Memo 4 – Tech transfer Flow chart Pt2 – Planning & Readiness

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”.

Memo 3 – Flow chart part 1 initiation

Welcome to the third of my memo’s on Technology Transfer. This month I would like to start looking at the workflow of a typical technology transfer project, which assumes that the product will be outsourced to a CMO. 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.

In this memo I will cover the “initiation” phase of the transfer process which covers the initial setting up of the project, information gathering and gap analysis, and will follow up with the “planning” phase in my next memo.

Select RU / CMO

No two CMOs are the same – they all have different strengths and weaknesses, and no two sponsors will look for the same requirements.

While hiring a CMO might not strictly be a function of technology transfer, it will be a critical decision regarding the success or failure of the technology transfer process.

The starting point should always be to define your own requirements, and to decide which CMO capabilities will be the most important for you such as cost, speed or history of regulatory compliance. You can score your potential CMO’s against your requirement to help you create your shortlist and decide your best fit.

There are many checklists / topics available on the internet (and I’ll expand in future memos) but I would like to add a few “practical” items to the list. Communication is key they say – so finding a CMO with key staff that speak your language fluently – and that includes technical “speak” is crucial and selecting a CMO in your time zone can be classed as important – unless you don’t mind only being able to talk to them in the early hours of the morning!

A very important point to consider, especially if your chosen CMO will be performing analytical or process development for you – you MUST consider your intellectual property, who owns it and what is the CMO’s country’s approach to protecting IP assets.

And lastly – you want to select a CMO you feel comfortable with — not only one that can handle the work. And in this respect the cultural fit — or the ability to work together — may be the most important criterion of all.

Technology Transfer Charter

It is crucial to set clear expectations and responsibilities between partners in order to avoiding confusion and/or conflict later. The initial charter agreed upon by both parties must include the scope of the project, transfer timelines, as well as the team structure, specifying clearly defined roles and responsibilities. The charter should also establish clear paths of communication and a governance structure for addressing issues. Most importantly, success criteria must be clearly documented in the project charter. 

Form / Define Steering Team

There is usually a “Governance” structure sitting above the project team who role is to:

  • Oversee transfer activities
  • Ensure information is effectively shared
  • Identify the Project Managers
  • Assign a support team and senior management steering committee
  • Establish a clear RACI matrix

Tech Transfer and Regulatory Strategies

  • Quality and Technical agreements

Quality and technical agreements are legal documents that defines both specific quality and technical parameters for a project and which party is responsible for the execution of those parameters. The level of detail may vary depending on the developmental stage of the project.

  • Documents required

The donor (sponsor) / Sending Unit (SU) and receiving unit (RU) must gather and prepare several documents to ensure a successful technology transfer, such as:

  • Technology transfer plan: This describes all the activities to be transferred, responsibilities, and the expected outcome.
  • Detailed analytical methods: They are crucial to technology transfer success as the results of the analyses are used for validation & comparability assessments as well as for the release of products from the transferred process.
  • Manufacturing process description: Describes the manufacturing process in detail and will be used as a reference source for all parties.
  • Critical process parameters (CPPs): They are generally identified by assessing the extent to which their variation could impact the quality of the drug product.
  • Critical quality attributes (CQAs): A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
  • Technical gap analysis: This is a formal documentation of the assessment of known and potential gaps between the donor and receiving sites’ capabilities and of their readiness for the transfer. The document should include a risk assessment.
  • Adequate change control management system: Any changes made to the process or equipment should be documented, assessed, and justified with regards to their potential impact on the CQAs and the Quality Target Product Profile (QTPP).

Tech Transfer Scope and Critical Success Factors

Critical success is the demonstration with data conformance of the success factors as outlined in the technology transfer agreements and plan and typically cover process parameters and control mechanisms, material supplies, analytical methods, health, safety and environmental concerns and compliance with regulatory requirements.

Technology transfer can be considered successful if there is documented evidence that the RU can routinely reproduce the transferred product, process, or method against a predefined set of specifications as agreed with the SU [WHO Technical Report Series, No. 961, 2011 Annex 7, WHO guidelines on transfer of technology in pharmaceutical manufacturing].

Appointment of Project Manager

There is often a separate project manager at each of the RU and SU sites. The Project managers have a key role in the technology transfer process, he is often the main point of reference and is responsible for effective and efficient management of the project team and technical support and for co-ordinating, leading, tracking all the project activities to ensure successful technology Transfer.

