Technical Equivalence Report

Under the scope of Directive 98/8/EC

New manufacturing location/change in method of manufacturing for

XXX

CAS No.: XXX

Active substance in Biocidal Products, PT X

Applicant: XXXX

RapporteurMemberState: XXX

Month 20XX

CONFIDENTIAL

Applicant: XXX
RMS: XXX / Active ingredient (PT X) / Technical equivalence report / Month 20XX

Table of Contents

1.Statement of subject matter and purpose for which the report was prepared

2.Evaluation of equivalence of sources of the substance (Tier I)

2.1Data requirements

2.1.1Name and address of applicant (Annex point IIA, 1.1)

2.1.2Location of source applied for (Annex point IIA, 1.1)

2.1.3Location of reference source (Annex point IIA, 1.2)

2.1.4Chemical name (Annex point IIA, 2.1 and 2.2)

2.1.4EC- and CAS-number (Annex point IIA, 2.4)

2.1.5Molecular and structural formula, and molecular mass (Annex point IIA, 2.5)

2.1.6Method of manufacture (Annex point IIA, 2.6)

2.1.7Specification of purity (Annex point IIA, 2.7)

2.1.8Specification of impurities and additives (Annex point IIA, 2.8)

2.1.9Analytical profile of the substance of at least five different representative batches (Annex point IIA, 2.7 and 2.8)

2.1.10Analytical methods (Annex point IIA, 4.1)

2.1.10.1Analytical method for the determination of the active substance in the technical material

2.1.10.2Analytical method for the determination of impurities in the technical material

2.2Evaluation of equivalence of sources of the substance (Tier I)

2.2.1Conclusion of Tier I assessment

2.3Evaluation of equivalence of sources of the substance (Tier II)

2.3.1Conclusion of Tier II assessment

2.4Overall conclusion on technical equivalence

3.References relied on

1.Statement of subject matter and purpose for which the report was prepared

This report was prepared in accordance with the TNsG on Technical equivalence[1] for the following reason:

Table 1:

Technical material from a new/different manufacturer
Data from large-scale production vs. pilot scale production.
Change in the manufacturing process, and/or manufacturing location.

2.Evaluation of equivalence of sources of the substance (Tier I)[bc1]

2.1Data requirements[bc2]

2.1.1Name and address of applicant (Annex point IIA, 1.1)

AddressXXXX

XXXX

Telephone+XXX

Facsimile+XXX

E-mailXXXX

2.1.2Location of the manufacturing plant (source)[a3](Annex point IIA, 1.1)

Address XXXX

XXXX

XXXXX

Telephone +XXXX

Facsimile+XXXX

E-mail XXXX

[JC4]

2.1.4Chemical name of the active substance ([CÖ5]Annex point IIA, 2.1 and 2.2)

XXX (CA)

XXX (IUPAC)

XXX (ISO)

2.1.5EC- and CAS-numberof the active substance(Annex point IIA, 2.4)

EC-No.: XXX

CAS-No.: XXX

2.1.6Molecular and structural formula, and molecular mass of the active substance(Annex point IIA, 2.5)

Molecular formula: XXX

Structural formula:

Molecular mass:XXX g/mol

2.1.7Method of manufacture for the active substance (Annex point IIA, 2.6)

XXX[d6][bc7]

If the method has not changed, please state so. In case of a new method, please give a detailed description of the method. [a8]

2.1.8Specification of purityof the active substance (Annex point IIA, 2.7)

Note that claimed purity should be justified by the findings in the 5-batch analysis (see 2.1.10 below)

In case of mono-constituent substances:

Minimum purity XXX g/kg (typical purity XXXg/kg)

In case of multi-constituent substances:

Main constituent 1: lower content: XXX g/kg, upper content: XXX g/kg (typical content: XXX g/kg)

Main constituent n: lower content: XXX g/kg, upper content: XXX g/kg (typical content: XXX g/kg)[CÖ9]

2.1.9Specification of impurities and additives (Annex point IIA, 2.8)

a- additives

b- impurities :

[bc10]Impurity 1

Common name (ISO): XX

Function:XX

IUPAC-name: XX

CAS-No.:XX

EC-No.:XX

Molecular formula:XX

Structural formula:
Molecular mass:XX

Concentration of impurity:≤ XX g/kg (Note this should be justified by the findings in the 5-batch analysis; see 2.1.10 below)

Classification[bc11]XX

2.1.10Analytical profile of the substance of at least five different representative batches (Annex point IIA, 2.7 and 2.8)

5-batch data for the new source generated [a12][CÖ13] using analytical method(s)[CÖ14] (see Section 2.1.11) are presented in table 2.10-1.Please indicate whether the data has been generated under GLP or not. If not done according to GLP give brief justification [d15]to the acceptance of the data.

