Q. What is the difference between parametric release and real-time release testing?
Heribert Häusler
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Compliance with release specifications can be demonstrated by performing a complete set of tests according to approved specifications
before the final product is released onto the market. Under certain conditions, however, it is possible to use an alternative
strategy called parametric release. Rather than conducting an approved sterility test, parametric testing involves utilising
information collected during the manufacturing process to demonstrate that the product was made according to defined GMP and
sterilisation procedures (1).
Parametric release can only be applied to products terminally sterilised in their final containers by steam, dry heat or ionising
radiation, but recent guidelines adopted in the International Conference on Harmonisation (ICH) context (ICH Q8, Q9 and Q10
Guidelines) now enable a similar release strategy to be adopted for other tests too (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.
To demonstrate, a combination of in-process tablet weight, blend content uniformity measurement, drug substance purity and
particle size could serve as a control strategy for ensuring the drug content of a highdose tablet, if the relationships has
been demonstrated. In this example, the above-mentioned factors would serve as the RTR tests. Based on the outcome of these
tests, as well as other required tests in the product specification, and GMP compliance, the production batches are released
by the qualified person.
Q. What preconditions have to be given for parametric release of sterile medicinal products?
Parametric release is defined by the EMA as a sterility assurance release programme where a demonstrated control of the sterilisation
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 optimised 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 sterilisation
process in any single unit of a product can be calculated to less than one in a million.
At the very 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 sterilisation 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 sterilised 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.
