Potential Introduction of ATMP-Specific GMP Standards in the EU

During June of 2016 the European Commission opened a three-month consultation on proposed Good Manufacturing Practice (GMP) guidance for Advanced Therapy Medicinal Products (ATMP). The purpose of the consultation was to allow academic groups, CMOs and commercial developers of ATMPs to provide feedback on the proposed ATMP-specific manufacturing rules. Perhaps, surprisingly for the European Commission, the draft guidance document received a lukewarm reception from the industry. The commission’s aim was to develop ATMP-specific manufacturing standards which would expedite the access to these products by clarifying the guidelines associated with manufacturing them. However, notable responses from the Alliance for Regenerative Medicine and PIC/S (Pharmaceutical Inspection Co-operation Scheme) have questioned some of the details contained in the guidance document.

One of the starkest rebuttals of the guidance document came from PIC/S in an open letter, PIC/S is not alone with its concerns regarding the possibility of having separate GMP standards for ATMPs and non-ATMP products.  Several QPs have questioned the logic associated with this potential scenario.  Furthermore, there is discontent regarding the potential for lowering GMP standards for first into man manufacturing of ATMP products. Another key observation was the missed opportunity to develop a pan-European approach to interpretation of the EU’s directives associated with the collection and handling of blood, tissues and cells. Currently, European Union member states are allowed some discretion when interpreting and enforcing the details of the European Union directives. For example, the German interpretation of the Blood Directive requires QP certification of blood products whereas other European countries do not necessary require this as part of product release. This may seem like a minor detail, but with the current preference for centralised manufacturing strategies for autologous therapies, a single European approach to the way in which patient-specific starting materials are managed would have been welcomed by the Cell Therapy Industry.

The guidance document also addresses traceability, which is a key attribute to a successful autologous supply cycle.  Indeed, the requirements must not be overlooked for allogeneic therapies; for both autologous and allogeneic products records associated with the collection of starting materials and manufacture must be maintained for thirty years (which agrees with current EU directives), this contrasts with the FDA’s requirement for ten years’ record retention. Interestingly, the proposed new guidance allows for traceability records to be kept outside of manufacturing batch records providing that these are auditable and inextricably linked to the manufacturing records. Furthermore, and in contrast to some practices for autologous supply outside of the EU, the draft guidance details that traceability must be recorded up to delivery of the therapy to the patient; some autologous treatments in North America have only been traced to delivery at the hospital/treatment centre. TrakCel’s software platform has been used to provide full traceability throughout supply cycles of ATMP products, demonstrating both chain of identity and chain of custody from collection of starting material to the treatment of patients and facilitates long-term, compliant, data storage and controlled access to records.

The uncertainty regarding borderline ATMP products could be very challenging, if two separate GMP strategies exist, manufacturers must be sure of their product classification, in order to apply the correct GMP standards during manufacture. However, the Committee for Advanced Therapies (CAT) will be able to determine if the investigational product meets the scientific criteria which qualifies it for ATMP status.

The complexity associated with the regulatory environment could become exacerbated following the UK’s exit of the European Union, although it is unlikely that the UK would turn its back on the existing legislation framework, there are no certainties regarding QP certification by a UK-based QP being accepted by mainland-Europe QPs once the UK has waved goodbye to its membership status. Whatever the case, detailed scrutiny will be given to the outcomes of the guidance document and the protracted UK-EU Brexit negotiations.

Consultation Document Good Manufacturing Practice for Advanced Therapy Medicinal Products

Reflection paper on classification of advanced therapy medicinal products

Standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components

Standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells

Conducting Trials and Commercial Activities with Cellular Orchestration Platforms

When the FDA recognised that the ‘orchestration’ of Provenge was Dendreon’s biggest manufacturing challenge a significant regulatory marker was placed for the management of cell therapy products.

To counter the FDA’s concerns, at great expense Dendreon developed its own IT system to manage and control the complex supply of its autologous therapy, Provenge. The system known as Intellivenge, was used to identify starting materials and intermediates using barcodes, manage shipping of starting materials and the final therapy. Without such a system in place and validated it is questionable whether the FDA would have approved Provenge.

“The major challenge in manufacturing this product is not in the manufacturing protocol…

Logistics is perhaps the more challenging aspect of producing this product due to the short shelf life of both the incoming apheresis units and the final product.

Given the tight manufacturing schedule, short process time limitations, overlapping production schedules, QC testing, and complex shipping situations.

It will be difficult to generate this product at high throughput without substantial attention paid to coordinating and orchestrating these events.”