Form Project Team

Technology transfers are usually performed by dedicated cross-departmental / cross-functional and integrated teams including from both sending and from receiving sites.

Ideally, all functions from both sites are involved to a certain extent with respective partners in the other organization. In this way, subject matter experts can directly communicate with their peers.

As always with such potentially diverse teams the roles and responsibilities should be clearly defined. This is sometimes set out in the form of a RACI matrix or chart.

Information Collection

The client should provide as detailed and complete knowledge transfer package as possible with product information such as:

  • raw materials
  • analytical methods
  • validation reports
  • manufacturing procedures
  • process parameters
  • equipment requirements
  • regulatory requirements, etc.

Contract manufacturers refer to these documents as a technology transfer package. The information supplied is assessed by the CMO to help them determine the requirements for any additional equipment and supporting studies as well as to help develop the project plan.

Process Flow Diagram / draft Process Description

Pharmaceutical process flow charts are diagrams of pharmaceutical processes, usually in the form of a series of individual blocks each block linked together to describe a specific process such as a manufacturing process. Each block can depict a specific operation or item of equipment and may include additional information such as flowrates or other operating conditions.

Alternatively, the process can be described in mainly text format.

Gap Analysis and Risk Assessment (GARA)

A gap analysis is usually performed to compare the manufacturing process at the SU and the RU to determine differences in items such as equipment, facility, and methodology.

Once any gaps or differences have been identified these are risk assessed against the impact on product quality using traditional risk assessment tools such as FMEA and mitigation actions determined against medium / high risk items. The gap analysis and risk assessment should be jointly performed by the RU and SU. The outcome of the analysis and assessment are often combined into a single document.

Technology Transfer – memo 2 Rules, Regs and Guidance

Blog 2 – September 2022

Technology Transfer – Regulations & Guidelines

There are few if any “rules and regulations” issued by regulatory agencies such as the FDA or EMA. There are probably several reasons for this, but high on the list must be:

  • Technology Transfer is so varied that no set of rules or regulations could hope to cover all the combinations of processes, analytics and facilities.
  • In the main Regulatory agencies tend to state what activities – such as equipment cleaning – need to be regulated and what standards these activities need to achieve, but they want to don’t regulate HOW these standards should be achieved.
  • In order to achieve regulatory harmonisation, the agencies are instead increasingly adopting the regulatory guidelines introduced by the ICH (International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use).

EMA

ICH guideline Q12 on technical and regulatory considerations for pharmaceutical product lifecycle  management – Annexes

https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-guideline-q12-technical-regulatory-considerations-pharmaceutical-product-lifecycle_en-0.pdf

Released for consultation. Discusses changes (with examples) to parameter classification (e.g. CPP, KPP) with enhanced process knowledge. I will cover this further when I cover CQA, CPP parameters.

ICH guideline Q10 on pharmaceutical quality system

This document describes a model and components of an effective quality management system for the pharmaceutical industry. It includes technology transfer activities as are part of knowledge management. It confirms that tech transfer is part of process performance, product quality monitoring system and change control system throughout the product lifecycle.

This describes tech transfer in terms of product and quality management, but this could be misleading as it places tech transfer between development and commercial and as we know transfer of commercial scale activities involves a great amount of tech transfer activity.  It is concerned with quality and knowledge transfer not the practice of tech transfer.

https://www.ema.europa.eu/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human_en.pdf

World Health Organization (WHO) Technical Report Series, No. 961, 2011 Annex 7 WHO guidelines on transfer of technology in pharmaceutical manufacturing

States that transfer of technology requires a documented, planned approach using trained and knowledgeable personnel working within a quality system, with documentation of data covering all aspects of development, production, and quality control.

It provides “guiding principles on transfer of technology [which] are intended to serve as a framework which can be applied in a flexible manner rather than as strict rigid guidance and concentrates on the organisational and documentation “recommendations” which would be required.

From my point of view – a good starting point and checklist but doesn’t really help with timeline of process flow.

This guideline is current being updated and is available as a draft document on the internet:

https://cdn.who.int/media/docs/default-source/essential-medicines/norms-and-standards/qas20-869-transfer-of-technology.pdf?sfvrsn=2a4723bc_5

 ISPE Technology Transfer Guide (third edition published December 2018)

The ISPE Technology Transfer Guide describes itself as being designed to provide a standardised process and recommends a minimum base of documentation in support of the transfer request, and to describe the appropriate information that needs to be compiled to support the transfer of the information and provide regulatory filing documents. It this it does what it says – concentrating on the documentation required but perhaps not showing how this interacts with the workflow of tech transfer.

