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EIs vs BIs – Enzyme Indicators vs Biological Indicators
Obtaining accurate qualification results as quickly as possible is the minimum expectation and this is certainly the case when it comes to decontamination performance validation.
As such, the use of Biological Indicators (BIs) for decontamination qualification are a significant bottleneck and Enzyme Indicators (EIs) are an exciting potential solution for the biopharmaceutical industries.
The Limitations of BIs
The conventional method for Vapor Phase Hydrogen Peroxide (VPHP) cycle development is to use resistant BIs to challenge the decontamination of enclosed spaces, which range from positive pressure isolators to whole rooms.
With this approach, the aim of the biodecontamination cycle is to demonstrate a 6-log reduction of the BI -despite this acceptance criterion usually being applied to terminal sterilisation processes, rather than for decontamination (i.e. disinfection).
To put this into context, the Environmental Protection Agency (EPA) classification of cleaning agents describes VPHP as a disinfectant treatment, for which demonstration of 4-log reduction of bacterial spores would be an acceptable result. However, BIs can only provide a kill (6-log)/no kill result.
This is a time-consuming process, since a seven-day incubation period is required for definitive confirmation of a successful cycle. This in turn means that cycle development is costly and requires a huge amount of manual processing.
Recent developments in thermally stable adenylate kinase (tAK) technology Enzymatic Indicators (EIs) are presenting an exciting alternative to the use of BIs, an alternative which is both rapid and capable of providing a much more precise indication of the level of disinfection.
In comparison with processes utilising BIs, cycles using EIs can be analysed rapidly, assuring confirmation of decontamination performance.
Any active enzyme remaining on strips following exposure are analysed on an indicator utilising a luciferin reaction which provides an immediate residual light output that is directly comparable to the remaining activity on the test strip.
The test strips can be manufactured to a high degree of consistency, with none of the quality issues that BIs may be vulnerable to.
Public Health England and Protak Ltd have carried out detailed enumeration studies using BIs and tAK EIs to develop inactivation profiles of tAK against log kill. In this way, a rapid and reliable assay for a range of desired log kills, including those suitable to demonstrate decontamination, is available to industry.
With the instant results provided by EIs using tAK before release, decontamination cycles can be quickly modified in the event of failure, meaning that cycle development is accelerated and the time to successful manufacture reduced. Additionally, the technology means that microbiologists can obtain a full product decontamination and manufacturing history, lowering the risk of batch failures.
EIs could be the future of decontamination performance validation for reasons ranging from accuracy, to time to production and cost.
However, the future of EI solutions such as those using tAK (or other developing technologies) requires further comparative work against previously validated systems. One entry possibility is the validation of EIs alongside BIs during periodic revalidations of existing systems.
For 2019 we have chosen Macmillan Cancer Support as our Charity of the Year.
Macmillan believes no one should face cancer alone and the charity does a range of fantastic things to support those living with the disease, from raising money to fund nurses and therapists to providing support centres with information resources such as booklets and leaflets.
But it doesn’t stop there! Macmillan also works hard to run campaigns to improve cancer care and fight discrimination, and to provide more information and support centres offering free and confidential advice.
We recently donated £4,000 to the charity to show our support for the amazing and life-changing help and care that Macmillan provides. Donations help the charity be there every step of the way for those living with cancer as well as for their friends, families, carers and communities.
Last year, our Charity of the Year was Alzheimer’s Research UK, the leading dementia research charity dedicated to making life-changing breakthroughs in diagnosis, prevention, treatment and cure.
As a team, eXmoor is always looking for fun ways to raise money for its chosen charities. Head to https://www.macmillan.org.uk/get-involved/all-ways-to-help.html to find out more and let us know if you have any great ideas!
Cell and gene therapy manufacturing consultancy eXmoor Pharma is working with Orchard Therapeutics (ORTX: NASDAQ) on the concept design of a new gene therapy manufacturing facility in Fremont, California, US.
Orchard, a leading commercial-stage biopharmaceutical company dedicated to transforming the lives of patients with serious and life-threatening rare diseases through innovative gene therapies, recently announced it has signed a long-term lease agreement to build-out a new facility in California.
eXmoor will be working with Orchard and its local partners to develop the concept design of the new gene therapy manufacturing facility which is expected to create more than 100 new jobs in the San Francisco Bay Area to support the company’s extensive gene therapy pipeline and enhance its capacity to develop and deliver lentiviral vector and gene-corrected hematopoietic stem cells for a wide range of diseases on a global scale.
