31 st March 2015 Submission of comments on ' Concept paper on the revision of annex 1 of the guidelines on good manufacturing practice manufacture of sterile medicinal products EMA/INS/GMP/735037/2014 Comments from: The Pharmaceutical and Healthcare Sciences Society - PHSS On behalf of the PHSS Pharmaceutical and Healthcare Sciences Society (UK). For PHSS Contact: jamesdrinkwater@phss.co.uk (PHSS Chairman) or tamsinmarshall@phss.co.uk (PHSS Operations manager) Please note that these comments and the identity of the sender will be published unless a specific justified objection is received. When completed, this form should be sent to the European Medicines Agency electronically, in Word format (not PDF). 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged.
1. General comments Stakeholder number Introduction The Pharmaceutical and Healthcare Sciences Society - PHSS would like to offer the following supportive comments to the EMA working group and associated participating authorities working on the concept paper regarding update of EU GMP Annex 1; Guidelines on good manufacturing practice (GMP) of sterile medicinal products. The Pharmaceutical and Healthcare Sciences Society - PHSS fully support the concept for update of GMP Annex 1 and recognise the opportunity such an update presents to correct or clarify current statements as well as to introduce new risk / science based initiatives to the manufacture of sterile products. The drafting of a revised Annex 1 is such an important development that the PHSS as a Not for Profit society involved in GDP/GMP education, preparation of best practice guidance monographs, white papers and regulation change impact papers would welcome an opportunity for contribution, consultation and draft review. It is recognised different working groups are already developing detail point by point recommendations on updates for Annex 1 and these will need review and harmonisation. 2/18
The PHSS have shared general points to consider for change of Annex 1 with the A3P working group and in principle the PHSS are in agreement with the general points put forward by A3P. The PHSS consider it useful to focus comment on inclusion of developing concepts; initiatives and principles, that follow the risk based initiatives and scientific approaches but also propose a few detail revisions to consider. The current guideline, including its title, is focused on the manufacture of sterile medicinal products. However, this Annex is the only source of guidance in EU-PIC/S GMP for the conditions of manufacture of some non-sterile finished products and for the early stages in the manufacture of a range of products. In this respect it would be useful to provide clarification on the scope of Annex 1 guidance. Guidance for non-sterile products or materials which are not subsequently used in sterile products potentially varies with guidance on sterile product manufacture hence could benefit a distinct section in Annex 1 or referred to elsewhere in other relevant sections of the GMP. 3/18
Some ISO standards are in final revision drafts and have relevance to Annex 1. It is considered important to ensure there is alignment. Examples here include; ISO 14644-1 and ISO 14644-2 classification / reclassification by airborne particles and ISO 13408-1 and ISO 13408-2 (filtration) the latter is especially important as more and more combination products are developed. With the development of aseptic processing, particularly in manufacturing biological products that cannot be terminally sterilised, the requirements for Barrier separation technology, Isolators and RABS Restricted Access Barrier Systems, should be clearly stated in Annex 1. There should be an emphasis in Annex 1 on contamination control where monitoring is used to assess the state of control and instigate investigations following excursions from specified levels and typical/characterised levels of total particulates and microflora in a given process/ facility. 4/18
As recognised in the Concept paper it is important to consider new technologies that support new sterile manufacturing / aseptic processing developments and involve new manufacturing practices. In particular it may be useful to cover guidance in use of Single use systems / technologies (disposable sterile components) and use of ready to use sterilised final containers / container closures. Product fluid path systems that are preassembled/ sterilised reducing the amount of aseptic assembly in manufacturing operations require consideration in Annex 1 related to use and introduction to Grade A processing environments. The location of the final sterilising filter in a product delivery path for filling requires consideration in view of new developments. The current GMP text states as close to the point of fill as possible with consideration to reduce downstream aseptic connections. However where CIP/SIP is used the location of the filter, within reason, is less of an issue. Final sterilising filters could be located outside of isolators/ RABS to reduce occluded surfaces, clutter and manipulation inside more restricted Barrier technology where ergonomics can be challenged. The PHSS consider the revised Annex 1 should reflect position of the final sterilising filter when SIP is used. 5/18
