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White Paper

Author:Dr Tim Sandle

EU GMP Annex 1: The New Draft and the Implications for Sterile Products Manufacturing

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AbstractEU GMP Annex 1 is the primary document governing the manufacture, control and release of sterile pharmaceutical products (both terminally sterilised and aseptically filled medicines). The Annex will shortly undergo a comprehensive update, as signalled by a new draft issued in February 2020. This white paper assesses many of the key points within the draft, focusing on those areas that have a direct impact upon sterile product manufacturing.

Contents

Introduction 3

What is EU GMP Annex 1? 3

Key Changes 4

New Structure 4

Contamination Control Strategy 4

Centrality of the Pharmaceutical Quality System 5

Premises 5

Personnel 8

Microbiological Environmental Monitoring 9

Quality Control 10

Filtration 10

Product Inspection 10

Cleaning and Disinfection 11

Utilities 12

Summary 12

References 13

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Annex 1 of EudraLex “The Rules Governing Medicinal Products in the European Union” forms part of Volume 4 of the European guidelines covering the manufacture and release of sterile products, which are subject to special requirements (1).

The Annex is going through a revision process, with the final version expected in 2020. This review process began with the issuing of a draft in December 2017. This draft was subject to over 6,000 comments submitted by professional organisations. After a review of these, across a two-year period, the European Medicines Agency (EMA), issued a new draft (described as ‘version 12’) (2). The new draft addresses some of the issues in the first version and contains some additional requirements. The scope for the review of version 12 is more limited, with specific areas marked for consultation and the group of professional bodies invited to comment has been narrowed. This signals that much of the draft content will be in the final version, and that the final version will be issued within a relatively short timeframe.

The trigger points for the revision to the Annex included emergence of new technologies, and what regulatory inspectors have highlighted as inadequate root cause analysis and ineffective CAPA. Other points of regulatory concern included poor implementation of ICHQ9 (which relates to quality risk management) (3). A further reason for revision was to address various points of ambiguity in the interpretation of the Annex 1 requirements.

This white paper provides an overview of the draft Annex 1 and considers the focal points for sterile products manufacture, control and release.

Introduction

What is EU GMP Annex 1?

There are two major, global guidance documents for sterile products manufacture: the FDA guidance, last revised in 2004 (4), and Annex 1 of EU GMP. Annex 1 of EudraLex “The Rules Governing Medicinal Products in the European Union” forms part of Volume 4 of the European guidelines (1) (there is also a WHO guidance. The purpose of these guidances, is to detail the controls required around the manufacture of sterile products. Special requirements are needed in order to minimise risks of microbiological, particulate and pyrogen contamination of sterile products; and also, to provide guidance as to how sterile products are best protected. Annex 1 includes key areas like personnel training, equipment qualification, cleanroom design and environmental monitoring.

The scope of Annex 1 relates to pharmaceutical companies who manufacture products within the European Union and those companies who import products into the European Union (including a post-Brexit United Kingdom).

Annex 1 of EU GMP has undergone no major revision since 2007 and no change whatsoever since 2009 (where there was a minor point of clarification about the required air supply grading for oversealing - Grade A air supply). The lack of an update through the intervening years was especially notable in the context of updates to cleanroom technology and the appearance of new types of rapid microbiological methods. As part of the revision process, the current title of “Annex 1: Manufacture of Sterile Medicinal Products” is now tweaked to read “Annex 1: Manufacture of Sterile Products”.

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Key Changes There are five broad areas of change to the draft, in terms of tone and emphasis. These are reflected at various intervals in the document (often through repeated occurrences). These areas are:

1. The global acceptance and implementation of ICH Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System), is not reflected in the current Annex. The new draft contains many references to Quality Risk Management (QRM) in particular, emphasising that QRM should be used as a proactive tool.

2. There is the requirement for a formal, holistic contamination control strategy. The expectation is for a formal document which reflects the site-wide strategy for minimising contamination control with respect to sterile manufacturing. Such a strategy, as outlined below, is for each organisation to fully-understand and review design, procedural, technical and organisational controls.

