How do I implement the new requirements of Annex 15 and of the EMA Process Validation Guidance? This question was just one subject at the GMP Conference on 28th and 29th of October 2015. The participants engaged in lively discussions with the experts, Dr. Christine Oechslein (gmp-praxis) and GMP Inspector Dr. Rainer Gnibl (Regierung von Oberbayern – Regional Government of Upper Bavaria). We have prepared a summary of the results for you, which you will find below:
The participants in the GMP conference asked Christine Oechslein and Rainer Gnibl to explain to them whether or not a bracketing approach can be applied in process validation and how a master validation plan should be used if the products on which it is based are no longer being sold.
First of all, the two experts presented the key principle that every process and every product must be validated! “According to Annex 15, bracketing is only possible for a process that was originally validated and is now being transferred to another manufacturing site”, explained Rainer Gnibl. “What’s more, this approach can only be used for different dosages of the same product but not for different products manufactured using similar methods.”
For working with a validation master plan Christine Oechslein advised: “Adapt the master plan to valid requirements. Apply the status quo: What products are you still marketing? What was the risk analysis like at that time? Perhaps the risks have changed. Add the experiences you have had in the meantime.”
Continuous Process Verification (CPV), which was introduced in Annex 15 for quality-by-design products, raises a number of questions concerning practical implementation.
What are the expectations for qualification of the supply technology and the equipment in cleanrooms?
“Ongoing system qualification throughout the entire product life cycle must be assured. A data review can be adequate for this purpose,” explained Christine Oechslein. Rainer Gnibl added: “The requirements for qualification are identical for CPV and for the traditional validation“.
Do I have to adapt my authorisation even if the changes are minor?
The experts‘ answers were unequivocal. In addition, Christine Oechslein recommended continuously observing the processes: “The criticality can also change (sometimes drastically). In time, process steps that were originally considered to be crucial can become less so, but the opposite is also true. Something once assessed as uncritical can eventually prove to be critical due to small changes in the framework conditions.“
According to Annex 15, changes in validation plans should be treated, documented and evaluated as “deviations“. This goes a bit too far to suit the experts, since – unlike deviations – changes are not an indication of flaws. However, it is important to have all data in a structured, documented form. This is particularly crucial for knowledge management and if someone wishes to take advantage of the opportunity to receive EMA’s scientific advice in the course of an authorisation procedure.
The discussion also included the question of whether there is a connection between ongoing process verification and PQR. It was important to the experts to stress that both must be linked. Parallel worlds must not be allowed to develop.
“For ongoing process verification the CPPs must be defined and the reviewing frequency and a mathematical tool for trend analysis must be specified”, says Rainer Gnibl. “Interim reports, for example, should be issued every two months. These data should be included in the PQR. Then, all that remains to be done is to establish the connection to change management.”
Participants complained that critical process parameters (CPPs) are currently not included either in the Product Quality Review (PQR) or in the Annual Product Review (APR). “The PQR is only one component of Ongoing Process Verification. In addition to this, technical parameters such as CPPs and CQAs must also be considered”, says Christine Oechslein. Rainer Gnibl: “Considering the CPPs in the PQR once a year would not serve the purpose. Ongoing process verification helps in this regard. The CPPs are considered and analysed for trends at higher rates.”
Ongoing Process Verification has been mandatory since Annex 15 went into effect on 01 October 2015. However, the regulations do not reveal what mathematical and scientific methods are to be used to conduct the relevant Trending.
The GMP Inspector commented on this: “Since there is currently no legal definition of the word “trend“, the opportunity to provide our own definition opens up. The important thing is to have a solid concept.” Christine Oechslein adds, “The mathematical tools must be simple and feasible if they are also going to be applied“.
Access to documents
Contract manufacturers often encounter problems in obtaining validation documents from the contract giver. Data from the developmental phase are frequently missing as well. Christine Oechslein reassured the participants: “Technology transfer is the catchword! As of immediately, a reasonable transfer of information between contract giver and contract taker is mandatory. Anyone who outsources manufacturing activities must also provide appropriate data packets.” Rainer Gnibl added, “Quality agreements become all the more important.” Process knowledge of the manufacturing site could be used supportively.
Very small-scale production
“If the production volume is very low – as little as one single batch per year – it is not possible to conduct a statistical evaluation for the PQR“, said Rainer Gnibl. In that case, all manufacturing procedures of the preceding years should be taken into account. The authorisation owner is responsible for the PQR. The contract on limitation of responsibility should stipulate which data the manufacturer would have to provide.
Dr. Sabine Paris, Editor
Maas & Peither AG – GMP-Verlag, Schopfheim, Germany