Q&A summary report from PHSS Annual conference 2015; EU GMP Annex 1 revision discussion panel.

Transcription

1 Q&A summary report from PHSS Annual conference 2015; EU GMP Annex 1 revision discussion panel. PHSS panel Discussion on questions set relating to revision of EU guidance to Good Manufacturing Practice (GMP) annex 1 manufacture of Sterile Medicinal Products. This years (2015) PHSS Annual conference held in association with the Q3P UCL course, and hosted by the UCL School of Pharmacy, London, was well attended by 148 delegates including colleagues from the UK, U.S, France, Germany, Belgium and Scandinavia. MHRA senior GMP inspector Andrew Hopkins head of the EMA inspectors working group and PIC/S committee coordinating the annex I revision kicked off the conference with his informative presentation entitled Revision of Annex 1 manufacture of sterile medicinal products a GMP Inspector s point of view. He summarised the key reasons for revision and specific areas which need to be addressed, which were detailed in the concept paper published in February Kay O'Hagan (Hospira QP, EJPPS Editor in Chief and former PHSS Vice Chair) then hosted a lively panel discussion on the proposed revision of Annex 1. The discussion panel included a variety of stakeholders from the pharmaceutical industry educational platforms/ not for profit associations and societies and regulatory authorities including representatives from the PHSS, PDA (UK and USA chapters), ISPE, A3P, R3 Nordic and ECA together with ex-regulatory GMP inspectors. Andrew Hopkins also joined the discussion panel. The panel answered pre-prepared questions contributed by PHSS and the discussion panel member associations as well as fielding questions from the conference floor. Discussion Panel members PHSS Moderator: Kay O Hagan: Senior Qualified person, Hospira UK. MHRA, EMA/PICS: Andrew Hopkins: Senior GMP MHRA Inspector, Head of EMA Annex 1 revision working group and coordination of revision with PICS. PDA Worldwide: Richard M. Johnson, President & CEO, microbiologist. PDA UK Chapter President: Dr Siegfried Schmitt Principal Consultant PAREXEL international PHSS: Di Morris: GSK Compliance Audit Manager, Compliance Audit Group (CAG), Quality Systems and Compliance. PHSS Management team member. EX-MHRA GMP inspector. PHSS: James Drinkwater: F Ziel GmbH, Head of Aseptic processing Technologies & GMP compliance. Chairman of PHSS. ISPE/ ISO: Gordon Farquharson: Chair BSI LBI030, Chair CEN TC243, Convenor ISO TC209 wg1, and member ISPE Sterile and HVAC CoP. Consultant Critical systems. 1 P age

2 A3P France: Dr Roland Guinet, Ex AFFSAPS GMP Inspector, WHO GMP auditor, GMP Consultant, University Professor of Microbiology, Head of A3P Annex 1 Interest group. R3 Nordic: Berit Reinmüller, PhD, Associate Professor in Safety Ventilation, Chalmers University of Technology, Gothenburg, Sweden, R3 Nordic journal editor. ECA (European Compliance Academy): Dr Jean-Denis Mallet, NNE Pharmaplan, Senior Technology Partner, GMP Expertise, QP, Pharmacist. Head of ECA annex 1 comment working group. Ex AFFSAPS GMP Inspector (head). Panel discussion questions: 1 to 14 Questions on General Concept/ Principles or annex 1 revision. Question 1 The Annex 1 revision concept paper considered that the revision may cover sterile and non-sterile product manufacturing. How does the panel think guidance can be differentiated? It was felt that completely differentiating guidance for sterile and non-sterile applications by writing separate sections would be difficult to accommodate in the annex 1 revision. Panel members discussed that something in the revised annex 1 which suggests cleanliness grades can be adapted for non-sterile product manufacture would be useful, but that the EMA IWG should ensure it does not become a set requirement in annex 1 so case by case scenarios could be accommodated. It was noted that there has been a lot of feedback from the industry that being held to a sterile standard for non-sterile manufacture is not always appropriate, and this may present a problem in some circumstances, so needs to be made clear. As Annex 1 is now part of the PIC/S environment, and in emerging markets in particular, a lot of confusion exists with regard to non-sterile manufacture - there is often an inappropriate use of cleanliness grades. The WHO tackled this for oral solid dosage form by providing a supplementary guide, however, a different approach will most likely be used in the annex 1 revision, with more clarity negating the need for supplementary guidance. Most of the existing guidance is applicable to both sterile and non-sterile applications, so long as it is adapted appropriately. The main thing is to be clear in the revised document whether applications with special requirements, such as a facility running biotechnology process with low bioburden requirements or similar, can still use classifications. It was discussed that the German authorities has proposed the use of controlled not classified (CNC) to the EMA IWG. Andrew Hopkins explained that some sort of level of CNC may be included in the revised annex 1, though this would be hard to regulate it would save having a separate section. It is understood that some set ups remain difficult to classify. In these circumstances he would suggest using cleanliness grade C or D, then doing a risk assessment to put in place process steps (such as more frequent monitoring) to verify a good state of control and make the use of the cleanliness grade appropriate. If good environmental monitoring is carried out together with good trending of data this can help to show a good state of control. It was discussed that a separate section on classification groups might be useful. Various EMA subgroups will be working on sections of the annex 1 revision and will give consideration to sterile and non-sterile applications. 2 P age

