Parametric Release and Real-Time Release Testing

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

Häusler: 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 utilizing information collected during the manufacturing process to demonstrate that the product was made according to defined GMP and sterilization procedures (1).

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.

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.

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.

PharmTech: Will real-time release testing replace the final release procedure?

Häusler:The main benefit of RTR testing when combined with quality by design and process analytical technology (PAT) tools is increased quality assurance for patients. In addition, such a strategy can lower manufacturing costs through improved yields, less waste, faster cycle times, and fewer deviations and rejects.

Process understanding and the definition of a robust control strategy are key aspects of RTR. The interaction of material parameters and attributes, as well as the dynamics of processes, must be taken into account, and are one important part of submission dossiers for marketing authorisations. As such, when implementing RTR systems it is essential to use PAT to efficiently monitor and record all quality-relevant parameters. In this area, there have been a number of improvements, including advances in NIR- and Raman microscopy, fluorescence microscopy, image analysis and laser-based methods. Using chemometics and multivariate analysis, it is now also possible to monitor production processes in real-time. However, a move towards RTR is not only about using advanced analytical and physical measurement techniques, but also involves performing statistical calculations on the resulting data masses. Importantly, regulatory authorities worldwide have to accept the move from final product testing to RTR applications. RTR has to be accepted by all regulatory authorities because the current varied acceptance can be a major issue. The equivalence between RTR-testing and pharmacopoeial testing must also be explained.

If one wishes to implement new tests and procedures, then it is important to adapt the whole quality assurance system. This approach is mandatory for compliance. The new quality system must also be aligned with ICH Q10.

These steps constitute the transition from rigid to risk-based cGMP, and a mindset change from reactive to proactive quality thinking, which could be quite a challenge. In particular, there will be a huge impact on qualified persons or other persons responsible for product release. Specifications will need to be elaborated carefully, and the definition of deviations that require investigation and the process to declare analytical results as outliers or invalid data must be described in SOPs.

RTR will be implemented over time as industry understanding increases and regulatory expectations are clarified. There is a long road ahead, but as the saying goes: a journey of a thousand miles begins with a single step.

Heribert Häusler is head of quality systems excellence at Boehringer Ingelheim GmbH (Ingelheim), haeusler@ing.boehringer-ingelheim.com.

References

1. EMA, Note for Guidance on Parametric Release (March 2001).

2. EMA, Guideline on Real Time Release Testing (February 2010).

3. 21 CFR Part 11 Title 21 (April 2010).