A revision to chapters 3&5 of the EU GMP Guide including modifications to the control of cross contamination sections came into effect on 1st March 2015.
A subsequent guide to setting health based exposure limits (HBEL) (EMA/CHMP/SWP/169430/2012) came into effect on 1st June 2015 for products introduced to a facility for the first time and on 1st December 2015 applicable to products already manufactured in shared facilities (applicability for veterinary only facilities is from December 2016). Subsequently a series of Q&As has been published by EMA to provide clarification of the intent of the above documents.
This Q&A is published for consultation with comments to be submitted to EMA by 30th April 2017
The draft guidance allows manufacturers to determine, with the assistance of health based exposure limit assessments and consideration of technical and organisational controls, whether products can be safely manufactured in shared facilities.
Health Based Exposure Limits (HBELs)
A health based exposure limit is a limit (permitted daily exposure (PDE) or equivalent) at which a product is regarded to be safe in humans. It can be based on either clinical dose or non-clinical safety data, depending on which would give the lower exposure limit.
The guide to setting health based exposure limits (EMA/CHMP/SWP/169430/2012) is only required to be used in full for products believed to fall into the category of highly hazardous. Clarification of this and a definition of highly hazardous can be found in the EMA Q&A.
An HBEL is required for all products. Where a product does not fall into the highly hazardous category it is considered that 1/1000th of the minimum clinical dose, can be considered as the HBEL.
The HBEL should be used when considering the opportunities for cross contamination. When using non-clinical safety data to establish the HBEL a further 10 fold safety factor reduction is required to establish cleaning limits. Conversely to compare 1/1000th of a clinical dose against a PDE calculated from non-clinical safety data the former should be multiplied by 10 to provide comparable data sets for risk assessment.
Although guidance is provided in the Q&As for determination of highly hazardous products, this is to identify those products that require the EMA guide approach to health based exposure limits to be used. This does not infer that other products are safe or that strict controls are not required for products falling outside the highly hazardous category. The expected degree of hazard is relative to the HBEL determined.
The flow diagram below indicates a broad decision process with respect to determination of whether the EMA guide should be applied in full and what action is required on organisational and technical control measures:
Main changes and emphasis of Chapters 3 & 5 related to control of cross contamination
Chapters 3&5 no longer refer to “certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs” etc but provide the above mentioned tools to determine health based exposure limits (HBEL) of specific products. This allows an evidence based determination of whether it is safe to manufacture in shared facilities and if so what level of technical and organisational measures would be required. Note; further guidance is being developed for definition of ‘highly sensitising’ products and such products will be expected to be manufactured in dedicated facilities.
‘Higher hazard’ products
Although a process is in place to determine those products that should be considered ‘highly’ hazardous, risk management of determination of controls required should not consider this a cliff edge change from non-highly hazardous products. The level of the HBEL should be seen as the guide for hazard level with controls gradually increasing as hazard level increases.
There should be a clear documented, factual justification for the suitability of organisational and technical controls relative to the HBEL where products are manufactured in shared facilities.
Records should demonstrate that products have been assessed against the highly hazardous definition and the rationale used. For highly hazardous products, not just the PDE but also, the nature of the relevant hazards should be considered in the risk assessment of the type of facility and organisational and technical control measures required.
The intent of Chapters 3&5 updates and the EMA guide is for manufacturers to determine the health based exposure limit and ensure that a holistic approach is taken to development/justification of organisational and technical controls in the facility. This should provide assurance that controls will not allow the appropriate HBEL to be exceeded and thus lead to cross contamination of a product.
Risk Assessment for required controls
Via a risk management process manufacturers need to consider how cross contamination at or above the HBEL can be prevented. Risk management should include all cross contamination routes and consider both planned control measures and potential errors/failures in the measures. How/where excursions may occur that would breach the HBEL and how much would be required to contaminate a single dose (e.g. on packing lines or other unit dose contact surfaces) should be identified and incorporated into assessments. Manufacturers should consider how a quantity of a probable contaminant equivalent to the HBEL could be left in the equipment and transferred to the next or subsequent product.
