Dear Yeradesi Venkataraju,

For the calculations permitted daily exposure for an active ingredient that has minimal data, please read the following text:

Calculation of a Permitted Daily Exposure (PDE)

The procedure proposed in this document for determination of health based exposure limits for a residual active substance is based on the method for establishing the so-called Permitted Daily Exposure (PDE) as described in Appendix 3 of ICH Q3C (R4) “Impurities: Guideline for Residual Solvents” and Appendix 3 of VICH GL 18 on “residual solvents in new veterinary medicinal products, active substances and excipients (Revision)”. The PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime. Determination of a PDE involves (i) hazard identification by reviewing all relevant data, (ii) identification of “critical effects”, (iii) determination of the no-observed-adverse-effect level (NOAEL) of the findings that are considered to be critical effects, and (iv) use of several adjustment factors to account for various uncertainties. Appendices 3 of the ICH Q3C and VICH GL 18 guidelines present the following equation for the derivation of the PDE:

PDE = (NOAEL x Weight Adjustment) / (F1 x F2 x F3 x F4 x F5)

In relation to the establishment of health based exposure limits that can be accepted in veterinary medicinal products, it would in principle, be possible to use the PDE approach to establish different limits for different target species. However, this would be highly impractical. Consequently, it is considered pragmatic that PDEs should be derived assuming human exposure. The level of contamination that can be accepted is then calculated from the human PDE, even when the product that will be contaminated is a veterinary medicinal product. This is considered to represent a pragmatic approach and is in line with the approach taken in VICH GL 18, in which human PDEs are used to calculate residual solvent limits applied for veterinary medicinal products The derivation of limits will need to take account of the dose to be administered, which will be influenced by the body weight of the species to be treated. In order to facilitate this, the PDE should

be calculated on a mg/kg bw basis (i.e. using a weight adjustment figure of 1) rather than on a per person basis. When the product that may become contaminated with a residual active substance is a veterinary medicinal product for administration to food producing animals, the carryover limit applied must take account of both target animal safety considerations and consumer safety considerations. It should

therefore be demonstrated, based on worst case exposure scenarios, that neither the target animal nor the consumer will be exposed to residual active substance levels exceeding the PDE. Alternative approaches to the NOAEL such as the Benchmark dose may also be used. The use of other approaches to determine health based exposure limits could be considered acceptable if adequately and scientifically justified.

Establishing NOAEL(s)

For all critical effects identified, a NOAEL should be established. The NOAEL is the highest tested dose at which no “critical” effect is observed. If the critical effect is observed in several animal studies, the NOAEL occurring at the lowest dose should be used for calculation of the PDE value. If no NOAEL is obtained, the lowest-observed-adverse-effect level (LOAEL) may be used. A NOAEL based on clinical

pharmacodynamic effects should correspond to the highest dose tested which is considered therapeutically inefficacious.

Application of adjustment factors

The PDE is derived by dividing the NOAEL for the critical effect by various adjustment factors (also referred to as safety-, uncertainty-, assessment- or modifying factors) to account for various uncertainties and to allow extrapolation to a reliable and robust no-effect level in the human or target animal population. F1 to F5 are addressing the following sources of uncertainty:

F1: A factor (values between 2 and 12) to account for extrapolation between species

F2: A factor of 10 to account for variability between individuals

F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks

F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity

F5: A variable factor that may be applied if the no-effect level was not established. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.

The use of additional modifying factors to address residual uncertainties not covered by the above factors may be accepted provided they are well supported with literature data and an adequate discussion is provided to support their use e.g. lack of data for reproductive and developmental toxicity.

For more on this topic, please see the following link:

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/11/WC500177735.pdf

Hoping this will be helpful,

Rafik

Dear Rafik,

Thank you for your patience and answering me. I am using the same guideline. However, there is no sufficient literature for non-clinical data and I am unable to get NOAEL and other uncertainty factors. Hence, I am facing a tough challenge. Could you help me in this aspect if possible?

Best regards,

Venkat

Dear Venkat, 

I principally agree with Rafik but a quick check for your compound in PUBMED and ChemIDadvanced revealed that quite a lot of published animal data exist (e.g. mouse, rat, dog). You can certainly use these data for derivation of a PDE. Don't be afraid to use interventional animal studies for your considerations. From my experience with determination of PDEs it is highly adviced not to limit yourself with human data. A QSAR approach can always be included and many structurally and pharmacologically related NO donators for this are available.