It may, with justification, also be acceptable to place filling pumps outside an Isolator or RABS on a mobile cart, together with an interconnected product vessel (possibly single use product bag). Such a mobile system would be directly connected to a fluid path sterile connector on the Isolator/ RABS barrier boundary on entry to the Grade A processing zone. If such mobile product transfer carts are used it should be made clear if Grade A air supply is required or not. Where mobile carts are used for Grade A continuity between classified areas it should be made clear if continuous particle monitoring is required during transfer or not. Proposed concepts to be added to Annex 1 Control strategies for manufacture of sterile medicinal products A. The PHSS encourage the inclusion of Control Strategies for manufacture of sterile medicinal products and drug substances. A Control strategy is considered of benefit to regulators, industry/ researchers and ultimately to the patient. Proposed content of Control strategies for sterile product manufacture, has been recently published by the PHSS as a White paper and included as best practice guidance in the PHSS Monograph 20 on the Bio-contamination life cycle (published September 2014). 6/18
It is important that throughout the product / process lifecycle that a Control Strategy has been developed and is prepared before entering into the detail of risk assessments. Failure to do so might result in risk levels being under estimated and subsequent risk mitigation being inadequate. An approach to manufacture set out as a Control strategy could become a primary reference in defining the path forward for sterile medicinal product manufacture and the subsequent approach to risk management via applied technical and organisational measures. Proposed structure of Control strategies for sterile medicinal product manufacture: As presented in the PHSS Control strategy White paper such a document should be live, iterative and follow a proactive approach to control in manufacture of sterile medicinal products with consideration to three inextricably linked parts. 7/18
1. Approach to risk based manufacturing: detailing product types, processing type e.g. terminally sterilised or aseptically processed, Facility type: multi product or dedicated, material and personnel flows in manufacturing, approach to outsourcing and supply chain together with any special considerations. 2. Listing of Critical Quality Attributes, CQAs, for products to be manufactured and in principle how these will be controlled. 3. Approach to contamination and cross contamination control by technical and organisational measures. 8/18
Holistic Environmental monitoring and trend metrics B. With an increasing understanding of the challenges in environmental monitoring using conventional growth based techniques; limitations in sampling and recovery, together with challenging investigations into environmental control excursions or failed sterility tests where the deviation response is purely reactive there is a need to develop more Holistic environmental monitoring programs and trend metrics. Trend metrics could be considered as key performance indicators where incidence rates in deviation above alert and action levels together with incidence rates for OOS; Out of Specification events, related to the critical control parameters and OOT: Out of trend deviations inform on the state of control. Trend metrics provide warning in changes of control conditions and associated increased risk of contamination thereby facilitating a proactive response, possibility before Grade A critical areas become contaminated. The PHSS recommend the introduction of the term Trend metrics into Annex 1 to recognise the importance of trend data and review. 9/18
Holistic Environmental monitoring Environmental monitoring (EM) programs trend and compare typical cfu counts and characterised microflora profiles (genus and when required species) across interrelated controlled areas that are under a formal state of control. Areas outside Grade A have measurable cfu counts and typical microflora that can be characterised and identified providing an opportunity to create an area to area profile where a proactive response to risk escalation of Grade A environmental contamination can be initiated as profiles adversely change in surrounding areas. A proactive response would facilitate early investigation and intervention to prevent potential contamination in critical Grade A processing areas where products are exposed to the manufacturing environment. For reference the Holistic environmental monitoring initiative detailed in the PHSS Biocontamination monograph 20 is called; Biocontamination - Risk Profiling and Proactive Response (RPPR). 10/18