CMC Review BLA 125197 Sipuleucel-T (Provenge®) Dendreon Corporation

‍Intellivenge was perhaps a portent for the current Cellular Orchestration Platforms (COPs) which are now being adopted throughout the Cell and Gene Therapy industry. These platforms manage, provide control, and base-line automation for the supply of cell therapies.

COP systems are designed to introduce efficiencies into complex, heavily regulated, supply chains. Cornerstone functions should include real time reporting, chain of identity management and chain of custody management; these features facilitate faster decision making, provide real time control, and protect each patient being treated. Chain of identity management is key when applying COPs to autologous therapies. Growing patient populations and the demands that an autologous therapy places on chain of identity and chain of custody management protocols has led to sponsor companies finding it difficult to justify the absence of COP in their supply strategy.

‍The COP should provide a detailed view of each therapy’s progress and a complete overview of all therapies being manufactured, including patient-specific starting materials. The control systems implemented by COP should also promote process standardisation and allow standardisation to be demonstrated to reviewers, auditors and regulatory bodies. Without using COP systems, demonstrating process standardisation is difficult, especially when the number of patients being treated increases.

The key to expedited implementation of these systems is a configurable process engine and a validated and tested core software base. The value associated with tested and validated core software should not be underestimated; this can reduce the lead time for implementing these systems by 18-36 months compared with bespoke software systems. Not surprisingly, the costs to a cell therapy company attempting to manage development of a bespoke IT system for the control of cellular therapies is significantly higher (55%-70%) than using configurable software. Indeed, developing systems in-house can introduce a litany of problems; hiring an expert to spearhead these projects is challenging enough because identifying the proficiencies required to deliver the project can be complex, separating the skilled from the charlatan is not simple.

Leveraging expertise for the implementation of a COP is vital to success, TrakCel’s team has configured its software for several different supply chains and therapies, each one being unique but with common challenges and themes. A keystone of TrakCel’s approach is to insist upon a multidisciplinary team from the sponsor, which encapsulates all business and department functions associated with the delivery of the therapy, and all touchpoints in the delivery process; this is not a simple as it sounds. Each team tends to have their own introspective requirements for a COP, however to maximise the value from COP software a harmonised, non-siloed approach is necessary, after all no man is an island.

The COP should be at the centre of your planning for commercialisation, realistically this should be introduced during the clinical assessment of the therapy to develop experience using orchestration software throughout the supply chain. All regulators will be wanting assurance that the controls detailed in licensing applications have been assessed and scrutinised before being used for commercially available treatments. A CEO and shareholders do not want to hear about delays to clinical programmes and commercialisation due to supply control problems, whether they be regulatory or control related.

By installing and using a COP system, companies developing cell therapies are sending a clear message to regulators and patient groups; process control, identity and custody management has been addressed to deliver therapies safely and efficiently.

Open Innovation in the cell therapy supply chain

At TrakCel, we firmly believe in open innovation – a more distributed, more participatory, more decentralized approach to innovation, based on the observed fact that useful knowledge and capability today is widely distributed, and no company, no matter how capable or how large, can innovate as effectively on its own.

What does that mean for our customers and partners?

Well, first off, let’s look at what Henry Chesbrough, the author credited with coining the term, defines open innovation as:

…the use of purposive inflows and outflows of knowledge to accelerate internal innovation, and expand the markets for external use of innovation, respectively.

It’s about looking beyond the four walls of our company – to a wider ecosystem of supply chain partners, academics, suppliers of complementary products and services and other firms – to identify and capitalize on new opportunities for innovation in cell therapy.

For TrakCel that means real and valuable collaborations between our partner companies, individuals and public bodies to ensure we continue to innovate and deliver more effective solutions to our clinical customers.

In a world of distributed knowledge, and particularly in emergent platforms such as Cell and Gene therapy, companies can’t rely exclusively on internal capabilities to effectively orchestrate the supply chain, meet manufacturing demands at scale and deliver end-to-end traceability and chain of custody throughout – instead our customers benefit immensely from our commitment to open innovation with best in class industry partners.

It’s often been asked – How do you know when to partner, and what to avoid? 

We look for ideas, partners and technologies that fit with our business model and, ultimately, allow us to deliver a better solution to our customers. Simple as that.

What are the benefits to TrakCel of open innovation ?

