关于EMA共用设施相关的指南和问答，大家是怎么看的 ？？

beiwei5du

关于EMA共用设施相关的指南和问答，大家是怎么看的 ？？很多的问题不是很清楚，望指教。希望讨论！

yuansoul

一句话 ： 尽可能不共线

beiwei5du

Q2. What products/active substances are considered to be highly hazardous?
A: Highly hazardous products are those that can cause serious adverse effects at low doses and that therefore would benefit from a full toxicological assessment in order to derive a safe HBEL.
Highly hazardous products are identified based on their inherent toxicological and pharmacological characteristics and include the groups below (this list is not an exhaustive list and if evidence is available indicating that the product may cause adverse effects at low doses by other mechanisms it should be considered as highly hazardous).
Manufacturers should consider, via a safety assessment against the guidance below, if products/active substances should be considered highly hazardous. Evidence indicating a product or active substance falls within any of the categories below should result in a product being considered highly hazardous. If in doubt, manufacturers should consider the product potentially highly hazardous and apply the EMA guide (EMA/CHMP/CVMP/SWP/169430/2012) in full to derive a safe HBEL.
1. Genotoxic (specifically mutagenic) compounds that are known to be, or highly likely to be, carcinogenic to humans. Compounds of this group are easily identifiable, since genotoxicity would be related to the pharmacology, e.g. as DNA alkylating cytostatics, and their use is usually restricted to oncology indications with respective warning statements in the Summary of Product Characteristics.
2. Compounds that can produce reproductive and/or developmental effects at low dosages, for example where evidence exists of such effects being caused by a clinical dose of <10 mg/day (veterinary dose equivalent 0.2 mg/kg/day) or dosages in animal studies of ≤1 mg/kg/day.
3. Compounds that can produce serious target organ toxicity or other significant adverse effects at low doses, for example where evidence exists of such effects being caused by a clinical dose of <10 mg/day (veterinary dose equivalent 0.2 mg/kg/day) or dosages in animal studies of ≤1 mg/kg/day.
4. Compounds with a high pharmacological potency i.e. recommended daily dose of <1 mg (veterinary dose equivalent 0.02 mg/kg).
5. Compounds with a high sensitising potential.
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Question#2
In this question the EMA defines a highly hazardous product as one that “can cause
serious adverse effects at low doses”. It lists certain categories (which is not an
exhaustive list) of compounds that should be considered highly hazardous. The list
includes genotoxic/mutagenic compounds that could be carcinogenic, compounds with
reproductive or developmental effects, compound with specific serious target organ
toxicity, highly potent compounds (those with a daily therapeutic dose of <1 mg/day in
humans), and compound with that are highly sensitizing.
I also find it difficult to clearly define what I mean by highly hazardous actives. While I
am not fully comfortable with the EMA’s descriptions, I don’t think I can come up with a
better list. One area to consider carefully when an assessment is being made using these
criteria is the emphasis on effects at “low doses” (<10 mg/day) for mutagenic and
reproductive effects. I would think that compounds that were mutagenic should have a
full PDE or TTC assessment even if the daily dose was greater than 10 mg/day. I have
not yet covered question #4, but it doesn’t make sense to me (as a non-toxicologist) to
make that distinction based on the daily dose. There should be a distinction between the
daily therapeutic dose and the dose at which highly hazardous effects are observed.
The second area of concern is listing “highly potent” compounds, those with a daily dose
of < 1 mg/day, as highly hazardous. My assumption here is that the EMA is referring to
“potent” compounds that are not mutagenic, etc. With other things being equal I would be
more concerned about the safety effect of a potent compound as compared to a nonpotent
compound. But if the major safety concern for the highly potent compound is the
therapeutic effect, then the safety concern from 0.001 of a therapeutic dose of a highly
potent compound should not be of more concern as compared to 0.001 of a therapeutic
dose of a non-potent compound. In my comments to the EMA I recommended that this be
changed.

beiwei5du

Q3. Could Occupational Exposure Limits (OELs) or Occupational Exposure Bands (OEBs) be used to support assessment of products to determine whether they may be highly hazardous?
A: Yes. Extrapolation of an OEL or OEB (lower end of the range) to a preliminary Permitted Daily Exposure (PDE) can be simply done by using the following formula: PDE (μg/day) = OEL (μg/m3) x 10 m3 (the volume air breathed by a worker in 8 hours). Additional adjustment factors may be needed due to potential differences in target population (worker vs patient), route of exposure etc. If the resulting PDE value is 10 μg/day or lower the product should be considered as highly hazardous.
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Question#3
This question addresses the applicability of using OEL or OEB values to “support” an
assessment of whether a product is highly hazardous or not. The EMA’s answer is
“Yes”, for determining a preliminaryPDE. The typical formula of multiplying the
OEL/OEB value by 10 m3 of air is given. The EMA adds that adjustment factors based
on the target population and on administration routes may be needed. It also states that
PDE values determined in this way that are less than or equal to 10 μg/day should be
considered highly hazardous. I am unclear why this last statement is given as to a “highly
hazardous” category. My speculation is that the OEL only gives a preliminaryPDE. If
this preliminary PDE is at or below 10 μg/day, then a fullevaluation should be done to
establish the PDE using the approach given the 2014 document. If the OEL/OEB
approach gives a value above 10 μg/day, then that compound can be considered nonhazardous
and the approach given in Question #4 could be used. However, this is my
speculation of the intent here, and I may be wrong.

beiwei5du

这个哪位老师清楚的话，可以重点讨论一下，谢谢！
Q4. Can calculation of HBELs be based on clinical data only (e.g. to establish the HBEL on 1/1000th of the minimum therapeutic dose)?
A: Many existing commercial products and new products for which clinical safety profiles are well-established and that do not belong to the highly hazardous category (see response to Q2) have a favourable therapeutic index (also referred to as the therapeutic window or safety window). This means that unwanted or adverse health effects (that may have been identified as toxic effects in animal studies at high doses) may occur - if at all - at dose levels orders of magnitude above the therapeutic dose range and the pharmacological activity would therefore be the most sensitive/critical effect. In this situation, therapeutic dose information could be used as the ‘Point of Departure’ for calculation of an HBEL (e.g. the PDE). Under these circumstances, HBEL based on the 1/1000th minimum therapeutic dose approach would be considered as sufficiently conservative and could be utilised for risk assessment and cleaning purposes.
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Question#4
This is the one I think (or hope) should clearly survive in the final Q&A. This is dealing
with products that don’t belong to the highly hazardous category and have a “favorable
therapeutic index”. I think a description of what this means is given later in the answer as
compounds where the “pharmacological activity would therefore be the most
sensitive/critical effect”, with the therapeutic dose being the point of departure for
determining the HBEL. Here is the key sentence in full:
“Under these circumstances, HBEL based on the 1/1000th minimum therapeutic
dose approach would be considered as sufficiently conservative and could be
utilized for risk assessment and cleaning purposes.”
This appears to mean that for compounds that are nothighly hazardous (as defined in
Question #2), 0.001 of a dose can be used as the HBEL, and it is not necessary to do a
full PDE assessment as given in the 2014 guide.
That said, I believe it would still be prudent to perform a preliminary PDE based on the
OEL/OEB if that OEL/OEB data is available.
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Industry presentations focused on the sci -ence of HBELs and their value in determining
the hazard of a compound. Bruce Naumann’s
discussion of the life cycle approach to HBELs
explained that appropriate toxicological exper -tise is required at all phases. Use of traditional  
1/1,000 of the (lowest) clinical dose lacks sci -entific rigor and was universally opposed.
Cleaning limits established using traditional
approaches can help set priorities for those
still working through their portfolio, but formal
HBELs for all compounds being handled should
be determined by a qualified toxicologist ac -cording to an appropriate standard operating
procedure. The HBEL is then used in risk-identi -fication processes.

oxicological expertise would always be
required to establish a robust classification,
and relevant data should be readily available
for legacy compounds. It was acknowledged
that the 1/1,000 of the minimum clinical dose
proved appropriately conservative in around
85% of cases, but sufficient exceptions exist
such that a toxicology review is recommended
to ensure that the categorization is scientifi -cally valid.

beiwei5du

Q5. Is the use of LD50 to determine health based limits acceptable?
A: No, LD50 is not an adequate point of departure to determine an HBEL.
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Question #5
This answer states that an LD50 value is notan “adequate point of departure to determine
an HBEL.” My only concern here is that perhaps the context of that statement is limits
for actives. Clearly for actives there has to be relevant data other than an LD50 study.
However, for cleaning agents and for intermediates in API synthesis, LD50 data may be
the only relevant safety data available. I hope that this answer is interpreted only in the
context of drug actives. We’ll have to wait and see what is in the final Q&A document.

beiwei5du

Q6. How can limits for cleaning purposes be established?
A: Although the EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012) may be used to justify cleaning limits (as per Introduction paragraph 3), 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.
For products classed as highly hazardous, where a thorough risk assessment can justify manufacture in shared facilities, cleaning limits should include safety factors beyond the HBEL and should not be higher than the traditional cleaning limits approach.
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Question #6
The first five questions were about setting HBELs. This question addresses how to set limits for cleaning validation purposes. It states that limits should be not be set on a calculated HBEL alone, but other factors should be considered. Those other factors include “uncertainty in the cleaning process and analytical variability”. Although not stated by the EMA’s answer, I would add factors such as effects on product quality and product purity as possibly affect cleaning validation limits, even though those factors are not part of a health based exposure limit. For non-highly hazardous products, the EMA states that this can be achieved by “traditional cleaning limits used by the industry such as 1/1000th of minimum therapeutic dose or 10 ppm of one product in another product”. This is additional support for not requiring a full PDE assessment for these non-highly hazardous products. Although not clearly stated by the EMA, the traditional industry approach for these non-highly hazardous active has been themore stringentof 0.001 of a dose and 10 ppm in the next drug product, not an “either/or, choose one”.
For highly hazardous products, the EMA also states that limits beyond the HBEL may be appropriate, and then further states that limits for highly hazardous products “should not be higher than the traditional cleaning limits approach”.（这句话是不是理解错误了？？上面说的是在计算清洁限度时，可以在HBEL上加一个安全系数，并且按照HBEL计算得到的清洁限度应不高于传统按照1/1000 dose或下一个产品的10ppm计算出的清洁限度，而不是作者说的清洁限度高于HBEL计算的清洁限度？？？）This is apparently a reference to “traditional approach” mentioned earlier in Question #6, namely the idea of 0.001 of a dose and 10 ppm in the next product. If this is the case, what it means is that for highly hazardous products, the limit for an active should be themost stringentof these three criteria:

Calculated HBEL by PDE or TTC criterion for active
1/1000th daily dose of the active in the next drug product
10ppm of active in the next drug product