Best regards

Geertje

Hi Lewin,

Thank you so much for your suggestion. However, the data required like NOAEL, duration, dose, toxicities is not available. In such scenario, what is the best way to calculate PDE. Can I use 1/1000 of the effective low dose? Kindly suggest.

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You can use min. dose used in toxicity study. As LOAEL considering F5 value 10

I have a similar problem as Venkat mentioned. For the molecules which were approved on or before 1970s - 80s do not have complete non-clinical studies or NOAEL. Sometimes the safety information is available only as summary of product characteristics where the safe dose is mentioned as 2 or 3 times the maximum human dose on mg/m2 basis. In these cases also, there was no mention about the actual dose in animals, only total human dose is available which is considered as the maximum safe dose. In this condition, how should we approach for the PDE calculations? Please help.

Dear Raju,

As I see and understood that you have insufficient data to calculate PDE for an API. If the case is like that. The following explanation could be helpful to you. If you know then ignore this message.

When we don't have proper and sufficient data, it always recommended to go traditional option i.e 1/1000 th of compound.

If you are still curious then you go for old approach such as deriving the NOAEL from LD50 with respect to the route. 

If you are more interested try to focus on the study of compound on sensitive organs which are more sensitive toxicity. Then you can opt for LOAEL if you're confident enough.

From any one of the options you can use for PDE calculation when you don't have adequate data.

Also please follow the ISPE updates. They give full details.

Hope this is useful.

I think through genotoxicity data on AMES, we can use TTC approach(Toxicology Threshold Concern) to approach for PDE concerns. TTC approach is also used to calculate DAp of a chemical based on the log P data on the chemical and it is widely accepted by regulatory bodies too.

I raised a similar question in my training and this was answered by an expert. Probably a right person can shed some light I guess as I am not expert in TTC approach for PDE.

If you have an Occupational Exposure Level (OEL) you can extrapolate this to an interim PDE value; also it might be useful to search for Derrived N o Effect Level (DNEL) values (somethimes available on ECHA website). And any of the approaches above - the key thing is that you have a sound scientific rationale for which option or data you use.

From my experience in PDE evaluation, a TTC approach solely based on AMES data and physico-chemical data is not sufficient for a solid PDE calculation. At least some in-vivo/in-vitro data/clinical data are required for the scientific rationale. In case of profound data gaps, use a (Q)SAR approach with better assessed compounds.

The TTC approach is often misused and has numerous limitations, such as:

1. TTC is limited to the database it is built on.  If you are applying the TTC to a different “chemical space” it may not represent your compound.

2. Cohorts of concern, highly potent carcinogens are not covered by the TTC

3. Metals are not covered by the TTC

4. Biologics are not covered by the TTC

5. The TTC is a conservative estimate based on a database of compounds.  It should not be assumed to be a precise number.  It is typically lower than the true limit.

6. The TTC can mean a lot of things and it can be confusing for those not knowing what they are doing.  For example, there is a TTC for mutagens, non-carcinogenic c ompounds based on the Cramer classification, active pharmaceutical ingredients, oncology products, etc.

7. The TTC cannot cover immune hypersensitivity, with exception of skin sensitization.

8. TTC can be specific to a specific route of administration

Hi, you can use the methodology given for PDE calculation of residual solvents, given under ICH Q3C - R6 and derive the PDE value of an API also.

You can verify the value obtained against the 10 ppm concept and justify the limits.

How to calculate PDE Data for Levosulpride.

Vija,

You need a registered toxicologist to review and evaluate previous (old) clinical studies and calculate the PDE. The PDE or ADE was not a factor for calculation in these old clinical studies.

For new molecules or which have limited data, toxicologist preferrably use therapeutic daily dose while some uses 1/3 of daily dose.

Can you share NDBA impurity PDE Value .

Ashraf,

Your 'real' question is not how to live with a known deadly impurity but to control and even prevent its synthesis. This may mean you will have to develop a 'new' synthesis process for your API.

Bruce Neagle 👏

Ashraf,

You will need an an 'analytical method' to follow your impurity.

https://methods-content.waters.com/tb/highly-sensitive-robust-uplc-ms-ms-qualification-of-nirtosamine-impurities?

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