- GIC A3P Validation of Cleaning prepares a practical guide for 2017 Autumn on 10 Chapter of 15 Annex of European GMPs: Presentation & Discussion.
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With the official publication of the new Annex 15 of the European GMPs Eudralex Volume IV in October 2015, if there was a major subject of vigilance to highlight the recent audits of the European Health Authorities, it would, no doubt , The validation of the cleaning that should be chosen. Chapter 10 of this Annex 15 has been enriched with 8 additional paragraphs for a total of 15. Therefore, this is a regulatory "upheaval"!
These changes have created many questions on our industrial sites regarding the implementation of all these points.
Take for example the case of the famous PDE (Permitted Daily Exposure): "How will we find the source data to calculate this value? Should we only rely on toxicological studies? How to calculate this value? Should we calculate it for all products? Is there an obligation to call on a "recognized expert" toxicologist for this PDE calculation? ... "
All attention has been focused on this PDE and its practical application described in the EMA Guideline "Guideline on setting health based exposure limits for use in the identification of medicinal products in shared facilities". This posed a number of problems and consisted not in treasure hunting, but rather in "fishing".
However, it is important to recall the following point: if the PDE calculation is an indispensable prerequisite for many cleaning validation strategies (its permanent use seems to be called into question by the last draft published in January 2017 on the site of the EMA), all other aspects described in Chapter 10 are essential. Too often, we encounter errors on the "field".
Example of regulatory discrepancies in the ANSM audit:
- "No consideration of toxicity in the choice of worst case product"
- "Clean Hold Times are not defined and therefore not validated"
- "The product used for the validation of the cleaning of the tank X is not manufactured on this tank in routine"
- "The rationales to justify the location of the critical points to be taken in the validation protocols of cleaning did not take into account the surfaces in indirect contact"
- "The manufacturing processes are poorly defined and it was noted the lack of consideration of the cumulative effect of the equipment train for the calculation of acceptance criteria!" ...
Also, beyond the PDE, all the points in this 10 paragraph must be clearly taken into account in your VMP (Validation Master Plan) so as to show how you manage them.
However, these 15 paragraphs are not obvious to understand and especially to interpret. In addition, they can serve as a reference for several production areas (including sterile and non-sterile medicines in human health, biotechnology, veterinary industry, cosmetics, medical devices).
In these circumstances, we thought it advisable to set up a working group on the subject, the most comprehensive group possible, made up of producers and suppliers, with as many sectors as possible. This is how the 26 September 2016 was born the GIC A3P Cleaning Validation (VN).
List of participants
• Margaux ARTHUS, Continuous Improvement Manager, GIFRER
• Thierry BESNARD, Pharmacist Toxicologist, CARSO
• Sophie BOURGOIS, Cleaning Validation Expert, ASPEN
• Ludovic DEMOOR, Validation Manager, LFB
• Pierre DEVAUX, Expert Control of Contamination, UPS CONSULTANTS
• Maryline DOUEZ, Cleaning Process Engineer, NOVO NORDISK
• Sandrine DUCLOS, South West Project Manager, COPHACLEAN
• Françoise DURAND, Scientific Manager, ANIOS
• Guillaume GARREAU, Validation Cleaner, GALDERMA
• Isabelle GONZALEZ, Validation Engineer, TEOXANE
• Solenn JANVIER, Laboratory Manager, SERVIER
• Christine LENS, President, KEYBIO
• Etienne MICHEL, Global Worldwide Cleaning Expert, GSK
• Stéphane MONESTIER, Packaging and Process Support Manager, FERRING
• Marie-Véronique MUNEREL, Manager AQ, VIRBAC
• Jean-Baptiste NOIROT COSSON, Manufacturing Technical Support Supervisor, MERCK
• Julie RACAUD, Qualification Validation Manager, AGUETTANT
• Thomas ROHAUT, Referent Validation Cleaning, AKTEHOM
• Emilie SOLLIER, Expert Process and Validation of Cleaning, SANOFI PASTEUR
• Lauriane ZUCHUAT, QA Manager Process and Cleaning Validation, VIFOR PHARMA
Every month, the group meets at the premises of A3P in Lyon, to synthesize the work of the sub-working groups created, with the aim of proposing to you in the autumn 2017 a guide of interpretation of the 15 Paragraphs of Chapter 10 of Annex 15, for all the sectors listed above. Through this work and our rich exchanges of information, we measure all the difficulties encountered in our organizations to define and implement these cleaning validation strategies. That is why we want to build you a guide that is as pragmatic as possible and, above all, the most adapted to best answer the day of a client audit or a regulatory inspection.
This guide will repeat step by step all the steps essential to this validation process :
1 // STRATEGY
Project management and verification, control of cross-contamination, work in the field and train (s) of equipment
2 // RECIPES
List of cleaning recipes by equipment and selection of "worst case" equipment by recipe: Grouping of equipment
3 // BORNES
Identification of the limits of each critical parameter on each cleaning recipe: Critical parameters and Test Until Clean
4 // WORST CASE
List of products in contact for each equipment and identification of the "worst case" product (s): grouping of products and substitute products
5 // TRACERS
Choice of plotters
6 // SAMPLING
Location of critical points to collect: rational sampling
7 // CRITERIA
Acceptance criteria : calculation methods
8 // CONTROLS
Sampling methods and analytical methods validated for each tracer: different control methods
9 // PROTOCOL
Writing and execution of a validation protocol on the basis of a master validation plan and cleaning instructions (operating modes): documentation
10 // RUNS
Determining the number of validation trials
11 // REPORT
Drafting of the validation report (enriched protocol of results, associated analyzes, possible modifications and conclusions): reproducible and effective recipes
12 // FOLLOW-UP
Monitoring and control of trends, anomalies and changes: maintaining the validated state.
Validation of cleaning is a critical process in our health product manufacturing business. This process is difficult to apprehend from a psychological point of view, since it is difficult to assimilate that pheromones of surface residues, which can generate a significant pharmacological effect in the many units of the following lot, and economically because it yields nothing and Especially can be very expensive especially if, after an inspection or a rejection of lots, one forgets the famous saying of the fable of Jean de la Fontaine "the hare and the tortoise": Nothing serves to run; It is necessary to start from scratch.
Pierre DEVAUX - UPS CONSULTANTS
- Annex 15: Quali cation and Validation EudraLex Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use
- 15 December 2016 EMA / CHMP / CVMP / SWP / 463311 / 2016 Com mittee for Medicinal Products for Veterinary Use (CVMP) Committee for Medicinal Products for Human Use (CHMP)
"EMA / CHMP / CVMP / SWP / 169430 / 2012" (EMA / CHMP / CVMP / SWP / XNUMX / XNUMX) in production and "Guideline on setting health based exposure limits for use in risk identification in the manufacture of di erent medicinal products in shared facilities"
- 20 November 2014 EMA / CHMP / CVMP / SWP / 169430 / 2012 Committee for Medicinal Products for Human Use (CHMP) Committee for Medicinal Products for Veterinary Use (CVMP) manufacture of di erent medicinal products in shared facilities