TGA Licensing and Quality Management Issues for the BMT Network NSW
A Discussion Paper distributed by the Bone Marrow Transplant Network NSW (BMT Network)
The current cost estimates and recommendations currently with NSW Health are here.
Background
In early 2003 the Therapeutic Goods Administration (TGA) signalled its intention to remove the exemption for licensing currently enjoyed by Public Hospitals and their laboratories who are involved in the collection, storage and processing of Haematopoietic Progenitor Cells (HPCs or Bone Marrow Stem Cells). Public Hospital facilities involved in Bone Marrow Transplantation activities will now be required to meet licensing requirements using the Foundation for the Accreditation of Cellular Therapy (FACT) Standards.
Anticipated Funding Implications for NSW Public Hospitals providing Bone Marrow Transplant Services
This will require an additional financial commitment from each transplanting site to implement and maintain these standards. The main areas where additional costs will be expected are:
- Nursing - significantly increased documentation, equipment tracking and consumables management, use and management of Standard Operating Procedure monitoring, non conformance reporting and Quality Procedures
- Scientists - greatly increased workload in Standard Operating Procedure monitoring, non conformance reporting and Quality Procedures
- Quality Manager - the appointment of a 0.5 FTE Quality Manager and Quality Management Software at each site (unless the BMT Network is successful in obtaining funding for a State Wide Quality Manager and a State Wide Quality Management Software Application)
- Implementation Project - It is anticipated that each site will need a dedicated Project Implementation Officer for at least 3 months to establish the policies, procedures and monitoring strategies in order to comply with the regulations.
There are currently 2 facilities in Australia that have achieved licensing with the TGA - Royal Adelaide Hospital and Peter MacCallum Cancer Institute in Melbourne. The Peter MacCallum Institute opted to completely rebuild much of its physical infrastructure and build 'Clean Rooms' to the Australian Code of Good Manufacturing Practice (GMP) - Human Blood and Tissues standard, at a cost of approximately $2m. Royal Adelaide Hospital invested a similar amount of funds in validating existing procedures and implementing a complete Quality Mangement System.
Current TGA Activities
The TGA has outlined where Blood and Blood Products are exempt from regulation. Click Here to go to the TGA Website for this outline. The proposed Legislation and the complete list of actions by the TGA can be found here on the TGA Website. In addition the TGA Website also provides detailed PDF Files with discussion papers and corrigendas.
The TGA has now officially established stakeholders for progressing the regulatory outcomes, and has called for the formation of a Working Committee to advise the TGA on implementation strategies. The working group consists of:
- Two Clinicians from the Bone Marrow Transplant Society of Australia and New Zealand (BMTANZ)
- Two Scientists from the Bone Marrow Transplant Scientists Association of Australasia (BMTSAA)
- One representative from the Australian Bone Marrow Donor Registry (ABMDR)
- An Apheresis Nurse
- A representative of the Hospital Based Bone Marrow Transplant Coordinators
- A nominee from the Manufacturing Assessment Section of the TGA
Can your facility Demostrate these processes?
Below is an example of the types of procedures and documentation that will be required in each facility to meet the requirements. The BMT Network has drawn up an implementation plan to assist Area Health Services achieve compliance, which includes the establishment of a State Wide Quality Manager Position and the implementation of a State Wide Quality Management Software Application.
Facilities must be able to demonstrate:
- A non conformance (variance) reporting system which captures all non conformances, flags consistent non conformances, enforces corrective actions and tracks resultant changes to Standard Operating Procedures (SOPs).
- The ability to retrospectively track the batch numbers of all consumables used in every HPC l collection and processing event.
- A monitoring system for all staff which ensures that staff who perform any procedure are appropriately qualified, trained and have documented competancy in that procedure.
- Documented records that all supplies and reagents used in every HPC collection and processing event have been correctly stored at the required environmental conditions from the time they departed the supplier's production facility, including documented temperature monitoring records.
- Documented scientific validations for all laboratory and clinical procedures to demonstrate efficacy and safety.
- An equipment maintenance and service monitoring system which alerts and enforces regular maintenance schedules.
- The correct use of current, version controlled, approved and regularly reviewed Standard Operating Procedures (SOPs).
- There use of a documented approval and change process for new SOPs including validation.
