Prevention of cross contamination in shared facilities – Chapter 3 & 5 and the Guideline on Setting Health Based Exposure Limits

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The draft guidance allows manufacturers to determine, with the assistance of health based exposure limit assessments and consideration of technical and organisational controls,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.

Don’t miss the next post, sign up to be notified by email when a new post is published on the Inspectorate blog.

Access our guidance on good practice for information on the inspection process and staying compliant.


  1. Comment by Paul posted on

    You should add a "Print" button so we can print this without corruption of the text.

    • Replies to Paul>

      Comment by Mark Birse posted on


      Government Digital Service have advised that with WordPress to print a blog you need to use keyboard shortcuts "Control P" or "Command P"



  2. Comment by Sandip V. Patel posted on

    Hi there,
    Comment on flow diagram,
    Highly hazardous--> Yes-->Dedicated facility-->No--> Set cleaning limit from HBEL to include reduced 10 fold safety factors and validate cleaning.
    Que- What is the meaning to reduced 10 fold safety factor ? Does it mean that the MACO value (which came by putting PDE value, MACO=PDExBS/LRDD) shall be further divided by 10?
    Sandip V. Patel
    Quality Assurance- Pharmaceutical

    • Replies to Sandip V. Patel>

      Comment by Mark Birse posted on

      In the model proposed by EMA and explained in the MHRA blog post the intention of the 10-fold safety factor is to apply this to the PDE such that a PDE would be divided by 10. This lower figure would then be converted into a MACO taking account of future product batch size and surface area of product contact equipment. Consideration should also be given to unit dose contamination and not just that homogenously distributed.
      Please also be aware that PDEs should be used to risk assess the organisational and technical controls such that contamination above PDE will be prevented.

      The consultation on the Q&A is now complete and as a result of comments received EMA are considering amending the Q&As. This is likely to provide stronger focus on the need to set cleaning limits based on a process capability approach with alert and action levels tighter than PDE to control the process and prevent excursion above PDE.

      Please look out for a future update within the next few months.

      • Replies to Mark Birse>

        Comment by Sandip V. Patel posted on

        Hi Mark,

        We are waiting for another blog on this as you have mentioned.

        Thank you in advance !

        • Replies to Sandip V. Patel>

          Comment by Sara Berry posted on

          Dear Sandip, Thank you for your comment. We should be publishing a further blog later this year. Kind Regards Sara

  3. Comment by Sandip V. Patel posted on

    Hi Mark,

    Thanks for update, awaiting update as you have mentioned. Have already gone through the presentations of EMA July 2017 workshop.

    Thank you,
    Sandip V. Patel

  4. Comment by Farzan Meh posted on

    Would it be possible to help me out how to calculate PDE? I did not understand how to calculate this from its formula.
    Best Regards

    • Replies to Farzan Meh>

      Comment by Sara Berry posted on

      Dear Farzan,
      It is not intended that personnel without appropriate toxicological knowledge and experience would determine PDE Health Based Limits. Such personnel would be familiar with the application of such a calculation and as such we would suggest that, if the enquiry is made on behalf of a manufacturer, you engage a person qualified and experienced in toxicology to make the determination. Evidence should be held of the persons suitability for making these determinations.
      Kind Regards Sara

  5. Comment by Sima posted on

    Dear Sir,
    Would you please let me know how to use PDE or ADE to calculate MACO for cleaning validation of hazardous drugs?

    • Replies to Sima>

      Comment by Sara Berry posted on

      Dear Silma,
      Personnel should be familiar with the application of such a calculation and we would recommend you engage a person qualified and experienced in toxicology to make the determination. Evidence should be held of the persons suitability for making these determinations.
      Kind Regards Sara

  6. Comment by anonymous posted on

    "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"
    what is the scientific justification for 1/1000th of the minimum clinical dose is equal to HBEL? on what basis?
    where is the definition of highly hazardous

    • Replies to anonymous>

      Comment by Sara Berry posted on

      Since publication of the MHRA blog, comments have been received from industry on the EMA Q&A consultation and as a result the approach is being reconsidered.
      The Q&As are currently under review and it is hoped to publish a revised set in Spring 2018. EMA advise that the Health Based Exposure Limits guide should be applied in full pending update of the Q&As.
      As such the basis of your question is not part of the updated approach and it would no longer be appropriate to respond.
      MHRA will issue an updated blog once the Q&As are finalised for publication.
      Kind regards Sara

  7. Comment by Martin Crawford posted on

    The original guidance stated that PDE values should be used to set cleaning validation acceptance limits. After much work was done by industry, the EMA guidance was then published which stated that "the HBEL should not be higher than the traditional cleaning limits approach" and that "additional safety factors should be used" - does this mean that we need to calculate acceptance limits based on both PDE values and also the 1/1000th traditional limits and take the lower value (accepting the additional requirement from the MHRA that the value calculated from the PDE needs to be further divided by 10)?

    Is it possible to have one set of rules which are communicated out in one stage so that we do not have to keep revisiting the previous work carried out each time the goalposts move?

    • Replies to Martin Crawford>

      Comment by Graeme McKilligan posted on

      Dear Martin, MHRA apologise for mixed messages that have been published on this project. The change in approach has been required due to consultation with industry. MHRA tried to brief out the expected approach but then that changed following consultations. In hindsight we agree that it would have been better to remain silent until the approach was agreed. The current situation is that the EMA Working Group are preparing revised Q&As based on the 2017 consultation and it is hoped that these will be published in the next 2-3 months. When these are published they should answer your questions. MHRA will publish a further blog on the topic but not until the EMA Q&As are published.


Leave a comment

We only ask for your email address so we know you're a real person