The concept design will comprise process design as well as architectural plans for the lentiviral vector and cryopreserved cell therapy manufacturing suites and their associated support facilities. eXmoor will deliver a package suitable for Orchard to have initial discussions with regulatory agencies and to allow local partners to progress to finalisation of the architectural and engineering designs.
“The expansion of our California operation to include a manufacturing facility is a critical step in advancing Orchard’s capabilities to supply products for our ex vivo gene therapy programs,” said Stewart Craig, Ph.D., chief manufacturing officer of Orchard.
“We are very pleased to be able to collaborate with such an expert group as eXmoor and our local partners to efficiently advance our plans to support the potential launch of our gene therapy clinical product candidates.”
eXmoor Pharma managing director Angela Osborne commented: “We’re thrilled to be working on the concept design for Orchard’s new facility and to support the company’s mission of transforming patient’s lives through gene therapy.
“We are expert in delivering innovative end-to-end GMP biomanufacturing projects and, with our knowledge, experience and structured process, eXmoor will provide Orchard with the tailored design solution to suit the specific requirements of their new gene therapy manufacturing facility in California.”
Angela founded eXmoor Pharma in 2004 and has since grown it into a globally recognised leader in its field that has completed more than 300 projects across 12 countries including the design of 27 cell and gene therapy facilities.
Notes to editors:
eXmoor Pharma is a cell and gene therapy and biopharmaceutical manufacturing consultancy which was founded in 2004 and has since grown into a globally recognised leader in its field that has completed more than 300 projects across 12 countries.
The company works closely with clients to help them with commercialising a research process, developing fully licensed facilities and providing QP services. eXmoor has won repeat business from nearly two thirds of all its clients since its launch.
eXmoor’s offices and process development laboratories are in Bristol, UK.
Orchard Therapeutics is a fully integrated commercial-stage biopharmaceutical company dedicated to transforming the lives of patients with serious and life-threatening rare diseases through innovative gene therapies.
Orchard’s portfolio of autologous ex vivo gene therapies includes Strimvelis, the first autologous ex vivo gene therapy approved by the European Medicines Agency for adenosine deaminase severe combined immunodeficiency (ADA-SCID). Additional programs for neurometabolic disorders, primary immune deficiencies and hemoglobinopathies include three advanced registrational studies for metachromatic leukodystrophy (MLD), ADA-SCID and Wiskott-Aldrich syndrome (WAS), clinical programs for X-linked chronic granulomatous disease (X-CGD) and transfusion dependent beta-thalassemia (TDBT), as well as an extensive preclinical pipeline.
Orchard currently has offices in the U.K. and the U.S., including London, San Francisco and Boston.
For further information contact:
Tel: 0117 925 1358
Angela founded the biopharmaceutical and cell therapy manufacturing consultancy eXmoor Pharma in 2004 and has since grown it into a globally recognised leader in its field that has completed more than 300 projects across 12 countries.
In September 2010 she co-founded the Advanced Therapy Medicinal Products (ATMP) Manufacturing Community, or amc, to build critical mass and facilitate the sharing of expertise in ATMP manufacturing. The amc now boasts 170 fee paying members.
Angela is a member of the BioIndustry Association (BIA)’s Cell Therapy Industry Group and Manufacturing Groups’ advisory committees, .
She has now been named alongside 49 other ‘outstanding’ female healthcare business leaders in the 2018 BioBeat list which aims to emphasise the role of women leading and innovating to ensure new technologies and treatments continue to improve UK research, health and society.
Angela said: “It is a real honour to be included on this BioBeat list alongside so many other inspiring women working in UK healthcare businesses.
“There is amazing work being done by women across the board developing new products and processes and pushing the boundaries of bioscience in ways that will hopefully benefit everyone in years to come.
“My inclusion on this list is really thanks to the hard work and dedication of all our talented team at eXmoor who between them have more than 300 years’ combined experience in gene and cell therapy and biopharmaceuticals.”
eXmoor Pharma works closely with clients to help them with commercialising a research process, developing fully licensed facilities and providing QP services. The company has won repeat business from nearly two thirds of all its clients since its launch.
Miranda Weston-Smith, BioBeat founder, said: “Congratulations to the outstanding women leaders who are recognised as the 50 Movers and Shakers in BioBusiness 2018.
