Q&A session in relation to new guidance material ‘Demonstrating the quality of listed probiotic medicines’

Rachel

Okay. Now, without further ado, I am going to pass over to the pre-recording of this session with Dr Jenny Chang. So, Jenny has worked at the Therapeutic Goods Administration for 13 years, spending time in Medical Devices, Authorisation branch, Scientific Evaluation branch, Complementary Medicine and Over The Counter Medicine branch. Currently, Jenny is the director of the Listing Compliance section, responsible for conducting post-market regulatory activities to ensure compliance of listed medicines.

Jenny has a PhD in biomedical engineering and her regulatory career over the last decade spans across compliance and enforcement, policy development and pre-market evaluation and reforms. So, as I mentioned earlier, this is a pre-recorded session but we do have our panel members, Dr Jenny Chang and a couple of other colleagues that will be joining us live after the session. So, please hold.

Jenny Chang

Welcome to today's webinar on the recently published guidelines on demonstrating the quality of listed probiotic medicines. I'll be providing highlights from the guideline as it is a long document, but please ensure that you read the full guidelines closely.

I'd like to begin by acknowledging the traditional owners and custodians of the lands on which we meet today, and pay my respects to elders past and present. I'd also like to extend that acknowledgement and respect to any Aboriginal and Torres Strait Islander peoples here today.

As a preface, the guidelines are not mandatory or law. Instead, it provides transparency for what TGA's expectations are, and what TGA delegates consider when deciding whether relevant laws are being complied with. However, each circumstance may be different and will be considered on an individual basis to determine whether risks have been appropriately managed and, ultimately, compliance.

So, you can think of the guidelines as showing the mainstream way quality can be adequately controlled. But TGA will consider divergence from the guidelines on an individual basis to determine compliance. The guidelines is divided into three main parts.

The first chapter explains why it's so important to control the quality of probiotics and how this relates to the safety and efficacy of the product. Chapter two is probably the one that sponsors and manufacturers will be most interested in. It explains the ways in which a sponsor or manufacturer can comply with the quality requirements and demonstrate that the controls in place sufficiently manage the quality risks.

Chapter three is probably the most dry, but is a necessary part of the guidelines as it links the information in chapter two to the legislation, such as the Therapeutic Goods Act, regulations and any relevant legislative instruments.

The webinar today will mainly focus on the contents of chapter two. I want to reiterate here that quality control and managing of quality risks can be done in a multitude of ways.

There's no one size fits all control strategy, and the most appropriate and/or efficient control strategy will depend on the specific circumstances of the product, its formulation, its design specifications, what its efficacy relies on, the manufacturing process and so forth.

Although PIC/S guide to good manufacturing practice and default standards may be prescriptive in describing how an outcome can be achieved, TGA generally takes an outcomes based approach when it comes to managing risks and demonstrating compliance. What this means is that an outcome is described as the end goal, but how the outcome should be achieved is not prescribed or mandated.

This provides sponsors or manufacturers with the flexibility to control risks in ways that fit their capabilities and circumstance the best. It also promotes innovation and allows for efficiencies to be made. The guidelines focuses only on controlling these quality parameters. Now, there may be other additional critical quality parameters that are important to control for a specific probiotic. This will be up to the sponsor and/or manufacturer to determine for their specific circumstance.

Under the Therapeutic Goods Act, medicines are subject to standards. You'll see the terms ministerial versus default standards used in the guidelines. Ministerial standards are legislation made under the Therapeutic Goods Act called Therapeutic Goods Orders, and you may find a list of them on the TGA website.

Default standards, on the other hand, are defined in the Act to be monographs in the British, European and US pharmacopoeias. To determine whether a pharmacopoeia monograph is applicable, you have to look at the definition and scope described in the monograph. For background, there are also individual monographs, which can also be called specific monographs.

These can apply to a final product with a particular formulation in dosage form, or they can apply to the raw or starting materials as an ingredient or substance within a product.

There are also general monographs, which apply to anything that falls within the scope described in the general monograph. General monographs are to be used in conjunction with individual monographs, where an individual monograph exists. In the guidelines, we've conveniently outlined which default standards and ministerial standards may be applicable to a probiotic medicine. Again, this will depend on the probiotic formulation and dosage form.

Chapter three in the guidelines, titled Applicable Legislation, goes into detail to help sponsors determine whether a monograph in the default standards is applicable. The standard most relevant to all probiotics is the general monograph 3053 called Live Biotherapeutic Products for Human Use in the European and British pharmacopoeias. This general monograph is identical in both these final copies.

It's a monograph that applies to products containing live microorganisms, such as bacteria or yeast, for human use, which is why listed probiotics falls within the scope under the Australian regulatory framework. I know there have been questions as to why Australia is applying such a standard to a dietary supplement, so to speak, whereas in Europe 3053 only applies to pre-market evaluated medicines.

The way Australian medicine legislation is written, any applicable standards must be complied with and, as I explained on the previous slide, to determine what is applicable, you have to look at the definition and scope of the monograph in the default standard. We did at some stage, while developing the guidelines, consider the requests to exempt listed medicines from needing to comply with 3053.

However, given the flexibility provided by the European pharmacopoeia, we felt that this was not needed as sponsors or manufacturers can continue using current approaches, such as quantified by input and still meet 3053. I'll explain this further in the following slides. Currently, there are no individual monographs for probiotic final products in the European pharmacopoeia.

TGO 101 provides some final product specifications that apply to tablets and capsules, and can be used in lieu of individual monographs for final products in the European pharmacopoeia. But it still has to be used in conjunction with general monograph 3053.

