Download PDF: WC500219500

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.

 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;

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:

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

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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

7^th August 2017

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

Article by Trefor Jones

The failure of a Technology Transfer process will, at best result in delays to product sales and increased costs, and at worst may lead to 483 notices, warning letters, loss of reputation and most importantly an impact on the health of potential recipients of the treatment.

During my observations of Technology Transfer projects, the following reasons rank as my top five reasons for Technology Transfer failure:

Product / process not properly defined.

If the product is not well characterised and the production process not well defined then assumptions usually get made (and you know what they say about assumptions). This can result in “minor” or cosmetic issues (such as tablets the wrong colour being produced) to major quality deviations, batch rejects and 483’s for lack of process control being issued.

Although in general each process step is described in the process definition, there is often a failure to define critical process steps and critical parameters in short – the failure to define the process Design Space. This usually results I unacceptable delays resolving process parameter deviations, unwanted side effects and unanticipated impurities leading to the inability of the product to meet product specifications.

Lack of Experience

By this I am referring to the lack of personnel experience with the manufacture of similar products or type of product. This 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.

Lack of a Technology Transfer Plan

There can be over 75 different processes which have to be performed during a typical technology transfer programme. These processes all have to be planned I properly in sequence and in concert with each other. There is often no pre-constructed Technology Transfer plan, and even if a plan exists, quite often there is a failure to assign specific responsibilities to the tasks within the plan. Making-it-up-as-you-go never works except for the very simplest transfers. Lack of a transfer plan usually leads to confusion, late delivery and often as not, the requirement to repeat tasks that have already been performed.

Use of substitute equipment

It’s very unusual for a receiving site to have exactly the same analytical and production equipment as the donor site, and even if it does, the chances are that one is a later version of the other.

This means that no two pieces of equipment will work exactly the same as each other which can lead to unintentional differences in both processing and testing the product. This is especially true for biologics production systems which can be very sensitive to even slight changes in process or testing conditions.

Sometimes I have even seen one piece of equipment substituted for another one that does the same (almost) as the first – such as membrane filtration units instead of depth filters, or impeller mixers instead of Z-blade mixers – resulting in amazement when the end products are not to the same specification. Of course scaling up of a process quite often falls foul of this type of thinking – a bigger piece of equipment although it looks the same and works in the same way often doesn’t perform in the same way as many people who substituted a larger bioreactor for a smaller one have found out to their cost.

Dedicated Technology Transfer Manager.

It always amazes me how often the task of managing a technology transfer project is given to someone who already has full time role on a secondary basis, on the grounds that it doesn’t need a dedicated manager or specialist. In all but the simplest transfers, it is a false economy to do this – one missed or mis-timed step can lead to significant time-delays and costs.

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