- The use of a documented cleaning schedule with validated cleaning agents for all storage areas and equipment which can be inspected at any time for compliance.
- There is a written Quality Management Plan to cover all of the above procedures.
- There is a nominated Quality Manager who oversees and enforces all Quality Management Practices and who is independent of the processing itself. (That is, it cannot be a person in the laboratory who has a dual role of cell processing and Quality Management).
Role of the Bone Marrow Transplant Network NSW
The discussion paper that follows outlines the standards in more detail, and compares some of the relevant FACT standards with the more stringent GMP standards, which the TGA has also indicated it is considering for use in licensing BMT facilities.
The TGA has indicated this licensing strategy is firmly in place, with only the time line yet to be confirmed. The BMT Network is actively campaigning for action by NSW Health immediately, and has already drawn up an implementation plan. The BMT Network is strongly lobbying for a State Wide approach, to ensure a consistent and streamlined Quality Management System is in place rather than the more expensive site by site approach.
As this legislation is enacted the BMT Network will continue to be the lead agency in developing an implementation strategy. We will be keeping all NSW Public Hospitals informed of the progress of the implementation plans.
FACT standards
Clinical
B4.000 The program shall have a written quality management plan that describes, at a minimum, the methods for oversight of patient care (including detection of errors, accidents and adverse reactions), significant outcome parameters, the means for review of aggregate data on a regular basis (audits), and requirements for meetings, review, documentation, corrective actions and reporting.
B4.110 The Program Director is responsible for the quality management plan as it pertains to the clinical program. The performance of this activity may be delegated to an individual within the program with sufficient expertise.
Collection
C4.000 The collection facility shall have a written quality management plan that describes, at a minimum, the methods for oversight of donor care (including detection of errors, accidents and adverse reactions), significant outcome parameters, the means for review of aggregate data on a regular basis (audits), validation of significant processes of the collection program and requirements for meetings, review, documentation, corrective actions and reporting.
C4.110 The Collection Facility Director is responsible for the quality management plan as it pertains to the collection facility.
C4.120 The collection facility shall establish and maintain a program of quality management, under the supervision of a designated person. The individual shall review and approve policies and procedures that document compliance with regulatory requirements and standards, and the performance of quality audits.
Processing
D3.300 The shall be a Laboratory Quality Management Supervisor designated by the Laboratory Director to establish and maintain systems to review, modify as necessary, and approve all procedures intended to monitor compliance with these Standards and/or the performance of the facility. The Laboratory Quality Management Supervisor should participate regularly in educational activities related to the field of HPC processing, transplantation and quality management.
D4.000 The cell processing laboratory shall establish and maintain a program of quality management as it pertains to the laboratory, under the supervision of a designated person. The individual shall review and approve policies and procedures that document compliance with regulatory requirements and standards, and the performance of quality audits.
Australian code of GMP - Human Blood and Tissues
107 It is ultimately the responsibility of the Director to manage the quality system and its implementation, and in conjunction with staff with specialised skills, to develop, compile and record the policy for the organisation.
109 The quality assurance nominee must have the necessary independence and authority to ensure that quality measures are employed in the manufacture (including testing) of product. This person should report to the Director.
111 The quality assurance and production nominees should usually have a relevant tertiary level qualification and have had practical experience, at managerial level and under professional guidance, in the manufacture of blood and/or tissue products, in accordance with GMP requirements.
Potential options for management of the quality system
There are a number of options for management of the quality system. This can either be approached individually by each hospital involved in collection, processing or transplantation, or it can be managed centrally via the network. Thoughts, potential advantages and disadvantages are indicated below.
Hospital management of the quality system
Medical testing (ie. Pathology) laboratories in Australia are already required to operate according to the ISO 17025 standard, which is based on ISO 9001 family of quality management standards. All HPC processing laboratories in NSW are associated with a pathology laboratory and hence should already be operating under a suitable quality management system.
The existing quality management system in pathology should be able to manage the quality system for the processing laboratory. It is not clear whether the pathology Quality Manager would also be able or willing to handle the additional workload for the clinical and collection sections of the transplant program.