“They are changing what is possible for the benefit of humanity and helping to build a more inclusive, responsive healthcare ecosystem – whether that’s by developing revolutionary products, shaping bioscience through investment, accelerating the innovation pipeline, transforming patient access to healthcare or supporting innovation from concept to market.”
Jane Osbourn, vice-president research and development at MedImmune, which supported the report, said: “On behalf of the numerous partners and supporters of the 50 Movers and Shakers in BioBusiness 2018 report, we are delighted to celebrate the achievements of this group of talented women. We hope shining a spotlight on these female leaders will support them to forge stronger networks and realise new opportunities to improve patient health.”
An innovation platform for healthcare entrepreneurs which brings together scientific and business expertise, BioBeat has celebrated 50 Movers and Shakers in BioBusiness every year since 2014.
BioBeat connects entrepreneurs with leaders in biotech, by working to respond to challenges and open opportunities through the inspirational experience of women leaders. Miranda Weston-Smith founded BioBeat to bring fresh energy and insights into biotech for a healthier world.
BioBeat is grateful to long-standing partners the Cambridge Judge Entrepreneurship Centre and Innovation Forum.
Each autumn, BioBeat releases the 50 Movers & Shakers in BioBusiness report, which identifies 50 women in the UK who are shaking up biotech translation. The annual autumn summit also brings together pioneers in biotech to nurture innovation and new partnerships.
Find out more at http://www.mws-consulting.co.uk/biobeat/
At eXmoor, we wanted to share our top 10 ‘must have’ requirements when sourcing a new site for a Generic ATMP Manufacturing Facility.
1. Area and Capacity
The prospective site area must be a suitable size to include the manufacturing site and warehouse, laboratories, offices, meeting rooms, reception and any other rooms or buildings that may be required. It’s important to consider all planned projects as these will give a good indication of the capacity required at the new site.
In accordance with regulatory guidance, between 6-8m of space will be needed above the cleanrooms to include a walk-on ceiling which will allow these areas to be serviced from the outside. Space will also need to be made available for suitable heating, ventilation and air conditioning (HVAC) through the manufacturing and office areas. If the prospective building has sufficient height, the HVAC units could be located above the cleanrooms.
3. Vertical Distribution
Isolated lifts must be included for the movement and distribution of supply materials, waste and the final product. The number of lifts will depend on the layout of the prospective building. An additional large goods lift installed to allow for the vertical transportation of motors and spares to the plantroom (if required).As per point 2, a walk-on ceiling must be included above the cleanrooms to allow for servicing. Finally, you should allow for door heights of 2.7m to enable movement of large pieces of equipment throughout the facility.
When choosing a site, always consider whether there is a suitable flow and segregation of personnel, materials and waste. It’s also important to take into account the number of lifts and external docking stations.
5. Co-occupancy and Access
Ideally the site and facility chosen should always be single occupancy and should never share incoming or outgoing routes with other occupants of the building. It should not be possible to mix materials, personnel or waste routes with other occupants of the building, and no one should not be able to obtain unauthorised access to the facility (via lifts or stairs).
The following raw utility services will need to be supplied as standard to the facility:
- Mains pressure water
- Surface and foul drainage
- Gas (optional)
- Electrical power
The following utilities should also be considered (if relevant to the facility):
- Water for injection
- Deionised water
- Pure steam
- Plant steam
- Process chilled water
- Clean in place
- HVAC units to service cleanrooms – depending on concept design
Ensure there is sufficient space on-site for the following items:
- Chiller compound
- Waste compound
- Gases and LN2 area
- Generator compound of sufficient size
The following items should also be considered in regards to the site proximity:
- Not near to standing water or falls in an area with a high flood risk
- Not near to heavily polluted industrial air exhausts
- Not near to an adjacent large scale construction site
- Ideally the manufacturing area would be >1m above the ground floor
The location of the manufacturing facility is important to consider. It should be in close proximity to public transport links, amenities and in a safe working area. As first impressions are always important, the buildings and larger site should be smart and well maintained, portraying a professional and high quality image to others.