The following information on the batches was provided[JC16]:

Batch Code / Date of manufacture / Weight of technical material[a17]
[CÖ18]

These batches can/cannot be regarded as representative of current manufacture. [d19][a20]

Table 2.10-1:Summary of the batch analysis data

Component / Batch data (%w/w) / Mean / SD / Mean ±3 stdev[a21][bc22][CÖ23]
Batch No 1
Batch Code / Batch No 2
Batch Code / Batch No 3
Batch Code / Batch No 4
Batch Code / Batch No 5
Batch Code
Active ingredient*
Impurity 1
Impurity n
Mass balance (%) / XX / XX / XX / XX / X / -

N.D.= Not Detected
N.A.= Not Applicable
<LOQ= less than the limit of quantification

* In case the active substance is a multi-constituent substance it should be divided into main-constituent 1 to n.[a24]

2.1.11Analytical methods (Annex point IIA, 4.1)

2.1.11.1Analytical method for the determination of the active substance in the technical material

Reference: / Title, Author, Year
Method:
Validation data: / Relevant validation data must be provided or reference to a previous evaluation e.g. the method is the same method considered for annex 1 inclusion and the validation data are applicable to the new source or reference to a recognised standard method made e.g. CIPAC method (example chromatograms from the analysis would still be required. [CÖ25]
. [d26][a27]
RMS comments:

Summary of the sample preparation details and the analytical technique used for quantification

A brief summary of the sample preperation preparation details and the technique used for final quantification should be given if new validation data have been considered[JC28][bc29]. [CÖ30]

A summary of the validation data are presented in table 2.1.11.1.

Table 2.1.11.1-1: A summary of the validation data for determination of the active in the technical material[JC31][bc32]

Recovery fortification level (%w/w) / Recoveries % range (mean) / Repeatability % RSD (n) / Linearity
(range, %,r2and n) / Specificity
N/A – not required for the active in the technical material* / [CÖ33]

*Usually recovery for the active in the technical material is not required. However, if the purity of the active as manufactured is low[d34] (e.g. TK) then recovery data maybe appropriate.

2.1.11.2Analytical method for the determination of impurities in the technical material

Summary of the sample preparation details and the analytical technique used for quantification

A brief summary of the sample preperation details and the technique used for final quantification should be given if new validation data have been considered[JC35]

A summary of the validation data are presented in table 2.11.2-1.

Reference: / Title, Author, Year
[CÖ36]Method:
Validation data:[JC37] / [CÖ38]
RMS comments:

Table 2.11.2-1: A summary of the validation data supporting the determination of the impurities/additives in the technical material[JC39]

Analyte / Level present in batch pre-fortification (% w/w[JC40]) / Recovery fortification level (%w/w) / Recovery, % (n) / Repeatability % RSD (n)* / Linearity
(range, % w/w, r2 and n) / Specificity / Limit of quantification (LOQ)[bc41]

[CÖ42]* As an acceptance criterion the repeatability could be compared to for example the mod. Horwitz value at that level (see for example SANCO/2020/99 used under Dir. 91/414/EEC) )[d43]

2.2Evaluation of equivalence of sources of the substance (Tier I)

The following specification was derived for the reference source (see CAR, PT XX doc III-A2.7 and Confidential Annex doc III-A2.8) (only relevant if a specification is not explicitly given in the CAR; if available use the next table directly)

Table 2.2-1:

Component / Specification
Active ingredient* / min. XX%
Impurity 1 / max. XX%
Impurity n[CÖ44]

* In case the active substance is a multi-constituent substance it should be divided into main-constituent 1 to n.

Table 2.2-2:

Reference source[2] / Different Source[3] / Variation[bc45] and conclusion
Certified values[bc46] / Certified values[d47] / (example)Variation[bc48]
Main constituent 1 / min. XXX g/kg / min. XXX g/kg / XX g/kg
Higher purity
Main constituent n[CÖ49] / min. XXX g/kg / min. XXX g/kg / XX g/kg
Impurity 1 / max. X g/kg / max. X g/kg / XX g/kg
higher content by more than 6 g/kg
Impurity n / max. X g/kg / max. X g/kg / XX g/kg
Lower content/
Identical content/
New impurity/
Higher content for a relevant impurity...

