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.

Considerations for the technology transfer of gene and cell therapy products. Part 2

This is the second of a series of articles I am writing looking at the technology transfer and industrialisation / commercialisation of gene and cell therapy products. In this part I will give an overview of some of the pitfalls that befall companies looking to perform the technology transfer of gene and cell therapy products. In future parts I will look at the role of analytical techniques, automation and closed systems.

In the meanwhile, if more information or help is needed, please do not hesitate to contact us.

Download PDF

Pitfalls are and how to avoid them in your manufacturing process


Timing

Biopharmaceutical manufacturing is known for its complexity, but gene and cell therapy manufacturing is an order more complicated. If you address manufacturing requirements too late you may then find that you need to change the process to make it economically or even technically viable and you face a huge risk with regard to comparability of products made by the original and new processes. Changing the process at this stage will incur significant time and cost penalties.

Issues:

  • Not thinking about what may be needed in the future
  • Not thinking of the end game at the beginning
  • Not starting “technology transfer early enough
  • Not performing a though risk analysis early enough

 Risk Analysis / Manufacturing Assessment

 It’s important to perform a strategic manufacturing assessment by reviewing the business goals for your product and identifying areas that can be invested in immediately, and areas where investment can be delayed.

For example, perhaps risks can be managed by ensuring that manual processes are changed at an early point to those that can easily be automated at a later date, or raw material risks can be reduced by ensuring that GMP grade materials are used whenever possible to start with minimising the risk of having to repeat development and comparability studies at a later date.

Raw Materials

  • Not using GMP grade materials (e.g. contains no material of animal origin). In this instance, raw materials can also include lenticular viruses
  • Not considering If the raw materials selected can be supplied in the quantities supplied for commercial manufacture
  • Not considering if the selected raw materials can be supplied for the next 20 years
  • Not considering the grade / purity of the raw materials – are you absolutely sure that the effect you are seeing is not due to impurities in the raw materials?

Analytics

The analytical processes used in the development of gene and cell therapy products are vitally important. A major challenge is developing suitable analytical assays to define and monitor the consistency of a therapy’s functional attributes for product release after manufacture. Appropriate analytics are especially needed for autologous therapies to assess potency and to be used for comparability across batches for a single patient, or across multiple patients. It is essential that these analytical techniques be non-destructive, or at least do not use up too much of the product.

Some of the pitfalls regarding analytical procedures can be associated with:

  • Not ensuring that the required analysis methods are available at the right time and available at the CMO. Some CMO’s outsource / sub-contract their analytics out.
  • Not keeping in mind that the analytics are a GMP process in their own right – and being so if new methodologies have to be developed – who has the IP on the analytical method?

 Many analytical strategies depend on the use of assays that are destructive and it can also be a hindrance if material is limited (though less of a problem if patient bio-samples can be banked for later use).

Sampling

Some of the issues around product sampling are:

  • Developing an appropriate sample plan so that as the product develops, you don’t end up using all the product for stability testing and analytical tests – leaving none for clinical trials.
  • Take the right samples at the right point in the process, and test the right parameters
  • If possible, think of taking samples prior to concentration phases.
  • Don’t leave potency and comparability to ph3 – it’s very tempting to save circa £200,000 during phase 1 rather than leave to phase 3

Documents

  • Make sure your documents are up to date and relevant to the products development history and manufacturing process, many products do not even have a cell history.

Manufacturing

  • Not manufacturing according to QbD principles – do you know what your products design space is? If not, can you really claim to understand your products manufacturing process, and are you happy to pay the cost and time for a CMO to do that for you?

Planning For Industrialisation

There are currently no “one-automated-platform-suits-all” approaches for commercial-scale development, and manufacturers are instead dependent on manual, skilled specialists working in accredited cleanroom facilities – which inevitably makes manufacture prone to human error and processing variability.

There are however automated solutions for some of the unit operations.

