GxP-Blog

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.

One question asked frequently is: What is the leading specification?

This issue comes up at different stages in a product's life cycle, causing repeated discussions and requiring no small amount of time for a variety of personnel functions in a GMP system. The question is especially prevelant when summarizing certain phases of the product life cycle in the form of summary reports or when using specifications as a prerequisite for GMP processes such as qualification of equipment and validation of processes. Classic examples are summary lists of specifications from the development of manufacturing processes, from the transfer of development to production or from production itself, including the associated change history.  

However, lists such as overviews of parameters and specifications within the scope of manufacturing notifications to the competent authorities or other descriptions of manufacturing processes, e.g. in the form of flow charts, are usually also available.

The background to the question of the leading specification is the uncertainty or lack of clarity as to which function and which update status the respective specification lists have should they at least partially describe the same parameters.

In the case of process validations or re-validations, at a minimum, the specifications officially reported as part of the manufacturing process description are binding. This means that the validation must show that the process functions in a reproducible and controlled manner and consequently also meet the specifications belonging to the "reported" process control.

If a manufacturer, in order to additionally increase the security of the control, internally maintains narrower specifications for his process parameters than the specifications reported to the authority, compliance with the narrower specifications shall be checked with regard to the (re)validation.

Asking for the leading specification becomes even more complex if the same product is produced at different sites of the same company and if there are differing specifications.

In such cases, "global" decisions may have to taken  to determine the degree of consistency or harmonization of specifications.

In any case, a clear functional description and a visualization of the hierarchy and dependencies of the specification lists, including the integration of these descriptions into the GMP system via the drafting of an SOP, will help in selecting the right specification for the task at hand.

Even if no regular changes to specifications are expected, different reasons for the necessity of specification changes make it essential that specifications be monitored and at least checked at regular intervals to ensure that they are up to date.

Production by pharmaceutical manufacturers is governed by legal and regulatory requirements. New requirements of this kind are constantly arising and a part requires specifications or establishing additional specifications. Examples of recent years are the required changes to minimize the content of metallic impurities or nitrosamines in pharmaceuticals. The changes must not only be documented in the manufacturer's quality requirements or quality system, but must also be integrated into the internal manufacturing, control and quality assurance processes. For example, the regulatory requirements for certain analytical test procedures must result in corresponding changes in the test regulations.

For the specification lists available from the manufacturer, clear frequencies should be specified, with which a periodic review is to be carried to ensure they are up to date. Appropriate resources must also be made available for these monitoring and updating activities. This also includes assigning the specification lists in the most appropriate manner possible to the various functional areas and responsibilities within the company.

A graphical representation of the hierarchy and dependencies of the specifications including a functional description for each specification (list) can help to illustrate the correlations between the specifications and their relevance with regard to a product and the manufacturing process.

In addition, the processes for reviewing and updating the specifications should be described and clearly presented with flowcharts in a work instruction (SOP). As a rule, these processes are not carried out by individual persons, but by persons from different departments and in different areas of the GMP system.

During official inspections, the GMP system is also checked with regard to the established processes for updating the regulatory and internal requirements as well as the results/status of this update. A good update status avoids the impression that there is a systemic problem in the form of a defect in updating the GMP.

A large number of specifications arise in the course of the life cycle of a pharmaceutical product, so that an overview of their relevance, validity and topicality can stray.

With the help of suitable processes and measures, the overview can be maintained and specifications used purposefully to preserve and improve product and process quality.