3 There will not be one section with a list of requirements for each application, but more clarity of regulatory expectations will be provided throughout the document with respect to both sterile and non-sterile applications. It was further discussed that classifications for non-steriles must include risk assessments for environmental monitoring for example, sometimes a company may decide for grade D to monitor once a month with no supporting justification. One of the key parts of the annex 1 revision will be to strongly suggest that the whole environmental monitoring program is set up on a risk assessment, and more clearly state that there is a requirement for justification for the process, and this will apply to both sterile and non-sterile. As a separate issue it was proposed that annex 1 should not deal with water and should deal with it separately as WHO does, because there are more issues surrounding water in non-sterile product manufacture than with traditional hot WFI. However, it was noted that to write a new section is a very long process and wouldn t happen very quickly. Question 2 The PHSS Bio-contamination special interest group prepared a White paper on Control strategy for manufacture of sterile products and drug substances. Does the panel believe the requirements for a Control strategy for sterile products manufacture should be included in the Annex 1 revision? The panel discussed the recommendation from this PHSS white paper that a requirement for a control strategy should be included in annex 1. The rationale for the recommendation is that as we have moved into such a complex environment with new products and new technology it seems logical to set out the chosen approach to manufacturing and contamination/ cross contamination control in an outset concept document. Control Strategy is referenced in annex 2 and it seems highly appropriate to reference it in annex 1. Andrew Hopkins felt that as control strategy is one of the foundations of what makes up QRM, it probably wouldn t explicitly be included in the annex 1 revision in great detail. QRM is very much designing the process properly, understanding where the weaknesses are, proceeding to explore those weaknesses and applying appropriate control measures (technical and organisational) with monitoring and deviation responses appropriately - In essence this is what is expected in the majority of validation qualification processes. It was highlighted by the panel that even if control strategy doesn t appear as a specific requirement in annex 1, the revision should be reviewed in line with GMP chapter 1; one of the key points it makes in more than one place, is that you have to demonstrate you are in a state of control and therefore you need a control strategy. 3 P age

