Is Real Time Release Testing and Certification by the QP the next Generation Process?

Real Time Release Testing (RTRT) has been a product release option since 2012 when EMA published the first 'Real Time Release Guideline' to replace 'Parametric Release'¹ and is further described and applied in: ICH Q8 (2008); Annex 15 (2015); the process validation guidance (2016); Annex 16 (2016); Annex 17 (2018)²; the continuous manufacturing draft guidance by the FDA (2019); and most recently, ICH Q12 (2020)³.

This concept has only been adopted by a few pharmaceutical companies but for those who have shared their experience, it has been a real success. This article will discuss what has happened to the RTRT concept, how it is being used in the industry, the experience QPs have had so far, and some future perspectives on RTRT including feedback from the last QP Forum in December 2019⁴.

Five years ago I was invited to the QP Forum to speak about Process Analytical Technology (PAT) and RTRT. At that time the topic was discussed a lot and was seen as 'not realistic right now'. I noticed that many QPs were worried about the role the QP would have in the batch certification process and how it should be managed. Was the QP expected to have a full understanding of the product, the process and its lifecycle history?

How would that be possible? Has anything changed? Is RTRT still feared or are we now, 5 years later, able to utilise the RTRT concept in a smart and efficient way to ensure product quality and to provide support to the QP in certifying safe batches for the benefit to the patient and the business?

What is Real Time Release Testing?

RTRT is the ability to evaluate and ensure the quality of the product during processing as it happens, i.e. in real time or near real time. The product quality is defined by a set of Critical Quality Attributes (CQAs) and these must be controlled and ensured through a valid combination of measured material attributes (e.g. raw material CQAs and in-process CQAs) and process data. When a CQA is ensured in real time, there is no need for a traditional QC test of the CQA and the data that will be used for the batch CoA will be represented by or referenced to the data from the RTRT programme.

RTRT provides real-time quality assurance. Material attributes and the process parameters that have an impact on a CQA are being measured during the manufacturing process at the point in time where this CQA is being generated by the process. Therefore, it is important to understand where in the manufacturing process the CQAs are established and to define the controls that must be in place to ensure these CQAs meets their acceptance criteria. Not only for RTRT must we have this level of process understanding but also for conventional product release. One of the reasons for manufacturing problems, OOS, and unfortunately also drug shortage is often lack of process understanding. An example is a raw material that shows variability in one of its CQAs and it ends up as an unexplained variability in the finished product CQA that can result in an OOS. For many of the products on the market, the extent to which variability of a raw material will influence product CQAs is generally not well understood and ultimately this can cause a risk of batch failure, scrap, and drug shortage.

Today we use a science and risk based approach (QbD) for developing pharmaceutical products as outlined by ICH Q8-Q115. The QbD principles are used to define CQAs and the final Control Strategy that outlines the controls to assure robust process performance and the right product quality, i.e. that the CQAs meet the specified acceptance criteria.

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The Control Strategy

The Control Strategy, Figure 1, is key to making successful products as it defines how to make a product. When it is based on enhanced product knowledge and process understanding, it will ensure product quality by design and CQAs can be controlled measured and predicted in real time for the final release.

Fig. 1: Control Strategy definition, ICH Q10⁵

As mentioned above, one of the most important tasks is to acquire an understanding of what is happening during processing so that the appropriate controls can be implemented and applied where they matter. Without taking this into account, it is impossible to establish a Control Strategy that can be used for RTRT.
This understanding is typically the outcome of theoretical studies involving first principle modelling or a more pragmatic understanding using Design of Experiments (DoE). This is in order to identify those process parameters and material attributes related to raw materials or in-process material that determines a CQA. The combination of ranges considering any interactions between parameters and attributes define the space in which the process can be operated to deliver the right quality in terms of CQAs. The gained knowledge of what is critical, how to operate and decide on how to control these critical steps make up the operational Control Strategy.

Fig. 2: The Control Strategy model

For CQAs where the Control Strategy is based on real time measurements and controls of the relevant Critical Process Parameters (CPPs), in-process and product CQAs, RTRT is an option. The final release strategy, Figure 2, may be based on RTRT of every single CQA or a combination of RTRT of some CQAs and end-product testing of others. The final chosen release strategy is a business decision that requires regulatory approval.

A classic and well-established example is the control of assay of an oral solid dose formulation (OSD) produced from a wet granulation process and where the Control Strategy is based on real-time process control and testing⁶. The process steps that can impact assay in this case are blending and compression, so these steps must be controlled. The blend uniformity endpoint can be controlled by e.g. inline Near Infra-Red spectroscopy (NIR). The tablet weight and weight uniformity controlled at the compression stage where the final assay can also be predicted using NIR, replacing conventional QC testing of assay. In this example, in-process CQAs (blend uniformity and tablet weight) are controlled by the in-process CQAs and CPPs for those stages and must be included in the Control Strategy.

