GxP-Blog

Careful management of specifications makes pharmaceutical products safe - Part 1

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.

Lists for better overview and control

During the life cycle of a pharmaceutical product, a large number of specifications are usually created; these are summarized in lists generally referred to as specifications, either thematically or for certain purposes. These include lists for applying for manufacturing permits, lists for development specifications, lists for process specifications, lists for in-process controls and lists for test and release parameters of quality control. The specifications must be modified, supplemented and updated under constant supervision at the various stages of the life cycle. This not only creates additional work, but also the risk that different specifications exist for the same parameters or that specifications are not up to date.

In the worst case, the employees of the pharmaceutical company no longer know which is the leading, i.e. relevant, specification. This can lead to specifications unsuited to the product or process and not reflecting the correct product or process characteristics. This affects both product safety and inspection safety.

Therefore, it is important not to lose sight of the situation and to gain a uniform understanding within the company of the different areas of production, quality control and quality assurance with regard to the function of the respective specification.

Depending on this function, a specification not only has a certain relevance, but also requires a different updating frequencies and should be managed within a defined accountability framework.

Scientifically substantiated specifications

In pharmaceutical manufacturing, the manufacturer must accurately describe, define and ensure the quality characteristics of its products. As a minimum, those parameters that influence critical quality attributes (CQA) of the pharmaceutical product must be documented accordingly. These are different types of parameters, such as parameters governing the quality properties of raw materials (e.g. purity specifications of raw materials) or process parameters that determine the sterility, effectiveness and other essential quality properties of the final product.

The specifications associated with these parameters must have been established for scientific reasons (Justification of Specification).Pharmaceutical development, including its objectives, rationale and results, must provide this justification for selecting and determining specifications. Unsubstantiated specifications are a cardinal error in pharmaceutical production.

The basis for the scientific justification of specifications is for the most part knowledge and understanding based on the current state of science and technology. This includes, for example, specifications limiting maximum contamination in medicinal products as well as requirements for minimum degree of sterility of a product, known as the sterility assurance level. Appropriate rationales support the justification for setting specifications. Where such a theoretical consideration and justification is inadequate, laboratory tests or trials in the technical center, for example, must provide results in the form of development studies and series of tests to achieve a justified specification.

The importance of justifying specifications should not be underestimated. Ultimately, this is what ensures that the product has all the necessary quality properties and that the manufacturing process functions within the defined limits. Unjustified specifications thus increase the likelihood that a product and its manufacturing process are not sufficiently controlled and are therefore not sure to pass inspection.

Check specifications periodically or as required

It should be noted that when defining parameters and determining the specifications for the various phases in the life cycle of pharmaceutical products, changes often occur.

Adjustments are made at different times in product life cycles depending on changing knowledge. As a result, additional parameters and specifications may be added as products transfer from development into production, but also during pharmaceutical production. Nor can it be ruled out that parameters originally assessed as critical be classified differently when levels of knowledge increase, or be replaced by other parameters.

Specifications are not cast in stone. If routine production shows that process parameters have been set too tightly and justification exists that extending the specification will not impair the defined quality characteristics of the product, a modification of the specification should be possible.

However, selecting specifications that are too narrow for the product as part of the development specifications and if a company is requested to continue these development specifications into routine production, in the worst case this can lead to extreme costs or even to failure after years of development and production.  It is not uncommon for specifications to be drawn up based on marketing requirements or with regard to the performance and quality characteristics of competing products that are not feasible in practice. The specifications issued for competing products cannot be achieved if, for example, the equipment used for production is not suitable. Theoretically, appropriate requirements for manufacturing equipment are stated in associated specifications for ordering the equipment from a supplier. However, practice repeatedly shows that equipment was ordered injudiciously and essential requirements are not included or unsuitable existing equipment is used due to cost pressures.

In the case of filling machines, for example, a lack of accuracy can lead not only to commercial losses because the quantities of the drug filled into the primary packaging are subject to high fluctuations, but also from to failure to comply with desired specifications in the manufacturing process (e.g., a certain range for the lethality value F0 during sterilization) or specifications of the design of the primary packaging.

Company management, with its scope for monitoring and decision-making, is often too far away from it to recognize the discrepancy between requirements and their feasibility. Also, employees involved in development and production may be reluctant to point out the problem or take their case to management.

In such a case, clarification by an external consultant, who is not directly associated with internal processes, can ensure timely clarity with regard to requirements and feasible solutions. Early assimilation of the actual situation by company management will then help to avoid unnecessary development or transfer work and save costs.

Contact

This website uses cookies to provide you with the best possible experience. If you continue to browse our site, you consent to our use of cookies and to our privacy policy.