Whether the manufacturing process is to be scaled-up or scaled -out the successful commercialisation of a product will depend to a large degree on how well it can be automated. A major late stage problem many companies now face is that they are now looking to automate a labour-intensive process which cannot be automated and they now find that they have to re-develop the process (and suffer the time and cost implications). By thinking ahead and planning for industrialisation, companies may be able to save themselves time (typically TWO years) and money (£/$ millions).

Need Help or additional resources?

Bluehatch Consultancy works in both the Biopharmaceutical and Gene / Cell Therapy sectors (R&D, Development, CMO and commercial environments) enabling us to bring you the best and up to date solutions from both worlds. We are always happy to provide initial free consultations.

 

EMA Q&A on Health Based Exposure Levels

Download PDFWC500219500

On Dec 15th. 2016 the EMA published a draft set of Q&A on the setting and use of Health Based Exposure Levels (HBEL). However in this document they stated that “it is not intended to be used to set cleaning limits at the level of the calculated HBEL (using the guideline methodology). The cleaning limits should continue to be based via risk assessment and additional safety margins to help account for uncertainty in the cleaning processes and analytical variability. Traditional cleaning limits used by industry such as 1/1000th of minimum therapeutic dose or 10 ppm of one product in another product, may accomplish this for non-highly hazardous products”.

Please use the “download” link above to see a full copy of the document.

Cleaning validation – MOC sample coupons unavailable?

 Download as PDF:MOC coupons unavailable for Cleaning Validation

What to do if you can’t use or obtain samples of materials used in your manufacturing process for cleaning validation recovery studies.

 

Regulatory Expectations

It is a regulatory expectation (e.g. FDA, EU, Health Canada)[1],[2],[3] that the ability to recover chemical residues after cleaning and the efficacy of disinfectants used, be demonstrated for all materials used within the manufacturing process. These regulatory expectations are that studies are performed from every product-contact Material of Construction, regardless of how prevalent it is in the manufacturing process.

The FDA Guide to Inspection of Validation of Cleaning Processes [4] states that firms need to “show that contaminants can be recovered from the equipment surface and at what level…”.

The EU Guidelines for GMP Annex 15 [5] states that “recovery should be shown to be possible from all materials used in the equipment with all sampling methods used”.

The Health Canada [6] and the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) [7] cleaning validation guidance’s also require that residue recovery experiments be completed.

Performing the effectiveness of the disinfectants and chemical residue recovery on the actual equipment or within the actual cleanrooms themselves can take 6 – 12 weeks to perform and may require the closing down of the equipments or cleanrooms themselves for this length of time.

Instead, coupons (samples) of representative material of each or the equipments or cleanroom surfaces s are used and can be tested in the laboratory instead.

 

Consequences

Failure to consider all surfaces will, and have led to warning letters and FDA 483 notices being issued:

“All surfaces that are used in critical processing and manufacturing areas were not evaluated.” (FDA Warning Letter January 29, 2013)

It is also important to consider that the Materials of Construction (MOC) used in the testing not only fairly represent the manufacturing surfaces themselves, but that they represent the condition of the surfaces as well. It is not always possible to repair or replace damaged or worn surfaces but if such surfaces are to be kept in use for an extended period of time (e.g. until the next scheduled maintenance event), then damaged surfaces must also be represented in coupon studies.

 

 “The stainless-steel coupons tested did not represent these damaged surfaces.” (FDA Warning Letter May 25, 2011)”.

:”The coupons used ….. were not representative of the surfaces found in the ……. Areas” FDA Warning Letter January 29, 2013)

 

Cleanability

Measuring the effect of the “cleanability” of a residue from a surface depends on three main parameters – residue solubility, sampling method used to sample the surface and the material of construction. These three parameters are interrelated

  • Each residue has an inherent cleanability, which may be related to its solubility [8].
  • The swab material must be able to absorb sufficient residue and solvent to remove the residue from the equipment material surface. The swabbing technique should be standardized to minimize subjectivity.
  • Finally, the material of construction of the manufacturing equipment needs to be considered. The swab recovery of residue from each material of construction should normally be determined to accurately quantify residue levels and assess material cleanliness.

And so, if the same residue is used and sampled in the same way, then the residue sample recovery will depend on the material of construction.