Many process steps can be controlled by feedback or feedforward controls based on output measurements rather than input only, to ensure the CQAs and consistent product quality. This is a performance- based Control Strategy per the new ICH Q12 description3. This concept is similar to the 'PAT' concept introduced in 2004 with the FDA PAT guideline⁷. The focus on output rather than input of the process provides higher confidence in product quality and supply consistency.

RTRT today and the impact of RTRT on batch review, -release and -certification

Small molecule, OSD formulations seem to be at the top of the RTRT hit list. There is an increasing number of continuous manufacturing applications being approved where the Control Strategy must be based on real time control of CQAs during processing to ensure a 24/7 process consistency, product quality and a bonus is the RTRT opportunity.

RTRT does not change the fundamentals of batch release and certification. Annex 16⁸ § 1.7.3 states: "Finished product quality control (QC) test data complies with the Finished Product Specification described in the MA, or where authorised, the real time release testing programme". Hence, the QP must ensure compliance with the RTRT based Control Strategy and review off-line, at-line, and in-line data and analytical results and other batch records as required by the Control Strategy including investigation of nonconformities to their conclusions.

In the assay example above, the review must verify that all CPPs (e.g. compression force), in-process CQAs (e.g. blend homogeneity) and the assay prediction itself have been met, if requirements in the batch production record are not met, the impact must be evaluated using a risk-based deviation system. The results (e.g. predicted values), if required, must then be transferred from the manufacturing shop floor to the LIMS system or other reporting systems rather than from the QC lab to the LIMS.

QP's experiences with RTRT

I have had the opportunity to talk about RTRT with some QPs who had certified batches using RTRT and to discuss the topic at the QP Forum in December 2019 in Munich⁴, where I posed a minipoll question on the RTRT use. Despite this not being a proper study, it still provides some interesting indications on RTRT which are shown below.

Fig. 3. poll result of the question “what is your experience with RTRT?” from the QP Forum

From Figure 3 it can be seen that out of those who answered, just under 20% has some experience with RTRT. From speaking to the QPs who had RTRT experience, it was clear that the QPs have a range of involvement from lots to limited. Some companies have a full RTRT programme in place with no end-product testing, others have chosen the hybrid version where the release is a mixture of RTRT for one or few CQAs and conventional QC end-product testing for the remaining CQAs. Finally, there is a group of companies with a RTRT based Control Strategy in place but which is not used for release. In those latter cases, the RTRT based Control Strategy is implemented to ensure consistent product quality, process robustness and to minimise the risk of losing a batch and not being able to supply products to the market. However, the release is performed in the classic way of verifying the CQAs using conventional QC end-product testing. This is a common scenario. One of the reasons may be to overcome the lack of internationally harmonised CMC regulation and the hurdle of getting approval from every region/ country.

One QP told me that they had released more than 500 batches using RTRT successfully and had not faced any problems with the programme.

The QPs did experience a steep learning curve when first faced with an RTRT application as they needed to understand the concept and the Control Strategy, the purpose of each control and how the CQAs are controlled and tested. However, implementing RTRT is a cross-functional team effort with many different capabilities involved. It is essential that roles and responsibilities are clear. The development scientists are the ones who understand and can explain the science and rationale behind the controls and why the controls will provide a high degree of assurance that the product CQAs will be met by the process. The QP does not need to know everything. This is no different from a traditional product and process with end-product in place where a QP would also rely on a cross-functional team with the right skills. Just as with other products, the QP must be informed of deviations, changes and variations in materials and equipment that might impact the product, process, and process controls. It is an integrated team effort consisting of, for instance, QC, QA, manufacturing, technical support, development, and other relevant SMEs with the QP as an important member of that team. The importance of a transparent Control Strategy cannot be emphasised enough. It is not only used to define the QP review activities before certification can take place, but it is also used to plan, prepare and drive an inspection. The QP must, during an inspection, be able to explain the product story from a batch quality, Control Strategy and release perspective.

Gains - QP Quotes	Pains - QP Quotes
• Faster and more efficient process	• Steep learning curve in the beginning of the RTRT Implementation
• Very efficient for high volume products	• Models for controlling and predicting CQAs requires maintenance. Under the current EU regulation this might require variation applications
• Increased level of process understanding
• Robust and effective control strategy
• With the current control strategy in place we have real time conrtol and quality assurance
• A significantly larger number of samples tested
• Process robustness and product consistency is demonstrated in real time
• We are happy, we have a stable process, no major problems
• I can sleep peacefully at night

Fig. 4: Gains and Pains using RTRT from a QP perspective

The proof is in the pudding

I asked the QPs how they felt about the RTRT concept, and if they had experienced any gains and pains specifically related to the application of RTRT. It was a relief for me to hear that they liked the concept very much, have manufacturing processes they can trust, test many more samples throughout processing that verifies the consistency and quality and that they know they would not encounter release or supply issues. As one QP phrased it "with RTRT in place, I can sleep peacefully at night". To me this is the 'proof in the pudding'. Furthermore, this feedback confirms the importance of the Control Strategy and that the product manufactured is an outcome of a robust and effective Control Strategy.

