Denehurst Chemical Safety Ltd

PPORD Dossier creation for submission

This short guide has been prepared to help with PPORD completion. The guide does not consider the functions and purpose of PPORD and when it can be used, but only covers practical issues.

For more information on when PPORDs can be used, information can be found on the ECHA and REACHReady web-sites.

This guide is only supplementary to the official ECHA guidance on submission found on the following site

 

http://echa.europa.eu/reachit/ppord_en.asp   

 

There is also a ‘completeness’ tool to help that can be downloaded from the IUCLID web-site   http://iuclid.eu/

This guide assumes a working knowledge of IUCLID 6 and the REACH IT system.

More support  is found on this web-site 

 

 

If wanting to manufacture or supply over 1 tonne of a substance for your own trials or customer trials, it is possible to apply for a Production and Process Orientated Research and Development (PPORD) exemption. This can last 5 years and re-application for a further 5 years is possible if it can be justified (for example supplying intermediates to permit clinical trials of a pharmaceutical).

The dossier is prepared using IUCLID and submitted through REACH IT and an ECHA fee will apply. Part of the submission is a justification.

 

Denehust can offer support for justification and training on IUCLID for dossier preparation.  It is not difficult.


IUCLID 6 data input
The PPORD can be entered directly into REACH IT or can be created as an IUCLID 6 file, completing sections 1,2 and 3 (identity, classification proposals and uses) with dossier type identified as PPORD.  The infomration requirements are the same either way and if familiar with IUCLID, it is perhaps best to use IUCLID as this will then form the starting point for any subsequent registration.

1 Assuming the substance to be manufactured or imported is not EC Listed, it will not be found in the reference substance lists that can be downloaded from the IUCLID web-page. To create a new Reference Substance, right-click the 'cube' image in the 'Inventories' section of the home-page menu). When creating a new reference substance, it needs naming and if not even on the pre-installed EC Inventory list, the drop-down option below for 'no inventory information available' needs to be used. Complete as much as possible and either add a structure (picture file) with formula etc, or (for UVCB) add something in the 'remarks' box. Describe the substance as well as possible - many dossier fail through poor descriptions. 

2 Having saved the reference substance details, select ‘new substance’ from IUCLID home page (right click the 'flask' image).

3 Click on ‘section tree’ under 'TOC' to activate the list of sections and then select PPORD from box immediately below the section tree tab. The sections to be completed are now indicated with a red star.

4 Starting with substance identity, imported your newly created reference substance by using the link (chain)

5 All other sections that are highlighted should be completed and key areas are described below.

Specific input on analysis (Section 1.4)
This is probably the technical part that is most likely to cause questions back on the the dossier and the simple rule is that there should be sufficient evidence presented in Section 1.4 to confirm the identity described in 1.1 and 1.2. Therefore, if claiming a certain structure, molecular weight and purity, section 1.4 needs the evidence.  This is less critical for a PPORD than with an Inquiry as it is acceptable to claim the substance is under development and precise chemical identity and purity is perhaps part of the process research.

In many cases, this will need a variety of methods and if the substance is still in pilot plant or laboratory stage of development, methods may not have been considered fully and this method development could indeed be part of the justification for the PPORD development work. Evidence may therefore be based on both measured results and on theoretical chemistry based on firm evidence of the identity of starting materials.

There is no simple guidance to follow and will need input from experienced analytical chemists.

The basic requirements are:

NMR spectra
IR spectra
UV-Vis spectra (at pH range of 4 – 9 if water soluble)
Chromatography method

If any of these cannot be provided, there must be a good reason – there are few valid reasons not to perform the spectra and suggesting that the spectra is meaningless is unfortunately not considered a good reason. However, unlike making an Inquiry, the basic analysis is less critical, but the more evidence that can be provided, the better.

Chromatography is often not possible, but if GC or LC methods can be performed, liking them to Mass Spectroscopy may give a sufficient level of evidence for chemical identity. Other methods like Gel Permeation Chromatography (GPC) may be used for high molecular weight materials and a good chemist may be able to suggest other methods. Inorganic substances, for example, lead to a range of analytical issues and element analysis may be decided as the best options.

