environmental monitoring in modern biopharmaceutical drug product … · 2019. 12. 15. · and usp ...

ENVIRONMENTAL MONITORING IN MODERN

BIOPHARMACEUTICAL DRUG PRODUCT FACILITIES:

A PROPOSAL FOR A HARMONIZED RISK-BASED APPROACH TO

SELECTING MONITORING POINTS AND DEFINING MONITORING PLANS

CONNECT COLLABORATE

ACCELERATETM

Risk-based environmental monitoring 2

RISK-BASED ENVIRONMENTAL MONITORING©BioPhorum Operations Group Ltd

AuthorsThe authors formed a multi-company collaboration comprising 30 subject matter experts (SMEs) from 17 biopharmaceutical manufacturing companies. The experts are experienced in managing Environmental Monitoring programs in large- and small-scale facilities, making a wide range of biopharmaceutical product types and incorporating bulk drug substance and bulk drug product operations.

The work was facilitated by BioPhorum, which is a cross-industry collaboration that aims to share and develop operational best practices across manufacturing, process development, IT and the supply chain. Established in 2008, the BioPhorum community comprises more than 2,000 active SMEs from over 50 companies. SMEs from BioPhorum member companies collaborate to develop common solutions to current and developing industry challenges, facilitate knowledge sharing in biopharmaceutical manufacturing and to accelerate thinking and best practices within the industry.

The authors drew upon their collective experiences, current company practices, consultations with stakeholders and colleagues, and a review of current regulatory guidelines. Unresolved questions were debated fully and solutions tested in dry-runs in an iterative process over three years. The length of time taken reflects the wide range of practices and the challenge of developing an easy-to-use tool with wide applicability across the industry.

BioPhorum Fill Finish comprises 26 member companies listed below. Subject matter experts from 17 of these companies collaborated on this document. A full list of authors and acknowledgements will appear on this page in due course.

AbbVie

Alexion

Allergan

Amgen

Amicus

AstraZeneca

Bayer

Biogen

Bristol-Meyers Squibb

Catalant

Celgene

CSL Behring

Eli Lilly

Merck KGaA, Darmstadt Germany

GSK

Janssen

Lonza

Merck & Co. Inc, Kenilworth NJ

Novo Nordisk

Pfizer

Regeneron

Roche

Samsung Bioepis

About BioPhorumThe BioPhorum Operations Group’s (BioPhorum’s) mission is to create environments where the global biopharmaceutical industry can collaborate and accelerate its rate of progress, for the benefit of all. Since its inception in 2004, BioPhorum has become the open and trusted environment where senior leaders of the biopharma industry come together to openly share and discuss the emerging trends and challenges facing their industry. Growing from an end-user group in 2008, BioPhorum now comprises 53 manufacturers and suppliers deploying their top 2000 leaders and subject matter experts to work in seven focused Phorums, articulating the industry’s technology roadmap, defining the supply partner practices of the future, and developing and adopting best practices in drug substance, fill finish, process development and manufacturing IT. In each of these Phorums, BioPhorum facilitators bring leaders together to create future visions, mobilize teams of experts on the opportunities, create partnerships that enable change and provide the quickest route to implementation, so that the industry shares, learns and builds the best solutions together.



Contents

Introduction ..................................................................................................................................................................................................................6

1 Scope........................................................................................................................................................................................................................7

1.1 In scope ...............................................................................................................................................................................................................................7

1.2 Out of scope ......................................................................................................................................................................................................................8

2 Foundational concepts and recommendations ..........................................................................................................................................8

2.1 Grid-by-grid assessment .............................................................................................................................................................................................9

2.1.1 Grouping grids into functional sections .................................................................................................................................................9

2.2 Factors to assess the risk of contamination .....................................................................................................................................................10

2.2.1 Factor 1: Amenability of equipment and surfaces to cleaning and sanitization .................................................................10

2.2.2 Factor 2: Personnel presence and flow ...............................................................................................................................................11

2.2.3 Factor 3: Material flow ...............................................................................................................................................................................11

2.2.4 Factor 4: Proximity to open product or exposed direct product-contact material ...........................................................12

2.2.5 Factor 5: Interventions/operations and their complexity ...........................................................................................................12

2.2.6 Factor 6: Frequency of interventions/process operations .........................................................................................................13

2.3 The scoring system......................................................................................................................................................................................................13

2.4 Additional considerations ........................................................................................................................................................................................14

2.5 Recommendations on frequency of sampling and methods of sampling .............................................................................................15

2.5.1 Sampling methods ........................................................................................................................................................................................15

2.5.2 Principles for selecting sampling methods and locations ............................................................................................................15

2.5.3 Recommendations for minimum sampling standards ...................................................................................................................16

