This also applies to non-US sites from which goods will be imported into the US. GTP applies to such issues as the establishment of donor eligibility and the features of subsequent processing of cells and tissues that may influence the transmission of communicable disease. In the EU the accreditation takes the form of a Manufacturing Authorisation and a Marketing Authorisation the latter is often referred to as a Product License.
Such certificates apply just to the site and are issued in the context of the product types that are made there. The certificates, or a record of non-compliance if appropriate, are entered into a central database for transparency [EMA]. QA management has a central role in assuring continued compliance to the prescribed standards. The mechanisms for doing this can be summarised under these headings:. Regular review of controls and history of the performance of the accredited areas through maintenance of an internal inspection process.
Coordination of regular Management Review of trends in site compliance, manufacturing controls and emerging changes in standards. Although the intentions for QA and cGMP are broadly the same across the ICH region there are differences in the way that the applicable regulations, standards and guidance has been written and this extends to differences in control of goods entering the market.
Table 2 shows a comparison of the main features of control for the US and EU regions. For a site embarking for the first time upon the development and launch of a CBT it may be pragmatic to develop the QMS in alignment with the phases of clinical development. For an established site with a steady flow of products through the development pipeline a decision must be made about what levels of control to invoke at what stages of development. Some businesses develop in-house levels of QMS that increase in stringency as development stage-gates are passed.
This requires careful design and good operator discipline, sometimes segregating operators at different stages of QMS by department, in order to avoid inadequate control at later stages of development. This is a voluntary scheme but will provide a high level of confidence in control of each aspect of tissue procurement, processing and storage.
In the EU requirements vary. For example the UK requires that compliance with the Human Tissue Act be observed for research and development using primary cell isolates. The QMS may be paper-based or electronic but, whichever format is used, the primary records must be managed so as to protect them from post hoc tampering. If electronic records are used a key feature must be compliance with the electronic signatures regulations [CFR 11] in order to show unique traceability to identifiable, responsible individuals.
The security provided by 21 CFR 11 was seen by some researchers as being a potential impediment to the application of new technology in process development. The revised guidance [CFR 11] made it clear that legacy systems i. The guidance also reinforced the requirement that careful documentation be made of the decision to implement either paper or electronic records as the primary quality record for the purposes of the data trail. For this reason it is prudent to apply Quality Agreements to upstream suppliers of those raw materials and consumables that are critical to quality. Without such agreements the possibility exists that the supplier may make changes to the quality of supplies which may move production controls outside the Design Space described below , particularly if the supplier is unable to appreciate the reason why such a change may be significant to the customer.
Cell Therapy Manufacturing - The Bioprocessing Summit
The Standard sets out minimal requirements and may be enhanced for specific centres. It covers all activities from collection to administration, whether minimally or more-than-minimally manipulated cells are used. JACIE conducts inspections and issues certificates of compliance to recognise good practice. Compliance with the Standard is voluntary and enables an operation to demonstrate that it has an excellent and appropriate QMS. The Standard is aligned with both US and EU requirements subject to the usual caveats concerning current practice.
A general principle to be observed is that staff members who are directly responsible for production duties should have a reporting line to senior management separate from that for the Quality Unit i. This is to avoid conflicts of interest in the day-to-day management of production especially with respect to decisions regarding batch release. An organisation operating to cGMP will carry out a schedule of self-inspections as a part of the quality management activity.
In addition the organisation will be subject to inspection from regional authorities. There are three types of such inspections:. In practice a pragmatic approach has been operated since in which a risk assessment is used to assign priority for inspection to manufacturing establishments. If the deficiencies are not addressed the FDA may respond without further warning, imposing criminal penalties.
- One of Thirteen (Crimson Lore Book 5).
- The Princess Who Saw Everything (with panel zoom)/n/t/t/t - Classics Illustrated Junior;
- Cell Therapy Manufacturing.
- The Big Red Fire Truck;
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The Pharmaceutical Inspection Co-operation Scheme was formed in in response to the arrival of new Accession States, allowing for the lack of alignment between European Law and the Convention. The Pharmaceutical Inspection Co-operation Scheme is an informal arrangement between national health authorities.
The response must be robust, appropriate and timely and is one of the most important elements in an effective QMS. Instances of formal application of the CAPA process should be reviewed at regular Management Review meetings and assessed for the appearance of trends that may justify continual improvement measures. See also section 10 concerning recall.
Sufficient capacity should be allowed and in the case of CBTs it is prudent to provide back-up capacity in case of equipment failure for materials that require low temperature storage. Depending on the value and status of the inventory it is good practice to establish an alarm system with warning levels within the range of critical temperatures.
A call-out rota of qualified members of staff is an essential part of this provision. CBT manufacture generally requires a perishable raw materials inventory and low temperature finished goods store and so it is important to provide a back-up power supply, preferably with an uninterruptible power supply to bridge the momentary pause between power failure and start of back-up generator to ensure continuity of digital monitoring and control.