The USP, on the other hand, works a little differently in that the general chapter 64 for probiotics only applies to a final product if it's referred to in an applicable individual monograph. Since there are currently no multi-strain individual monographs in the USP, the USP is unlikely to be relevant to most probiotics on the market. That is why, for most multi-strain probiotics, irrespective of its dosage form, 3053 will apply.

So, now that we've established that 3053 is the most applicable to most probiotics on the market, let's delve into what this means and what compliance can look like. The European and British pharmacopoeia, through the General Notices section, provides flexibility to take an outcomes-based approach. This means that, although the monograph prescribes that probiotic active ingredients are controlled at strain level, and provides a way in which this can be achieved through testing the final product, it also allows for other ways to achieve this outcome.

As long as the outcome of controlling at strain level is achieved, the final product is considered to be compliant with the pharmacopoeia. This is irrespective of whether the AITG entry or label contains the species, not the strain. It's also irrespective of whether the efficacy is at genus or species level. Additionally, controlling a strain level is not a new requirement. This monograph 3053 has been in place since 2019. The guidelines only outline current laws that are in place.

So, why is there a constant emphasis on controlling probiotics at strain level? The current evidence landscape shows that the safety and efficacy of microbial active ingredients are unique to each strain. Additionally, controlling at strain level ensures the intended active ingredient that goes into the final product is distinct from other microbial ingredients, with potentially different or unwanted characteristics and risks.

Because of the way the Australian legislation is structured, where the pharmacopoeia is a default standard, other means of achieving compliance, other than doing exactly what the standard says, we've termed as alternative strategies in the guidelines. Since current strain identification and quantification techniques aren't at the stage that can distinguish strains within a multi-strain blend, such as within a final product, quality control measures generally occur earlier on in the manufacturing process.

An important checkpoint can be making sure that your strain supplier is reliable and have the facilities and processes in place to ensure what they supply to you is indeed the strain you want and is free from other contaminating microorganisms. TGA will be putting out more guidance on supplier qualification in mid-2025. So, if you haven’t yet sufficiently qualified then the manufacturer may need to test the identity and quantity of the raw material upon receipt to verify the strain.

If none of this is possible, then the sponsor should rethink their probiotic formulation to enable control of the active ingredients of strain level. Another risk to control is that each strain ends up in the final product in the right proportions and concentrations. If you can't test the final product to verify this, then an alternative control measure is to validate the blending process sufficiently.

Further examples of how this can be done are in the chapter titled Quantified by Input in the guidelines, and figure six in the guidelines provides a hypothetical example of the various evidence you can generate and hold to demonstrate strain control in the final product without testing the final product.

I also want to reiterate here that the guidelines goes through examples of ways this can be achieved, but does not prescribe exactly what to do, because sponsors or manufacturers are best placed to determine what the most appropriate control measures are suited to their circumstance. The guidelines also outlines the various aspects a sponsor should consider when controlling their active ingredients throughout shelf life.

In the past, we've seen sponsors conduct total genus or species counts in stability studies, but when asked about the risk of certain strains outcompeting other strains, no data was available to show that this risk was controlled. The guidelines emphasises the importance of controlling to strain levels throughout shelf life. I reiterate, this does not equate to testing to strain level throughout shelf life, and that this needs to be supported by scientific evidence.

The examples of scientific evidence provided here on this slide, such as stability data from individual strains, water activity data, are in addition to what I mentioned in the previous slide, about appropriate supplier qualification and blending validation. This is to ensure that the identity and quantity of each strain is maintained throughout shelf life, not just at batch release.

So, when you're controlling your active ingredients to strain level, what amount do you have to target? The legislation that you have to follow in this instance, for this quality parameter, can be found in the applicable standards mentioned previously. Even if you choose the Australian-specific requirements in TGO 101, because 3053 is a general monograph, it has to be complied with in conjunction with TGO 101 and the statements in monographs from a relevant default standard.

For example, statements about an assay limit for content are interpreted according to the general notices from that standard. The general notices of all three pharmacopoeia state that the limit or acceptance criteria set in the monographs include or allow for analytical error already, and that no further tolerances can be applied to the limit. So, to put simply, if a product states, it has a certain quantity of a probiotic ingredient on the label, it must contain no less than this quantity until the end of its shelf life.

It's the sponsor's responsibility to ensure that stability studies demonstrate each batch will contain at least the labelled quantity throughout its shelf life. Measurement uncertainties should be considered during product development to ensure that the active probiotic ingredient meets the label claims for stated content and shelf life under the labelled storage conditions.

The sponsor determines the amount of active microbial ingredient required in the final product, based on efficacy evidence, which is claimed on the label.

The content in the final product at batch release should include the stated content plus any measurement uncertainty and any overage to account for content changes over the product's shelf life, so that at the end of shelf life the content limit required in the standards are still met. With test methods for controlling the risk of microbial contamination, what may come as a surprise to people is that TGA 100 does not apply to medicines that contain viable microorganisms as active ingredients.

The limits the monographs in TGA 100 refers to do not distinguish between the live active ingredient versus the contaminating microorganism. As such, for probiotics, the test methods and limits referred to in European pharmacopoeia monograph 3053 are more appropriate, and they're summarised here on this slide.

Under the ministerial standard for labelling, TGO 92, Australian-approved name, or AAN, of the active ingredient must be used on medicine labels, and it must appear as a cohesive unit with the medicine name and active ingredient quantity. The AAN and quantity must be placed together on separate lines of text. This cohesive unit rule also applies when the ingredients are displayed on the side or rear label.