·         We can implement internal ideas that might otherwise remain unexplored

·         We can ensure seamless access to additional external capabilities

·         We can share efficiencies in resource allocation

If we get it right, and we’ve done well so far (according to our customers at least!), then the benefits are clear. Open innovation delivers a myriad of enhanced opportunities including:

·         Enhanced capability in the management of your valuable cell therapies

·         Reduced supply chain costs,

·         Accelerated time-to-market, and

·         Increased differentiation

All of this ultimately leads to a real competitive advantage – and that is particularly important in the current race to market with many of the next generation of CAR T cell therapies in particular.

So, the next time you read or hear about TrakCel’s latest partnership or industry alliance, take a moment to think about what that means for you and your company.  If we get it right, you’ll be better placed for success. That makes us all winners.

Stemming the Tide of Cybercrime: Protect your Patients’ PHI

Human beings are not designed to handle large numbers. If someone owes you $100, but they only pay you $1, you would rightly be upset. However when considering two people who are worth $1billion and $2billion dollars respectively, most people would consider them to be of similar wealth, when in fact one is vastly wealthier than the other.

Maybe this is why the PHI data breach statistics that the HHS make public on their website don’t make big news.

They should. Last year (2015) 111,818,172 patients and healthcare individuals had their data exposed by the hacking of US companies working in the Healthcare industry.

This year alone, in the four months from January to April, the PHI data of 2,352,180 patients has already been hacked.

The numbers are staggering.

In practical terms, data breaches from US companies impact more people annually than the population of Germany.

But it gets worse. Not content with stealing data, attackers are now turning their attention to the booming business of Ransomware, where the PHI data is encrypted by the attacker, who then demands payment in return for the key to unencrypt the data. Some attacks make the news, but most don’t.

And it’s not that the attackers are getting smarter. The 2016 Verizon Report published last week reiterated that the same 10 vulnerabilities accounted for 85% of exploit attacks, with some vulnerabilities being older than the attackers who have been found to be exploiting them.

In an effort to encourage companies to find ways to close the floodgates themselves, last month the OCR initiated a new, stricter, set of HIPAA audit protocols and have been increasing the number of multimillion dollar fines levied as a result of data breaches. Time will tell if this makes a difference.

So how do you ensure that the PHI you’re holding remains private?

There are two simple things you can do right now:

Ensure there is a Business Associate Agreement in place with any supplier or business partner that will potentially handle PHI. There is guidance on this from the HSS website, however it is also important to get your legal team involved before any agreement is signed.

Put in place an SOP for regular security risk assessments of your systems. There is a free tool provided by HSS, but you will always gain more from an assessment performed by a qualified security expert. Ensure that the results are reviewed by your Senior Management Team. Put a plan in place to implement any critical recommendations and ensure someone owns that plan.

If enough organisations followed these two simple steps, maybe the breach numbers would reduce enough for us to get our heads around them.

Schrödinger’s Temperature Monitor

In 1935 Erwin Schrödinger devised a thought experiment in which he described a paradox of quantum mechanics. A cat was sealed in a box with a flask of poison, a source of radiation and a radiation detector. The flask of poison was linked to the radiation detector and would break if the monitor detected radioactivity. Although the half-life of the radioactive material was known, the precise moment that the radioactive energy was released and the cat became an ex-cat could not be determined in advance. Thus, as long as the box was sealed the cat could be simultaneously alive and dead. Only when the box was opened could the fate of the cat be observed.

 

Cell therapy products typically are more challenging to ship that traditional pharmaceutical products, you are after all shipping living cells (perhaps a little less challenging than a cat with a flask of poison). Even with robust mitigation strategies temperature excursions do occur; using conventional temperature monitors the manufacturing centre/treatment centre will only discover if there has been a temperature excursion once the shipment of starting material or therapeutic agent has been delivered to its final destination and the shipper opened; similar to the fate of Schrödinger’s cat, so while cell therapies are in transit one could assume that they are both within and outside their shipping specification.

TrakCel has integrated with temperature monitors that can provide real-time data and by configuring TrakCel’s platform warnings and alerts can be received should shipping temperatures exceed pre-set parameters. However, to effectively use real-time data, strategies need to be formed for addressing temperature warnings during shipments to prevent temperature excursions. Real-time data is of great value when shipping therapeutic agents (and starting material) from patients who may only have one chance of treatment or if collecting starting material is an invasive procedure which a patient may not want to repeat.

It is pointless to use these real-time monitors if you are unable to obtain access to the shipment in transit. To effectively use real-time data the following needs to be considered:

·        If access to the shipment is possible how will the current custodian be notified should a temperature warning be issued?

·        What can be done, or what equipment is required to return the shipment to the desired temperature at each step of the journey?