In the manufacturing area there will be large items of equipment that will impose a significant live loading on the floor, and there are therefore minimum loading requirements:
- In the office / general areas, the minimum requirement for live floor loadings is 2.5kN/m2 above ground floor and 3.0kN/m2 at ground floor
- In the manufacturing and plant areas, live loads need to be in accordance with the minimum standard (BS EN 1991-1-1:2002) of 7.5kN/m2, ideally 10.0kN/m2 to allow for 1000kg pallet (8.2kN/m2)
10. Support Areas
In the warehouse areas, storage should be of a sufficient capacity to allow various categories of materials and products to be stored in an orderly manner. Enough space should also be allocated to avoid any mix-ups or cross-contamination during the quality checking process and testing. Quality control laboratories should also be kept separate from the production areas. Rest and refreshment rooms should be kept separate from the production, storage and quality control areas. Toilets and washrooms should not directly link with production, storage and quality control areas.
Typical walk on ceiling, allowing for external maintenance and HVAC.
Typical corridor, design and constructed
eXmoor has a new cell and gene therapy project to evaluate the CMC documentation of several product portfolio’s as acquired by a client. Available documentation will be reviewed to determine the feasibility and gaps for (further) commercialization.
eXmoor has acquired a cell therapy project to help a client develop a comparability program to implement significant changes to the manufacturing process. To identify what needs to be part of the comparability program, a risk analysis will be performed to determine criticality to the product and related QC profile.
In March this year the MHRA published its guidance on GxP Data Integrity.
We have welcomed the guidance at eXmoor. It provides specific information which is invaluable to companies around the practical steps which should be taken to ensure best practice at every stage of handling, managing and storing data.
In the past companies relied upon a perceived best practice along with general references to GAMP5 and 21CFR11 compliance, which has led to inconsistencies in the way data was managed. We believe this document will help companies understand the expectations around assurance of data integrity and that we will now see a more uniform approach and a move towards better managed data integrity practices.
The time is also right for this guidance. Technology and data storage products are now more advanced and becoming more common place within the industry; for example, the use of cloud-based technology for data storage has its benefits for the industry, but also holds risks which should be controlled.
We know from the manufacturers we work with that the guidance has helped them to review their data lifecycle and has resulted in updated processes in how they deal with data.
A major focus of the guidance has meant more emphasis on risk assessments of facilities and processes specifically around the data produced and how it is used. This is enabling a more holistic view of data management. The recommendation is to invest time in performing comprehensive Data Integrity Risk Assessments (DIRA) allowing companies to categorise their data management systems and to apply an appropriate level of control.
As part of this and to ensure compliance we are advising on how best to invest in the preparatory phase of any new facility or project and analysis of all the data which will be produced once operational.
Understanding the data lifecycle from start to finish, i.e. from when data is generated to when it is disposed of, is paramount. This then facilitates the validation of those systems used during that data lifecycle. The MHRA describes the data lifecycle as the ‘generation and recording through processing (including analysis, transformation and migration), use, date retention, archive/retrieval and destruction.’
Examples of where risk to data integrity can occur, which may impact on established working practices, are as follows:
- Non-synchronised clocks: important when setting up systems that need to ensure the time and date on data is accurate and consistent ensuring concurrent recording of actions.
- Access rights: unique user identification is vital to prevent unauthorised amendment of data. The guidance emphasises that having a single user access that does not uniquely identify the operator should not be used.
Companies with legacy systems may not have this feature. This will require them to assess the need for having other support systems in place (third party software or paper based) which provide a record of unique user identification.
- Provision of a suitable work environment: As part of our facility design work we consider whether sufficient space has been allocated for an operator to be able to record data. Companies should always consider space for laying out of a batch record and SOP as part of the process.
Further features of the MHRA Data Integrity guidance:
- Scribes: the use of scribes should be contemporaneous with the task being performed and the records should identify the person performing the task. The person performing the task should verify the actions taken at a suitable time after task completion.
- Raw data: the guidance states that where the system permits dynamic storage then this cannot be replaced by paper systems.
- True copies: these are considered to be a copy of the original record which has been verified as having the same information as the original.
- Electronic signatures: Companies should ensure signature processes are appropriately validated to ensure that suitability and control is maintained.
- Computerised systems validation: The MHRA has expressed the need for companies to look at all the systems they use within their processing and understand the computerised elements and the risks they pose and then apply a suitable level of control.
It is not acceptable to take a suppliers’ statement of compliance as the sole guarantee as to the acceptability of a computerised system – there needs to be some level of qualification performed by the company purchasing the system; the level required should be determined through risk assessment in the same manner as any processing equipment. As an example, an analytical instrument will be supplied with 21CFR 11 compliant software, but how the company intend to use the software needs to be assessed. This will need to take into account user set up and access rights, baseline configurations of the software, the programming of methods, data analysis, data reporting and data storage.