Since there are only species level AANs available currently, the cohesive unit of the AAN and the quantity cannot be disrupted by the strain information. Technically, because there are only species level AANs and the default standards require labelling at the strain level, both should be on the label in separate locations. Here on the slide is an example of how this can be achieved on the medicine label.

However, we recognise that this is not ideal for consumers, as it may be confusing, and it takes up a lot of space on the label. That is why we have a consent under section 14 of the Therapeutic Goods Act, where the Secretary is allowing sponsors of listed probiotics to not have to comply with all the applicable standards at once. This consent expires on 1st October 2026. This means that active ingredients on labels can either be labelled as species level to meet TGO 92 or at strain level to meet the default standards.

The labelling at species or strain level cannot be mixed and matched. This means that either all ingredients are at species level or all ingredients are at strain level. The consent also covers the circumstance where the active ingredients are allowed to be moved to the side or rear label. When on the side or rear label, the same cohesive unit requirement applies, and sponsors can choose to either label at species or strain level. Again, this cannot be mixed or matched.

Once this consent expires, both the AAN and strain name are to be shown on the label in a similar manner as the example shown in the previous slide and in the guidelines.

The TGA is working on getting strain names into the AAN list in the AITG, but this is going to take some time. Of course, if you want to do this now, then choose not to access the section 14 consent, that is have the names of actives in quantities at species level and somewhere else on the label, as at the strain level. This is also possible.

Separately, we've received many questions already about transition periods associated with the requirements explained in the guidelines. As mentioned earlier, the guidelines explain current laws that are in place, and that has been in place for a while.

Additionally, the examples in the guidelines of scientific evidence that can be used to support QBI were provided to us by industry through the consultation process, which means the guidelines already reflect current practice for controlling at strain level. This is why there is no transition period associated with the guidelines other than in relation to labelling at strain versus species level provided by this section 14 consent.

That is the end of this webinar presentation, and we will now move on to questions.

Rachel

Wonderful. Thank you, Jenny. As mentioned earlier, this was a pre-recorded session, and I do have Jenny here on the line with me. But, first of all, we do want to ask that you participate in a short little survey that is now available using the Slido app. So, if you could scan that code there, or use the link that I provided in the chat function earlier, and then I'll introduce you to our panel who is joining us here live in just a moment.

And for those of you who are asking questions in relation to the session being made available, it will be made available on the TGA website, and I will provide that link to you shortly as well, so you can access the recording again and the frequently asked questions that will be provided as well. So, I’ll just take a moment now, thank you. The survey is very short and sweet, so I'm grateful for as many of your feedback as possible.

So, as mentioned earlier, we are moderating questions. So, can you please make sure that questions are relevant to today's topic? But if you do need to communicate further past today's webinar, there is the email address available on the screen for you to make further contact.

Okay. I'd now like to introduce our panel members that will be supporting Dr Jenny Chang today. We have Gaye Camm and Matt Davis from the Manufacturing Quality and Inspection Section who are joining us today for the Q&A session. So, over to you all now. Thank you. 

Jenny Chang

Thanks, Rachel. So, I hope you found the webinar useful, and hopefully it's answered a fair few of your questions already.

I'll firstly go through a list of pre-submitted questions to give you some time to put through new questions. One thing just to keep in mind is that we're unable to provide specific regulatory advice, especially given there's often not enough details in the question for us to say whether something is compliant or not. Also, we can't be doing a compliance review during this live Q&A, so please bear that in mind when you formulate your questions.

The first set of pre-submitted questions I'll read out together, because I think they're essentially asking the same things. Can the TGA clarify that QBI is related to the strain and species level, and that genus level testing and ID still applies to all products, regardless of whether they are single or multi-strain products? Can we test starting materials to species level and finished product to genus level, given that is the maximum TGA licensed labs can do?

What is expected for probiotics testing, finished product, raw material and stability, given the testing limitation? If the species can't be identified or enumerated in a blend when the genus is the same, would total cell counts be considered sufficient. What documents are required for QBI justification as supporting evidence?

So, I've grouped them together because I think they're essentially asking the same things. And the answer to all those questions is, it really depends. This isn't a tick and flick exercise where you just test total genus or species population, or even a total cell count or state that you do QBI and then your quality control is done. The 3053 standard, and even in the USP, requires control at strain level.

So, this means if you want to do a total genus count or total species count or total cell count or use QBI, you still need to demonstrate how you've controlled your active ingredients at strain level. As mentioned in the webinar, this doesn't mean testing the finished product at strain level. In a compliance review, we'd want to know how you, as the sponsor or manufacturer, ensure that you know the strains you put into the manufacturing process is what ends up in the finished product at the right proportions.

So the steps you have in place to ensure this are what's needed to support testing at genus or species level. The guidelines provides examples of what these steps can look like, such as including blending validation, controlling water activity, supplier control.

Okay. The next question is, has TGA accepted that generally freeze-dried probiotics, when stored under suitable conditions, are not metabolically active? So, if you're relying on strain dormancy as part of how you're controlling your strain quantities across the manufacturing process and throughout shelf life, then you'll need to show at what water activity level your strains remain dormant, how you've controlled the water activity during manufacture and throughout shelf life.

We can't just assume because a probiotic’s freeze-dried, then it will automatically be at the right proportions in the finished product and be stable.