If pathology was unable to manage the clinical and collection sections, substantial duplication may occur if two separate quality systems were required. Many SOPs will be generic to all sections (eg. product labelling, transport, supplies, donors with communicable disease, etc) and hence would need to be controlled through more than one system at each hospital. Non-conformance and corrective action needs to encompass clinical, collection and the processing sections (eg. adverse clinical effects may need corrective action by the laboratory and/or the collection facility).
All costs incurred would need to be met by individual hospitals.
This system would permit re-formatting of network documents and insertion of logos to conform with departmental and hospital requirements.
If the TGA requires facilities to conform to the Australian code of GMP, it is unlikely that the pathology Quality Manager would meet the requirements specified in section 111. This would then necessitate employment of a dedicated BMT quality manager (potentially 0.5 FTE per hospital).
Network management of the quality system
Central management of the quality system would only be feasible if commercial quality management software was used. Q-Pulse software is a UK developed application based on Borland Database Engine, a flat file database system. There is no need for Q-Pulse to interface with Pathnet, AusLab or other patient related information systems. It can reduce the time and paperwork necessary to manage the required areas of quality management (ie. document control, training records, equipment, suppliers, audits, non-conformance and corrective action) and facilitates automated analysis.
Use of a centralised quality management system would facilitate integrated management of the quality system for clinical, collection and processing. It would also permit common non-conformance reporting and corrective action across the network, which is likely to result in significant cost benefits and quality improvement.
With all centres working from common SOPs and a common quality system, it is envisaged that 1-2 FTE with good BMT and quality system knowledge would be sufficient for the entire BMT Network in NSW. This would fulfil the section 111 requirement of the Australian code of GMP.
With this option, it would not be feasible to format documents to local requirements or to insert hospital/departmental logos. Hence, approval would need to be obtained from each hospital administration for use of external documents bearing the Network logo. All BMT Network NSW hospitals have contributed to the development and approval of the common SOPs which would become part of the facility's manual. It would need to be accepted that the presence of the Network logo does not render the Network legally liable.
November 2005 - Proposed 4 Classes of Regulation
In November 2005 the following discussion paper was circulated by the TGA. Clarification was sought from Dr Richard Pembery that this document was meant to include HPC's. His reply indicated a definite YES - and that the BMT Network was advised to make a response.
Discussion paper on
regulation of human cell and tissue therapies
(HCTs)
Classes, approval process
and responsible people
For consideration by
jurisdictions
A. Background
At the workshop of 28 September 2005,
it was agreed that the TGA would develop a draft Report addressing the
issues discussed and documented on the whiteboard. One of the
major issues for consideration by the TGA was providing greater clarity
regarding terminology and the roles and responsibilities of individuals
regulated by the TGA.
Since the workshop the TGA has reviewed
the proposed approach to the regulation of HCTs and identified more
appropriate and consistent terminology and also greater clarity regarding
the proposed regulatory arrangements.
The purpose of this paper is to describe
the TGA's proposed approach. Subject to comments from jurisdictions,
this will then be incorporated in the Report which the TGA intends to
circulate in early November 2005.
B. Proposed approach
Class 1
Human cells and tissues captured in
Class 1
- Organs that are for direct
transfer from donor to recipient (other than part of a single surgical
procedure1). For example, heart, lung, kidney and
pancreas.
- Reproductive tissue (other
than reproductive tissue that has been manipulated such that it would
fall in a higher class).
- Submission of a Declaration
(previously referred to as a 'Standards proforma') regarding compliance
with relevant Standards.
- The Declaration will
require the applicant to:
- Specify the organ types (for
which approval is sought)
- Specify the Standard to be
applied in relation to the organ types
- Specify the testing laboratory
- TGA approval is evidenced
by the issuing of a TGA "Class 1 HCT Approval" (previously
referred to as a "Class 1 HCT licence). The Class 1 HCT Approval
will detail:
- the organ types for which
the approval has been issued; and
- the standards that must be
complied with.
Responsibilities
The Class 1 HCT Approval will be issued
to an organisation and not an individual. In the case of organs,
the organisation that will be responsible for ensuring compliance will
be the organisation responsible for donor selection. This organisation
will be responsible for ensuring that donor selection and testing occurs
in accordance with the Standard. In the case of reproductive tissue,
the responsible organisation will be the Assisted Reproductive Technology
(ART) clinic.
