New ema guide - Ingelyt Clean Room Engineering - GMP Consulting

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The EMA has approved on the 20th of November 2014, the new guide “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”. Once approved, this guide will have to be complied from the first of June 2015.

 Download guide



As indicated in the guideline, the goal of this guide is to define the way the pharmacological and toxicological data of the different active substances have to be revised and evaluated, with a double aim:

  • Its use for the risk analysis for the balance or not of products in a multiproduct facility.
  • Its use for the theorical calculation of the admissible cleaning limits. 

3.Data of interest about the guideline


1. Reference documents


It states that the document used for the determination of the exposition limits of active wastes is the method for the specification of the PDE (daily acceptable exposition) described in the annexe 3 of the ICH Q3C (R4) “Impurities: Guideline for Residual Solvents” and annexe 3 of VICH GL 18 on residual solvents in new veterinary medicinal products, active substances and excipients (Revision)”

Download annexe 3 of ICH Q3C (R4) Impurities: Guideline for Residual Solvent

Download Appendix 3 of VICH GL 18 on residual solvents in new veterinary medicinal products, active substances and excipients

2. Security factors


Both annexe 3 of the ICH Q3C (R4) and annexe 3 of VICH GL 18 give some guidelines to fix the security factors (f1,f2,f3, f4 y f5).

3. Requiring dedicated facilities


Those active substances and final product with a high potential sensitising degree for which the scientific data doesn’t endorse an acceptable exposition level for its use in a facility and that the facility can not adequately control with technical or organisational methods, will require dedicated installations. No products are detailed a priori.

4. Proteines, macromolecules and peptides


It speaks specifically about the macromolecules and peptides for which it is known that they degrade and denature when they are exposed to extreme pH or warm, they convert into inactive products, as they cause the deterioration and inactivation of products based on proteins. For this case it has no sense to apply the exposition risk methodology based on the PDE limits.

5. Toxicological and medical expert


The toxicological data and the toxicological expert are key for the definition of the starting values for the calculation of the cleaning limits and the product harmonization risk analysis. The role of the expert is to realize an evaluation of the potential health adverse effects risk, after the exposition to the studied medicine. It is a sistematic scientific caracterisation to identify, describe and measure the risk after the revision of the relevant toxicological data available related to the studied product. For that purpose, it is necessary to validate the existing toxicological data and make a balance of the toxical effects found.

6. Toxicological and medical revision


The toxicological revision will be done through the access and analysis of the information obtained in medical databases (Pubmed, scifinder…), and specific toxicological database (TOXNET, specific pages of each country…). In the final report and in the definition of the toxicological values, all the factors that define the international guides defining the toxicological values as the potential genotoxic and carcinogenic, security factors (that assure for example the extrapolation between the animal and human toxicology) via of administration (which among others can modulate the exposition related to the administration orally or topically, for example) bioavailability, tipology of the patients, are taken into account, appart from the bibliographic revision.


As the guideline annexe shows, the CV of the toxicologist has to be annexed and it is also recommended the CV of the medical expert in medicines evaluation.

3. Implementation


The phases are the following :

  • For new products introduced for the first time in multiproduct facilities 6 months from the publication of this guideline. We understand that from the 20th of May 2015 the analysis has to be done.
  •  For current manufacturers and products currently manufactured in multiproduct facilities and produce human pharmaceutical  products or combine human and veterinarian products the timeline is 1 year from the publication of this guideline.
  • For current manufacturers that produce exclusively veterinarian products the timeline is 2 years long.

4. Ingelyt Support 

Ingelyt in collaboration with toxicological and medical department of Azierta ( is realizing this type of risk analysis for the product combination study as well as for the scientific fixation of the cleaning limits based on toxicological data endorsed by toxicological and medical experts that have already been approved by the AEMPS and other regulatory agencies.

Alberto Carazo

Director of pharmaceutical advisory Ingelyt

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