Optical analysis is identified in IUCLID as a requirement – obviously, this only need to be considered if different isomers exist.

It is worth spending the time on this as rejections of the PPORD will be time consuming itself and the level of analysis developed for the PPORD will in turn be required later if a full registration is sought.

Other important notes for submitting analysis details:
• Try to get all the spectra into one report to attach to the IUCLID file; it is possible to create repeat blocks to add separate files, but a single spectra report is the best way.
• The chromatography and other analysis should again be condensed to a single report and attached to the IUCLID section prompting these details.
• For all analysis work, try to use the same sample, recording a batch number or laboratory code with dates, identity of the facility where analysis took place, details of equipment, sample preparation, methods etc
• GLP is not required, but it is recommended that work is performed to Good Laboratory Practice standards with maintenance of records, signatures of responsible people, and internal checking.

Until industry has more experience with submitting dossiers to ECHA, we cannot judge the level of standard expected. These recommendations are based on accepted standards under the pre-REACH New Substance Notification system, although it should be noted that some Member States were more strict than others when it cam to analysis acceptance.

Specific input for recipients (Section 1.8)
It is possible to enter a link to sites of non-official legal entities; the only way to get the official legal entity for your recipients is to obtain their LEOX file details and import to your own IUCLID – many organisations are reluctant to pass on their LOEX files to other companies, even though this does not compromise security.

 

It is possible to 'create' a legal entity in IUCLID, but this will be an 'unofficial' legal entitiy and will be effectively for your own internal purposes.


It is also possible to add the address  to the ‘remarks’ section.

PPORD details (Section 1.9)
This section is only visible in the section tree if you either select ‘complete’ or ‘PPORD’ file type options in the drop down menu at the top of the headings.

This field is repeatable and allows more than one process research application to be described if necessary. It also prompts the question of whether it is a medicinal product or is just not placed on the market. Note that to be valid for a PPORD, the substance should not be placed on the open market, but should only be supplied for restricted uses to specified recipients; it should never be supplied to non-skilled users or the general public.

The section allows the option to add a document and it is recommended to use the pre-REACH PORD application form as a guide. An example of a completed version is attached to this guide.

The justifications for a PPORD must meet the restrictions laid down in the legal text and in associated ECHA guidance and include indications of tonnage, use patterns, levels of exposure etc. Again, until industry has more experience, the standards expected by ECHA are not yet known, but the attached example is of a standard that was accepted for pre-REACH PORD requests.

Classification and labelling (Section 2)
Although there are no formal data requirements for testing substances for a PPORD, it must be remembered that European supply and transport legislation applies to all chemicals and the supplier must have sufficient knowledge about the substance to allow recommendations to be made for labelling and safe handling. A Safety Data Sheet is required.

The phrase ‘Caution: not yet fully tested’ is recommended for the SDS and label.

Section 2 can be completed using GHS / CLP end-points, but there needs to be some justification if claims are made that the substance is non-hazardous. If data are available, for example melting point, flash point etc, then these can be entered as fully as possible in subsequent IUCLID sections (eg 4.2 and 4.11 for melting point and flash respectively). To enter data, right click and open the ‘new endpoint study record’. Only use the ‘end point summary’ if summarising more than one test result for the same end point.

Most parts of these data entry sections will not be possible to complete, but as they show up green on the PPORD dossier, they are considered supplementary and are not part of the completeness check. Fill these sections in the best as possible.

Sites (section 3)
As indicated above, only the sites of ‘official legal entities’ need be added here and the only entry will be either yourself as the manufacturer or yourself as the importer or both, (by using the repeat option) if you have the LEOX file of the non-EU manufacturer and the EU importer.

 

 

 

Creating the dossier
Once complete and the attachments included, you need to create the dossier for submission.

1 When in the Click on ‘search’ tab (top left of navigation pannel), right click on the substance (listed) and select the ‘create dossier’ option. It may prompt you to save changes (say yes).


2 Select the correct dossier type (ie. REACH PPORD).  You have a chance later to add or delete any supplementary data you may have added (eg melting point, flash point etc) Advanced options allow other filtering.