Some of the main gains and pains voiced by the QPs are summarised in Figure 4.

The models for end-point determination, feedback, feedforward controls and for predicting in-process and finished product CQAs must be a robust to normal variability in raw materials and the process equipment. The variability in the material will often change over time and the models must, therefore, be updated to be able to manage this variability. This is an inherent element of the models. Unfortunately, the models cannot be updated and managed within the company's own PQS' yet and typically require regulatory variation application⁹ which, from a scientific perspective, would be a nonvalue-added activity which makes the normal lifecycle management of RTRT impossible. This is particularly the case for continuous manufacturing that is designed with RTRT. The good news is that the current guideline is in the process of being updated and with the new lifecycle management opportunities (ICH Q12³), hopefully, a joint global recognised solution will be developed by the industry and the authorities.

Will we see RTRT at the new QP certification process in the future?

Fig. 5: poll result from the QP Forum ‘ How could you benefit from implementing RTRT in your organisation’

Figure 5 shows that, more than 68% of the QPs who took part in the poll at the QP Forum³, could see that they would improve process understanding and have more reliable and robust processes if RTRT was implemented.

Fig. 6: poll result from the QP Forum: “When do you think your organisation will implement RTRT?”

The QPs were also asked 'if and when' they believed their company would implement RTRT, Figure 6. A high number of companies, 57%, would consider RTRT for monitoring and control and most of these also for release. It is very exciting that around a third expected to have some sort of RTRT implemented within the next 1-5 years which is very promising and I assume that many of these cases will be related to continuous manufacturing.

Conclusion

RTRT is being used in the pharmaceutical industry today although not as much as anticipated. Those QPs with experience of RTRT are all very pleased. They experience faster more efficient and reliable processes, avoid product loss, understand the power of the Control Strategy, and they highlight that the QP must rely on an integrated team approach.

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There is still a need to update some of the PAT-based regulations before RTRT can really kick-off. A hope is that with the performance- based control concept and the support of lifecycle management now being introduced with ICH Q12, that RTRT will be more applicable.

Finally, many QPs see RTRT as a huge opportunity to gain process understanding and have more robust processes and expect that RTRT will be implemented in some form in the next few years. I hope you have been inspired to engage more in the concept of RTRT as it is real - it is happening, we are starting to see RTRT as the next generation process for release and certification.

Acknowledgement

Thanks to those QPs who shared their experiences with me and to Wolfgang Heimes, Concept Heidelberg, for the poll support.

 

Author:
Dr Line Lundsberg-Nielsen
... is a scientist, runs her own consultancy business focusing on applying a science and risk-based approach for pharmaceutical development, process design, technology transfer, qualification and process validation.

 

Source:
1 Guideline on Real Time Release Testing, 29 March 2012 EMA/CHMP/QWP/811210/2009-Rev1 - https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-real-timerelease-testing-formerly-guideline-parametric-release-revision-1_en.pdf
2 EudraLex - Volume 4, Annex 17: Real Time Release Testing and Parametric Release https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/pdfs-en/2018_annex17_en.pdf
3 ICH Q12, 04 March 2020 EMA/CHMP/ICH/804273/2017, https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-q12-technical-regulatory-considerationspharmaceutical-product-lifecycle-management_en.pdf
4 The QP-Forum 2019, https://www.qp-forum.org/
5 ICH Q8, Q9, Q10, Q11, https://ich.org/page/quality-guidelines
6 PQLI Guide: Part 2 - Product Realization using QbD: Illustrative Example, 2011 https://ispe.org/publications/guidance-documents/pqli-qbd-product-realization
7 FDA guideline PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, 2004. https://www.fda.gov/media/71012/download
8 EudraLex - Volume 4, Annex 16: Certification by a Qualified Person and Batch Release https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/v4_an16_201510_en.pdf
9 Addendum to EMA/CHMP/CVMP/QWP/17760/2009 Rev 2: Defining the Scope of an NIRS Procedure, 5 June 2014 EMA/CHMP/CVMP/QWP/63699/2014 https://www.ema.europa.eu/en/documents/scientific-guideline/addendum-ema/chmp/cvmp/qwp/17760/2009-rev-2-defining-scope-nirs-procedure_en.pdf