 

Risk Based

However, sometimes it’s just not possible to obtain coupons of some or all the materials used in process (I had a case recently where surfaces used to construct an old cleanroom where no longer available from the supplier and obtaining coupons would have meant cutting up parts of the existing cleanroom) – so what should you do?

The use of a risk based method may be the answer.

The International Conference on Harmonization’s (ICH) guideline on risk management [9] clearly states that any risk methodologies should be based on scientific knowledge.

Two studies in the past have examined the effects of using groups of representative materials to test for cleaning validation recovery factors.

RJ Forsyth et al [10] have proposed a risk based approach where they state;

The material of construction is a factor in the recovery of residue in cleaning validation. An analysis of existing recovery data showed that recovery factors for drug products on various materials of construction may be categorized into several groupings”.

This shows that materials can be “grouped” together by Identifying the physical characteristics of the materials and parameters that influence recovery-data results. This will allow the cleanability of a process to be assessed by selecting a representative material from each group.

In that article, data was collected on swab recovery studies from 16 Merck manufacturing sites, involving 1262 recovery factor values for 48 different substances (including actives and detergents). This involved 29 different MOC’s. Based on statistical analysis the materials of construction were classified into groups with similar recovery factors.

Le Blank [11] tabulated these groups as;

 

Group MOC’s in Group
A Nylacast Oilon Plastic, Perspex, Cast Iron (polished)
B Glass, PTFE, Stainless Steel, Delrin, Silicone, HDPE, Brass, EPDM, Bronze, Nylon, Carbon Steel (plus 6 other various MOC’s)
C Plexiglass, Latex Rubber, Butyrate, PTFE / Latex Rubber
D ABS Plastic, Aluminium
E Neoprene, Butadiene-Acrylonitrile, Methacrylate

 

The grouping shows that for a given residue, essentially the same swab recovery would be obtained for any MOC in that group.

Forsyth et al proposed this analysis to simplify recovery studies on a scientific basis by using a given MOC in a group to represent the recovery value for any material in that group.

This being the case then a sample representative of the material in each group could be used if samples coupons of the actual material was not available.

A similar study by Pack Hofer [12] using s smaller number of samples but using two different actives (one with a low solubility and one with a high solubility), at several different spiked levels, and to see if there were any trends among MOCs produced a similar grouping:

 

Group MOC’s in Group
1 Stainless Steel 316L, Stainless Steel 304, Anodized Aluminium, Nickel, Polyamides,

Teflon (PTFE), Acetal, Polycarbonates, Ertalyte

2 Cast Iron, Stainless Steel 420, Stainless Steel 630, Bronze
3 Type III Hard Anodized Aluminium

 

Conclusion

While it could be justifiable to simply use a representative material of construction coupon from each of the groups above if coupons from the actual materials of construction were unavailable, the justification for this approach would be strengthened if materials from some of these groups could be tested using specific facility or company residues and using the specific facility or company sampling techniques and be shown to be consistent with the groupings shown above, combining  published results with actual results from that facility/company.

There are commercial companies that can supply suitable MOC coupons in most materials.

 

References

 FDA,Guide to Inspection of Validation of Cleaning Processes (Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs, Washington, D.C. July 1993).

  1. EC,EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification and Validation (2014).
  2. Health Canada,Cleaning Validation Guidelines (Guide-0028) (2008).
  3. FDA, Guide to Inspection of Validation of Cleaning Processes (FDA, Rockville, MD) , July 1993).
  4. EC, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification and Validation (2014).
  5. Health Canada, Cleaning Validation Guidelines(Guide-0028) (2008).
  6. PIC/S, Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation and Cleaning Validation, 2004.
  7. Sharnez et al., “In Situ Monitoring of Soil Dissolution Dynamics: A Rapid and Simple Method for Determining Worst-case Soils for Cleaning Validation,” PDA J. Pharm. Sci. and Technol., 58 (4), 203–214 (2004).
  8. ICH, Q9 Quality Risk Management,Step 5 version (2005).
  9. RJ Forsyth et al, “Materials of Construction Based on Recovery Data for Cleaning Validation”, in Pharmaceutical Technology 31:10, pp. 102-116, October 2007.
  10. Le Blanc, Cleaning Memo – “Grouping for Surfaces for Swab Recovery Studies?” December 2012
  11. BW Pack and JD Hofer, “A Risk-Management Approach to Cleaning-Assay Validation”, in Pharmaceutical Technology 34:6, pp. 48-55, June 2010.