Next question. In discussing the newly published guidelines with the IPA at a meeting recently, IPA, which is the International Probiotics Association's understanding of the agreement at the meeting with the TGA and with Complementary Medicines Australia, was that quantification by input would be accepted, and that adherence to label, claim and assurance of shelf life would be achieved through total enumeration for multi-strain products. Please clarify what was agreed with and why the guidelines may differ.

So, at the IPA meeting, we discussed that QBI can indeed continue to be used and, where supported by appropriate evidence or justification, can be considered to comply with the European general monograph 3053. As mentioned in my previous answer, total enumeration for multi-strain products can still be used, as long as you're able to show that you have additional controls in place, together with your total enumeration approach, to control your active ingredient identity and quantity at strain level.

Otherwise, if you're just doing a total enumeration, we may, in a compliance review, want to know how you know the strains are in the right proportions in the finished product. Okay. Next question has a few example scenarios. So, in relation to figure five in the probiotics guidelines, examples two and three, what happens when you have different mixes of strains and species? For example, the formulation has two different strains of bifidobacterium breve and a strain of lactobacillus.

Would genus identification be sufficient, or species or QBI? So, as mentioned already, you'll have to control your probiotic ingredients at strain level. There's no one size fits all answer and it's not just about doing a genus test or stating something is QBI and quality is controlled. It depends on what evidence you have to support a QBI approach or what evidence you have to support a genus level test to demonstrate you've controlled at strain level.

Keeping in mind that QBI is generally the option of last resort when you simply do not have a test that can be used, so in the example of formulation with two breve strains and an acidophilus strain, given you can conduct a genus test for the acidophilus strain, given there's only one, then QBI would not be justifiable.

For the breve strains, it depends if there’s a test that can distinguish between the two strains. If not, then you can opt for QBI, but you still have to hold evidence such as blending validation, supply control, etc., to support the use of QBI and demonstrate control at strain level.

Next question. Can the TGA provide examples of what labelling would look like in different scenarios, complying with the default standards and the section 14 consent? Does it matter if the strain part of the name has brackets or not? The overarching principles of TGO 92 still apply.

Without giving specific regulatory advice, you should consider whether the brackets or no brackets allows the strain information to be clear, not confusing, not misleading to the consumer in the context of your overall label. Next question. If the section 14 consent allows sponsors to choose to comply with either paragraph 93A of TGO 92 or British/European pharmacopoeia 3053 or USP, doesn’t this result in significant differences in probiotics labelling in Australia, and provides inconsistent information for consumers?

If you choose to comply with TGO 92, does this mean that strains shouldn't be declared in the ingredient list? If you choose to comply with the pharmacopoeia, how do strains need to be labelled? The section 14 consent is a temporary measure to allow sponsors to transition to strain labelling, which is what’s required by the applicable standards. The choices provided by the section 14 consent essentially means some labels are at species level and others are at strain level.

This, from what I’m aware, is essentially current status quo, given probiotic labels are already doing this. You have some probiotics that are labelled at species level and then you've got other probiotics labelled at strain level. So, yes, if you choose to comply with TGO 92, you label at species level but you can choose to put additional strain information elsewhere on the label, away from the ingredient and ingredient quantity list. The guidelines also provide some examples of how you can label at strain level in figure seven of the guidelines.

Next question. Can the TGA confirm that all excipients do not need to be on labels? So, we recognise that 3053’s requirement to label with excipients in stabilisers is inconsistent with current practice across all listed medicines. We're working on a legal instrument to officially exempt sponsors from having to do this. That's why this requirement is no longer mentioned in the guidelines.

Next question. If a product contains a probiotic which is used and tested at the genus level only and also contains a probiotic used and tested at the strain level, can both be used and labelled as such on the final label? Can the TGA clarify this because the section 14 consent implies this may not be the case once the transition period has ended. Can the TGA provide examples?

Under the section 14 consent, you can either label all the actives at species level or all at strain level. As mentioned in my presentation, there's no mixing and matching allowed. Even if you were to ignore the section 14 consent and not access it, you're currently supposed to at least be using the Australia-approved name, which are all at species level. So, labelling at genus level would not be compliant.

Next question. There are two, which I’ve bunched together. Will it be acceptable to also label claim the actual amount of probiotic at the time of manufacture along with the shelf life target? If I list my species on the main label complying with TGO 92, can I voluntarily discuss the strain names on other parts of the label?

For example, my compliant ingredient list only includes species. However, the side label includes mentions of the strains used in the product. So, you'll still need to comply with the other requirements of TGO 92, even if, under the section 14 consent, you choose to label at strain level. Things like the cohesive unit of the active ingredient and quantity still needs to be complied with. So, if you want to add other information that’s not required by TGO 92 and relevant instruments, you can choose to do so. But the overall presentation still needs to be clear, not confusing, not misleading, etc.

Next question. When will the TGA update to new scientific taxonomic genus names, and how long will the transition period be? So, we're working on adding strains into the Australia-approved names list over the next year or so. Part of that will likely be updates to new taxonomic names. Length of transition periods, it's still very early days. It's still being discussed internally. But don't worry, there will be a public consultation, so you'll get a chance to voice your views about the names and transition periods then.

We now head into questions that relate to the not less than stated value aspect and relate to GMP stuff. So, I will defer to Matt and Gaye to answer the next few questions. I'll read it out, though. Is it expected that minor or infrequent deviations can be addressed through ongoing trend analysis and PQR?