The Standard for organs will be based
on the Transplantation Society of Australia and New Zealand Australian
National Organ Allocation Protocols and the Standard for reproductive
tissue will be based on the existing Reproductive Technology Accreditation
Committee standards.
Further explanation of concepts
- Declaration - The term "Declaration"
has been adopted (rather than "Standards Proforma") as the
"Standards Proforma" was causing confusion for some stakeholders.
"Declaration" better reflects the nature of the information
that will be required to be provided to the TGA in order for a Class
1 HCT Approval to be issued by the TGA.
- The Declaration will be a
very simple document that will be able to be lodged electronically.
- One Declaration may be made
in respect of a number of different types or organs.
- If the Declaration is completed
appropriately (addressing the information noted above) the issuance
of a TGA Class 1 HCT approval will be automatic.
- The organisation in whose
name the approval is issued (eg the organisation responsible for donor
selection) will be responsible for ensuring that the relevant Standard
is complied with.
Class 2
Human cells and tissues captured in
Class 2
- A tissue or cell that is stored,
maintained or preserved for future use and:
TGA approval
Applicants (the majority of which may
be tissue banks) will be required to seek from the TGA, Quality System
Certification (in respect of the facility in which the tissue will be
banked) and a Class 2 HCT Approval for each tissue type (requiring compliance
with relevant Standards for the particular tissue type).
- Quality System Certification.
- The applicant will be the
tissue bank or facility
- The application for certification
will be in respect of the site on which the tissue will be released
- The application must demonstrate
compliance with Quality Systems Principles (issued by the TGA and as
described in more detail below)
- Class 2 HCT Approval for each
tissue type that is stored, maintained or preserved by a facility for
future use.
- A separate application will
need to be made by the facility in respect of each tissue type.
- For each tissue type there
will be a separate Standards file.
- The Standards file submitted
by the applicant in respect of each tissue type must demonstrate compliance
with relevant Standards in relation to each tissue type.
Responsibilities
The tissue facility will be responsible
for ensuring, on an ongoing basis, that:
- the Quality Systems Principles
are observed; and
- any conditions that form part
of the Class 2 HCT Approval are observed (including requirements for
ongoing compliance with the relevant Standards in relation to the tissue
type).
Further explanation of concepts
- Quality System Certification
- the TGA would issue a Quality System Certification following an initial
audit of the site on which the activity will be occurring and after
being satisfied that the organisation is compliant with the Quality
Systems Principles
- Tissue banks are currently
required to be audited to verify compliance with the Code of GMP for
Blood and Tissues.
- The "Quality Systems
Principles" will replace the old Code of GMP.
- Tissue banks that are currently
in compliance with the Code will not require another initial audit in
order to be Quality System Certified by the TGA.
- Class 2 HCT approval for each
tissue type - As discussed with jurisdictions, the TGA had initially
considered that one approval could be issued covering all tissue types
held by a tissue facility. However, on reflection, the TGA considers
that it is more appropriate for different approvals to be issued for
different tissue types. This is because each of the different tissue
types will be subject to different Standards.
Class 3
Human cells and tissues captured in
Class 3
A cell or tissue processed in a manner
that may alter the structure and properties of the cell or tissue but
does not purposefully alter the biological activity.
Examples:
- Islet cells disaggregated
from the pancreas
- Demineralised bone
- Ex-vivo expansion of progenitor
cells which include tissue stem cells
TGA approval
Applicants will be required to seek from
the TGA, Quality System Certification (in respect of the facility in
which the tissue or cells will be manipulated) and a Class 3 HCT Approval
for each individual product.
- Quality System Certification.
- The applicant will be the
organisation intending to manipulate the cell or tissue.
- The application for Quality
System Certification will be in respect of the site on which the manipulation
will occur.
- The applicant must demonstrate
compliance with the Quality System Principles.
- The TGA would issue a Quality
System Certification following an initial audit of the site on which
the activity will be occurring and after being satisfied that the organisation
is compliant with the Quality System Principles.
- Class 3 HCT Approval
- In order to obtain a Class
3 HCT Approval the applicant will need to submit to the TGA a Product
Dossier (previously referred to as a Technical Master File).
- The Product Dossier will need
to show evidence of compliance with relevant Standards and that the
HCT is safe, efficacious and of high quality. The Product Dossier
will need to include all scientific and technical information to support
the product including the details of compliance with applicable and
relevant standards.
