Erwinase® / Erwinaze® (Erwinase) is a complex biological medicine critical for saving the lives of children with leukaemia. The manufacturing of such medicines is a lengthy and challenging process; for example, from start to finish it takes over six months to make a batch of product.
At Porton Biopharma Limited (PBL) we strive to make high quality medicines for patients and are acutely aware that any interruptions in the supply of Erwinase have serious consequences for patients being treated for Acute Lymphoblastic Leukaemia. As a result, we wish to keep all stakeholders informed of the supply status of Erwinase and commit to do our utmost best to ensure that patients are able to access this life saving product.
As manufacturer PBL is responsible for producing the Drug Substance and the Drug Product, filling into primary packaging (unlabelled “naked” vials), quality control and testing the product, thus ensuring that it meets the required specifications. The unlabelled “naked” vials of Drug Product are then released and made available for collection by Jazz Pharmaceuticals who are responsible for the vial labelling, secondary packaging and final release to designated markets.
PBL’s Commitment to Quality
The PBL manufacturing facility at Porton Down, Wiltshire, UK is licensed by the MHRA under the Human Medicines Regulations 2012 (as amended) (SI 2012/1916) Manufacturer’s Licence No. MIA 44403 and The Medicines for Human Use (Clinical Trials) Regulations 2004 Manufacturer’s Licence No. MIA (IMP) 4403.
In December 2019, following our most recent inspection October 2019, the MHRA confirmed that the operations are in general compliance with the principles and guidelines of good manufacturing practice as laid down in Commission Directive 2003/94/EC.
PBL has total confidence in the quality of all its batches of product; they have been manufactured to the required Marketing Authorisation specification(s) and released by a PBL Qualified Person named and on the Manufacturing Authorisation issued by MHRA. The product also has an additional independent review and certification from third party consultants experienced in global Quality, Good Manufacturing Practice (GMP) and regulatory standards from a reputable international company.
- Since November 2018 PBL have manufactured and delivered all eleven batches of product on time according to mutually agreed binding dates
- All Erwinase batches are released by a named Qualified Person in accordance with EU pharmaceutical regulation
- The release of batches is supported by the continued assessment and review of manufacturing events further supported with successful history of process simulation to demonstrate Sterility Controls
- The product is supplied from PBL with a Certificate of Analysis to the specification required by all intended markets
- Jazz is then responsible to ensure timely collection, labelling, secondary packaging, final QA/QP review, release & certification, and distribution in accordance with the requirements of each market
- PBL recognises that it is was issued a USFDA Warning Letter dated January 2017. However, PBL has completed all its Corrective Action Plans on time and reported this to the USFDA. PBL were due to be inspected in April 2020 although this has been delayed due to COVID 19
- PBL’s most recent inspection was conducted by the MHRA in October 2019 and we received no critical and no major observations. In December 2019, the MHRA confirmed that the PBL manufacturing facility is in compliance with the principles and guidance of cGMP
- PBL has been making product available to Jazz, meeting agreed contractual binding dates on a regular basis since 2018
- PBL manufacturing facilities are working at capacity and the Company has made significant multi-million-pound investments to increase these to allow more product to the market
- PBL would not release a batch if it thought there was any issue with the quality or safety of product
Erwinase Batch Supply On Time To The Agreed Contractual Intervals
PBL continues to supply Erwinase batches at the agreed specified contractual interval to Jazz. Jazz is responsible for collection, labelling, secondary packaging and release to designated markets.
Table of Batches Released to Market
|Batches||3rd Party Certification||PBL Batch Release||Jazz Collection||Jazz Release to US Market (Reference for Last Market Release)||Time: PBL Release to Jazz Collection
|Time: Jazz Collection to Market Release
From the above table it can be seen that there has been a considerable increase in the length of time taken for the collection and to market release step over recent months. Previously, release to collection was typically 1 to 18 days, compared to 140 days for batch 201. These delays may be contributing to supply shortages.
- CAMR 200; PBL’s QP and third-party consultants experience in global quality, Good Manufacturing Practice and regulatory standards deemed the batch suitable for release and it was released on Friday 21st February 2020
- CAMR 201; as released by PBL on Wednesday 8th April 2020
- CAMR 202; as agreed with Jazz 60% is available for release and is acceptable for patient use, the remaining portion is under review
- CAMR 203; the batch did not meet PBL’s robust and stringent release procedures and consequently PBL will not release this batch
- CAMR 204; product filled, QC testing ongoing
Adherence to Good Pharmaceutical Manufacturing
PBL fully complies with Good Manufacturing Practice (GMP) requirements in all our pharmaceutical facilities. The product is manufactured according to international specifications set for pharmaceutical clean-rooms. PBL has a robust release system for batches where sterility and compliance considerations are fully incorporated. No batches of Erwinase released by PBL have breached the accepted standards and PBL would not release a batch if it thought there was any issue with the product.
Although PBL received a Warning Letter in 2017 which included an issue with particulate matter on stoppers used to seal the product, those issues were completely resolved by sourcing and validating an alternative supplier in 2018. Since then, 15 batches have been manufactured without a reoccurrence of the issue and PBL has presented this data at an international conference: Particular about Particulates PBL Presentation 2019 updated 2020. This information was also made available to Jazz and the key graph is reproduced below:
PBL’s Investment to Address the Growing Demand of Erwinase
Demand for Erwinase has been steadily growing and PBL has invested into addressing the capacity constraints since 2015 by the introduction of several measures including:
- The introduction of 24/7 manufacturing shifts to maximise production
- Reviewing the manufacturing process to identify where operational efficiencies could be made
- Increased staff recruitment across the whole organisation to support all manufacturing functions
These changes have allowed PBL to increase capacity by 15,000-20,000 vials.
PBL recognises further capacity is required to meet the demand for this critical life-saving product. Consequently, PBL has sought support from its stakeholder and invested more than £50 million in new manufacturing facilities. This has involved the construction of a new 3000 Litre state-of-the-art fermentation facility, tripling the current fermentation capacity. Full details of the facility can be found on the PBL website.
PBL is aiming to double its production capacity over the next year subject to obtaining appropriate regulatory approval for the facility. That will be followed by further facilities for downstream processing including an integrated filling line as reported in the pharmaceutical press.
Ensuring Future Supply
PBL is acutely aware of the importance of supply of Erwinase to children suffering from acute lymphoblastic leukaemia (ALL) and is committed to manufacturing the product such that it conforms to the highest specification meeting all quality standards required.
PBL is committed to the long-term supply of Erwinase to treat childhood leukaemia. PBL announced in April 2020 that it had signed a new exclusive worldwide licensing agreement with Clinigen coming into effect from January 2021.
Under the new agreement, PBL plans to hold all Marketing Authorisations for Erwinase and will therefore, be able to control and optimise the introduction of improvements directly to these product licenses without partnership restrictions. PBL will be able to interact directly with the regulatory authorities globally and provide greater transparency. As Marketing Authorisation Holder, PBL will perform batch release directly to market, and work directly with the Authorities to ensure optimal supply of product to patients.
PBL is confident that this approach along with the production capacity improvements, will lead to an improved supply so globally more children with ALL can be treated with Erwinase.
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24th September 2020