4 Question 3 Considering data trends are key performance indicators what trend metrics would the panel consider should be covered in the Annex 1 revision? The panel discussed another PHSS recommendation introducing the term trend metrics. FDA quality metrics are being developed to apply to the industry as a whole. However, the PHSS feel that it would be useful to define more specific trend metrics for sterile products manufacturing. One consideration of trend metrics to consider incident rates of deviation in an environmental monitoring program. This was explained in real terms as; incident excursion rates (IER) are the number of incidents of excursion above action and alert levels when you look at all of the samples taken in an EM program. Another trend metric consideration is amount of occurrence of out of specification (OOS) deviations - that is also a trend of performance - as deviating from specification regularly does not provide assurance that there is a good state of control. Also as user specific trends are developed to consider the extent of out of trend (OTT) deviations. Together trend metrics can provide an indication of how well a facility are performing in environmental control in sterile product preparation and manufacturing environments. Di Morris reiterated that one of the things she has seen a lot in her ex-role as an MHRA GMP inspector and in her current GMP compliance auditing role, is that the trend for environmental monitoring (or at least the reports that she sees) seems to be focused on whether the facility has gone above the agreed alert and action levels. So if the facility design and the metrics are done around how many excursions have occurred, it doesn t consider the fact that that facility may have been running for 6 months 1 CFU below an alert or action level with increased risk. There is no consideration of CFU levels that may have changed to just below the alert/ action levels and such change may indicate a move towards loss of the required control state that should have been investigated. If metrics are concentrating on just showing efforts in the over action limits, then the health of a facility could be grossly at risk, and that is not being monitored and not being measured. When you look at metrics you ve got to look at all of your data, and the knowledge it gives you - not the selective parts you want to use. Furthermore, talk of numbers in environmental monitoring is not enough, especially in grade A and B the type of microorganisms/ microflora is important not just cfu numbers. It was reinforced by the panel, the knowledge trend data gives you and managing that knowledge with appropriate actions is critical and not just the process of collecting data to present at an audit/ inspection for others to review and interpret. Andrew Hopkins explained why Annex 1 will not have detailed requirements for trending. Although monitoring trends will be a requirement, there will be no specific incident rate level or type of microorganism to monitor, as these guidelines will be misused. Specials manufacturing guidance were updated this year and talked about trending, for example a trend would look at three consecutive alert limits but there is a regulatory concern if generic limits are specified it stops people thinking about specific requirements and unique risk. Andrew shared a worrying example of a facility he inspected where the monitoring data showed very sporadic action level excursions every two months or so, which had been ignored because it was a non-consecutive trend. However, there was a peak every few months showing that there were vegetative organisms and spore forming organisms being recovered from inside their grade A Isolators. 4 P age

5 This was a serious problem being ignored because limits had been specified; so a common sense approach to analyse their data was not used. The whole point of QRM and risk assessment process is that each facility should know their process. They should know what they are trending and why, and hopefully that should stand up to an inspection. Monitoring data can show sporadic issues, with trends you are normally looking for consecutive issues but if it happens now and again it may still a problem so think, don t just follow rules. There is no one stop shop for trending requirements or guidance. There was a further consideration that annex 1 revision will include more on Process monitoring considering a combination of process (CCP critical control points) and environmental monitoring. The panel thought this was a good development and look forward to hearing more details. The panel concluded by commenting that Inspectors and auditors are in favour of the word trend metrics to make people aware of keeping and consolidating results together with managing and interpreting data as trends. Question 4 Should Annex 1 include more detailed guidance on Aseptic processing with the increase of aseptic processing used in manufacture of biological products that cannot be terminally sterilised? The panel differed on the interpretation of the guidelines in annex 1 relating to aseptic processing; aptly demonstrating one of the reasons revision is necessary. It was felt by some that annex 1 does contain enough information applicable to all sterile products - both aseptically produced and terminally sterilised, though it was acknowledged that the language in some areas is currently ambiguous and unclear. It was noted that the FDA provided specific guidance to Industry on aseptic processing and EU GMP annex 1 is for all sterile product manufacturing, whether aseptically manufactured or terminally sterilised. The current annex 1 has just a few paragraphs on aseptic preparations and other members of the panel felt this was insufficient given the changing landscape of product profiles, particularly biological products that require aseptic processing, together with increasing use of new technologies that support aseptic processing and possible need for GMP guidance on their use. The panel reflected on the fact that there are more and more applications for aseptic processes using barrier separation technologies in manufacturing; with use of isolators and RABS becoming the convention, but that there is a poor trend towards meeting the minimum requirement set in the guidance rather than consider specific process and operational risks. One example discussed was the background environment for an Isolator is referred to in annex 1 as Grade D minimum and is minimum is often the starting position for a facility whether the sterile product is aseptically manufactured with open or closed system processing. 5 P age

