An extract from an article for Biopharm Asia
Continuous processing, as to an extent with closed processing, is a difficult area of engagement for the pharmaceutical industry. The article considers why this is the case and whether there are fundamental issues that prevent taking continuous processes on board.
With concerns about drug shortages and the opportunity to work openly with the regulators in resolution of issues the adoption of continuous processing would seemingly become more beneficial in responding to supply concerns, and therefore more accessible. Its introduction, given the significant controls improvements both in quality and operation available, would be thought to be considered essential to maintain a secure and low cost product flow to market. The following is an extract from the article:
Engagement in continuous processing, or, in fact, any novel process within the pharmaceutical industry is, on the face of it, expensive and disruptive of pre-existing systems. The issues are affected primarily by three significant criteria:
- Investment risk
- GMP interpretation
- Implementation disruption
Investment risk: The development of new systems for manufacture is inevitably specialist lead personnel time and cost heavy with risk and time in development of drug product compatibility; especially when transferring existing products. Further, significant regulatory and quality control responses through the implementation of quality by design (QbD) techniques need to be addressed with their own element of risk and surety attached. Easy comparisons with food and non-ingested chemical manufacture tend to pale into insignificance when given the levels of accuracy of characterisation and content required to meet in vivo efficacy requirements. It is always easier to implement a tried and tested, possibly 40-50 year or older, batch processing method even given its apparent inefficiencies and wastage as it provides a known risk, uses known equipment and vessels and is understood by the regulators and operatives alike.
There is more opportunity of convincing companies to use new processes when the product is also new and the development time, including clinical trials, QbD, risk development and filing can be agreed following a once off development path. From decision to manufacture to first sale there is always a significant time and cost restraint no matter which of the three manufacturing formats, the instigator (“big pharma”), generic or contract manufacturer (CMO), or is the implementer of a programme/schedule. This inevitably means that changing the initiating manufacturing process is commonly seen to be risk prohibitive; also older facilities with familiar equipment have been amortised and are perceived to be cheap to operate.
GMP interpretation: The US FDA and European EMA are verbally encouraging a change in process towards acceptance of QbD developed product using risk based manufacturing. A process that, in the case of the FDA, has so far taken a ten year period and that is still in its implementation phase. PAT (process analytical technology) is essential to the operation of continuous processes for both feed forward and feedback application of characterisation and control. The FDA, through its PAT initiative[i], is actively pursuing both methodologies and systems through its establishment of a dedicated team supported by a research team and led by a structured management.
Inevitably, at least initially until process principles are proven, individual inspectors will naturally err towards caution in acceptance of new processes as they are applying regulatory guidance that is still founded on batch based GMPs. The risk environment is reliant on appreciation of drug characterisation. In this respect the revisions to GMP proposed by the EMA are currently stalled by incapacity to agree the case around a new toxicology model that may allow a more enlightened attitude towards cross contamination issues around multiproduct manufacturing. This is likely to take a further year to settle and, therefore, has stalled some of the ease of development of the case for continuous processing for which a major benefit, given a focus on smaller drug runs, is multiproduct manufacturing.
Implementation disruption: Making the best, most efficient use of continuous manufacturing once fully accepted and implemented, will involve significant changes in the structure of organisations and facilities to make it fully cost beneficial. Inevitably, initially until such processes are proven, batch processing will remain for most drug production. However, the benefits and ease of manufacture of continuous processing linked with the implementation of QbD methodologies and risk based product and process engineering and proven PAT using feed back/feed forward control and clear product characterisation become a norm structures of organisations and facilities will change significantly.
An element of disruption is bound to ricochet through current organisational structures with a threat to the recognised pharmaceutical management tree if continuous processing is accepted. It is likely that quality departments will significantly change as electronic systems confirm product character and quality parameters, that system operators will be fewer but be expected to be more highly qualified on employment. Changes to the manufacturing process will inevitably challenge the methods used to feed raw materials, quarantine and export final product. It is likely that with significantly smaller plant producing continuous product current pharmaceutical warehousing systems may be challenged with the supply chain methodologies questioned. Size reduction available through continuous processing may change the overall operational parameters around throughout the process allowing production at point of need with a more sustainable operational structure.