Matt Davis

So, I'm happy to take that first question, Jenny. The short answer is no. So, PQR have a specific purpose in the pharmaceutical quality system and in this example, when we're referring to minor or infrequent deviations, they are indeed deviations. They need to be documented and evaluated in accordance with the deviation system. Remember, deviations as they occur, they need to be dealt with in a timely manner. So, waiting for the PQR, which in some cases might be every year or even less frequently, if you've got less batches produced, would not be a timely review of the event that has occurred.

Jenny Chang

Thanks, Matt. Next question. Given the tightness of the new requirements, the TGA has not addressed how measurement variability can be managed other than overages, which is both a commercial issue and potentially a therapeutic issue for consumers. What has the TGA done to address this? For example, will the TGA hold third party contractors accountable to minimal testing variations when performing GMP inspections? Gaye, thank you for answering this one.

Gaye Camm

Sorry, that’s actually Matt’s.

Matt Davis

Yes, I’m happy to answer, Jenny.

Jenny Chang

I’m sorry.

Matt Davis

No, that’s okay. So, there's two parts to that. There's the question, really, of overages and whether or not there's a therapeutic concern with overages.

I think that's really a question for the sponsors. So, in a number of cases, or in most cases, the challenge in relation to the viability of probiotics over their shelf life is often addressed by adding in overages. A sponsor and a manufacturer need to have a good understanding of the addition of an overage to a certain degree, does that have any negative effect in relation to the quality or safety of the product?

So, we put that onus back onto the manufacturer or the sponsor to say, you need to fully understand what overages are required and whether they are appropriate. With regards to the second part, which is in relation to third party contract laboratories, yes, absolutely. If third party contract laboratories are providing a contract service to do enumeration of probiotics, we would be ensuring that they apply appropriate calculations to the determination of any population results that they are giving back to their customers.

So, it would mean that they shouldn't be applying a plus or minus log reduction, an increase or a reduction to a result. They should be providing the raw result back to whoever supplied the sample.

Jenny Chang

Thank you. Thanks, Matt. The next question is for me. Under TGO 101, the lower assay limit is not less than 90% for all types of active ingredients, except probiotics. Why is the limit not less than stated content for probiotics in TGO 101? Applying not less than 90% would allow for well understood analytical variability seen with probiotics.

It would also align with probiotics with all other types of active ingredients, which is not considered to impact on their efficacy. So, this requirement has been in place for over a decade. My educated guess is that because we know these live microorganisms have a tendency to die off during manufacture.

And once taken, the environment, such as stomach acid, alkalinity in the duodenum, can all reduce the population that ends up in the GI tract. The risks associated with overdosing tends to be low. So, that may be why the limit is not less than stated content. Additionally, it aligns with the pharmacopoeia requirements, which are all not less than the stated value as well.

Okay, so the next few questions are also for Matt and Gaye. Regarding supplier testing, there are no TGA-certified labs that can ID test to the strain level. Is it sufficient to rely on the the CofA from the supplier for strain identification. Especially for identification when received, probiotics can only be identified to the species level if in a single species raw material.

Gaye Camm

I'll take this one, Jenny. The answer is it always depends, but it may be sufficient to rely on the CofA from the supplier of the strain identification, if you have evidence to support that you can trust that certificate of analysis, and that would be via supplier approval processes or via on site or site-based audits.

So, yes, you could, but you can't just rely on the CofA with no additional evidence to back up that that CofA can be trusted. And I think that then leads into the next question which Jenny is going to ask, which is, does the TGA have supply chain verification expectations for probiotics outlined in TGA guidances?

An answer to that, unfortunately, is not yet. We will be developing them and, as Jenny said at the start of the presentation, hopefully by the middle of this year or, if not, very shortly thereafter we'll have the appropriate guidance out to industry related to what would be appropriate supplier approval, so that you can rely on that certificate of analysis.

Jenny Chang

Thanks, Gaye. Next question. Are there other specific quality attributes that manufacturers must independently confirm or can they rely on the supplier’s certificate of analysis, other than the requirement to ID to the species level?

Matt Davis

I'm happy to maybe add to that question. So, referring back to Gaye’s previous answer, the vendor qualification, the supplier qualification, is going to significantly influence how you view these materials and what additional testing may or may not be required. So, with a really robust vendor qualification process, your reliance on the results that are on the survey can increase, and that might mean that some of those tests, you're able to rely on the supplier’s information rather than having to repeat itself.

But I think one of the things we should all bear in mind, and this goes to the supplier qualification for listed medicines guidance that's out there currently, one of the first steps is understanding the nature of the material you're dealing with. So, understanding how these things are produced, understanding how these things are controlled, understanding the level of control from the supplier and then things like supply chain, how they control the supply chain, etc., would influence, through risk assessment, what you might need to do from a testing perspective.

So, we've discussed identification and strain management but I think enumeration, i.e. determining the population of the probiotic bulk material, is going to be something that you would do routinely to, obviously, determine how much you need to put into your product. It's going to be particularly important for things like if you're applying QBI.

Depending on what information is in the CofA, it would need to bear in mind the requirements of 3053 of the EP and BP in that you might need to do, as Jenny was discussing before, additional microbiological testing to ensure that the presence or absence or otherwise of organisms that might be objectionable or specified pathogens, you might need to do that testing if that's not being done by the vendor.

So, I guess you'd need to look at what the requirements are of the default standards, understand the materials, understand the level of control that the vendor has, and then come up with a risk-based approach to what additional testing you may have to do.

Jenny Chang

Thanks, Matt. Next question. Do the TGA have any comments or guidance on transport or storage, including from supplier to manufacturer, manufacturer to sponsor and sponsor to retailer? What is expected if temperature excursions or deviations occur during transportation?