The importance of data management has never been more pronounced, and we believe this new guidance will provide both manufacturers and suppliers a clearer understanding as to the expectations from the competent authorities.
The hope is that companies will be able to manage their data more appropriately rather than taking the historical approach of ‘keep everything’ and that it will galvanise industry to use the data it generates to assist them in ensuring the quality of the products produced.
For more information and to access the full guidance document click here: https://www.gov.uk/government/publications/guidance-on-gxp-data-integrity
For more information on how eXmoor help our clients with this topic click here: https://www.exmoorpharma.com
Pharmaceutical Water is, perhaps, the most important of all pharmaceutical utilities. It is used as an excipient in many pharmaceutical formulations, as a cleaning agent, and as a separately packaged product diluent. In addition to non-compendial systems, pharmaceutical facilities typically include systems for delivering pharmacopoeial Purified Water (PW) Water for Injections (WFI), and Highly Purified Water (HPW).
This classroom course has been substantially updated to feature the guiding principles of the ISPE Baseline Guide: Water and Steam Systems (Second Edition) with particular emphasis placed upon microbial control and laboratory water as well as key design philosophies. The principles of design and operation of water systems used directly in pharmaceutical manufacturing and laboratory applications, including the essential concepts and principles of systems used to generate USP, EP and non-compendial waters will be covered. These concepts include specification, design, operation, testing, and maintenance of equipment and systems for water generation.
eXmoor Process Consultant Andrew Provan will be presenting at talk entitled “Next Generation Technologies – Gene Therapy and Viral Vaccines as a UK USP” with Allergan and Cobra Biologics at the Bionow Pharma Manufacturing Conference on Wed 23rd May 2018.
The Bionow Pharma Manufacturing Conference is a one-day conference addressing the needs and requirements of pharma manufacturers who compete on the global stage.
The programme is being developed in conjunction with large pharma Members of Bionow to explore and address routes to efficiency, improved cost of goods, process development and the capabilities needed to exploit next generation technologies.
Through a combination of workshops, lecture and panel sessions, delegates will hear about and be able to contribute to the discussions in the key areas of:
- Skills & Mindset – how can we do it better with a new approach
- Next Generation Technologies
- Steriles Manufacture
- Innovation in Analytics
- Regulatory Challenges and Opportunities
- The Innovation Supply Chain
eXmoor process consultants helped to organise and accompanied some of our client representatives at the ISPE workshop on VPHP Decontamination & Validation held in February 2018. https://www.youtube.com/watch?v=NF-yy8c7AG4
The use of Enzymatic Indicators are an exciting development given their potential to accelerate vapourised hydrogen peroxide (VPHP) gas cycle development (GCD) studies, qualification and requalification. It also enables studies to give an accurate measure of the degree of sanitisation achieved in terms of equivalence to a target log reduction that is relevant for decontamination instead of always effectively looking for the 6-log reduction that is only really relevant to terminal sterilisation.
Contact eXmoor here if you would like an impartial view in the section of decontamination techniques and qualification methods for the cell and gene therapy and related industries.
The R&D version of our novel CPrep equipment is now ready for trials. This equipment gently and automatically thaws and washes a cell therapy and then fills a syringe ready for administration. It will help to extend the shelf life of valuable products, remove uncertainty in the final processing step and increase patient safety.
Commercially available CPrep has resulted from a joint project with Amercare Ltd, and a grant from the UK’s innovation agency, Innovate UK. R&D versions may be trialled in our labs in Bristol and are manufactured by Amercare Ltd. The supply chain for the GMP version will be finalised to suit the specific needs of individual cell therapies.
Will Milligan (Exmoor bioprocess engineer) has been selected for the BIA MAC Bioproduction Leadership Initiative.
The programme was created to support the development of the next generation of bioprocess leaders, as part of BIA MAC’s objectives of connecting, advising and influencing. The development of managers in the biopharmaceutical and cell and gene therapy industries is an important part of the training landscape to deliver senior leaders of the future. Two key aims of the MAC initiative are:
1) to promote cross-sector learning by offering an overview of the work of other companies across biopharma, vaccines and cell and gene therapy by seeing them in action
2) to develop a network with peers to promote best practice