It does however devote a significant amount of space to analytical technology transfer which is missing from most other guidance documents. In addition to this it covers API’s and a variety of different dosage forms but admits it doesn’t cover biologics which these days could be seen as a major omission.

PDA Technical Report 65 Technology Transfer (PDA, 2014)

Provides an overview of the technology transfer process. It “walks through” technology transfer process and while not providing a “roadmap” it does step through the main steps and describes the activities and responsibilities of each of the different functions clearly showing how each function interacts with each other as the technology process progresses. Indeed its stated purpose is to provide a “reference Guide to the Technology Transfer Activities and Deliverables” which it does well.

https://www.pda.org/bookstore/product-detail/6680-tr-65-revised-technology-transfer

EMA

Guidance for individual laboratories for transfer of quality control methods validated in collaborative trials with a view to implementing 3Rs (Replacement, Reduction and Refinement).

https://www.ema.europa.eu/en/documents/scientific-guideline/guidance-individual-laboratories-transfer-quality-control-methods-validated-collaborative-trials_en.pdf

You may also consider:

1. Eudralex Volume 4 Chapter 7 Outsourced Activities (EudraLex Volume 4 Chapter 7, 2009)

2. Food and Drug Administration. 2011. “Guidance for Industry Process Validation: General Principles and Practices.”

3. EMA/CHMP/CVMP/QWP/BWP/70278/2012. 2014. “Guideline on Process Validation for Finished Products—Information and Data to Be Provided in Regulatory Submissions.”

4. ICH Q8R2

5. ICH Q9

6. ISPE PQLI guidelines

Technology Transfer – Memo 1 what is Technology Transfer

Technology Transfer is essentially the name given to those activities concerned with the moving of a manufacturing process from one place to another within a company such as R&D to pilot plant or one manufacturing line to another, or from one company to another and it can happen for many reasons. Quite often Technology Transfer is associated with process improvements or scale-up or modernisation of the analytical methods as well as with the physical movement of the process itself.

In times past, Technology Transfer was performed by means of handing over a process and Analytical Technology Package (P&A-TP) or similar, usually consisting of a process description, equipment list, Bill of Materials (BOM), and analytical package and then implementing the process described as best able to do so. The end product was then sampled and tested and if the release specifications were met the technology transfer process was considered to be complete (I know that this may be a bit of a simplification, but it describes the general methodology which, although sometime formalised, was often as not more of an informal process in other than the largest companies).

All this changed with the advent of a formalised structure for Process Validation (FDA Process Validation: General Principles and Practices 2011). From this point onwards the role of technology transfer also included the requirement to ensure that the Process Validation requirements were also fully complied with, and formalised and documented. Formalised Technology Transfer became more almost mandatory as a result. In some respects, technology transfer has become a specific element of design and development for pharmaceutical drugs; it’s governed by ICH Q10.

There is still no single definition of technology transfer, with many varieties existing as exampled below:

  • WHO: a logical procedure that controls the transfer of any process together with its documentation and professional expertise between development and manufacture or between manufacture sites. [WHO Technical Report Series, No. 961, 2011 Annex 7].
  • FDA: Technology Transfer is the process of transferring skills, knowledge, technologies, and manufacturing methods.
  • ISPE (Novartis Pharmaceuticals Corp. September 10, 2009Presentation): Transfer all the knowledge needed to perform a given (biotech) process from a Transferring Site to a Receiving Site.

However, it is the definition given in ICH Q10 that ties the technology transfer process into the process validation process:

The goal of Technology Transfer activities are to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realisation. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach and ongoing continual improvement. [ICH guideline Q10 on pharmaceutical quality system].

This definition means that a more formal technology transfer process is needed in order to ensure that all process validation requirements are met, and perhaps a better general definition could be used:

It should be remembered that Technology Transfer also involves the development and successful transfer of the analytical and microbiological test methods and specifications.

Changes in process scale or materials used can result in process variability, and critical process parameters may need to be optimized, or in worst cases the entire process may need to be redeveloped before a successful Technology Transfer can be performed.

It is sometimes said that the aim of technology transferred is to get to market quickly with the development of a drug and product of the appropriate quality and to do it “right first time, every time”.  My view is that the primary aim of technology transfer should be to ensure that the transferred process can consistently manufacture product commensurate with its efficacy, safety and quality requirements. While speed is good, it should never be at the expense of product quality.