Storage areas should be subject to regular performance review and inspection, including assessment of potential ingress of weather or pests. The status of the goods in inventory should be clearly signed e.
In particular defective goods must be stored away from those that may qualify for use. Goods in quarantine, e. Records must be kept of the performance of environmental controls for the storage areas of sensitive stock, typically this comprises temperature and humidity controls. Repeated exposure of cells to ambient temperature, even without thawing, can affect cell health over time.
Commercializing Cell-Based Therapies
An organisation will do well to arrange liquid nitrogen storage vessels in such a way that straws of cells are withdrawn in the order that they are expected to be used. This avoids repeated withdrawal and replacement of unused cells. The QMS must be detailed and prescriptive enough to specify how the documents are maintained, how the current versions are issued, reviewed, updated and withdrawn and to define the levels of authority required to manage aspects of the system. The types of documents must be defined and these definitions must be adhered to in practice.
Instructional documents must carry the date from which they are effective and must be issued by identifiable persons with an adequate level of authority. Records see above must be completed at the time of the events to which they refer, must be clearly legible and must be traceable without ambiguity to the person making the record. Handwritten records must be completed in indelible ink. Any additions, corrections or alterations to handwritten records must be signed and dated and the reason for the change entered on the record where appropriate. Minimum retention periods for records vary according to type of record, context and type of product, and reference should be made to applicable legislation and best practice.
USCGF is in cancer immunotherapy clinical trials with Torque Therapeutics
Many organisations establish longer-term retention policies than those required by law. It is good practice to maintain such quality records in a protected environment and to establish a disaster-recovery system. The guidance requires protection of the integrity of the record and so access to any repository should be by authorised personnel only and a record should be kept of instances of access.
Inspection of the effectiveness of the Document Control system should be part of the internal audit and inspection process. The completeness and integrity of the system should be assessed through both top-down and bottom-up sampling to ensure that there are no omissions and that the review cycles are effective. In the US the decision on batch release is the responsibility of the Quality Unit. In either case the decision to release is based upon evidence that the product meets specification and that the Critical Quality Attributes CQAs of the product have been conserved.
Staffing, Training, and Competency Chapter Cleaning Procedures Chapter Environmental Monitoring Chapter Supply Management Chapter Facility Equipment Chapter Quality Chapter Product Manufacturing Chapter Product Review, Release, and Administration Chapter This in-depth book also includes detailed reviews of quality, the framework of regulations, and professional standards.
It meets a previously unmet need for a thorough facility-focused resource, Cell Therapy: cGMP Facilities and Manufacturing will be an important addition to the cell therapy professional's library. Standard operating procedures - Supply management - Facility equipment - Product manufacturing, review, release and administration - Facility master file. Subject Cellular therapy. Cell transplantation. Facility Regulation and Control. Manufacturing under cGMP should be very boring. As Dr.
Huls emphasizes, it is never too early to start to document processes and gear data collection towards compliance. She suggests to start with a strong quality management system QMS that captures written procedures to ensure there is manufacturing oversight, that proper reviews and approval processes are in place, and that the testing criteria for meaningful measures of sterility, identity, purity and potency are reviewed and understood by the general group.
An experienced quality professional knows what is important, what information needs to be captured, and the minimal standards required to transition from a research bench. Although hospitals and translational facilities have quality assurance programs they may not be familiar with the regulations for cellular therapy. If timing is not right to hire a quality manager, consultants can advise on the steps and how to appropriately gather the data.
Quality must be built into the design and manufacturing process at every step to avoid unnecessary problems.
It is true that quality systems are expensive, take time and resources, and are always a work in progress due to continual improvements, but, like insurance, they are invaluable when a problem occurs. From a practical perspective it is all about the documentation that backs up the label claim. Consistency is imperative; procedures that meet the guidelines must be followed exactly the same every time. Think of a QMS as the overall umbrella that covers quality, manufacturing, and marketing personnel to make sure they are all performing to the requirements that are in place for manufacturing and marketing drug products.
Not to be confused with an IT system, a QMS is the entire set of documents, systems, and facilities that are involved in helping make the product. A QMS needs the ability to evolve; the field is still learning about manufacturing cellular therapies. Starting out with too much complexity is not recommended. An initial strictly-defined manufacturing process may be hard to reproduce simply because a new facility has no manufacturing data thus zero learnings.
In addition, the number of batches needed for Phase I and II clinical trials of any one product is low, limiting learnings. Processes may not be ready to be locked down until the commercial level is reached, emphasizing the importance of a continual optimization mindset, and the need to begin as early as possible to document the procedures and changes. The guideline is entirely risk based and takes a very broad understanding of the complexities and the real changes that need to take place in the traditional small molecule regulation to ensure that cellular therapies can get off the ground.
A well-structured data and implementation plan will help to move the process forward smoothly. Expect new items to emerge that will need resolution. As previously stated, cGMP incorporates how to design, control, and monitor processes. Testing on a small sample of a batch after manufacture does not ensure quality. Processes must be under control and always produce a useable product. To change behavior is challenging and cGMP includes a lot of behavior management.