Responsibilities
The organisation to whom the Quality
System Certification is issued will be responsible for ensuring, on
an ongoing basis, that the Quality System Principles are observed.
The organisation to whom the Class 3 HCT Approval is issued will be
responsible for ensuring that any conditions that form part of the Class
3 HCT Approval are observed.
Further explanation of concepts
- Product Dossier - it has become
apparent that the reference to a "Technical Master File" was
confusing to some stakeholders. The TGA therefore intends using
the term "Product Dossier" as this is a better description
of the information required to be submitted and is consistent with terminology
currently used within the TGA.
- Adoption of two stage process
(Quality System Certification and individual product approval) - In
previous discussions with jurisdictions it was proposed that the TGA
would issue one "licence" that would incorporate both the
Quality System Certification and the "Approval" for the individual
HCT. On reflection, the TGA considers that it is more appropriate
to separate the two types of approvals. This is because, as is
currently the case with medicines and devices, it is possible that one
company may wish to hold the "HCT Approval" (eg product approval)
and sub-contract another company to manufacture the HCT. The second
company would therefore hold the Quality System Certification (eg manufacturing
approval).
Class 4
Human cells and tissues captured in
Class 4
A cell or tissue processed
a) so that the biological properties
are deliberately manipulated; or
b) for a purpose for which the
cell or tissue is intended to be used is not its usual biological function.
Example:
- Cells subject to genetic manipulation
TGA approval
Applicants will be required to seek from
the TGA, Quality System Certification (in respect of the facility in
which the tissue or cells will be manipulated) and a Class 4 HCT Approval
for each individual product.
- Quality System Certification.
- Class 4 HCT Approval
- In order to obtain a Class
4 HCT Approval the applicant will need to submit to the TGA a Product
Dossier.
- The main difference between
the Product Dossier for Class 3 and Class 4 HCTs is that the Product
Dossier in respect of a Class 4 HCT will also need to contain relevant
clinical data and analysis.
Responsibilities
The organisation to whom the Quality
System Certification is issued will be responsible for ensuring, on
an ongoing basis, that the Quality Systems Principles are observed.
The organisation to whom the Class 4 HCT Approval is issued will be
responsible for ensuring that any conditions that form part of the Class
4 HCT Approval are observed.
Please note that if organs are transferred as part of a single surgical
procedure they will be exempt from regulation by the TGA
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Click here to see this document on the TGA Web Site
Status of the regulatory oversight of haematopoietic progenitor cells (HPCs)
November 2005
HPCs for bone marrow transplant (BMT) are harvested in two settings:
- As adult HPCs from peripheral or (rarely) marrow collections
- As cord blood HPCs from placental cord blood collections
HPCs were defined as blood components in 2000. Cord blood is banked and used for autologous or allogeneic transplant. It has been regulated though licensure of the manufacture under the Australian Code of GMP for Human Blood and Tissues [http://www.tga.gov.au/docs/html/gmpbltic.htm] (cGMP) since 2000. It is also subject to a product Standard for quality and safety. From 2000 to 2003 this Standard was the chapter on HPCs from the Council of Europe Guide to the preparation, use and quality assurance of blood components. When this Guide excluded HPCs from its purview, the TGA removed HPCs from the definition of fresh blood components. Cord Blood was then brought under a new Standard, Therapeutic Goods Order 73 [http://www.tga.gov.au/docs/html/tgo/tgo73.htm] which specifies compliance of cord blood with the international standards published by the Foundation for the Accreditation of Cellular Therapy (FACT) and NETCORD as the product Standard. Regulatory oversight via the cGMP Human Blood and Tissues was retained. This framework for cord blood was developed with full input by the sector and ratified by the Therapeutic Goods Committee.
The situation with adult HPCs is more complex. According to the Australasian Bone Marrow Transplant Recipient Registry, the sector's activities in 2003 included:
- Total transplants: 1253
- Australia 1112
- New Zealand 141
- Autologous transplants
- Australia 752
- New Zealand 92
- Allogeneic related
- Australia 210
- New Zealand 35
- Allogeneic unrelated
- Australia 150
- New Zealand 14
- Institutions
- Australia 37
- New Zealand 6
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Australasian Bone Marrow Transplant Recipient Registry Annual Data Summary 2003
In all the Therapeutic Goods Orders relating to blood components, the TGA has always excluded from regulation autologous and directed components. This has been a reflection of the TGA's detachment from medical practice and was also influenced by the need to allow rapid access to emergency donor panels in the event of local and national emergencies when regulation of fresh blood was established in 2000.