Gaye Camm

Matt, do you want me to take that or are you going to take it?

Matt Davis

Yes, that’s okay.

Gaye Camm

No, I’m not gagging for it. 

Matt Davis

Right, okay. So, just in a general sense, there's some guidance that we have in our interpretation and expectations guidance for the PIC/S guide’s GMP that quite clearly states, as does the guidance within the TGA arena, that goods should be stored, shipped, transported in accordance with their labour requirements. All of your stability is based on that.

So, the base expectation would be when you ship something between sites, you should meet the labelled storage requirements. So, excursion should be the exception, not the norm. If there was an excursion, then obviously you'd have to look at what additional stability data you have.

Depending on where it is in the supply chain, if it’s a bulk material that happens to experience an excursion when it's been sent from the vendor overseas to your site, you may have to do a risk assessment and look at additional, do we do we look at population, do we need to speak to the vendor and understand what temperature fluctuations may result in relation to the product?

Conversely, if it's at the other end of the process and you've got a product, a probiotic that you know needs to be refrigerated, for example, for stability purposes and you get a temperature excursion, you need to be speaking to your sponsor. Your sponsor needs to be speaking to the manufacturer and potentially the authorised person and making a decision as to whether those goods are still going to fulfil the details that have been registered with the TGA and their label claims.

Jenny Chang

Thanks, Matt. And one more for you, Matt. Is supplier-provided stability data on strains acceptable to use in a QBI justification?

Matt Davis

So, I guess the answer to that is it may be. It really depends on the nature of the information that's been supplied to you. I could imagine a situation where you've got supplier data that indicates, either for a single strain or for multiple strains, what their stabilities may be over a period of time. That's going to be very important in regards to the bulk raw material that's used in a probiotic for determining do I need to assay or do a population determination at each individual time I use that probiotic, particularly if I've got containers that are opened up and I only use half the container, and then I reseal it and place it back in the freezer or the refrigerator.

That information could be useful for QBI from an input perspective. The question as to whether that data from the supplier is going to be useful from an ongoing stability perspective, i.e., you're using a QBI approach to manufacture and then you're going to try and use that stability, I think that would not necessarily be helpful.

I think it's going to be fairly limited, noting that the vendors stability data, if you will, will be based on the way that it's packaged from the vendor, usually in foil, hermetically sealed pouches that are stored in refrigerators. That's a very different condition to being encapsulated or in a liquid probiotic. So, I think it may be useful from an input perspective but potentially would have limitations as to any further value down the track.

Jenny Chang

Thanks, Matt. Only a few more to go and then we'll go through the Slido questions. If the finished product release process relies on QBI justification due to complexity of the multi-strain product, then stability testing should consider the QBI approach. If QBI justifications are adopted or acceptable for multi-strain products at release stage, then stability testing should not require to justify presence of each strain.

So, my answer is, yes, this may be true, but it doesn't absolve you from having to control that strain level, even until end of shelf life. So, the evidence you hold to support QBI, such as control of water activity, maybe even how this is impacted once a consumer opens the bottle, it will be needed to support the stability and shelf life.

Next question. Regarding strains in multi-strain blends, can the TGA confirm if stability is applied to every strain within formulation? If not every strain is contributing to an efficacy claim but is only present in a supportive role because of its efficacy at a genus or species level, then is stability of the genus or species acceptable for those strains?

So, as mentioned in my presentation, irrespective of efficacy and whether the ingredient is in the AITG at species level, the quality standard requires the active ingredient to be controlled at strain level. Similar to what I've answered previously, whether genus or species level testing is sufficient depends on what other evidence you hold to show that together with this level of testing, your strain identity and quantity is controlled in the final product.

And that then leads us to the Slido questions. Okay. If we only use species level on front and side of the label, then no section 14 is required. Please clarify. So, the section 14 consent already applies to all probiotics that fall within the scope of what's described in the section 14. So ,you don't have to go and apply for a section 14. That already covers probiotics and it's already in place. So, if you choose to label at the species level on the front and side label, and then you don’t mention elsewhere about what strains are in your products, technically that’s not complying with the default standards, although you’re complying with TGO 92, where you only label at species level.

Next question, why probiotics product shelf life testing does not allow any tolerance on expiry limit. I'm not really sure what this question means about expiry limit, but I'm assuming you mean the active ingredient content amount at the end of shelf life. You think that there should be some tolerances there. So, the reason being is that's what the standards require. That's the simple answer. And the standards do not allow tolerances to be applied to the not less than stated content limit.

Matt Davis

Jenny, can I, just to add to that?

Jenny Chang

Yes.

Matt Davis

The nuance difference with probiotics is that the whole concept of probiotics relies on alive living cells. It must be living to do something. The living probiotic, the quantity of those is linked to efficacy. A biological assay, as in plating, is the only thing that tells you what's living. The focus is really in ensuring that the product contains the correct number of living cells that are stated on the label. That’s why these limits don’t have a tolerance of less than. It’s whatever that is labelled. You must demonstrate that there is a viable population at that level. Thanks, Jenny.

Jenny Chang

Thank you. Thanks, Matt.

Rachel

Jenny, I just wanted to acknowledge the time. What are your thoughts on going over to answer some of these questions? Or what’s the plan?

Jenny Chang

Let's extend for another 15 minutes. Is that okay with the other panellists?

