Dedicated facilities or not?
In times of changing regulations, only a brave person would try to guess where the EU GMP regulations are going for medicinal products produced in shared or dedicated facilities. At the moment, it is a little like gazing into a crystal ball, trying to understand the consensus of the many participating authorities involved, with their often strongly differing views based on their in-country experiences (disasters). Existing facilities really only have “Organisational Measures” to control the potential risks of cross-contamination, as often it is impractical to retrofit the “Technical Measures” as referred to in Chapter 3 and 5 in the EU GMP guidance.
The rationale and logic of dedicated/non-dedicated facilities is being debated this week at the PIC/S conference in Paris, and is sure to be an interesting event. If you would like to follow up and see what was discussed, hopefully, the PIC/S website news section will have some detail in the coming weeks or stay tuned to the PharmOut blog section.
Note added later* The PIC/S guideline on setting health-based exposure limits for use in risk identification in the manufacture of difference medicinal products in shared facilities was issued in 2018.
With the recent release of the final version (13 August 2014 – effective 1st March 2015) of Chapter 5 Production, of the new EU GMP Guidelines, we see the withdrawal of the health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. ISPE published the Baseline Guide Risk-MaPP, which has been challenged due to the change from draft version of Chapter 5 to the abovementioned final version, as one of the committee members described it, “the carpet had been pulled from out of under them”.
EMA guidance document titled “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities” is available here. This document was drafted back in 2012, however based on discussions that I had with several subject matter experts in the EU last week at the Annual ISPE conference, Chapters 3 and 5 are still actively being discussed, and currently still undergoing revision. (The final chapters have now been released and can be found here.
In this article, I will attempt to highlight the differences between the draft and final versions of Chapter 5 on a line-by-line-basis, and I have summarised in the Table below:
| Chapter 5 Production - Draft Version: | Chapter 5 Production -Final Version |
|---|---|
| Clause 5.17 Normally, the production of non-medicinal products should be avoided in areas and with equipment destined for the production of medicinal products but in exceptional circumstances could be allowed where the measures to prevent cross contamination with medicinal products described below and in Chapter 3 can be applied. The production of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of medicinal products. | Clause 5.17 Normally, the production of non-medicinal products should be avoided in areas and with equipment destined for the production of medicinal products but, where justified, could be allowed where the measures to prevent cross-contamination with medicinal products described below and in Chapter 3 can be applied. The production and/or storage of technical poisons, such as pesticides (except where these are used for manufacture of medicinal products) and herbicides, should not be allowed in areas used for the manufacture and / or storage of medicinal products. |
| Clause 5.18 Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, vapours, sprays, genetic material or organisms from active substances, other starting materials, products in process, from residues on equipment, and from operators’ clothing.The significance of this risk varies with the type of contaminant and of product being contaminated. Products in which cross contamination is likely to be most significant are those administered by injection and those given over a long time.Cross contamination should be avoided by robust design of the premises, equipment and processes which take place within a manufacturing facility. This should be supported by appropriate procedures and technical or organizational measures, including reproducible cleaning and decontamination processes of validated effectiveness. | Clause 5.18 Contamination of a starting material or of a product by another material or product should be prevented. This risk of accidental cross-contamination resulting from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances, other starting materials, and products in process, from residues on equipment, and from operators’ clothing should be assessed.The significance of this risk varies with the nature of the contaminant and that of the product being contaminated. Products in which cross-contamination is likely to be most significant are those administered by injection and those given over a long time.However, contamination of all products poses a risk to patient safety dependent on the nature and extent of contamination. |
| Clause 5.19 A toxicological evaluation should be the basis for the establishment of threshold values in relation to the products manufactured (see Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities). Where the toxicological evaluation supports a threshold value, this should be used as an input parameter in risk assessment. | Clause 5.19 Cross-contamination should be prevented by attention to design of the premises and equipment as described in Chapter 3. This should be supported by attention to process design and implementation of any relevant technical or organizational measures, including effective and reproducible cleaning processes to control risk of cross-contamination. |
| Clause 5.19 continued A Quality Risk Management approach should be used based upon this toxicological evaluation and the potential cross contamination risks presented by the products manufactured. Factors including; facility/equipment design, personnel flow, physico-chemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the threshold values for products should also be taken into account. The outcome of the Quality Risk Management process should be the basis for determining the necessity for and extent to which equipment and facilities should be dedicated to a particular product or product family. This may range from dedicating specific product contact parts to dedication of the entire manufacturing facility. It may be acceptable to confine manufacturing activities to a segregated, self-contained production area within a multiproduct facility, where justified. | Clause 5.20 A Quality Risk Management process, which includes a potency and toxicological evaluation, should be used to assess and control the cross-contamination risks presented by the products manufactured. Factors including; facility/equipment design and use, personnel and material flow, microbiological controls, physio-chemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the relevant limits established from the evaluation of the products should also be taken into account. The outcome of the Quality Risk Management process should be the basis for determining the necessity for and extent to which premises and equipment should be dedicated to a particular product or product family. This may include dedicating specific product contact parts or dedication of the entire manufacturing facility. It may be acceptable to confine manufacturing activities to a segregated, self-contained production area within a multiproduct facility, where justified. |