2.5.4 Practical limitations .....................................................................................................................................................................................18

2.5.5 Mimimum monitoring principle ..............................................................................................................................................................18

3 Practical steps with illustrative example .................................................................................................................................................. 19

Acronyms/abbreviations ....................................................................................................................................................................................... 27

References .................................................................................................................................................................................................................. 28

Contents



List of tables

Table 1: Typical types of rooms and locations covered ........................................................................................................................................................................................................................................ 7

Table 2: Examples which grids can be grouped into functional sections based on process steps ....................................................................................................................................................... 9

Table 3: Six ratings are assigned to each grid and multiplied for a risk score. The minimum and maximum risk score scenarios are shown ............................................................... 14

Table 4: Possible risk scores, their ranks and interpretation .......................................................................................................................................................................................................................... 14

Table 5: Minimum monitoring method and frequency recommendations by grade ............................................................................................................................................................................. 17

Table 6: Minimum monitoring principles by relative probability of contamination based on the scoring system .................................................................................................................. 18

Table 7: Summary of sampling recommendations for each grid ................................................................................................................................................................................................................... 18

Table 8: Description of process activities in the grids in the in-feed functional section ...................................................................................................................................................................... 20

Table 9: Rating each grid against six factors and calculating risk score ...................................................................................................................................................................................................... 22

Table 10: Description of process activities in the grids in the in-feed functional section ................................................................................................................................................................... 25

List of figures

Figure 1. High-level steps from EMPQ plan to routine EM sampling plan .................................................................................................................................................................................................... 8

Figure 2: Room layout with overlaid grids, process step description and functional sections .......................................................................................................................................................... 21

Figure 3: Example of ratings against the six factors and applying the scoring system to each grid to create a heat map of relative probability of contamination (Note the functional sections in the filling line encased in blue edging) ...................................................................................................................................................................................................... 23

Figure 4: Example sampling plan for the in-feed functional section ............................................................................................................................................................................................................. 26



IntroductionClassified environments for the aseptic manufacturing of sterile drug substances and drug products require strict control to minimize the potential for microbiological and particulate contamination of the product. A well-designed environmental monitoring (EM) program is important to evaluate environmental controls in classified environments. Furthermore, it supports the evaluation and control of personnel-gowning performance and aseptic behavior, the effectiveness of cleaning and disinfection programs, and the detection of contamination patterns that might indicate a change in a facility’s state of control. An easy-to-use, standardized tool is required based on objective criteria that facilitates an EM program.

Despite the importance of EM, best practice has not been described in sufficient detail in current guidance documents. According to ISO 13408-1 [1], the FDA’s Aseptic Processing guide [2], ISO 14644-2 [3], EU guidelines to good manufacturing practice Annex 1 [4] and USP <1116> [5], sampling site selection shall be based on a documented contamination risk assessment (RA) considering aseptic processing operations that represent the highest risk for a product in cases of microbial and non-viable particles (NVP) contamination.

There is, however, not enough detail in these documents about the risk factors, how to define risk levels and how to monitor facilities according to risk levels. Typical RA tools, such as failure mode and effects analysis (FMEA) and hazard

analysis and critical control points (HACCP), are difficult to apply or not suitable when establishing a risk-based EM program. The absence of an agreed guidance template can lead to wasted efforts in the industry and among regulatory agencies.

This guidance template addresses these needs and attempts to capture best practices in a useable ‘toolkit’ format. The guide incorporates good practices from 17 biopharmaceutical manufacturers and adheres to current regulatory guidelines mentioned above.

The following questions were posed and have been answered about the design of an EM performance qualification (EMPQ) program and subsequent routine EM program:

1. What are the risk factors to consider?

2. How should we systematically assess a room with these risk factors?

3. How should we define risk levels?

4. What are the minimum standards for monitoring different risk levels?

Regulatory agency adoption and industry implementation of this harmonized approach will lead to these benefits:

1. Consistent application of current best practices

2. Better informed and structured discussions with regulatory inspectorates

3. A foundation for continuous improvement and evolution as facilities change with technology.



Table 1: Typical types of rooms and locations covered

1.0 ScopeThe EM RA is part of the quality assurance process and the microbial control strategy for a facility. Companies have adopted quality risk management tools such as the well known FMEA and HACCP. These tools are used to identify potential sources of contamination and serve as a basis for the EM RA. Users of FMEA and HACCP will recognize the ordinal scoring system used in this BioPhorum method and will find that the BioPhorum tool facilitates the thinking process of performing an EM RA. The tool is sufficiently detailed so that similar outcomes are expected if different people were to perform the same RA.