 

Considerations for the technology transfer of Cell Therapy products. Part 1

Considerations for the technology transfer of Cell Therapy products. Part 1

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This is the first of a series of articles I am writing looking at the technology transfer and industrialisation of gene and cell therapy products. In this part I will give an overview of some of the considerations for the technology transfer of each of the main technology platforms. In future parts I hope to be able to delve into each of these in more detail.

Although there are many similarities, cell therapy products differ from mainstream biopharmaceutical products in that the living cells are the product, not just an intermediary.

There are two main types of cell therapy products: –

Autologous cell therapies are based on cells that are harvested from the patient, cells with the desired properties are isolated and then expanded. The cells are then reintroduced back into the original patient.

 

Allogeneic cell therapies have cells derived from universal donor cells, which are harvested, isolated, expansion and banking for multiple doses. A single product has the potential to many different patients.

 

The autologous cell therapies are patient-specific, and as such there is no requirement to increase the scale of the process (scale-up), instead increased production depends on the ability of the organisation to create multiple copies of the same scale process (scale-out). The challenges in the technology transfer of this type of operation lie in the provision of small units capable of quick “product” change around and the provision of high throughput quality control / analytical systems. A considerable degree of flexibility would need to be built into any manufacturing facility for large scale autologous therapy cell production, such a facility will have to be able to cope with great variations in demand.

 

An upside of this of type of production methodology of course is that “scaling-up scale-out” should be in essence just a repeat of the process already developed and not requiring radical re-design.

Prevention of cross contamination will be a major issue but in the whole, should be minimised by the proper use of cGMP procedures. Cost savings due to increases in scale are not possible, however, as the manufacturing process for each “product” can be very similar this type of manufacturing can benefit greatly from the introduction of automated and semi-automated equipment to reduce costs and increase throughput.

 

One of the main challenges for this type of cell therapy is in dealing with what is intrinsically a variable quality of raw material – the cells from the patient.

Usually this type of therapy is developed in a clinical environment where the patient and the manufacturing unit are in close proximity, they may even be co-located. Technology transfer will in most cases involve the physical relocation of the manufacturing unit, meaning that factors that have never been considered before now have to be taken into account (e.g. effects of transportation time delays, storage conditions – even the need to introduce cryopreservation techniques).  These can introduce significant changes to the processing method and may even require the process to be substantially re-developed meaning studies such as stability need repeating.

 

Cells for allogeneic cell therapies could be given to many (hundred or even thousands) of recipients and thus this type of cell therapy lend itself to being scaled-up from laboratory bench up to perhaps 2000 litre batch size – or even continuous manufacturing techniques. One of the main challenges in the technology transfer of this process is that cell cultures of this kind are very sensitive to their environment and process scale changes (e.g. from cell culture flask to bioreactor) may be difficult, if not in some cases, impossible. Significant process development will usually be required to both run the process at these scales in the first instance, and to develop the understanding of the key process parameters to control the developed process.

Facilities for scaled up manufacturing often use many of the same techniques and equipment as are found in classical biotechnology products, particularly making use of closed and single used systems such as single use bioreactors. Closed systems are almost essential at the larger scale as downflow booths etc cannot be used and working within cleanrooms with a Class B background incurs significant capital and running costs. Closed systems can safely be used in a Class C environment, and there is an argument for allowing them to be run in Class D environments.

The larger scale operations also provide many opportunities for process optimisation and cost reduction through the development of modular process steps and automation in both production and analytical operations.

As well as a deep scientific knowledge of the product being manufactured, successful technology transfer will also require the use of existing technology transfer methodologies and project management techniques coupled with the application of process optimisation and commercial manufacturing expertise combined with knowledge of facility design, quality, and regulatory systems. For help, talk to us at contact@bluehatchconsultancy.com .