3. There have been advances in sterile manufacturing technology, especially with RABS and isolators. There have also been advances with rapid microbiological methods, which the draft Annex acknowledges

4. There was some ambiguity with the current version and these needed correction or clarification

5. Annex 1 is often beyond sterile manufacturing, including aspects of non-sterile manufacturing. The scope of the new draft has been modified and broadened to reflect this.

6. In particular the references to Quality Risk Management are more extensive, with requirement to use QRM to review existing products and processes; new products and processes (where risk assessment needs to link to Quality by Design); and to address problems with procedures and processes, with the expectation that QRM becomes a key part of deviation management. This reflects a significant shift in regulatory thinking towards a more risk-centric approach.

New StructureThe new draft is divided into eleven parts, which are presented across 52 pages (which means that it is two pages longer than the 2017 version and considerably more than the current Annex’s 16 pages).

1. Scope2. Principle3. Pharmaceutical Quality System (PQS)4. Premises5. Equipment6. Utilities7. Personnel8. Production and Specific Technologies9. Viable and Non-viable Environmental and

Process Monitoring10. Quality Control (QC)11. Glossary

Contamination Control StrategyA substantial part of the draft Annex is given over to each organisation having a detailed, facility-specific contamination control strategy (abbreviated to CCS). To be effective this needs to be an approach that can assess seemingly isolated contamination events holistically and which is capable of putting appropriate corrective and preventive actions (CAPA) in place. This requirement is intended to signal a new paradigm in terms of contamination control, shifting the risk review process to one that assesses the impact of a contamination event in a far wider context.

The main elements of such a control strategy are:

• Design of both the plant and process

• Equipment and facilities

• Personnel

• Utilities

• Raw materials control – including in-process controls

• Product containers and closures

• Vendor approval – such as key component suppliers, sterilisation of components and single use systems, and services

• For outsourced services, such as sterilisation, sufficient evidence should be provided to the contract giver to ensure the process is operating correctly

• Process risk assessment

• Process validation

• Preventative maintenance – maintaining equipment and premises (planned and unplanned maintenance) to a standard that will not add significant risk of contamination

• Cleaning and disinfection

• Monitoring systems - including an assessment of the feasibility of the introduction of scientifically sound, modern methods that optimise the detection of environmental contamination

• Prevention – trending, investigations, corrective and preventive actions (CAPA), root cause determination and the need for more robust investigational tools

• Continuous improvement based on information from the above systems

With each of these different elements it is notable that they are not confined to biocontamination, since reference is also made to subvisible particles (the classic appearance tests) and the overall appearance of the pharmaceutical product.

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The first main section of the draft refers to the Pharmaceutical Quality System, a quality system that each manufacturer should have in place. While general matters are covered in Chapter 1 of EU GMP, the draft Annex makes reference to specific aspects for sterile products manufacture. These include:

• The proactive use of risk management

• Regular review of risk assessments

• Rationales in place to address different categories of risk arising from risk assessments

• Employing staff with sufficient expertise to undertake risk assessments

• Use of effective root cause and CAPA

• Those tasked with releasing products must be fully conversant with risks and quality issues

• The first two bullet points signal the continuing reference to risk management and risk assessment throughout the document

The reference to risk assessment should not simply confined to manufacturing, it needs to extend to packaging (primary and secondary) and to the distribution of the finished medicinal product, thereby embracing the requirements of Good Distribution Practice (GDP).

Centrality of the Pharmaceutical Quality System

The main changes under the premises section relate to cleanroom design and operation. With the overall design of cleanrooms, the draft stresses the importance of ‘quality-by-design’, with particular reference made to lay-out and process flow, where the process steps are reflective of an intent to maintain contamination control. This design concept extends to the necessity of conducting all non-essential processes outside clean areas. Reference is made to Annex 15 of the EU GMP guide (“Qualification and Validation”) in relation to ensuring that equipment has been suitably qualified.