3 On the next page (not advanced option), you can name the dossier for later reference (optional) and add comments if needed. The final screen allows you to copy protect – again, only use if giving it to other people in your organisation or customers to check if you do not want them fiddling with it and duplicating the data.

When you finish, you can view the dossier. Note that the dossier is locked and no changes can be made. If finding an error or if further editing needed, the substance file needs changing and the whole dossier creating process repeated.

Exporting the dossier
The Dossier file can now be exported by selecting ‘search’ (top left) and ‘export’. Remember where you save it, but if you lose it, search for ‘.i6z’ and this will narrow the search to IUCLID export and import files.


Submission
Submission is through logging into you REACH IT account; if you have no account, one will need to be created on the REACH IT. Only EU / EEA legal entities can have this account and if working outside Europe, the account must be in the name of the Only Representative.

REACH IT home page is https://reach-it.echa.europa.eu/reach/public/welcome.faces

(Note that REACH IT is essential for pre-registrations, CLP Notification etc so it is hoped that you are familiar with the process already).

Using the menu in REACH IT, make the submission by attaching the IUCLID dossier file saved earlier (.i5z) and submit.

What next ?
Within a few hours (working days) you will get a message in your REACH IT mail box (not a ‘regular’ e mail) with reference numbers and either get a rejection or acceptance comment – this first part is to check the administration and completeness.

If accepted, an invoice will be received and it is advised to pay as promptly as possible to ensure that the review period can start.

Note of warning for companies with complex vendor ‘supplier systems’. Setting up account systems with ECHA is not easy and it must be done in Euros and by electronic transfer (not cheque).


Annex – Completed generic PPORD justification
This template is based on the pre-REACH PORD requirements and still covers the justification for a REACH PPORD (the old PORD was a national submission and the PPORD is across Europe).  A 'Word' version can be provided on request.

 

 

Research & Development details

What is the envisaged use of the substance?

Substance x is required for the synthesis of a pharmaceutical intermediate. Previous trials have been quite successful and further scale-up is required, to remove or reduce impurities formed in these previous. At this time, without scale-up, the manufacturer does not know if the impurity targets can be achieved. Therefore, an R & D plan, including pilot plant production, is necessary to test the reproducibility of lab trial into production scale.

What R&D work has already been carried out either by yourself or, if appropriate, by the customers involved in the R&D programme (e.g. internally or under the <100kg p.a. scientific R&D derogation)?

Kilo quantities have already been synthesised, but scale up is required to ensure commercial production can produce the high specification material required.

What is your justification for wanting to use this derogation (including an assurance that you do not currently know whether you can achieve the desired effect)?
Scale-up of production processes

What additional information will be gained through the proposed R&D program?

Confirmation of methods and systems to be used to meet high standards of purity required

Please give a summary of the R&D plan, included the process to be investigated, the timetable and a proposed start date.


Plan is to ......


What is the justification for the quantity involved in the proposed R&D program (including the justification for the number of batches and the quantity per batch, etc.)?

It is considered four batches will be sufficient to complete the trials

Please confirm that the substance, or any preparation containing it, will only be handled by the customers staff under controlled conditions and will not be made available to the general public.

The substance will not be supplied to the general public or to any organisation other than the customer [details]
If supply is greater than 1 t.p.a., please supply sufficient information about the process, disposal procedures, etc. to demonstrate that the potential for environmental exposure will be kept to a minimum. Details of the process should include batch sizes, identification of any potential losses (e.g. process emissions to waste water, reactor washings and residual material left in containers) and information regarding any treatment of wastes and waste disposal practices for all potential waste streams.

The substance will be consumed in trials by the customer in [ ]. Any waste, including residue from packaging, will be disposed of as chemical waste with the warning that the substance has not yet been fully tested. There will be no loss of washings to waste water and all waste will be collected for chemical waste disposal. The substance is produced and used at dedicated chemical plants with high levels of control for worker protection and environmental loss.


Do you intend to use the substance to produce articles and, if so, would these be made available to the general public?
No