Risk assessments should always start from consideration of the hazard and determine how risk is/ can be controlled via the technical and organisational control measures. So that at the conclusion of the process, where the risk of cross contamination is considered acceptably controlled, this conclusion is supported by factual evidence and a science based control strategy is justified. Risk assessments must always consider how failures may occur and how errors may impact on cross contamination. As a result control measures must ensure failures/ errors are controlled incorporating redundant controls (appropriate additional back-up measures), at least for highly hazardous products, and ensure that failure will be detectable.
Risk assessments should recognise that manual activities, and typically most manufacturing facilities include some manual controls such as cleaning and inspection, are particularly prone to variability and error. The potential consequence of error needs to be assessed with controls being verified rather than assumed to be adequate. As with all risk management the level of detail should be commensurate with the starting level of the risk (this should always point back to the hazard, even where some risk reduction is already incorporated e.g. via the pharmaceutical form manufactured).
In general the evidence (instructions, records etc.) of control expected will be greater the higher the hazard of the product.
A broader approach than typical cleaning validation is expected, particularly for higher hazard products
Cleaning validation has typically been confirmed over three cleaning runs but these can often be based on a manual cleaning method where the effectiveness of the training personnel have had in cleaning is not assessed and the overall consistency is not proven. Other issues typically seen with cleaning validation (particularly with higher hazard products in mind) are;
The cleaning instructions are not defined in adequate detail, not all personnel take part in the validation yet following three batches meeting swab limits the method is considered validated for any personnel performing the cleaning. For higher hazard products in shared facilities this type of approach to cleaning validation is not adequate.
Chapter 3 requirements/ dedicated facilities definition:
Dedicated facilities are required for manufacturing when a medicinal product presents a risk because:
- the risk cannot be adequately controlled by operational and/ or technical measures,
- scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitising materials such as beta lactams) or
- relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a validated analytical method.
In the context of the above requirement ‘dedicated facilities’ means a separate facility or line with no direct or indirect links providing opportunities for cross contamination.
However in the broader sense ‘dedicated’ can be taken to be any equipment, equipment part, room, building used for only a single product as a means of controlling the risk of cross contamination (technical control measures).
The capability of the facility or sub parts thereof with respect to cross contamination should be recorded as part of the Validation Master Plan and the risk assessment.
The following scenarios will typically exist for manufacture involving human medicinal products:
- Creation of a new facility and introduction of new products.
- Introduction of new products to an existing facility
- Assessment of suitability of controls for existing products in an existing facility.
Considering each scenario;
Creation of a new facility for introduction of new products.
This scenario offers an opportunity to design the entire facility as well as specific technical and organisational control measures to meet the requirements of the products as assessed using the health based exposure limit and risk assessment.
As with all scenarios the opportunities for error/failure should also be considered and addressed along with robust design strategies; manufacturers should be focussing appropriately on primary containment measures and considering these as essential for highly hazardous products.
Introduction of new products to an existing facility
With this scenario the manufacturer will already have a facility, equipment and technical and organisational control measures in place. The introduction of new products should be assessed both in relation to current controls and what, if any, additional controls may be needed to adequately limit risk of cross contamination by or to specific new products. Once controls for existing products have been assessed then introduction of further new products may be conducted via comparison against hazards and risks of current products. Decisions should be made based on factual knowledge of the level of control offered by current equipment/systems. Completely new risk assessments may not be required for each product unless the hazard levels and required controls are significantly different.
Assessment of suitability of controls for existing products in an existing facility.
In line with the deadlines that have come into force manufacturers should have considered their current product portfolio and whether, when considering a health based approach and the above risk assessment process, there are any risks that need to be further controlled via strengthened/ modified technical and organisational control measures (and failure/error proofing). For those manufacturers with a high number of products, prioritisation, (with higher hazard products assessed first,) would be a sound risk based strategy.
Manufacturers who have previously determined PDEs for all products (including non-highly hazardous products) will have full information available to allow a direct comparison of relative risks of products. This data should have been used for assessment of the suitability of existing control measures.
Although application of the revised chapter 3 & 5 and health based exposure limits is applicable to existing products it does not infer that further controls will be necessary. However the inspection findings in cross contamination controls have typically indicated that manufacturers do not consider failure and error modes adequately so this in itself should be evaluated.
A further post on cross contamination controls will be issued following receipt of comments and full publication of the EMA Q&A later in 2017.
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