| Clause 5.20 Technical and organisational measures to mitigate risks of cross-contamination could include, but are not limited to, the following: | Clause 5.21 The outcome of the Quality Risk Management process should be the basis for determining the extent of technical and organisational measures required to control risks for cross-contamination. These could include, but are not limited to, the following: |
| Technical Measures: | Technical Measures: |
| 1. Dedicated facilities. | 1. Dedicated manufacturing facility (premises and equipment). |
| 2. Self-contained production areas having separate processing equipment and separate HVAC systems. It may also be desirable to isolate certain utilities from those used in other areas. | 2. Self-contained production areas having separate processing equipment and separate heating, ventilation and air-conditioning (HVAC) systems. It may also be desirable to isolate certain utilities from those used in other areas. |
| 3. Design of manufacturing process, facility and equipment to minimize opportunities for cross contamination during processing, maintenance and cleaning. | 3. Design of manufacturing process, premises and equipment to minimize opportunities for cross-contamination during processing, maintenance and cleaning. |
| 4. Use of “closed systems” for processing and material / product transfer between equipment. | 4. Use of “closed systems” for processing and material/product transfer between equipment. |
| 5. Use of physical barrier systems, including isolators, as containment measures. | 5. Use of physical barrier systems, including isolators, as containment measures. |
| 6. Controlled removal of dust close to source of the contaminant e.g. through localised extraction. | 6. Controlled removal of dust close to source of the contaminant e.g. through localised extraction. |
| 7. Dedication of processing equipment, dedication of product contact parts or dedication of selected parts which are harder to clean (e.g. filters), dedication of maintenance tools. | 7. Dedication of equipment, dedication of product contact parts or dedication of selected parts which are harder to clean (e.g. filters), dedication of maintenance tools. |
| 8. Use of disposable technologies. | 8. Use of single use disposable technologies. |
| 9. Use of equipment designed for ease of cleaning. | 9. Use of equipment designed for ease of cleaning. |
| 10. Appropriate use of air-locks and pressure cascade to confine potential airborne contaminant within a specified area. | 10. Appropriate use of air-locks and pressure cascade to confine potential airborne contaminant within a specified area; |
| 11. Minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air. | 11. Minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air; |
| 12. Use of automatic clean in place systems of validated effectiveness, for common general wash areas, separation of equipment washing, drying and storage areas. | 12. Use of automatic clean in place systems of validated effectiveness, for common general wash areas, separation of equipment washing, drying and storage areas. |
| Organisational Measures: | Organisational Measures: |
| 1. Dedicating the whole manufacturing facility or a self contained production area on a campaign basis (dedicated by separation in time) followed by a cleaning process of validated effectiveness. | 1. Dedicating the whole manufacturing facility or a self contained production area on a campaign basis (dedicated by separation in time) followed by a cleaning process of validated effectiveness. |
| 2. Keeping protective clothing inside areas where products with high risk of cross contamination are processed. | 2. Keeping specific protective clothing inside areas where products with high risk of cross-contamination are processed. |
| 3. Cleaning verification after each product campaign instead of a cleaning validation should be considered as a detectability tool to support effectiveness of the Quality Risk Management approach. | 3. Cleaning verification after each product campaign should be considered as a detectability tool to support effectiveness of the Quality Risk Management approach for products deemed to present higher risk. |
| 4. Cleaning of working areas and surfaces followed by execution of a comprehensive sampling protocol for critical surfaces. | 4. Depending on the contamination risk, verification of cleaning of non product contact surfaces and monitoring of air within the manufacturing area and/or adjoining areas in order to demonstrate effectiveness of control measures against airborne contamination or contamination by mechanical transfer. |
| 5. Use of air samples and wipe/swab samples taken in adjoining areas outside the working area to demonstrate the efficiency of mitigation measures for airborne and mechanical transfer of contaminant. | 5. Specific measures for waste handling, contaminated rinsing water and soiled gowning. |
| 6. Specific measures for waste handling, contaminated rinsing water and soiled gowning. | 6. Recording of spills, accidental events or deviations from procedures. |
| 7. Recording of spills, accidental events or deviations from procedures. | 7. Design of cleaning processes for premises and equipment such that the cleaning processes in themselves do not present a cross-contamination risk. |
| 8. Design of cleaning processes for manufacturing equipment and building facilities such that the cleaning processes in themselves do not present a cross contamination risk. | 8. Design of detailed records for cleaning processes to assure completion of cleaning in accordance with approved procedures and use of cleaning status labels on equipment and manufacturing areas. |
| 9. Design of detailed records for cleaning processes to assure completion of cleaning in accordance with approved procedures and use of cleaning status labels on equipment and manufacturing areas. | 9. Use of common general wash areas on a campaign basis. |
| 10. Use of common general wash areas on a campaign basis. | 10. Supervision of working behaviour to ensure training effectiveness and compliance with the relevant procedural controls. |
| 11. Monitoring of working behaviour to ensure training effectiveness and compliance with the relevant procedural controls. | |
| Clause 5.21 Measures to prevent cross-contamination and their effectiveness should be checked periodically according to set procedures. | Clause 5.22 Measures to prevent cross-contamination and their effectiveness should be reviewed periodically according to set procedures. |
This debate is set to continue for some time, so why not subscribe to our LinkedIn pages or follow our PharmOut blogs. In summary, the justification to manufacture certain products in a shared facility will come at a significant up-front cost. Tasks such as initial risk assessments and obtaining toxicology data (can be difficult to source and expensive to generate, although this is possibly a once-off exercise) are time-consuming. The potential routes and risks of cross-contamination must be understood, and mitigated through sufficient, facility design, qualification and operation, with sufficient Technical Controls in place. The lack of sufficient “Technical Controls” will result in the requirement in increasing the “Organisational Measures” such as ongoing monitoring and control. Direct product cross-contamination is sometimes easy to assess, but with the vagaries of airborne cross-contamination, the amount transferred by operator clothing, for example, might be more difficult to quantify and to demonstrate control.
An update from the TGA in 2017 on cleaning validation