Like other new technologies, Rapid Micro Methods; RMM, fluorescence based measurement technology is developing to add value to environmental monitoring and inform in real time (RT) on the state of environmental control. In addition use of fluorescence based technologies facilitate no operator intervention monitoring reducing risks in contamination as result of a sampling procedure using growth media/ plates. It would be useful if Annex 1 recognises these developments and In the case of RMM-RT to recognise the different data forms between cfu counts (growth based) and bio-counts (fluorescence based technology: non-growth based). Contamination and Cross contamination control by use of Barrier Separation Technology Contamination and cross contamination control requires implementation of Quality by Design (QbD) principles together with technical and organisational control measures where Holistic monitoring and trend metrics are used to verify the specified state of control is maintained. This linkage is important to current risked based initiatives and would benefit reinforcement in Annex 1. 11/18
With the increase in aseptic processing where barrier separation technology is employed it is considered there is a need to reinforce the understanding that barrier separation technology e.g. Isolators and Restricted Access Barrier Systems (RABS) are not an absolute barrier to contamination entry to Grade A process zones. When sterile products are exposed to the Grade A manufacturing environment inside a barrier separation technology system and open system processing is undertaken the surrounding environment, where operators are present, presents a risk as a source of contamination. With the 0cfu level of bio-contamination expected in Grade A environments and the understanding any Barrier separation technology is not an absolute barrier to contamination entry this imposes a necessary mind-set that is sometimes not present in production operations. RABS contamination risks related to operator open barrier door interventions should be addressed in Annex 1. Guidance should be provided on requirements if such open door operator interventions during aseptic processing are proposed by a system user. 12/18
Background environments for Isolators and RABS should be proposed in Annex 1 as risk based considering open systems processing where sterile products are exposed to the Grade A processing environment or closed system processing where sterile products are processed in closed containers/ systems inside the Grade A environment. Although for Isolators Grade D is currently stated in EU-GMP as a minimum requirement there is lack of clarity when this minimum is not good practice. In addition there has been some discussion on use of Isolators in non-classified environments. The PHSS do not support this view that non-classified environments are acceptable for Isolators in manufacture of sterile products although in manufacture of non-sterile products where bioburden control is required it may be justified with rationale and possibly some supporting monitoring data. The PHSS consider for Isolators used in aseptic processing of open systems a background environment of Grade C is good practice. For Isolators processing closed systems a background of minimum Grade D is acceptable. For RABS processing open systems the minimum background of Grade B would be considered good practice. RABS processing closed systems e.g. capping, a minimum background of Grade C would be acceptable. 13/18
It should be possible to combine Isolators and RABS within the same background environment if processing open systems (in Isolator) and closed systems (in RABS) e.g. Filling Isolator connected to RABS with a capper. Terminology in Annex 1 should be standardised: Standardisation of terminology with international guidelines e.g. Laminar replaced with unidirectional airflow, clean room replaced with cleanroom etc. The PHSS also recommend to replace the general term sanitisation with disinfection. The use of disinfection also aligns with standards/ guidance on disinfectant qualification. 14/18
2. Specific comments on text Line number(s) of the relevant text (e.g. Lines 20-23) Stakeholder number (To be completed by the Comment and rationale; proposed changes (If changes to the wording are suggested, they should be highlighted using 'track changes') Outcome General. Section 3 Page 91 Comment: Location required to demonstrate unidirectional airflow and associated velocities As unidirectional air approaches the working zone, it interacts with the machinery and equipment and is also directed towards the extract system and so changes course. Consequently, the determination of an accurate velocity measurement at the working position is dependent upon the test instrument being at the correct orientation with regard to the direction of airflow, which will also vary throughout the zone. A more appropriate method to consistently determine the air velocity is to measure it at a defined distance (typically 15cm) from the HEPA filter face, when it is travelling in the direction of supply before it begins to change direction. The effectiveness of the airflow within the working area should then be determined using airflow visualisation techniques (typically smoke studies). It may also be that velocities higher or lower than that specified in Annex 1 guide are more appropriate or adequate in attaining the required level of operational environmental cleanliness 1 and should be appropriately evaluated and utilised. 15/18
