19 April 2018
EMA/CHMP/CVMP/SWP/246844/2018
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Committee for Medicinal Products for Veterinary U (CVMP)
Committee for Medicinal Products for Human U (CHMP)
Questions and answers on implementation of risk-bad prevention of cross-contamination in production and
‘Guideline on tting health-bad exposure limits for u in risk identification in the manufacture of different medicinal products in shared facilities’
(EMA/CHMP/CVMP/SWP/169430/2012)
Q1. Are Health-Bad Exposure Limits (HBELs) required for all medicinal products?
A: Yes, HBELs should be established for all medicinal products.
The toxicological or pharmacological data, on which the HBEL calculation relies, requires periodical re-asssment th roughout a product’s lifecycle.
Q2. Is there a framework that could be ud to define the significance of the Health-Bad Exposure Limit (HBEL) such that there can be broad guidance on the extent of Quality Risk Management (QRM) and control measures required?
A: Firstly, it should be recognid that hazard varies on a continuum scale and that there are no firm cut off points, risk should be controlled on a proportionate basis. However, as a broad hypothetical model the following figure could be considered to show the increasing level of hazard (red being highest hazard) prented by products and there should be a commensurate increa in the level of control to prevent potential cross contamination in a shared facility. Actual HBEL values should be ud in QRM studies to determine the actual controls required.
Manufacture of Pharmaceutical Products, International Society for Pharmaceutical Engineering (ISPE), Second Edition, July 2017.
30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom
Q3. How should manufacturers u the HBELs?
A: The role of HBELs in determining cleaning limits is explained in Q&A 6. However, the purpo of generating HBELs goes beyond justification of cleaning limits.
the brainOnce the health-bad asssment has been completed and the HBEL confirmed, the data should be ud via a Quality Risk Management process to determine what controls need to be put in place and to asss if existing organisational and technical control measures are adequate or if they need to be supplemented. This Quality Risk Management process should be carried out prospectively in the ca of new equipment/facility to determine what control measures are required.
误解英语
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万圣节英语介绍It is expected that for products which prent a higher potential harm to patients/animals, more elaborate organisational and technical control measures will be required. Using a structured Quality Risk Management process, manufacturers should consider the risks of cross contamination down to the established level from the HBEL. During the QRM study manufacturers should consider how easily such a quantity of contamination could occur, without detection, at batch and unit do level.
The level of detail in the QRM process should be commensurate with the potential harm as indicated by the HBEL and the suitability of control measures supported by practical and science-bad evidence.
Manufacturers should be mindful that cross contamination controls implemented previously may not adequately assure control of the cross-contamination risk in the context of the HBEL approach.
Additional obrvation of working practices, investigation and analysis may be required to provide full practical confidence in the effectiveness of controls.
Where control measures cannot adequately assure that the potential contamination is consistently controlled to a level below that of the HBEL then the products concerned should be manufactured in dedicated facilities.
Q4. What competencies are required for the person developing the Health-Bad Exposure Limits (HBEL)?
A: Health-Bad Exposure Limits should be determined by a person who has adequate experti and experience in toxicology/pharmacology, familiarity with pharmaceuticals as well as experience in the determination of health-bad exposure limits such as Occupational Exposure Levels (OEL) or Permitted Daily Exposure (PDE).
Where experts are contracted to provide the HBEL, contractual agreements in compliance with Chapter 7 requirements should be in place prior to work being conducted. It is not considered acceptable for manufacturers to ‘purcha’ HBEL asssments without recording an asssment of the suitability of the provider (including the specific technical expert) as a qualified contractor.
Q5. What responsibility do contract givers have to contract manufacturers in relation to data to support a HBEL asssment?
A: Contract givers should either provide a full HBEL asssment to contract manufacturers or provide the data to allow the contract manufacturer to conduct the HBEL asssment. In either ca the HBEL asssment, including data references and relevant experts should be available on reques
t during inspection of the manufacturer.
