Q11).

The QbD objective is to ensure the quality of pharmaceutical products, preferably through appropriate development and design of the manufacturing process, rather than through testing of a finished product. They say: Quality is integrated into the product and process.

QbD identifies the factors that influence the quality of pharmaceutical products and their interactions. Design of Experiment (DoE) is used for practical implementation in development , in which the multidimensional combination and interaction of the influencing factors are examined with statistical tools such as ANOVA (Analysis Of Variance) and ANCOVA (Analysis Of Co-Variance). In addition, a risk-based approach is applied that creates a deeper understanding of the quality-relevant relationships, on the basis of which a robust manufacturing process and a suitable system of process control can be determined. Setting up this design space plays an important role in achieving this. This term describes that space or range of possible variability for influencing factors, compliance with which will provide sufficient certainty to produce a product with the desired quality characteristics.

If pharmaceutical manufacturing is applied for and approved on the basis of a QbD and a design space is specified, the pharmaceutical manufacturer is bound to comply with that and the associated specifications. The results of production must not violate the boundaries of the design space. In this way, Quality by Design does not protect against violations of specification limits, but only provides the scientific justification for the maximum specification range to be used.

As a rule, however, manufacturers will not change production conditions in such a way that the manufacturing process is carried out at the limits of the design space. They prefer to set safety margins and tighter process limits as necessary, on the basis of further development and production experience, especially where this can ensure an improvement in products and processes and a reduction in variability. This is also the aim of the QbD "idea/philosophy". It allows pharmaceutical manufacturers to optimize their manufacturing process within a determined design space.

Due to this possibility and the changes in specifications that occur as a result, there is basically an increased risk that specification lists will be mixed up in the pharmaceutical quality system, for example, that individual specifications will be "lost," or that incorrect specifications will be set. The use of QbD and Design Space requires that manufacturers also establish an efficient monitoring system for specifications and specification changes as early as possible in the development phase. If this has not yet been done, it should be rectified as quickly as possible.


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