6 Considering risk management, EM data management and contamination control, Grade D may not be appropriate for open systems aseptic processing of sterile products where the product is openly exposed to the grade A manufacturing environment, in this case Grade C could be considered more appropriate (as recommended in the PHSS Bio-contamination monograph 20). It was also considered that for closed system processing where products are processed in closed containers/ systems inside a barrier separation Isolator (separating people from process) where contamination risks are inherently reduced because of the closed system and limited to aseptic connections between closed containers, then a Grade D background could be considered appropriate. The panel discussed whether providing guidance on a generic minimum as sufficient and it may be more helpful to at least recognise the different levels of risk in open and closed system processing. It was stated that annex 1 revision would include new guidance on closed systems as this was an area of increasing development and application in GMP providing advantages and risk mitigation in contamination and cross contamination control, but details need developing of what is included in this new section. MHRA GMP Inspector Andrew Hopkins summarised the discussion by clearly stating that the correct interpretation of the current requirements set out in annex 1 is to use the best technology available to protect the patient. He informed the panel that the EMA IWG working on the revision are likely to make the language relating to requirements for aseptic processing stronger, however, he reflected that when following the current guidelines a correct interpretation would mean applying the best technology and practice available (i.e. a grade C background for a grade A open process in an isolator may be considered best practice) even if this is not a specific directive. The revised annex needs to be up to date and remain up to date, so going in to too much specific detail could lead to more and more revisions being required down the line. The panel concluded that though more clarification on aseptic processing is required, a dramatic rewrite to provide a section of annex 1 would not be required. Question 5 Concerning the various non-injectable sterile pharmaceutical dosage forms, does the panel consider Annex 1 revision should contain more precise details or dedicated paragraphs? The panel questions were prepared before the conference; the presentation given by Andrew Hopkins gave clear guidance that non-injectable sterile dosage forms will be covered in more detail in the revised annex 1. Before moving on the panel noted that when products are sterile but not injectable sometimes there are special dosage forms for example sterile tablets or sterile capsules that need consideration. The ophthalmic industry was given as a good example of sterile products which are not injectable. In Richard Johnson s experience of working in this area, he found nothing in annex 1 guidance that wasn t applicable to ophthalmic products. 6 P age

7 On the other hand for some combination products; where aseptic technology is being applied in a new setting, then some revision of annex 1 will be necessary to be applicable to this. The following questions related to more specific points in sterile product manufacturing. Question 6 - specifics Often firms/ end users implement minimum requirements for environmental control, followed by inadequate facility design layout. Should Annex 1 reinforce the risk based approach over minimum requirements or replace minimum requirements with more specifics? It was acknowledged by the panel that there is a spectrum of manufacturing expertise in the pharmaceutical/ biopharmaceutical industry and marketplace and that there will be companies who struggle to understand what is required. If there is already difficulty in understanding the design requirements then applying QRM properly may also be a struggle. It is not feasible or appropriate to put all of this information in annex 1 guidance. This is where organisations that provide a neutral platform (non-commercial) for providing reference information, education, best practice guidance and connection between the industry and regulatory authorities to understand each other s requirements or points of view, such as; the PHSS, PDA, ISPE, A3P, R3 Nordic can assist with best practice peer reviewed monographs/ technical reports or base line guidance. When there is a struggle to know what to put in place then best practice, baseline guidance and technical reports are something that can be consulted as recognised guidance. Also it was discussed that ISO standards are generic across different industries and best practice guidance can assist interpretation of what sections of referenced ISO standards are appropriate for pharmaceutical sterile product manufacturing. It was commented that ISO14644 is currently referenced in GMP but the EMA has no control or input into ISO14644 revisions. It was considered there may be less specific connection to ISO14644 in GMP and the annex 1 revision because of this disconnect of revision control and currently there are discussions on how the ISO standard connection will be covered in annex 1 revision. In some markets you can accept the principle that for any given process the risk is assessed, and the manufacturer then comes up with an appropriate solution for which they then seek approval from the regulatory authority. However, in many markets, in particular emerging markets which do not see these higher profile types of technologies; they expect the regulators to educate them in how to do things. Furthermore, if new technologies are not understood they are not used or not used appropriately. In the PIC/S environment it is not straightforward to apply regulation. It was discussed that there are definitely parts of annex 1 where it could be clarified what the expectations are for processing in closed systems and to differentiate true closed systems. 7 P age