2.2.1Conclusion of Tier I assessment[bc50]

The new source is chemically equivalent to the reference source[JC51]:

1)The minimum purity [d52]of the new source is equal to or higher than the reference source

2)There are no new impurities in the new source

3)The significant impurities do not exceed the following limits from those specified in the reference source:

By more than 3 g/kg for impurities ≤ 6 g/kg
By more than 50 % of the certified limit for impurities > 6 g/kg

4)The impurities regarded as toxicologically relevant do not exceed the certified limits (delete if no relevant impurities are identified in the active as manufactured).

It can therefore be concluded from the tier I assessment that the new source is technical equivalent to the reference source. [CÖ53]

The new source is not chemically equivalent to the reference source due to the following reasons:

(a list of the tier 1 criteria that the new source does not meet should be given)

As the new source is not chemically equivalent to the reference source then a tier II (toxicological and ecotoxicological) assessment is required. [CÖ54]

The specified minimum purity [d55]for the new source is equal (or higher) to the reference source. Moreover, no new impurities are detected in the new source compared to the reference source and the levels for the significant[JC56] impurities present in the reference specification do not exceeded (by more than 3 g/kg for impurities ≤ 6g/kg or 50% of certified limit for impurities ≥6[JC57] g/kg).[JC58][CÖ59]

Equivalence Criterium / fulfilled
The minimum degree [d60]of purity obtained with the new source is equal or higher than the one obtained with the reference source; / yes/no
In case of a multi-constituent substance, each main constituent remains in the 10-80% range and the concentration of each main constituent does not deviate by more than 5% absolute or 10% relative, whichever is larger / yes/no
No new impurity or additive is presentcompared to the reference source / yes/no
The limit of each relevant impurity or additive is not exceeded / yes/no
The limits of all non-relevant impurities as certified on the basis of a 5-batch analysis for the reference source, are not exceeded by more than the following levels: more than 3 g/kg for impurities ≤ 6g/kg or 50% of certified limit for impurities ≥6 g/kg). / yes/no[CÖ61]

The equivalence Tier I criteria are fulfilled. It could thus be concluded from the tier I assessment that the new source is technically equivalent to the reference source.

Technical equivalence could not be concluded from the tier I assessment. Tier II is necessary.[CÖ62]

2.3Evaluation of equivalence of sources of the substance (Tier II)

Give tox/ecotox/environmental data if relevant (i.e. if equivalence cannot be concluded on based on Tier I)[a63][CÖ64]

2.3.1Conclusion of Tier II assessment

It could thus be concluded from the tier II assessment that the new source is technical equivalent to the reference source.
Or

It is concluded that the new source is not technically equivalent to the reference source.

2.4Overall conclusion on technical equivalence

Technical material equivalent following Tier I assessment?
Technical material equivalent following Tier II assessment?

3.References relied on

Section No. / Reference No. / Author(s) / Year / Title
Source (where different from company)
Company, Report No.
GLP (where relevant) / (Un)Published / Owner

1(10)

[1] Technical Notes for Guidance on the assessment of technical equivalence of substances regulated under Directive 98/8/EC, adopted during the 29th CA-meeting

[2]Give the following in the footnote: Applicant for the reference source and exact location of the source (if known)

[3] Give the following in the footnote: Applicant for the new source and exact location of the source

[bc1]FR : Title proposition : “Summary, evaluation ans assessment of data”

[bc2]FR : Title proposition : “Identity of active substance”

[a3]UK:

Adding the term ‘source’ adds clarity that a source is a specific manufacturing plant and cannot be applied as a general term to cover a specific manufacturer which may include several different manufacturing plants.

[JC4]Such information (Location of reference source; comment by SE) is not needed here. It will be included in section 2.2. No need for duplication. Also the first sections should be about the new source only, the reference source only needs to be mentioned when the technical equivalence is performed in section 2.2.

In addition, while a new applicant may not have access to this information the MS will. Therefore, while the new applicant should submit the evaluation using this template this section can be completed by the MS. After all the final evaluation cannot be sent back to the applicant if they are not the same applicant as the annex 1 reference source i.e. section 2.2 contains the technical specification of the reference source which will be confidential to the data owner of the annex 1 reference source.

[CÖ5]SE response 2012-02-07: We think it is implied that all information under 2.1 (data requirements) refers to the source applied for and therefore it seems unnecessary to repeat ‘new source ‘here and below.

[d6]DE: this should be only required, if the method of manufacture was changed.

[bc7]FR agrees with SE comment

[a8]SE: Our idea is that if the method is the same as for the reference source, this could just be briefly stated.

If the method is different, a more detailed description of the new method is needed.