Rachel

I’ve just reminded everyone that these will be made available on the TGA website, both the presentation and the Q&A session. And if you do have to leave, we do apologise for going over time, but we understand the importance of getting through as many as possible.

Jenny Chang

And any unanswered questions, we’ll answer them and I’ll add them to the end of my PowerPoint slides and then we’ll publish it on the TGA website, so you can see the answers there. So, don’t worry if we don’t get to your question today. Okay, next question. Is there water activity and/or PH specifications given for probiotic powders?

So, as I mentioned in one of my previous answers, we don’t have a this is the number that you have to achieve, then, tick, you’re done. It depends on your formulation, depends on the strains that you're using, what water activity level below which that strain remains dormant. So, you, as the sponsor, need to find that information to support the control measures that you have in place. Same as with the PH specifications.

Okay, next question. Individual strain stability also required to demonstrate the finished product grouping stability justification. Does that mean no grouping of product allowed? Grouping is allowed and it is mentioned in the guidelines that you can still choose to use grouping. But the caveat is, you have to demonstrate how the representative product you’ve used to extrapolate your particular product’s shelf life is relevant.

So, there’s many factors that affect stability, things like the packaging, the formulation, etc. They all have an impact on your stability. So, whether the stability data of the representative product is even relevant to yours, you need to be demonstrating that through considerations of all those factors that might affect its relevance.

Okay, next question. In a scenario where a multi-strain probiotic product also contains non-probiotic active ingredients, would the microbial contamination criteria of 3053 or TGO 100 apply? I think this is a really, really good question, whether you would need to consider both for the different ingredients. I think, at the end of the day, you're trying to manage contamination risks.

As I mentioned, TGO 100, the methods referred to in that are not suitable for the viable ingredients, whereas the methods referred to in 3053 are. So, you will need to figure out what methods are most suitable, given you do have a combination product and then limit-wise, that’s going to depend on the methodology as well. But, yes, do you have anything else you want to add to that?

Matt Davis

Well, I think if it was a multi-strain probiotic, I think if the probiotic that's listed was to be used for route of administration, it’s included in 3053, which is oral use, non-aqueous and aqueous and then vaginal use, I think that you would just follow 3053. If, however, the probiotic, for some odd reason, is used for a different route of administration, I think you'd have to consider, I'd say, the general monograph in the pharmacopoeia with regards to microbiological quality of non-sterile products.

To determine the fact that it’s a probiotic and it’s used in a route of administration other than what’s specified in 3053, you’d have to work out if there’s a risk there of the probiotic being there, but I think you'd also have to consider the limits that are in the general monograph to come up with an appropriate specification. But I think if that was to be the...

The fact it’s a probiotic would probably be the dictating fact, and I think most of the probiotics would be taken by a route of administration that’s outlined in 3053. If you’ve got a probiotic that’s not used in accordance with the routes of administration in 3053, I think that’s something you should reach out to the TGA and have a further conversation about.

Jenny Chang

I think the key part about that question is there's a combination of ingredients, some that are viable and some that are, say, herbal or, I don’t know, a vitamin maybe.

And so in that scenario technically the vitamin component, TGO 100 might apply, whereas the viable ingredient, 3053 might apply. So, does that affect your answer, Matt, at all?

Matt Davis

Well, Jenny, the question is specifically around the microbial contamination criteria. So, I think in that context... Look, 3053 outlines the microbial contamination criteria for something that’s used by oral use or vaginal use. TGO 100 refers in large part to the default standard, the general monographs around microbiological quality of non-sterile/sterile materials and non-sterile goods.

So, if you find that your product doesn’t fit in accordance with the criteria of 3053... Because in both circumstances they’ve got a probiotic in, which would be the predominant factor as to what are the microbial contamination limits. I think if it doesn’t fit in accordance with 3053, the routes of administration, I think you’d need to speak to us about what you’re producing, what it’s going to be used for, so that we can have that discussion.

Jenny Chang

Thanks, Matt. Okay, next question. Probiotic methods are not accurate and in some cases could vary by 0.5 log, which is quite significant. Do you have any advice on how to manage test variances, knowing that expectation is to have not less than labelled amount? Matt, can I give that one to you?

Matt Davis

Yes. So, there is going to be some variation or variance within test results. Laboratories that are performing these tests need to take a lot of precautions to absolutely standardise their methodology. And it comes down to having very strict standardisation of the methods of the equipment that's used, even down to the branding and the ball size of the pipettes that are used, if they're doing serial dilutions, etc., to make sure that they can standardise the method as much as possible.

It takes a lot of training, it takes a lot of practice but good laboratories with standardised methods can narrow the variance in the methods as much as they possibly can. And you can see some significant improvement in laboratories that implement, I guess, very robust population determination methods. So, that's a conversation you should have with the laboratories that you use.

With regards to those test variances, once you understand those, as Jenny has mentioned previously, those variances need to be considered in the manufacturing process to determine what kind of overages you should include to make sure that the products, when tested, will meet the not less than limit.

Jenny Chang

Thanks, Matt. Next question. Are fermentation nutrients used in the fermentation process to increase probiotic biomass included as part of the starting material definition, or only excipients used in the manufacture of finished products?

Do you mean whether it should be an excipient that’s an ingredient in the final finished product versus whether it's counted as a starting material? Not really sure I understand this question.

Matt Davis

Maybe I can have a stab at this. So, the fermentation nutrients, if we're talking about the media that's used in the propagation and the cell expansion, etc., in probiotics, when you go through the probiotic manufacturing process, there’s a fair amount of downstream processing after fermentation that reduces the vast majority of these other solutions or media, etc., that are used in the process.