The text makes reference to the specific series of tests required when a cleanroom is qualified. These tests are (where relevant to the design):

Premises

• Installed filter leakage and integrity testing

• Airflow measurement - Volume and velocity

• Air pressure difference measurement (with the new draft the specification changes from 10 to 15 pascals to a minimum of 10 Pascals)

• Airflow direction and visualisation

• Microbial airborne and surface contamination

• Temperature measurement

• Relative humidity measurement

• Recovery testing

• Containment leak testing

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Notably here is the task of microbiological monitoring. This is something that has been discussed in relation to the update of the ISO 14698 biocontamination standards, about adding a microbiological monitoring aspect to the assessment of cleanrooms.

With particle assessments, the Annex keeps the requirement to count airborne particulates equal to or greater than 0.5 and 5.0 μm (which continues to create a difference with the FDA aseptic processing guidance, which refers to particles of ≥0.5 μm only). However, for Grade A zone and Grade B at rest, classification only needs to be for particles equal to or greater than 0.5 μm. The cleanroom classification expectations apply to the ‘at rest’ and ‘in operation’ states (with the ‘in operation’ state there is a suggestion that for aseptic processing areas that the exercise is undertaken during media fills, in order to represent worst-case). For selecting particle locations the draft Annex states that the ISO 14644 methodology is to be followed, along with the additional expectation that, for aseptic processing areas, sample locations are positioned so that all critical processing zones like the point of fill and stopper bowls are included and based on a documented risk assessment.

Whilst there are no changes to requalification intervals (Grades A and B six-monthly and Grade C and D annually) additional text has been added stipulating that re-qualifications should be undertaken following any remedial works needed on equipment or where the facility requires work or where new equipment is added to the cleanroom, as assessed through change control. Other reasons for undertaking a re-qualification include change of room use and to reassess areas following a loss of power.

Outside of classified cleanrooms, reference is made to ‘controlled but not classified areas’. Here the movement of material from controlled but not classified to Grade C needs to be based on risk management principles, with means that the level of cleaning and disinfection and the control of materials needs to be commensurate with the level of risk assessed.

For the first time the draft Annex provides guidance for Grade D particles, albeit for ‘at rest’ rather than for ‘in operation’. Here a value of 29,000 particles for the ≥0.5 μm size particle is provided as the limit. The current Annex simply lists Grade D particles as ‘separately determined’, with no further guidance supplied.

In terms of other critical parameters, the draft Annex offers more scope with unidirectional airflow velocities. With air speed, while the range of 0.36 – 0.54 m/s remains the general requirement at working height; however, there is scope for companies to operate clean air devices outside of this range should be designed, provided that this is scientifically justified and detailed in the contamination control strategy. With the related aspect of airflow visualisation (‘smoke’) studies these now need to be conducted in both the ’at rest’ and ‘in operational’ states (previously the reference was just to ‘in operation’). The draft Annex requires that following an adjustment to air velocities for qualified devices that

part of the acceptance of the adjusted volume includes an airflow visualisation to be conducted. For isolators that are ‘closed’ the Annex states that the air direction need not necessarily be unidirectional.

The revised Annex has added information relating to environmental controls in relation to pressure. In addition to revising the limit for pressure (as indicated above), there is a requirement that all areas with differential pressure have warning alarms in place, where the warning signals a potential problem with air supply.

Barrier Technology

The Annex does not go as far as mandating the use of barrier technology; however, there is a recommendation that manufacturers consider adopting “appropriate technologies”, such as Restricted Access Barriers Systems (RABS) or isolators. The recommendation extends to consideration of robotic systems, which will reduce the need for human intervention. With the emphasis upon barrier technology the Annex requires that any alternative must be robustly risk assessed.

With isolator technology used for aseptic processing, the text states that pass through of items should be minimised and ideally go through a rapid decontamination chamber. Gloves are recognised as the weakest point with an isolator system, so consequently there is the requirement for glove leak testing at a minimum interval of before and after each batch (the leak assessment also extends to the main isolator unit as well). In the text, the frequency of glove leak testing is detailed as “a minimum at the beginning and end of each batch.” Also, with gloves, there is reference to the importance of selecting the correct isolator gloves; those with good mechanical and chemical resistance. The period of time between the replacement of gloves now requires justifying in the contamination control strategy.

For the preparation of isolators for filling, the new draft stresses the importance of cleaning prior to disinfection (since the presence of residues can inhibit the ability of disinfectants to traverse microbial cell walls, which is necessary for the killing of microorganisms). In keeping with cleaning, the ‘clean hold time’ also requires qualifying. There is a requirement to verify that the disinfectant used, in relation to any remaining residues, does not have an adverse impact upon the product.

A further change, with the set-up of filling line contained within barrier technology, is that a sporicidal disinfection process is used following set-up, as mechanism to reduce any microbial contamination that may have been presented during the assembly process.

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Specific points relating to aseptic processing

The current Annex requires all connections for aseptic processing (such as vessel to manifold) to be performed under Grade A. The draft acknowledges advancements with sterile processing technology, permitting aseptic connections that use intrinsic sterile connection devices, designed to minimise any potential contamination from the immediate environment, to be performed in lower classified environments provided that the connection device has been appropriately validated to show no ingress of microbial contamination.

The control of operation time is discussed in several places, perhaps with the view that times outside what is ordinarily seen can lead to an increased contamination risk. Time is referred to with:

• Pre-fill time should be assessed as part of media fills

• A time limit required for aseptic assembly

• Maximum exposure time of sterilised containers and closures prior to closure. This infers oversealing times need to be set. This has an impact with regards to ensuring crimping is conducted expediently

• For items sterilised “in house” (such as by autoclaving), these need to be stored in Grade A or B, using appropriately sealed packaging and a maximum hold period must be established

• The Annex sets out the main elements for Grade A processing, which allows manufacturers to risk assess the essential elements. These are:

• Maintaining the critical processing zone

• The aseptic assembly of filling equipment

• Aseptic connections (these should be sterilised by steam-in-place whenever feasible).

• Special focus on aseptic compounding and mixing

• The risks around the replenishment of sterile product, containers and closures

• Concerns around the removal and cooling of items from heat sterilisers

• Staging and conveying of sterile primary packaging components

• Aseptic filling, sealing, transfer of open or partially stoppered vials, including interventions

• Loading and unloading of a lyophiliser

These elements could be cross-referred back to the contamination control strategy and implied risk assessment.

For transfer of items and equipment into aseptic processing areas, there is added emphasis upon unidirectional airflow and sterilisation or decontamination. Where possible, items should be sterilised and passed into the area through double-ended sterilisers (such as a through a double-door autoclave or depyrogenation oven/tunnel). Where sterilisation on transfer of the items is not possible, pass through hatches equipped with unidirectional airflow and with a method of transfer disinfection, in place should be used. With equipment sterilisation, as required for aseptic processing, the text requires all direct and indirect contact parts to be sterilised.

Single-use systems are technologies used in manufacture of sterile products as alternatives to reusable equipment. The systems are designed to maintain integrity throughout processing under the intended operational conditions and their application can help to reduce contamination risk, e.g. aseptic connections. The use of single-use systems and technologies continues to be encouraged within the draft Annex, albeit with the caveat that the interaction between the product and product contact surface (notably adsorption, leachable and extractables) is carefully understood.

Other revisions to the Annex which impact on operations conducted within cleanrooms include additional information about media fills (aseptic process simulations), where more ‘time based’ criteria have been added (such as assessing filling machine hold times and sterilised equipment hold times as part of the exercise). The importance of simulating all events remains (given that events, especially interventions are more important for the success or failure of a media fill than simply run time). There has also been a change to acceptable failure limits in media fill studies, based on filling run size. The formally specified statistical approach of >99.9% at 95% confidence interval is no longer applicable to determine acceptable failure limits. Instead the expectation is zero, irrespective of the media fill size. This will create tighter limits for those manufacturers who have yet to adopt more stringent, especially for large batch sizes. A further point with media fill failures is that, following investigation and root cause analysis, the previous note about running one media fill has changed to a near requirement to run three media fills.

Greater detail is provided for assessing the success of autoclave operations, such as the requirement to inspect sterilised packaging for its integrity and dryness. Such changes are designed to strengthen controls around sterile products manufacture.

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Personnel

The biggest section within the draft is dedicated to personnel. The section includes a requirement to restrict the numbers of personnel permitted to enter cleanrooms. The recommendation is that personnel numbers, especially in sterile manufacturing areas, is minimised based on risk assessment. This acknowledges that the biggest risk of microbial contamination in cleanrooms derives from people, principally through shedding and by touching critical surface.

In relation to controlling access to cleanrooms there is reference made to the importance of on-going quality assurance oversight. To minimise additional risk from people, there is a reference to such activities being completed outside of the cleanroom, such as by inspection windows or through the use of CCTV.

As expected, training plays a significant part in the personnel section. This extends to everyone entering the cleanroom, including cleaning and maintenance staff. The minimum basis for a training program is set out as to include: hygiene, cleanroom practices, contamination control, aseptic techniques, and potential safety implications to the patient of a loss of product sterility and in the basic elements of microbiology. For access into the higher-grade cleanrooms (Grades A and B) to work on aseptic processing lines, personnel are expected to have completed aseptic process qualifications (such as through a media fill). An exception is made for maintenance staff under exceptional circumstances, although procedures need to be in place to describe how this will be controlled.

With qualifying operators, the language of the 2020 draft refers to ‘qualified’ and ‘unqualified’ operators (it is also possible for qualified operators to become disqualified if there are concerns around microbial contamination). Part of the qualification is a gown test and the movement through a well-designed cleanroom system that seeks to minimise contamination. The requirements for entering

changing areas for access into Grade B and C areas have been strengthened. The draft states that outdoor clothing (other than personal underwear) cannot be brought into changing rooms. In terms of what is not permitted to be taken into clean areas, the Annex now calls out mobile devices (reflecting the ubiquity of smartphones and the like) unless these have been supplied by the organisation and are shown to be suitable for cleanroom used, and covered by a cleaning and disinfection process. With entry into Grade B changing areas, there needs to be a separate way in and a separate way out (the requirement to add this to Grade C areas has been dropped). This is in order to reduce cross-contamination.

With gowns, the text also requires that:

• Gowns must be suitable to prevent shedding and the environment in which operators work and the movements they may be undertaking needs to be taken into account

• The gown worn needs to be of a suitable size

• Gowns must not affect the product (this is a reference to the risk of fibres being released from gowns and ending up in the product)

• That gowns are assessed for their suitability (e.g. no signs of damage) prior to be being worn and once donned, prior to entering the cleanroom. There is a comment that visual inspection may not be sufficient to assess gown integrity. However, no further advice is afforded, and this is something for which there is no obvious solution for, prior to entering a cleanroom

• Gowns must be processed in dedicated laundry facilities and the process of cleaning, evaluating and sterilising gowns must be qualified

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Microbiological Environmental Monitoring

For cleanroom operators entering aseptic processing areas a gowning test is required (which is a combination of visual assessment and microbiological monitoring). The new draft expands the list of recommended locations on an operator’s gown that require monitoring as part of the gowning qualification: hands, arms, chest and forehead. Each one of these locations presents a different microbial contamination risk, in terms of the types of organisms and the route of contamination transfer. In addition, microbiological limits are presented for gown plates for the first time (these are afforded the same maximal values as finger plates). Further with gowning, the new draft now requires the maximum time that a gown can be worn for to be defined.

All staff working in cleanrooms are expected to have knowledge of hygiene, cleanroom practices, contamination control, aseptic techniques, and potential

safety implications to the patient of a loss of product sterility and in the basic elements of microbiology. As well as requiring that personnel are suitably qualified to work in cleanrooms, the new draft of the Annex states that each facility must have staff who are specifically experienced in microbiology, environmental monitoring regime and with conducting microbiological investigations.

With aseptic operations specifically, the revised draft places strong emphasis upon how operators are trained, especially in relation to any interventions with Grade A. It is stressed that practices must not disrupt Grade A unidirectional airflow in terms of movement or with the placing of objects that might cause air disruption. To aid with operator training a recommendation is made that airflow visualisation studies constitute part of the operator training program.

For viable monitoring expanded information is provided in relation to sample site selection, stating that this needs to be risk based and, where applicable, determined through a review of airflow visualisation studies.

A change has been made to the EU GMP Grade A limit; which changes from 1 CFU to ‘no growth’. This change is both a reflection of the expectation that microorganisms are not typically recovered from Grade A environments (and that every recovery requires an investigation) and with the different types of techniques that could be applied as replacements to the classic culture-based methods, such as the use of rapid and automated microbiological methods are permitted provided the facility has demonstrated their equivalency or superiority.

The Annex also sets out the expectation for continuous monitoring in relation to aseptic processing. This is mandatory for Grade A and recommended for Grade B. By continuous monitoring this means air samples (either settle plates or volumetric air samplers).

Trending is an important consideration and the Annex provides information about setting alert and action levels and for looking for data patterns. Where action level excursions occur, there is a necessity to investigate, determine root cause and to set alert and action levels. Trending is not only with numbers of colony forming units; trending also applies to microbial speciation. For microbial identification the draft Annex stipulates that all isolates from Grade A and B areas should be identified, and recommends that those isolated from Grade C and D areas are identified. The Annex does not appear to acknowledge that it is not always possible to obtain an accurate identification result although the intent is presumably for the microbiologist to try to obtain a genus or species level outcome.

To strengthen monitoring, a reference is made to qualifying some aspects of the technologies used, including verifying that contact plates are not providing false counts due to the presence of disinfectant residues. Most users overcome this through the use of a neutraliser being added to the agar.

A limitation is placed on monitoring (and testing) being no substitute for a robust sterility assurance system. With this there is an emphasis that testing is too imprecise to detect a weakness with the sterility assurance system. As the draft states: “Exclusively monitoring or testing does not give assurance of sterility.” Instead, design and control matter far more for patient safety.

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Filtration

Microbiological tests also feature in an expanded ‘quality control’ section. These tests include the examination of raw materials, where the specification applied should be based on the required microbial quality as defined in the contamination control strategy. Further tests include assessing intermediate bioburden of intermediate product and a bioburden test conducted immediately before the sterilising filter (for aseptically filled products) or prior to terminal sterilisation. In both cases, the samples should be representative of the worst-case conditions, such as at the end of a process hold time.

The quality control section contains a discussion around the sterility test. While full limitations with the sterility test are not discussed in detail, the Annex does emphasise that the value of the sterility test is diminished if sterilisation and environmental controls are not in place. To strengthen the sterility test, in terms of making the test more representative, the draft text provides guidance

on sampling from the beginning, middle and end of the batch, plus following any significant intervention. For terminally sterilised products the worst case locations relate to areas like cold spots; and with lyophilised products, samples need to be taken from different freeze-dryer loads.

Sterile filtration is a critical step for aseptically filled products, where products are passed through a μ0.22 μm filter, with pressure and time controlled (following validation of the filter, where a bacterial challenge has been used in the presence of product). A key measure is an assessment of the product bioburden prior to filtration.

The issue of pre-use post sterilisation integrity testing (PUPSIT) is set to apply to all large volume products. For small volume products, a risk assessment can be used, assessing the filter sterilisation process in terms of having controls in place ensuring that the risk of damage to the filter is minimised. There is also a requirement to understand the supply chain, such as having oversight

of contract sterilisation facilities; modes of transport; packaging of the sterilised filter, designed to prevent damage to the filter during transportation and storage. Further controls around filtration include process knowledge including the specific product type, including microbial challenge and whether there exists any risk of impact on filter integrity values, such as the potential to alter integrity testing values and therefore prevent the detection of a non-integral filter during a post-use filter integrity test. Finally, pre-filtration and processing steps, prior to the sterilising filter, must be in place to remove a microbial challenge and clarify the product prior to the sterile filtration.

Quality Control

Product InspectionSterile, medicinal pharmaceutical products need to be sterile, apyrogenic and particle free. This latter point relates to visual inspection, a subject that has not been covered in any great detail by the Annex before. Each facility is required to have a list of critical deficiencies – such as particle, hairs and turbidity – and to subject operators to regular assessment. The assessment should be under practical conditions, with control of inspection time, line speed, and component size. To capture operator fatigue the test should be executed at the end of the shift.

There are several references made to container integrity. The first is that containers sealed under vacuum should be tested for maintenance of vacuum after an appropriate, pre-determined period and during shelf life (which relates to a stability studies). The second is that container closure integrity testing needs to consider the

impact of transportation, a further reference to Good Distribution Practices (GDP). The third point is that microbial ingress studies (or alternative methods) should be utilised to determine the acceptable stopper height displacement.

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The references to disinfection have been expanded. The need to rotate between two different disinfectants remains, although the fact that one of these should be a sporicidal agent is a new one. Reference is also made to disinfectant qualification, for both cleanrooms and for transfer disinfection (the act of introducing items into cleanrooms or between cleanrooms of different grades). Not only is disinfectant efficacy testing described as important the Annex infers that this is a type of testing that needs to be carried out by a facility independently. One reason for this is because the different types of surfaces found in different facilities, together with regional variations with the microbial flora. With the discussions about disinfectants in section 5, references are made to the need to assess the bioburden of non-sterile disinfectants and to assign expiry dates.

Further requirements are that:

Cleaning and Disinfection

• Validation studies relate to the specific manner in which disinfectants are use (by this there will be differences between sprays, sprays followed by wiping, and pre-saturated wipes, for example)

• Validation needs to be extended to the in-use expiry periods of prepared solutions

• It remains that disinfectants used in Grade A and B areas needs to be sterile; to this point the text has been revised to state that disinfectants used in Grade C and D areas may need to be sterile (this generalisation is not especially helpful)

• There is a requirement that disinfectants that are not purchased ready-made and which are thus made up in-house as assessed for microbial contamination (the time point is not specified, but presumably this means end-of-use to represent ‘worst case’). For ready-made disinfectants, assessment can be undertaken by a review of certificates of analysis

• Monitoring the effectiveness of disinfectants through environmental monitoring does appear in the earlier draft; however, reference to “spore-resistant strains” has been replaced with “organisms resistant to the disinfection regime currently in use”, which is more scientifically accurate since a microorganism does not always need to enter into a spore state to be difficult to kill. By resistance this does not refer to ‘acquired resistance’ (for which there is little scientific support) but to the fact of innate resistance, where some microorganisms are more resistant (such as due to a factor of their cell wall, for example) to a given disinfectant

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Utilities

The section on utilities has a reference to heating systems for the first time. There is also an added requirement for the trending of critical utility parameters. This is expressed as an important step so alarms can be reviewed to determine if they are specific or common causes, thereby enabling the appropriate engineering action to be taken. With alarm-based monitoring particular emphasis is placed on Water-for-Injections systems where is stated technology for monitoring Total Organic Carbon and conductivity is put in place, at locations determined by risk. This is because this type of process analytical technology that permits continuous monitoring is seen as superior to the type of discrete monitoring that might be conducted by a chemistry department.

The main change with water systems follows on from the update to the European Pharmacopeia, permitting the production of WFI through methods other than distillation. Due to unspecified concerns with biofilm growth on filters and the potential risk of endotoxin, the draft Annex makes a recommendation that further techniques such as nanofiltration and ultra-filtration are considered in conjunction with operating reverse osmosis membranes.

As part of design controls the Annex requires that water remains in a state of turbulent flow through distribution systems (this minimises the risk of microbial adhesion and hence biofilm development) and that a sanitisation method is used. As an example, holding water at 70°C or above is provided (although there are other forms water control, such as chemical treatments). Another control measure for water systems is with filtration. In section 6.11 the new text states: “Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters, the filters should be sterilised and the integrity of the filter tested before installation and after removal following use.”