Line number(s) of the relevant text (e.g. Lines 20-23) Stakeholder number (To be completed by the Comment and rationale; proposed changes (If changes to the wording are suggested, they should be highlighted using 'track changes') Outcome 1. Eaton T. Cleanroom HVAC and contamination control: A green challenge to the Regulatory (Orange) Guide. Clean Air and Containment Review. Issue 4. October 2010 Proposed change (if any): A more appropriate method to consistently determine the air velocity is to measure it at a defined distance (typically 15cm) from the HEPA filter face, when it is travelling in the direction of supply before it begins to change direction. The effectiveness of the airflow within the working area should then be determined using airflow visualisation techniques (typically smoke studies). Processing. Section 66 Page 101 Comment: Process Simulation Trials With the increased complexity and diversity of aseptic formulation types, the classic use of a nutrient media to replace the formulation within process simulation trials is not always feasible, or scientifically justifiable. Alternative approaches based on risk assessment and scientific rationale could be regarded as equivalent in terms of ensuring an acceptable level of aseptic assurance. Proposed change (if any): In process simulation trials then alternative approaches to use of nutrient media based on risk assessment and scientific rationale could be regarded as equivalent in terms of ensuring an acceptable level of aseptic assurance. 16/18
Line number(s) of the relevant text (e.g. Lines 20-23) Stakeholder number (To be completed by the Comment and rationale; proposed changes (If changes to the wording are suggested, they should be highlighted using 'track changes') Outcome Clean Room and Clean Air Devices Classification. Section 4 Page 91 Comment: Measurement of Particles 5μm Particle counters, which utilise laser light technology, are known to be unable to record absolute numbers and sizes of particles 2 and trying to count low levels of particles at 5μm, is subject to a high degree of uncertainty. This is reflected in the current draft of the EN ISO 14644-1 standard where the monitoring of 5μm particles for ISO Class 5 is not recommended. It is understood there are different views relating to measurement of 5 micron particles together with 0.5 micron particles and this has been widely discussed within the EMA. Some believe it is more appropriate to record particle concentrations at one size only, specifically at the accompanying 0.5μm size, where the total allowable number of particles is sufficiently high to negate the inaccuracies of the particle detection metrology. Others believe 5 micron particles are vectors for microorganisms as microbe carrying particles (MCPs) so measurement is important. By measuring both 0.5 micron and 5 micron particles there can be an understanding of the amount of MCPs as part of the total particle count. Real time monitoring, particularly within EU grade A zones, is the most useful approach for managing excursions 3. Most particle counters operate at a flow rate of 1ft 3 /min where the proportioned per ft 3 limit for 5μm particles is <1. This anomaly causes considerable difficulties in setting a meaningful operational limit for particles 5μm but there are no such issues if the single particle size of 0.5μm is utilised. The approach used in particle measurement should be risk and scientifically based so guidance should take account of any scientific limitations. 17/18
Line number(s) of the relevant text (e.g. Lines 20-23) Stakeholder number (To be completed by the Comment and rationale; proposed changes (If changes to the wording are suggested, they should be highlighted using 'track changes') Outcome Proposed change (if any): PHSS recommendation on particle measurement: It is proposed to only use 0.5 micron particle counts in classification for the not to exceed limits in classified areas. However, 5 micron particles should also be measured but as monitoring values to contribute to understanding on the state of control. 5 micron particle levels, like microflora, could be characterised and typical trends set in monitoring for any given process. 2. Humphries A. A simple guide to how aerosol particle counters work. The Cleanroom Monitor, Scottish Society for Contamination Control, December 2003. 3. Eaton T. Annex 1 of the EC Guide to Good Manufacturing Practice (EC GGMP) and continuous particle monitoring help or hindrance for cleanroom manufacturing? European Journal of Parenteral and Pharmaceutical Sciences 2007; 12 (2): 29-37. Please add more rows if needed. 18/18