To encourage the development and adoption of emerging technologies and achieve an increasingly efficient drug manufacturing system, the FDA has launched the Emerging technology program (ETP). Among the emerging technologies, continuous manufacturing (CM) is recognized as the most imminent and promising change.
With continuous production, development and techonlogy transfer times are shorter, but at the cost of significant investments. In pharmaceutical industry, continuous manufacturing has great potential in terms of efficiency and flexibility. However, the challenges to be faced are many, starting with the lack of knowledge on continuous processes and the regulatory framework, up to global harmonization which risks to slow down its application.
2018, towards the ICH Q13 guideline
On 22 June 2018, the ICH (International council for harmonisation) announced that the new ICH Q13, scheduled for 2021, would support the introduction of continuous production in the pharmaceutical industry. The new guideline “Continuous manufacturing of drug substances and drug products” was born with the aim of providing key definitions, scientific principles and regulatory expectations. In addition to this it was announced that the new ICH Q13 would also host the control and validation strategies, in line with the other ICH guidelines (ICH Q8, Q9, Q10 and Q12). Furthermore, its aim was to harmonize the regulatory and quality perspectives of ICH members, including Fda (USA), Ema (CE) and Pmda (Japan).
July 2021, a new beginning
The first version of the document was published on 27 July 2021. The new guideline addresses the production of both APIs and pharmaceutical products. It applies to the continuous manufacturing of new pharmaceutical substances and products (e.g. new drugs, generics, biosimilars) as well as to the conversion from batch to continuous production of existing products. The principles described in this guideline may also apply to other biological / biotechnological entities. At the moment the public consultation phase is still going on, after which the final version of the document will be awaited.
The new document deals with scientific approaches to continuous production, such as:
- system dynamics,
- frequency monitoring,
- identification and removal of non-compliant material,
- process model,
- process controls.
The guideline also seeks to clarify the regulatory expectations on the subject.
Structure of the new guideline
The ICH Q13 draft guideline is presented in two parts: main body and annexes (I to V). The main body of the text follows the document already drawn up by the FDA in 2019, “Quality considerations for continuous manufacturing, guidance for industry“, with some minor variations – for example, the sources linked to the lot definition or process validation – and deals with some specific macro-topics:
- lot definition;
- control strategy (process dynamics, material characterization, equipment design, process monitoring and control, material deviation and process modeling);
- variation in production output (scale-up considerations);
- process validation;
- pharmaceutical quality systems;
- location of specific information on continuous production in the eCTD.
The 5 annexes are dedicated to the following topics:
- I: Continuous manufacturing of drug substances for chemical entities;
- II: Continuous manufacturing for drug products (solid dose);
- III: Continuous manufacturing of therapeutic protein drug substances;
- IV: Integrated drug substance and drug product continuous manufacturing;
- V: Perspectives on managing disturbances.
The importance of Quality by design (QbD)
Those who choose to implement a continuous manufacturing process need some equipment and technologies that are not traditionally used in pharmaceutical manufacturing. Although continuous manufacturing processes have been used in chemical and food manufacturing for many decades, this expertise in equipment, processes and technology is lacking in the pharma industry. Described in ICH documents Q8, Q9 and Q10, Quality by design (QbD) consists in a systematic and scientific approach to the development and production of the pharmaceutical product for a better control of its quality. Guideline Q13 recognizes the importance of sophisticated process models and the use of in silico experimentation.
The guideline notes that a broad characterization of the input material is required in addition to what has typically been done for the batch process. Continuous production systems can be sensitive to disturbances caused by incoming materials, with the risk of creating non-compliant products. Input material specifications may need to be more elaborate (such as three-level particle size distribution, bulk density) for continuous mixing processes in solid dose production.
Monitoring and control techniques
The necessity of real-time process monitoring and continuous production control will likely require the implementation of process analytical technologies (PATs). Gravimetric methods (such as loss-in-weight feeders or LIWF) and spectrophotometric methods (such as near infrared or NIR) are the most familiar technologies, with relatively fast data collection. This is particularly important for the concept of material deviation, where nonconforming material is separated from the continuous process flow in real time. However, more complex analytical methods (such as inline high performance liquid chromatography or HPLC) may require process modifications such as surge tanks to allow sufficient time for data analysis and implementation of a deviation decision.
Continuous production can also enable the real-time release testing (RTRT), in which in-process results are used instead of sampling each batch and retaining release test results. For anyone who prepares eCTD documents, guideline Q13 provides a useful table indicating where continuous production information should be located.
The challenge of the future
Continuous manufacturing is the future of the pharmaceutical industry. A transformation of this magnitude will also require strategic moves. Pharmaceutical companies should act now to develop the capabilities and partnerships necessary to exploit the benefits of more efficient, reliable and scalable operations.
The publication of the final version of the ICH Q13 guideline will enable manufacturers to adopt flexible approaches and develop, implement or integrate continuous production. It will also provide industry guidance on future regulations regarding the development, implementation and evaluation of technologies for continuous manufacturing. What emerges from the reading of the Q13 draft is that most of the obstacles to implementation are not regulatory, but technological and procedural. It is therefore up to drug manufacturers to be able to find, create and consolidate the skills to face this new challenge.
Continuous manufacturing, the advantages over the batch
- Cost reduction;
- Less manpower;
- Lower footprint (the impact is reduced by 25% and waste by 33%);
- Reduction of production time (in some cases the continuous production takes two days instead of 12);
- Less time dedicated to quality control and release tests (for the production in CM of darunavir the estimated reduction of the testing cycle time is 80%);
- Reduction of development time (speed-to-clinic) and 10% lower development costs;
- Greater flexibility and agility;
- Possibility of producing batches of variable size;
- Ease of moving to a new market niche (building a plant costs over 30% less);
- Reduction of possible drug shortages;
- Lower tech transfer time (speed-to-market);
- Increased quality;
- High levels of process understanding.
Companies that have received FDA approval for continuous production
- Janssen, J&J: for darunavir and tramadol hydrochloride / paracetamol
- Vertex: for lumacaftor / ivacaftor, tezacaftor / ivacaftor and ivacaftor
- Lilly: for abemaciclib
- Pfizer: for glasdegib
Many other companies (mainly big pharma) are moving more or less gradually to continuous manufacturing. Its use is increasing also in the world of generics and CMO.