·        What resources are required to continuously monitor the shipment?

Real-time monitoring can be an effective tool for ensuring that medical supplies arrive within specification. However, the resources and planning required currently preclude this technology from being used for low value shipments; real-time monitoring technology may be suitable for high value products and challenging supply chain models.

No cats were harmed during the writing of this blog.

CD19 a starting point for CAR-T therapies

CD19 a starting point for CAR-T therapies

At the time of writing there are 62 clinical trials examining the treatment of haematological (blood cancers) malignancies with Chimeric Antigen Rector T-Cell therapies (CAR-T). It may not be surprising that almost 80% of these studies are targeting CD19+ cell (B cells) malignancies, lymphoma and leukaemia with compelling results reported by:

·         UPENN  (http://www.uphs.upenn.edu/news/News_Releases/2012/08/novartis/)

·         Juno Therapeutics https://www.junotherapeutics.com/pipeline/clinical/

·         Kite http://kitepharma.com/pipeline/#car

to list but a few.

CD19 is an attractive target for CAR-T therapies because it is only found on B Cells, thus  reprogramming T-Cell to identify CD19 should provide a method for treating B-Cell related malignancies whilst excluding other healthy cell lines from the cytotoxic effect of these genetically modified T-Cells.

It has been breath-taking to see the clinical development of these genuinely curative therapies, which have provided hope to the previously incurable. However, these CD19+ targeting therapies do have both acute and chronic side-effects.

One of the acute effects is known as cytokine storm (prosaically known as cytokine release syndrome) which is a result of cytokine release follow T-cell activation when it binds to its CD19 target. The systemic inflammatory response gives the patient fever-like symptoms and can lead to pulmonary edema. Cytokine release syndrome can be life-threatening but can be manged at the point of care using a combination of therapeutic agents including IL-6 antagonists (tocilizumab) and steroids. The next generation CAR-T therapies may include a method of modulating the activity of these cells so that the cytotoxic activity of the CAR-T cells and the subsequent release of cytokines could be attenuated when the first symptoms of cytokine release syndrome present.

A chronic side effect is associated with the specificity and longevity of the therapy; modified T-cells cannot differentiate between malignant and healthy B Cells and so all B Cells are targeted and destroyed, furthermore these modified T-Cells remain within the patient and so long-term immunoglobulin therapy is required to counteract the loss of the patient’s healthy B-Cell population which would normally produce antibodies.

Until the chronic effects of CAR-T therapy for B Cell Malignancies are addressed, it is unlikely that these therapies will be used as frontline standard of care for newly diagnosed patients but will be reserved for patients whose illness has progressed to a refectory state and untreatable with traditional chemotherapeutic agents.

2020 Vision – CARAT in more detail

The CARAT project consortium comprises a multi-national team of renowned European key scientists for genetic and cellular engineering technologies with industrial leaders for cell manufacturing tools.

 

TrakCel will provide a pivotal role developing and delivering a technology platform which will facilitate the adoption of CAR T-cell therapies ensuring process standardisation at all parts of the therapeutic supply chain and provide close monitoring and control when starting materials and final therapeutic products are shipped. TrakCel will also simplify the way in which the manufacture processes of these products are documented.

 

Joining TrakCel in this project, will be:

 

·        Miltenyi Biotec GmbH

·        Ospedale San Raffaele

·        Paul-Ehrlich-Institut

·        Institut  National de la Santé et de la Recherche Medicale

·        University College London

·        Universitaetsklinikum Freiburg

·        European  Research and Project Office GmbH

 

Equipped with a total budget of €6 million, we aim to integrate innovative cell manufacturing tools and enabling technologies into a comprehensive and unique platform to facilitate the safe, automated, and cost-efficient manufacture of CAR T-cells; a revolutionary and highly effective treatment option to cure cancer.

 

Specifically, CARAT will:

Develop a comprehensive toolbox explicitly tailored for automated, easy-to-handle and cost-efficient manufacture of CAR T cells including novel tracking tools;

 

Establish complementary enabling technologies to obtain more effective and safer cellular products, improved gene delivery, better CARs design and innovative monitoring;

 

Demonstrate proof-of-concept and regulatory compliance of the CARAT platform.

 

CARAT will deliver proof-of-principle for an innovative integrated solution to generate genetically modified ATMPs (advanced therapeutic medicinal products) that are specifically tailored towards cancer killing and thus serve patients with so far incurable solid tumours and hematologic malignancies.

 

Read more about the project here: http://carat-horizon2020.eu/carat-network/