So, there’s a lot of filtration and centrifugation, etc, that occurs so that the amount that you would be left with is fairly small. The other components that you need to consider in regards to the probiotic, if you're receiving it as a bulk material, there'll be obviously cryo protection that's added to the cells, so that when they're freeze-dried, they don't just die.

There will be some kind of bulking agent. It’s often some kind of simple sugar that’s used to give mass to the final product. But I think we do view probiotics that have come from probiotic supplier as a single site material. We don't start to look into residual processing aids or media that may be utilised in the process. But that's with the assumption that those manufacturing processes are very well defined, such that most of those processing aids and media are removed in the downstream processing of the bulk cells.

Jenny Chang

Thanks, Matt. Was there more you wanted to add, Matt?

Matt Davis

No. Well, based on the question, I think that’s as much as I can say at this point.

Jenny Chang

Okay, thank you. Next question. How will the TGA review the sponsor’s evidence as the only data we can use for a justification for multi-strain enumeration to strains when we’re limited to culture techniques for CFU count, individual strain stability data, QBI and water activity? No other techniques are available in industry. Well, my question back to you is, if currently you have a multi-strain product, you label that you have the strains in your product, how have you been up until this point making sure that those strains are there?

From what I heard, things like supplier qualification that Matt has mentioned, to ensure that what you've got in is, in fact, the strain that you designed to be in your product, and then doing things like blending validation to ensure that each strain ends up in each tablet or capsule in the right proportions, all of that are current techniques that industry uses to control the amount of strains in their finished product.

So, whether you're limited in your culture techniques or not, to me it sounds like there are already ways for you to control to strain level through those alternative approaches.

Matt Davis

I think it's also worth pointing out, Jenny, that there is definitely the scientific methodology out there to do additional identification of strains within mixed cultures. It might not be something that, at this point, today, is commercially available within laboratories in Australia, but that shouldn't stop industry from looking forward to these methods and determining whether or not they can develop methods in conjunction with licensed laboratories to actually give them a much more robust test method.

And cost of testing gets reduced the more people start using it, etc., and as technology develops. So, it may be as of today it’s quite difficult, but into the future it should get more accessible and it should get easier.

Jenny Chang

Thank you. Okay, next question. Microbiological analytical methods are able to differentiate microorganisms required in TGO 100 and probiotics. Why microbe was removed from probiotic products. Can the sponsor take the approach to maintain microbiological testing?

So, I’ll just clarify. Microtesting or contamination control is still required for probiotics. My point in the presentation was that TGO 100, which is what people normally think is the standard by which, for medicines in Australia, we use TGO 100 to control microbial contamination, that doesn't apply to probiotics because probiotics have viable, active ingredients.

Instead, in 3053 the methods and limits that are described in 3053 are more appropriate for probiotics, because it takes into consideration that probiotics has viable, active ingredients.

Matt Davis

Essentially, if you tested a probiotic strictly in accordance with the methods outlined in TGO 100, your total aerobic microbial count is just going to be too numerous to count. It's not going to give you any information whatsoever. So, you need to look at a method that excludes the probiotic but looks for other organisms that may be there that has contaminants. So, that’s why TGO 100 doesn’t...

It cuts out probiotics in that regard. It does not mean that there are not other standards, i.e. 3053, that are applicable. So, just use a different method, don’t use TGO 100 to determine total aerobic microbial count or yeast and mould count for a probiotic, because you’re just going to get too numerous to count confluent plates of growth. It’ll be meaningless.

Jenny Chang

That's right. Thanks, Matt. I think we're getting close to the end. How will TGA decide which strains to add? There should be consideration for products already on the ARTG and those in development by the sponsors.

So, I presume you're meaning adding strains to the Australia-approved name list. As I mentioned briefly, there will be a public consultation where sponsors are asked to provide us with the strains that they're using or want to be using, to be added to the AAN list, and A will be conducting a reduced quality assessment to make sure that the strain you're requesting is legitimate.

And, yes, how we do that, the details of that project and that consultation, we’ll announce it sometime later this year. We’re still trying to figure out how we're going to go about this because it's going to be a large amount of work, especially with the ingredients that are currently not strain-specific in the ingredient determination.

So, most of the new microbial ingredients already are strain-specific, even though the AAN is at species level. But a lot of the older ingredients don't have any strain restrictions. So, there's going to be a lot of strains under those species that I'm sure sponsors will want to be added. So, there will be a consultation and you'll get to put forward the strains that you want to add.

Last question. If we are using strain-specific evidence for claims for QA testing, is it a requirement to test a strain level or just species level? The answer is it depends. It depends on your formulation. If you only have one genus of each species in your formulation, then maybe all you need to do is test at species level.

So, yes, it really depends. But, as I mentioned over and over again, the standard requires you to control at strain level. That's the outcome you need to achieve and how you achieve it depends on how well you've qualified the supplier, what your formulation is, etc., etc.

So, that's the end of all the questions. Thank you so much, Matt and Gaye for helping me today in answering questions. Really appreciate it. And I will hand it back to Rachel.

Rachel

Thanks, guys. You've done well and we will end it there. Thank you for going over time, everyone, and being patient and sticking around with us. As mentioned, this will be made available on the TGA website in the coming weeks. We do have to put some scripting along with it for digital analysis. I can’t get my wording right, I need my afternoon coffee.

So, give us a couple of weeks and that will be made available on the TGA website. At the very latest a couple of weeks. Thank you all.