 

Trefor Jones

Bluehatch Consultancy Ltd.

www.bluehatchconsultancy.com

7th August 2017

European Spray Dryer Technologies

Bluehatch Consultancy Ltd. is happy to announce that is is now supporting European Spray Dryer Technologies in preparing the validation documentation to be supplies with one of their new spray dryers. Congratulation to ESDT on their latest sale.

Seven Questions you should ask before starting technology transfer

Download:  7Questions you should ask before starting technology transfer

1 – Can your process be manufactured according to the concepts of cGMP?

According to the FDA: CGMP refers to the Current Good Manufacturing Practice regulations. CGMPs assure proper design, monitoring, and control of manufacturing processes and facilities. Adherence to the CGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations.

If for any reason your product cannot be manufactured according to cGMP regulations (such as it cannot be manufactured in a reproducible fashion or has variable potency) then you don’t have a licensable product.

2 – Have I got enough time?

It typically takes 6-9 months to transfer a simple product / process to a CMO, and this can be significantly longer if the product is a biotechnology / biologics product. Even if you have a well-defined product developed under QbD principles there is a lot of “practical” work to be done, such as transferring and validating analytical methodologies, demonstrating comparability of the equipment used and product produced. If any of the suppliers (materials, components etc.) are to change, then these must be qualified and the resultant finished product suitably qualified. There are many agreements to be completed (commercial, quality etc.) and for biologics looking for FDA approval, validation data for a biopharmaceutical (unlike small molecules) must be submitted up front in an IND filing so that FDA can evaluate the process development. A major issue is usually that the donor companies do not allow for any contingency time – for repeating or performing any additional tests or resolving any process issues that inevitably arise during the transfer process.

3 – Has the product been fully characterised / Do I have a robust process?

Has the process been fully defined, with critical control parameters and allowed variances? Sufficient data is required to be available to demonstrate how the product has been developed, ideally this data should have been collected through good designs of experiments. Is proper data available to support the operating ranges, alert and action limits?

4 – Is the process scalable, or will the CDMO/CMO/receiving site have to redevelop the process?

To be manufactured at a commercial scale the process must be able to be scaled-up otherwise the CMO will have to spend a lot of time (and your money) modifying the process and a great deal of time and effort will have to be expended demonstrating the comparability of the product from the new process with the original. Come to that – product comparability will have to be demonstrated perhaps through the use of scale-down studied.

5 – Do I have a comprehensive Technology Transfer Package (TTP) prepared?

The extent and level of detail in a technology transfer package can vary considerably depending on the stage of development of the product.  A comprehensive technology transfer package comprising relevant information from the donor (sending) site should be compiled for technical review, including process description, analytical methods and data, production equipment details, and historical process data. In particular, CQAs and the control strategy for both drug substance and drug product should be provided in final documented form by the sending unit. Once the technology transfer package is completed, the transfer team can use the data to work on the planning and writing of technical documents for the receiving unit. Based on the technology transfer package, the transfer team should also conduct a first high-level risk analysis.

6 – Have I defined acceptance criteria for the success of the technology transfer?

You will need to have an acceptance criteria defined – how else can you know when the technology transfer is complete and successful? This is usually defined in terms of documented evidence that the receiving site can routinely reproduce the transferred product, process, or method against a predefined set of specifications as agreed with donor site.

7 – Do I have an experienced dedicated transfer project manager?

Lack of technology transfer experience can lead to gross assumptions being made and an over reliance on process descriptions and SOPs, neither of which are usually detailed enough to allow inexperienced staff to carry out the process (be it the actual manufacturing or performing an analytical method) in the intended manner, or to be able to recognise and flag up anomalies, faults, or irregularities in a timely manner if at all. Quite often this will result in out of specification products and significant deviation / CAPA generation activities being required.

If the answers to any of the above questions is “no” – then one last question – Have you talked to Bluehatch Consultancy Ltd? If not – trefor@bluehatch Consultancy.com