[CÖ9]SE response 2012-02-07: Agrees to proposed changes

[bc10]FR proposition

[bc11]FR: we propose to report the classification (CLP-67/548) in order to identify relevant impurities

[a12]UK:

Generally batch data should be generated under GLP. However, there is a clause in the TNsG that suggests that on a case by case basis non-GLP data maybe acceptable (section 6.4 ‘Exemptions’). The wording needs to be considered carefully or all MS and the COM will need to agree that all batch data from now on must be GLP.

[CÖ13]SE response 2012-02-07: We agree. Possibly it could be given: “Please indicate whether the data has been generated under GLP or not. If not done according to GLP give brief justification to the acceptance of the data”

[CÖ14]SE response 2012-02-07: Here it was meant that either it should fully be referred to Section 2.11……… using the analytical methods shown in Section 2.11 below

or that the analytical methods used should be briefly mentioned…..using analytical methods ABC123 (active substance), ACB132 (impurity 1), etc.

Possibly this should be further clarified.

[d15]DE: As far as DE knows there is no legal basis for requesting a GLP-5-batch analysis. Next to this it is unclear which justification will be accepted and if any will be refused - what is the legal basis for refusing it?

[JC16]UK:

For completeness such information on the batches analysed to support the technical specification is required. This has previously been confirmed by the COM. Such information allows the assessment of the representativeness of the batches to be assessed. In addition, it will confirm if batches come from a pilot plant or full scale production. If the batches come from a pilot plant that further batch data will be required on the commencement of full scale production.

If the batches are say more than 5 years old then they may still be OK, however a justification that they are still applicable i.e. no changes to the manufacturing method etc must be submitted.

[a17]DE: From the DE point of view this table is not required. The information which batches were analyzed could be provided in the next table (see below)

[CÖ18]SE response 2012-02-07: We agree that code number, date of manufacture , and possibly weight of technical material is information that should be known and provided within the 5-batch analysis. However we questioned a bit the need to explicitly state it in this report. Wouldn’t it be sufficient to state in the report something like?
“5-batch data on technical material representative of full scale production produced during Sept-October 2012...... "

Personally I would accept a statement by the applicant confirming that the batch data relates to full scale production. In case we add it as a table in the template it must always be reported within such details.

[d19]DE: Can this be concluded based on batch numbers, manufacturing date and weight?

[a20]SE: This is not a conclusion from the above table. The applicant must confirm whether the batches can be regarded as representative or not.

[a21]UK:

A column on the mean ± 3 stdev (the rule of thumb) would be beneficial.

While the rule of thumb is only a guide using this ensures there is transparency and consistency in setting technical specifications. Obviously applicants can submit scientific cases based on the chemistry involved and nature of the impurity on why certain limits are required or supporting QC data.

[bc22]FR agrees with UK comment

[CÖ23]SE response 2012-02-07: Agrees, this could be added. Possibly to make it even more transparent this table should include the technical specification proposed in Section 2.1.8 and 2.1.9 above. This could be done in a table in landscape format.

[a24]SE response 2012-02-07: For multi-constituent substances it is evident what is meant by main-constituent. However, writing active substance here is to distinguish it from impurities. In case the active substance is a multi-constituent substance it has to be further divided into main-constituent 1 to n. Hereby as an example in the table, I still think it could say ‘active substance’

[CÖ25]SE response 2012-02-07: We perfectly agree. However, we are not completely clear on how informative one should be in a template like this. Possibly it is sufficient to state relevant validation data should be provided.

[d26]DE: Are we right in assuming that if the analytical method was already assessed for the annex I inclusion, no information regarding this method will have to be provided in this document and that a brief comment like “ method was assessed for annex I inclusion” would be sufficient to cover the data requirements of 2.1.11? If we are correct, this fact should be stated more clearly here.

[a27]SE: If DE has a proposal for a new wording, this could be used.

[JC28]UK:

Such information is required for the annex 1 source and hence these details should be provided in the equivalence report for a new source. There needs to be transparency in the method used to support the determination of the active.

Summarizing the validation data in a table is the most efficient way.

[bc29]FR agrees that it is more efficient to summarize the validation data in a table.

[CÖ30]SE response 2012-02-07: We agree that this information should be provided. In the reports we have previously prepared we have included this in the entry ‘Method’ above and depending on how informative this template should be this could be included as guidance in that entry.

[JC31]UK:

A more efficient way of summarizing the validation data for the active would be in a table like this.

[bc32]FR agrees with summarizing the data in such a table

[CÖ33]SE response 2012-02-07. We agree with and propose a small addition.. To be referred to in the ‘validation data’-entry above.

[d34]DE: Please clarify what “low” means. Will there be a case by case decision or are there any values defined?

[JC35]UK: