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Cleaning validation and toxicology: quo vadis?

Merely clean ist not yet valid: cleaning validation procedures must not be underestimated.
Merely clean ist not yet valid: cleaning validation procedures must not be underestimated.

A brief guide through the jungle of toxicological requirements of the revised Annex 15 of the EU GMP Guideline.

The revised Annex 15 brings not only innovations and clarifications for the qualification of devices and systems and process validations, but also several new requirements for cleaning validation that should not be underestimated. The previously used and accepted criteria  - the 10 ppm criterion based on the permissible quantity of a substance or the 1/1000 dosage criterion based on the therapeutic dosage of the precursor product (1/1000 in the next product to be manufactured) - have now been superseded by the “permitted daily exposure (PDE)” of the precursor product. This is a criterion based on a toxicological assessment. How is this criterion to be understood and applied and what do all the new acronyms stand for? Are there differences with regard to ADE and ADI? What is DNEL? How does the application of the toxicological criterion influence existing cleaning validation procedures?

 

What’s new in Annex 15?
The revised Annex 15 applies as of 1 October 2015. With reference to chapters 3 and 5 of the GMP guideline, the requirements for preventing cross-contamination are described in detail. In chapter 10.6 of the annex, a toxicological assessment is required for the establishment of the permitted maximum carryover of residues into the next product to be manufactured, which is described in the “EMA Guideline on setting health based exposure limits for use in risk identification on the manufacture of different medicinal products in shared facilities”. For this purpose, the PDE value is to be determined in accordance with the EMA guideline.

In the annex and the EMA guideline, the PDE is listed only for the contamination of drugs by active substances, but not for contamination by cleaning agents. Until now, the ADI has been used for the specification of the maximum residue for cleaning agents. The ADI is calculated based on the NOEL, which is derived from the LD50 value. As chemical substances, cleaning agents are subject to the REACH regulations (European Union Regulation Concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals). In conjunction with the REACH regulations, a further acronym comes into play, namely DNEL.

 

What do the abbreviations stand for?
Numerous new acronyms and calculations have been introduced for cleaning validation, and not all of them are easily understandable. Certain acronyms are also used synonymously.

Thus, it is important to understand the terms and acronyms in order to be able to implement the new requirements. The most common acronyms and terms are shown in table 1, together with explanations.

 

What do the new requirements mean for cleaning validation with regard to the active substance?
The inclusion of the toxicological properties of an active substance for the establishment of the limit values for the maximum permissible carryover to the next product to be manufactured poses a challenge. The available toxicological data for an active substance must be collected and analyzed in order to derive the PDE values. In accordance with the EMA guideline, all toxicological data must be traceable, so that listing the source is mandatory. The analysis of the toxicological data must be done in collaboration with an expert. The participation of a toxicologist is thus indispensable.

Why this is necessary is shown by the factors F1-F5, which are used in determining the PDE:

PDE = NOAEL × Body wegiht
            F1 x F2 x F3 x F4 x F5
 

F1:      Factor for the extrapolation between types.

F2:      Factor for the variability between individuals.

F3:      Factor for taking short-term studies (e.g. less than 4 weeks) on toxicity with repeated administration of the active substance into
           account.  

F4:      Factor in the case of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity.

F5:      Variable factor applied when no NOAEL is available. If only an LOEL is available, this factor must be applied depending on the severity
           of the toxicity.

 

If the PDE value is available for a substance, it can be used to derive the limit value for the maximum permitted carryover of residues (maximum allowed carryover [MACO]) to the next product to be manufactured.

 MACO = PDE x minimal batch size of the next product
                             maximum daily dose of the product for human treatment to be manufactured*

 

*Corresponds to the mass of the form of administration x the frequency of dosage per day

 

Depending on the PDE value, significantly different limit values may be obtained compared to those calculated based on the 10 ppm criterion or the 1/1000 dose criterion. If the limit values are stricter, the cleaning procedure may need to be improved and the method revalidated. If the limit values are less strict, this is not necessary. In any case, the limit values based on the PDE calculation must be used for new cleaning validation procedures. However, the general principle should be complied with that the cleaning should be done according to the latest standards of science and technology, and contamination must be excluded. Taking the technically feasible cleaning performance into account is therefore recommended. If this was documented using the 10 ppm criterion, for example, the limit values for new cleaning validation procedures should be based on the stricter 10 ppm criterion, even if the limit values should be higher based on the PDE calculation.

For the toxicological evaluation using the PDE calculation, it must be taken into account that no threshold value for genotoxic activity is available under any circumstances. In this case, the TTC defined in the EMA Guideline on the Limits of Genotoxic Impurities (1.5 µg/day) can be used as a criterion for calculating the limit values. For genotoxic substances for which sufficient data on carcinogenicity is available, the TTC approach cannot be used. A substance-specific assessment of the acceptable intake must be done instead.

 

What do the new requirements mean for cleaning validation with regard to the cleaning agent?

In the calculation of the limit values for cleaning agent residues, the toxicological properties of the cleaning agents were always taken into account, as the LD50 value is used as a basis for the limit values. Based on Layton’s assumption that no toxic effects are observed at 1/2000 of the LD50 value per day, the NOEL value is derived from this. Using a safety factor (SF) with regard to the form of administration of the drug (topical, oral or parenteral), the ADI value (ADI = NOEL/SF) and thus the MACO value can be calculated as follows

 

 MACO = ADI x Minmal batch size of the next product to be manaftured
                            maximum daily dose of the product for human treatment to be manufacture*

As chemical substances, cleaning agents are subject to the REACH regulations. This means that instead of the LD50 values, which are not always calculated for new chemical products, the DNEL value must be used, which is determined for new substances in accordance with REACH. The DNEL value must be specified for a substance in relation to the most likely forms of exposure (oral, dermal, inhalative) and the probable duration and frequency of exposure. Because the DNEL is stated in mg/kg/day, body weight must be taken into account in calculating the limit values:

 

 MACO = DNEL x Body weight x Minmal batch size of the next product to be manaftured
                                maximum daily dose of the product for human treatment to be manufacture*

 

As cleaning agents are often mixtures, DNEL values are usually available only for the individual components. In this case, the DNEL of the most critical substance in the mixture should be used, as more toxicological data are generally available for individual chemical substances.

As already described for active substances, the stricter limit value should be used for existing cleaning validation procedures. For cleaning validation procedures in which new cleaning agents are used, the limit values should be calculatd with the DNEL value. Only those cleaning agents should be selected for which the supplier of the cleaning agent provides DNEL values.

 

Conclusion
All cleaning validation procedures must be assessed with regard to the new guideline. If adequate toxicological assessments are available as PDE values for the active substances and as DNEL values for the cleaning agents, these can be used to calculate the limit values for cleaning validation procedures. In conjunction with existing validation procedures, the values should be compared and a decision made on the extent to which a validation procedure with new acceptance criteria is required. Should the available toxicological data be insufficient, a possible strategy for toxicological analysis and the limit values derived fom it should be developed in collaboration with a toxicologist. This may be the case particularly for clinical test preparations.

In general, the complexity of cleaning validation procedures should not be underestimated; they require extensive specialist knowledge in a variety of fields. Our compliance team looks forward to advising and supporting you in your upcoming projects.

 

References:

EU Guidelines for GMP for Medical Products for Human and Veterinary Use, Annex 15.

EMA/CHMP/CVMP/SWP/169430/2012: Guideline on setting health based exposure limits for use in risk identification on the manufacture of different medicinal products in shared facilities.

D.W. Layton, B.J. Mallon, D.H. Rosenblatt, M.J. Small, Deriving allowable daily intakes for systematic toxicants lacking chronic toxicity data. Reg. Tox. Pharm. 7, 96-112, 1987.

EMEA/CHMP/QWP/251344/2006: Guideline on the Limits of Genotoxic Impurities.

 

Dr. Hildtrud Lenke und Raimund Brett|Senior Consultants|The Business Designers

 

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