Where microbial counts occur, especially in response to an upward trend, a normal recourse is to disinfect the system (by heat or by chemicals). In relation to this, the draft Annex states: “To minimise the risk of biofilm formation, sterilisation or disinfection or regeneration of water systems should be carried out according to a predetermined schedule and when microbial counts exceed action limits.”

The latest draft Annex 1 expands considerably upon the current text. This white paper has considered many of the key aspects, focusing on the changes that impact sterile products manufacture. No review can cover every aspect, and readers are encouraged to read the proposed Annex in detail for themselves.

In summary, the key takeaways from the latest draft are:

• The expectation for each facility to have in place a formal, holistic contamination control strategy, focused on minimising contamination control with respect to sterile manufacturing

• Additional requirements for cleanroom classification (beyond ISO requirements)

• A major focus on risk-based approaches

• Recommendations for the wider use of barrier technology

• A strong focus on personnel controls, such as gowning, and training

Such stipulations are unlikely to alter when the final version appears and it is recommended that sterile product manufacturers invest some time in considering the impact of these changes upon their procedures and processes.

Summary

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About the author

Dr Tim Sandle

Dr. Tim Sandle has over twenty-five years’ experience of microbiological research and biopharmaceutical processing. He is a member of several editorials boards and he has written over six-hundred book chapters, peer reviewed papers and technical articles relating to microbiology. Dr. Sandle works for a pharmaceutical manufacturer in the UK, and is a visiting tutor at both the University of Manchester and UCL.

References

1. Eudralex The Rules Governing Medicinal Products in the European Union, Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use. Annex 1 Manufacture of Sterile Medicinal Products, European Commission, Brussels, Belgium, 2009: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2008_11_25_gmp-an1_en.pdf

2. EMA (2020) Second targeted stakeholders’ consultation on the revision of Annex 1, on manufacturing of sterile medicinal products, of Eudralex volume 4, at: https://ec.europa.eu/health/medicinal_products/consultations/2020_sterile_medicinal_products_en

3. ICH Q9 Quality Risk Management. ICH Harmonised Tripartite Guideline, Step 4, Geneva, Switzerland. 2005.

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Excellence in Science and Service

For over 30 years, we have been providing support to the Pharmaceutical Sterile Manufacturing Industry and recently launched Sterility Testing (membrane filtration and direct inoculation), with Mycoplasma Testing to be offered soon. Our expert team can also support with raw material, vial and stopper testing to microbial analysis such as TAMC/TYMC and endotoxin (LAL).

We work in partnership with our clients to ensure that they meet the regulatory requirements both with routine testing as well as more complex projects such as cleaning validation and environmental monitoring, using the wealth of experience from our multi-disciplinary team of technical experts and consultants.

Sterile Manufacturing Support Services:

• Sterility Testing

• Endotoxin Testing

• Environmental Monitoring

• Raw Materials

• Vial and Stopper Testing

• Mycoplasma (coming soon)

• Investigative Problem Solving

• 24/7 Emergency Response Service

• Training and Consultancy

To find out more about how we can support your Sterile Manufacturing or to discuss your needs further, please contact us on: +44 (0)118 918 4076, email enquiries@rssl.com, or visit www.rssl.com

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Contact us to find out more about our expertise and how we can support you:Tel: +44 (0)118 918 4076 Email: enquiries@rssl.com Web: www.rssl.com

Reading Scientific Services LtdThe Reading Science Centre, Whiteknights Campus, Pepper Lane, Reading, Berkshire RG6 6LA

About Reading Scientific Services Ltd (RSSL)

RSSL is an award-winning Contract Research Organisation (CRO), providing analytical, investigational, consultancy and training services to clients in the global pharmaceutical, biopharmaceutical and healthcare sectors.

Our chemical, physical, biochemical, biological and microbiological services

are wide ranging, and provide support through the full product lifecycle.

RSSL is routinely inspected by the MHRA, FDA and UKAS which ensures that our analytical services meet the needs of industry. We are trusted by industry to provide a solution with scientific excellence, outstanding customer service and professionalism.

© 2020 RSSL. All rights reserved.