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Q6. How can limits for cleaning purpos be established?归结
attenderA: Although the EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012) may be ud to justify cleaning limits (as per Introduction paragraph 3), it is not intended to be ud to t cleaning limits at the level of the calculated HBEL.
For existing products, manufa cturer’s historically ud cleaning limits should be retained and can be considered alert limits provided that when taking cleaning process capability into account, they provide sufficient assurance that excursions above the HBEL will be prevented. A similar process should be adopted when establishing cleaning alert levels for products introduced into a facility for the first-time.
Results above the alert cleaning limit should trigger an investigation and, where appropriate, corrective action to bring the cleaning process performance within the alert cleaning limits. Repeated excursions above the alert cleaning limit will not be considered acceptable where the indicate that the cleaning method is not in control. Recognid appropriate statistical methods may be ud to determine whether the cleaning process is in control or not.
Q7. Is analytical testing required at product changeover, on equipment in shared facilities, following completion of cleaning validation?
A: Analytical testing is expected at each changeover unless justified otherwi via a robust, documented Quality Risk Management (QRM) process. The QRM process should consider, at a minimum, each of the following:
∙the repeatability of the cleaning process (manual cleaning is generally less repeatable than automated cleaning);
∙the hazard pod by the product;
∙whether visual inspection can be relied upon to determine the cleanliness of the equipment at the residue limit justified by the HBEL.
Q8. What are the requirements for conducting visual inspection as per Q&A 7?
A. When applying visual inspection to determine cleanliness of equipment, manufacturers should establish the threshold at which the product is readily visible as a residue. This should also take into account the ability to visually inspect the equipment, for example, under the lighting conditions and di
stances obrved in the field.
maintain什么意思Visual inspection should include all product contact surfaces where contamination may be held, including tho that require dismantling of equipment to gain access for inspection and/or by u of tools (for example mirror, light source, boroscope) to access areas not otherwi visible. Non-product contact surfaces that may retain product that could be dislodged or transferred into future batches should be included in the visual inspection.
Written instructions specifying all areas requiring visual inspection should be in place and records should clearly confirm that all inspections are completed.
Operators performing visual inspection require specific training in the process including periodic eye sight testing. Their competency should be proven through a practical asssment.
Q9. Is it acceptable to simply gregate products of a common therapeutic classification in a dedicated area as a means of controlling risk of cross contamination?
英语 mp3A: Manufacturers cannot just gregate common products from other product types as a means of dealing with the risk to patient and animal safety. Although this may prevent contamination of other p
roduct class it does not address the possibility for cross contamination within product class. The approach taken to control cross contamination between individual products within a class produced in the same dedicated area should follow the principles in Q&A 3. This should include implementation of appropriate organisational and technical control measures to prevent contamination between such products within product specific HBELs.
Q10. Is the u of LD50 to determine Health-Bad Exposure Limits for drug products acceptable?
A: No, LD50 is not an adequate point of departure to determine a HBEL for drug products.
Q11. Can Ectoparasiticides be manufactured or primary packed in common equipment with other categories of medicinal products for human or veterinary u?
A: If a HBEL cannot be determined or data cannot support manufacture in shared facilities then the Ectoparasiticides should be manufactured in dedicated facilities.
Q12. What needs to be taken into account when manufacturing Veterinary Medicinal Products for different species in the same facility?
A: The guideline on tting health-bad exposure limits indicates that the carry over limit should ge
nerally be derived using the human HBEL.
However, in cas where there is concern relating to known susceptibility of a particular species (e.g. monensin in hors) the HBEL approach should take into account knowledge of specific animal toxicity when evaluating products manufactured in shared facilities/equipment.
Q13. Should the HBEL be re-assd throughout the phas of development of Investigational Medicinal Products (IMPs)?
A: Health-Bad Exposure Limits should be established bad on all available data, and particularly as the knowledge ba for IMPs is continually evolving the basis for establishing the HBEL, should be regularly reviewed taking account of any new relevant data.