As seen from the above 2001 breakdown, over 90% of adult HPC manufacture is currently exempt from the TGA's oversight if the same provisions for autologous and directed blood components apply. A number of developments have contributed to the TGA developing additional thinking on this issue:
- Over the past three years, a number of Australian hospitals producing adult HPCs have developed GMP facilities for these cells whose operation is detached from the medical environment.
- Two of these hospitals have sought TGA approval of their manufacture of adult HPCs as this was required by the sponsors of international clinical trials in which these hospitals were seeking inclusion.
- While autologous/directed components constitute a minority of products in the mainstream blood sector, they represent the majority of procedures in the adult HPC sector and their exclusion from oversight is therefore incongruous. This situation is exacerbated by the inclusion of cord blood HPCs, which are used for the same indication but which are a small minority of HPC transplants, in regulation.
- Increasingly highly manipulated HPCs are being used in innovative therapies, such as their use to repair damaged myocardium after myocardial infarction. These therapies represent a higher level of risk than mainstream transplant, but their oversight is difficult to envisage in an environment naïve to regulation.
- Internationally and locally, HPCs are now considered to be more appropriately classified as cellular therapies rather than blood components. The TGA's development of a regulatory framework for such therapies lends itself to the inclusion of HPCs to the framework.
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Therefore, in 2004 the TGA initiated a dialogue with the HPC sector with a view to extending the regulation of HPCs across the full spectrum of activity using a risk-based model. The TGA identified the Bone Marrow Transplant Society of Australia and New Zealand (BMTSANZ) and the Bone Marrow Transplants Scientists Association as the key professional stakeholders in the sector. Three meetings were held over 2004-2005 and a position was developed:
- All HPCs would be transferred to the new cellular therapies framework.
- The current arrangements for cord blood-derived HPCs would come into the framework as Class II therapies.
- HPCs which were supplied by hospital units which were:
- Not supplying HPCs which were manipulated beyond collection and storage; and
- Supplied by the transplant unit for use within that unit or by clinical units directly linked to that unit in their medical programs and infrastructure; and
- Solely supplying HPCs which were autologous and or directed
would be classified as Class I therapies.
- These Class I facilities would be regulated through:
- The establishment of a Standard which would be recognised by the TGA through an appropriate Therapeutic Goods Order
- The identification of a competent and responsible individual who would be legally charged with demonstrating the facility's compliance with the Standard to the TGA
- The use of a Declaration of Compliance with the Standard, which would be filled and submitted to the TGA by the responsible individual on a regular and pre-established basis.
- It was agreed that the following principles would apply:
- The responsible and competent person would be the medical director of the transplant facility or program.
- The Standard would be the FACT Standard for therapies other than cord blood. The TGA is currently engaging with the process of developing the next edition of the standard published by the National Pathology Accreditation Advisory Council (NPAAC) with the intent of developing this standard as a suitable Australian document reflective of the quality principles outlined in the FACT document.
- The structure of the Declaration to be drafted by the TGA and submitted for refinement and review by a sample of facilities, after which it would be adopted.
- Laboratories involved in the testing of HPCs would be assessed on the basis of the types of tests. Subsequently, the TGA has initiated a dialogue with the National Association of Testing Authorities, which accredits pathology testing laboratories to a number of standards including ISO 15189. The TGA is examining the feasibility of adopting this standard as the Standard for testing laboratories performing testing for HPCs in Class I facilities. If this is agreed as being feasible with the sector, the TGA will require NATA accreditation as evidence of adherence to this Standard.
- HPCs which are highly manipulated or used for non-homologous purposes, such as genetically manipulated HPCs, cord blood used for myocardial regeneration etc will be regulated as Class IV therapies requiring the highest level of pre-market review including assessment of therapeutic claims.
Currently, the TGA is continuing to work on this approach with the sector with a view to introducing this framework over 2006. The TGA will work with jurisdictions and other stakeholders to ensure a smooth transition for facilities which are currently not subject to regulation.
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