Welcome to the fourth of my memo’s on Technology Transfer – Planning & Readiness.
This month I am continuing my look at the workflow of a typical technology transfer project. As I said last month, depending on the exact circumstances these steps can be different or be performed in a different order. Usually, these steps are not performed in isolation and often in parallel.
This month I am looking at the “planning” and “readiness” phase of the transfer process which follows on from last month’s blog on project initiation.
At this stage in the technology transfer the process flow usually divides into two streams, the analytical method technology transfer and the process technology transfer. This month I will concentrate on the process technology transfer but will delve into the analytical methos transfer in a later post.
Detailed Project plan
A transfer plan is created by the Project Manager with the help of Subject Matter Experts (SMEs). The plan should cover all proposed activities, deliverables and their respective timelines. Although the first thing most people think of in this respect is the familiar Gantt chart, but this only forms part of the project plan.
It should also include the different functional strategies, roles and responsibilities as well as the resources required for each step so that resource planning is also addressed.
If the projects objectives and scope have not been finalised previously, then the project plan should also include these, beware of “scope creep” where the scope gradually expands, with no corresponding cost or resource increase.
The Plan is approved and executed by all the functional teams, and a kick-off meeting is held to ensure the team is aligned with the scope, strategy, and overall timeline.
Integrated Technology Transfer Strategy (ITTS)
The purpose of the technology transfer strategy is to clarify the technology transfer in sufficient detail for all the involved functions at the sending unit and the receiving unit to understand the timing, their role and the resource needed. You should consider including such items as Knowledge Transfer, Analytical Technology transfer, Packing Technology transfer, Design Transfer, Cleaning Validation, and draft plans for Process Validation. The ITTS is based on current product knowledge, identified key risks to the project and patient and mitigations to these risks.
The ITTS should be agreed by both the sending unit and the receiving unit.
The ITTS also provides documented evidence of the technology transfer process, for use in support of any regulatory inspections prior to product approval.
Define receiving unit (RU) process
A draft receiving unit either in text or flow chart form will usually have been created during the process initiation phase of the project and this should now be finalised, bearing in mind that the process description is a “dynamic” document, and should be upgraded during project execution.
It is usual to create and agree a sample plan at this point as well which can be included in the process description or created as a separate document.
Process Failure Mode Effect Analysis (pFMEA)
Having defines the RU process, the next step should really be a risk assessment of the process. FMEA is a widely used tool for identifying and evaluating the potential failures of a process. It evaluates each process step and assigns a risk score. This helps to establish the impact of any potential failure and to identify and prioritize the action items with the aim of mitigating any risks.
A crucial element is that the FMEA should be created using as many discipline functions as possible and not be completed by one person.
It is a living document that should be initiated prior to process of production and maintained through the lifecycle of the product.
Bill of Material (BOM)
This is not just a list of the materials that will be used in the process, (raw materials, ingredients, sub-assemblies etc.) but also their cost, vendors etc. This is used to help cost the process, compile parts lists for Extractables and Leachables data, it can also help in identifying critical of long lead time items.
Comparability protocol
This a written plan for demonstrating that a product manufactured as part of the technology transfer will be substantially the same as the product produced by the sending unit in terms of strength, quality, purity, and potency.
It is important to realise that it is highly unlikely that the transferred product will be EXACTLY the same or meet EXACTLY the original products variability (and the regulators do not expect that) but there should be a reasonable correlation between the various parameters and test results between the two sites.
Validation Master Plan (VMP)
A good summary of the requirements of the VMP can be found in the PIC/s 006-3 document. The VMP should present an overview of the entire validation operation, its organisational structure, its content and planning. The core of the VMP being the list / inventory of the items to be validated and the planning schedule.
The VMP should be a summary document and should be brief, concise and clear. It should refer to existing documents such as Policy Documents, SOP’s and Validation Protocols/Reports. The VMP should be agreed by management.
Quite often the Validation Master plan will refer to more detailed (Sub) Master Plans for Process Validation, Cleaning Validation, Analytical Method validation etc.
Define SUS and cleaning validation plan
At this stage a detailed cleaning plan is not necessary, but which parts of the process will use stainless steel / reusable equipment and will thus need cleaning validation and which parts will use “single-use-system” and thus not require cleaning validation should be defined.
Although defined as “single-use” there is no regulatory requirement preventing their re-use, and I know of occasions (such as during great component shortage during pandemic vaccine manufacture) where this was contemplated.
Material specifications / mass balance
Whilst most if not all materials used in the manufacturing process will be known by now (and listed in the Bill of Material- see earlier) it is important that the exact specifications of the materials used are defined and agreed. It is also important to ensure that a Mass Balance is performed to account for all material used in the process, and as a check on the amount of material (both waste and product) produced. This can be simple (as per a dilution stage) or more complicated (as in a biotechnology bioreactor). This is probably more important for reaction-based processes as this can help to confirm process understanding.
Demonstration / pilot batches
These are also sometimes called engineering runs.
These are manufacturing runs performed (often under non-GMP conditions) to confirm the feasibility of the process, capability of the equipment used, effectiveness of process parameters and controls. These runs can also be used to confirm the sampling and analytical methods used as well as being an operator training opportunity and confirmation of procedures and SOPs being used.
Product from these batches may also be used to demonstrate that the product manufactured at the Receiving Unit is comparable with that manufactured from the Sending Unit – in which case the runs may be termed “comparability runs”.
Process VMP / Cleaning VMP
Sometimes just called Process Validation Plans & Cleaning Validation Plans or validation sub-plans.
These are basically sub-sets of the Validation Master Plan referred to above, providing a more detailed overview of a specific validation process. Process validation, cleaning validation, analytic method validation, transport validation etc. can all have their own specific validation master plans relevant to that validation process. The content of the Process validation Plan etc. can be similar to the top-level Validation Master Plan but dealt only with the details and strategy of its own validation process.
Finalise Control Strategy
Following the execution of engineering / demonstration batches, the Critical Process Parameters (CPP) and their values will have been confirmed and these should be detailed in the products Control Strategy document and approved by both the sending unit and receiving unit.
Create / Train protocols & SOPs
Normally I would have expected SOP’s to have been written to cover all the tasks that are required for the transferred process prior to the Demonstration / Pilot / Engineering batch(es) and to have been used to both trial the draft SOP’s and train staff at that time. If not, SOP’s must now be finalised and approved, and staff trained on them.
Readiness review
Prior to starting the PPQ batches, a readiness review should be performed in order to demonstrate that all functions have completed their tasks, all documents and protocols are available and approved, all supporting validation & supporting studies have been completed and approved and all preventative maintenance plans are in place. This includes all third party (e.g. outsourced analytical laboratories) as well.
At this point no new conditions or changes should be made without a “re-review”.
It is often helpful to create a checklist for the readiness review.
There is no regulatory requirement for such a review, however it is recommended in the PDA publication “Technical Notes #65 (2022), Technology Transfer”.