8 For example an Isolator is a Barrier separation technology and not a true closed system. While a presterilised single use system (SUS) of product fluid path including product fluid lines, sterilising filter, filling needles would be considered a true closed system. Further a point of misconception may be clarified that isolators referenced in annex 1 are assumed to use a gaseous disinfection process, such as vaporised hydrogen peroxide, and there are other applications e.g. hospital pharmacies that use Isolators with manual disinfection procedures. There is generally a lack of understanding of the variety of isolator types which are available or appropriate for different applications so reference to Isolators as a generic terms needs consideration. It is nevertheless very important that the revised draft of annex 1 be careful not to ramp up standards by adding additional regulatory requirements which are not currently called for. The current document already talks about what is acceptable and implies the appropriate cleanliness grade, so this may need to be clarified and reinforced. If the revision goes too far in reinforcing requirements it won t get past the draft stage. It is important that for the revision of such an important industry guidance as GMP annex 1, it is taken into account that industry should be the experts in sterile product manufacturing process design and allow them to make good judgements. The guidance should give industry room for manoeuvre and flexibility so that they can make good decisions which fit their unique process requirements i.e. utilise the principles of QRM. Question 7 - specifics New technologies are to be considered in the revision of annex 1. Does consideration include new Rapid Micro Methods (RMM) and in particular real time environmental monitoring RMM and if so how can conventional microbiological Not to exceed CFU levels detailed in Annex 1 be reconciled with fluorescent based Bio-count levels for GMP compliance? PHSS comment: It is unlikely there will be widespread adoption of RMM-RT (Real time) methods in environmental monitoring of Grade A filling zones where environmental data is considered in Batch records and higher recoveries reported as Bio-counts will be difficult data to manage without an Annex 1 reference or guidance on correlation with CFUs. Using real time data from RMM environmental monitoring enables a facility to be responsive to conditions of change, and the fluorescent based technologies also negate the need for interventions to place a growth media plate in a sampling location, reducing contamination risk as a result of the required intervention. Outside Grade A environments RMM-RT may be considered useful to understand changing conditions of environmental control or support investigations into contamination events. It was considered that when fully developed there are lots of good reasons to adopt the RMM-RT environmental monitoring technology but there is a barrier to adoption due to the higher recoveries from these types of technology and possible false positive results as other non-biological fluorescing materials may result in a reported biocount. Typically when comparing CFUs with biocounts from RMMs, the biocounts are much higher. 8 P age

9 The term Biocount is the new term introduced in the recent PHSS bio-contamination monograph 20 in an attempt to standardise the term. It was then suggested by a member of the panel that the term fluoro-count as opposed to biocount may be more accurate accepting measurements of biological and non-biological counts may not be fully differentiated, it may not be a living particle which is detected so this should be considered as well. The panel discussed the difficulty with adoption of the new RMM real time environmental monitoring technology in managing the data if using RMMs is more likely to show the facility is out of current annex 1 compliance if bio-counts are considered the same as CFU s. RMMs environmental monitoring systems are being implemented in support areas but companies are reluctant to use them in grade A areas as the technology is so sensitive and the difference between bio-count and CFU levels is not fully characterised. It was suggested perhaps there is a need to differentiate CFU vs biocount in annex 1 and give some recognition to the type of data that you get, so that companies feel more comfortable using the technology. It was pointed out that biocounts could be independently (of conventional CFU counts) be characterised as a baseline in a facility environments and real time fluctuations reported and acted on and this may provide a more proactive than reactive (to growth media results) practice in responding to undesirable deviations in bio-contamination levels. Andrew Hopkins clearly stated that the working group will not be defining biocounts in annex 1 at this time. Suppliers haven t standardised the technology and terms of reference and it is not yet considered mature technology; once there is more consensus on what is meant by a biocount (or whatever term becomes standardised) and enough advancement to differentiate between viable/non-viable particles it will be different, but at this time it is too early for it to go into the regulation. Understanding and applying CFU as a measure is still a target for most industries involved in sterile and non-sterile product manufacture where bioburden control is required so it would not at this time be helpful to make the regulations more complex. There is also a risk that what is being recommended is actually a get out of jail free card to mask the significant event of 1CFU in a Grade A environment with characterised biocounts. It is understood biocounts are not the same as 1 CFU and correlation is not developed or may not even be possible. It was noted that just because a detected organism can t be cultured classically it is still relevant to the patient being injected! Sterile products should be sterile and even very low levels of viable particles being detected should be recorded. Just because it won t grow on a plate it could still be a real issue. This is not a clear cut discussion and is in the early stages. PHSS comment: This discussion did not include consider of other Rapid Micro Methods using part growth and part fluorescent technologies used to speed up sterility testing or Bioburden analysis with shortened processing time that are more developed and mature technologies. 9 P age

10 So care should be taken in interpretation of discussion panel comments when considering other RMM technologies than Real Time environmental monitoring RMM technologies discussed. Post meeting note: Andrew Hopkins confirmed agreement with PHSS comment and outlined that annex 1 encourage the use of RMM for appropriate types of activity. Question 8 specifics In an aseptic processing area what is the expectation for grade A continuity for product contacting parts, components and their primary packaging that are sterilised out of place and then subsequently transferred for aseptic assembly and sterile product manufacture. Is there an expectation that Grade A continuity can be provided by double wrapping parts, with bio-shield coverings, for sterilisation before one wrap is removed at Grade B to Grade A transfer and the final layer is removed in Grade A or is the use of a UDF grade A supply transfer carts recommended? There is some risk with use of double wrapping to transfer materials to grade A, but the MHRA currently accept this practice. The newest and best technology available should be used so regulators would prefer a move towards UDF Transfer carts as a more engineered solution for Grade A continuity where applicable; this is not necessarily always possible if the cleanroom is small. A word of caution was expressed in that within a hot autoclave air movements are very strong when the door is opened for unloading as cool air, possibly contaminated if from floor level, is drawn in at the bottom, so use of UDF Transfer carts alone does not provide Grade A continuity. To manage this contaminating air intrusion risk UDF (uni-directional airflow) down-flow is required that the open autoclave door with low levels air returns that facilitate supply of Grade A air to below that drawn into the hot autoclave when the door is opened. Berit Reinmüller referenced a research paper published in the European Journal of Parenteral and Pharmaceutical Sciences EJPPS on an autoclave air movement study at unloading. It was suggested that annex 1 should focus on the objectives and leave it open to the reader to choose an appropriate solution. Scale and complexity of process machinery has a significant influence on operational risks and required control measures so it is difficult to provide prescriptive guidance that covers all levels of scale and complexity. Filling machines can be so complex aseptic assembly is practically impossible so there has to be a risk based decision in process design to balance automation with manual interventions. There should not be a prescribed route or defined solution but the objectives should be unambiguous with clear, concise language to ensure they are easy to understand when translated or used by countries who don t use English as a first language. 10 P age

11 Question 9 specifics Is it expected to review in detail the way Annex 1 is written for years to prevent misinterpretation of some statements? It was considered by the discussion panel moderator that Andrew Hopkins presentation already covered this question together with discussion panel comments that the wording and ambiguity will be improved and the EMA annex 1 working party sub groups will consider these points in section revisions. Question 10 - specifics With the increased complexity and diversity of aseptic formulations, the classic use of nutrient media to replace the formulation for process simulation trials (PSTs) is not always feasible, or scientifically justifiable. Alternative approaches based on risk assessment and scientific rationale could be regarded as equivalent to ensure an acceptable level of aseptic assurance. Is this approach consistent with the intent of the revised Annex 1 document? The baseline expectation will remain the same in annex 1 with growth media used in media fills/ process simulations together with sterility testing of the filled media. Whether it is possible to fully risk assess a process simulation without use of the growth media and sterility test method is open to question so probably such a consideration would not be included in the annex 1 revision review. Question 11 specifics Concerning material airlocks (MAL) can it be considered that a two door MAL would be sufficient from Grade D to Grade B for material transfers providing it is separated with a line in the middle, and provided the D operators will never cross that line and additionally the B operators will also not cross the same line from the other side? The first reply to this question amused the panel with the jovial comment; make sure the bacteria are trained not to cross the line as well! demonstrating the difficulty of implementing this type of facility design. However the comment was made that two door MALs are currently used and accepted by the regulators, so long as there is careful management, the requirements are not expected to change in annex 1. Such devices need appropriate positioning between different controlled zones with rationale and risk assessment to support selection and operation. The panel considered the normal zone material transfer cascade would be from D>C>B>A. It was commented such a cascade is specified in WHO annex 6. Direct transfers from Grade D to B may be challenged to maintain both airborne and surface contamination transfer particularly as only manual disinfection procedures are typically applied. For airborne contamination transfer control it was emphasised that best practice would be to include a recovery/clean up after loading materials and the doors are locked before the higher classification can be unlocked and opened for material transfer. 11 P age

12 For material transfer from grade D to B surface contamination on loaded materials (and transfer carts if they pass through the MAL), as well as airborne contamination, would be a relevant risk, so there would need to be robust cleaning/ disinfection of the outer surfaces of materials to be transferred. Grade D to B material transfers were considered a challenged process with a MAL having just a barrier line demarcation between different zones and grades that could easily be misused. Also it was considered and use of manual disinfection procedures, which are subject to inherent variability, may not provide the necessary bio-contamination control when the transfer zone grades are so different. Hence the process was not considered robust. It was considered by the panel that annex 1 should reinforce the design of an aseptic pyramid based on a cascade and airflow from more clean to less clean. In addition it would be better to engineer a solution which does not allow an operator to do something you do not want them to do. The panel felt that facilities should be moving away from this type of design, where operator failure is a huge risk, but acknowledged that these processes though less than ideal are still used, and should be carefully managed and controlled. Question 12 specifics When using gamma irradiated single use systems with integrated point of fill filtration is pre use integrity testing appropriate for this set up? Pre use integrity testing will remain in the annex, you would need justification to support not using it with gamma irradiated single use systems. If you can do a traditional integrity test without compromising the process or sterile integrity of the single use system it will remain an expectation. Question 13 specifics When factoring a facility upgrade, in terms of dispensary operations is there a regulatory move for these to be carried out as a minimum within a Grade C environment? There is not a regulatory move to set a minimum, though members of the panel felt that for upgrading a facility grade C would be their selection for a background environment. Despite the panels opinion it is unlikely regulatory requirements will be changing to say so. The panel considered annex 1 should emphasise the principle and best practice to use the integrated zone cascade approach like protective layers where bioburden is controlled as soon as possible in a facility with cleaner and cleaner zones; CNC>D>C>B with progression to Grade A process zones where sterile products may be exposed to the manufacturing environment. Different stages of a process require different background environments but all should be based on an integrated zone cascade approach up to the required cleanroom grade so bioburden control is implemented in a controlled approach where control measures of airflow movements and pressure cascades can be applied. 12 P age

13 Question 14 from the Conference floor. One final question from the floor came from GSK France, regarding ready to use components e.g. syringes in Tubs the question asked was if there will be a focus and guidance on how to control and manage ready to use sterile components. The response from the panel was ready to use pre-sterilised components it is not something that will be covered in detail in annex 1 as it is quite a specific area. A syringe tub alone will not be considered a closed system in the new proposed section on closed systems however it is recognised how important sterile integrity of contract manufactured sterile components is to be maintained from outsourced manufacture, through supply and into use. Components entering the cleanroom are part of sterile manufacturing process so require full QRM. There has been some discussion if annex 1 guidance should be extended to outsourced sterile component/ product closure contract manufacturers and there are a lot of different opinions and a big discussion to be had if that were the case The debate was concluded and the discussion panel thanked for the contribution to this important topic of annex 1 revision. As a final note the PHSS encouraged all to remain informed and engaged in the annex 1 revision process so all can prepare and manage proposed changes as they develop and not wait for the final revision and the likely impact. End 13 P age