PharmTech: What is the difference between parametric release and real-time release testing?

Heribert Häusler

Parametric release can only be applied to products terminally sterilized in their final containers by steam, dry heat or ionizing radiation, but recent guidelines adopted in the International Conference on Harmonization (ICH) context (ICH Q8, Q9, and Q10 Guidelines) now enable a similar release strategy to be adopted for other tests as well (2). This approach is called real-time release (RTR) testing, and can be applied to both new and established products. As with parametric release, RTR testing provides assurance of final product quality based on information collected during the manufacturing process. The basis for establishing RTR testing mechanisms involves combining quality riskmanagement principles, enhanced product knowledge and process understanding, as well as applying an adequate pharmaceutical quality system. It is important to note that the other products mentioned may be chemical products such as excipients, active substances, pharmaceutical intermediates and finished products.

PharmTech: What preconditions have to be given for parametric release of sterile drug products?

Häusler: Parametric release is defined by the EMA as a sterility assurance release program where a demonstrated control of the sterilization process enables a company to use defined critical process controls in lieu of the sterility test to fulfil the intent of 21 CFR 211.165(a) and 211.167(a) (3).

Compared with performing sterility tests of units drawn from a finished batch, meeting parametricrelease requirements can provide greater assurance of a product's sterility. Traditional sterility testing methods are limited in their ability to detect contamination because the small number of samples required restricts the ability to capture microorganisms dispersed in large volumes. Additionally, the prescribed culture media has only a limited ability to stimulate the growth of all potential microorganisms. The sterility tests described in the European Pharmacopoeia, however, provide an optimized approach by taking into account different culture media, and their respective incubation temperatures and incubation times. Even so, sterility tests typically only detect major errors in the manufacturing process that stem from the contamination of a large number of product units. Data derived from in-process controls of a validated terminal sterilisation process, on the other hand, can provide more accurate information regarding product sterility because the probability of product bioburden surviving the sterilization process in any single unit of a product can be calculated to less than one in a million.

At the beginning, the accurate monitoring of relevant sterilisation cycle parameters, such as temperature, pressure, time and the fθ value, were sufficient for a parametric release. However, further requirements soon became mandatory. Today, the entire sterilization process must be described, and process validation reports have to comprise heat distribution and heat penetration studies for at least three runs for each load pattern used, according to good validation practices. Microbiological qualification must also show sufficient efficacy at the minimum level of the cycle, including information on the biological indicators used (type, D-value, Z-value and stability) and bioburden characteristics (number, type and resistance), as applicable.

The effort involved in the preparation phase of parametric release is high and a large amount of documentation is necessary, but in most cases, the same effort is also required when following the usual application processes for sterilized drugs. Sterility tests require large additional investments, but also offer additional protection in case of legal claims. The biggest advantage of using parametric release, besides quality assurance, is that it can shorten processing times by a few weeks. Depending on production costs, batch sizes and the amount of batches released, this can lead to significant financial savings. However, manufacturers also need to bear in mind that not all countries accept parametric release.