As stated earlier, the basic requirements for setting up a risk-based approach for EM are outlined in multiple guidance documents. This guidance comprises recommendations on the necessary practical details of an EM RA enabling the user to understand how regulatory expectations can be met in a structured way. It also follows good industry practice and makes the thinking process transparent and amenable to benchmarking.

1.1 In scope

The purpose of an EM RA is to provide information to determine how to distribute monitoring to best verify that processes are operating under control. The RA is a systematic process for determining the relative probability of contamination in all locations used for aseptic processing. This guidance document covers

the EM RA process in a step-by-step way and provides recommendations on monitoring methods based on the relative probability of contamination.

The most common and relevant room types in a facility are considered. Although the focus of this RA toolkit is aseptic processing areas (i.e. grades A and B), the tool will also give guidance for background/support and upstream manufacturing areas that support aseptic processes, such as grade C and D areas (see Table 1).

It is a prerequisite to have a detailed knowledge of the processes conducted in the respective area or interventions performed in grade A. This knowledge is gained from observing actual operations and process simulations. We expect the guidance to be refined as it is applied in a wider range of facilities and manufacturing processes.

After outlining some foundational concepts, factors are described that are known to impact on the probability of environmental contamination [1, 2, 5]. A step-by-step method is then described for applying these factors to gauge the relative probability (ranking) of contamination across an area or room in a facility. The first output of the method is a ‘heat map’ showing the relative probability of contamination in a defined area or room. Recommendations are then provided on how to use the heat map to provide direction on the number and location of sampling points and the selection of the sampling methods. The RA covers NVP monitoring, active and passive viable air monitoring, and surface monitoring.

Filling process Grade A isolators as well as open- and closed-filling RABS, including biosafety cabinets with uni-directional air

flow (UDF) for the preparation of active ingredients, and the following background areas:

• Grade B background to grade A (typical classical cleanrooms)

• Grade C background to grade A (isolator technology)

• Grade D background to grade A (isolator technology)

Upstream process • Grade B or C UDF cabinets or rooms, e.g. for cell culture, fermentation, formulation, purification steps, etc.

• Grade C, e.g. for compounding, preparation, storage, etc.

• Grade D, e.g. for compounding, washing areas, preparation, storage, etc.

Support areas • Personnel and material air locks

• Corridors, etc.



Figure 1. High-level steps from EMPQ plan to routine EM sampling plan

1.2 Out of scope

Process-related risks are not covered; the focus is on the potential contamination risks within the environment that the process operates in. Personnel monitoring is also not in scope, although a statement about minimum personnel monitoring is made in Step 7 in section 3, as it pertains to a sample site selection by contact-plate monitoring of personnel gowning. Anaerobic monitoring is mentioned in context but not covered in depth.

2.0 Foundational concepts and recommendations The high-level steps in the recommended RA process are shown in Figure 1.

YesEmergency change

Hiddenconditions:hazards, threats,unusual conditions

Accumulation

Inconspicuous andseemingly harmlessbuild up of unusualconditions, hazards,threats, at-riskpriorities etc., without warning

4.0

Saf

ety

High

Low

Safetymanagement

Map the layout of the room(s), overlay with grids and combine them into functional sections

Walk the process with an RA team noting in detail the process activities grid-by-grid

Asssess each grid against the risk factors and score them to determine the relativeprobability of contamination

Evaluate the results by functional sections to select sampling locations and methods

Create an EMPQ plan

Perform the EMPQ

Evaluate the EMPQ results

Determine routine EM sampling locations, methods and frequencies

Review the RA on a regular basis

Walk the process with an RA team noting in detail the process activities grid-by-grid

Asssess each grid against the risk factors and score them to determine the relativeprobability of contamination



The scope of the RA process covered in the guidance starts with generating an EMPQ plan. The processes and possible contamination risks are then noted systematically for each grid and the relative probability of contamination (lower, intermediate or higher) is assessed for each grid (see Sections 2.1 and 2.2). Grids are combined into functional sections for practicality (see Section 2.1) and with other relevant information, monitoring locations and methods are defined in a sampling plan.

Note that for new facilities/filling lines, the definition of the process and the RA is required before the final design of the rooms or filling lines. The RA process supports the design of sampling locations for sampling probes fixed on the equipment (isolators, RABS, etc.), which has to be determined during the design phase of the facility.

2.1 Grid-by-grid assessment

It is essential to systematically assess all operational activities, equipment and surfaces in all parts of a filling line or support room. Systematic and comprehensive evaluation of contamination probability grid-by-grid is recommended by ISO 13408-1 [1] and PDA TR13 [6].

Grid sizes should be small enough to differentiate process steps while large enough to be practical. The recommended grid sizes are:

• Grade A: 0.5m2

• Grades B, C and D: 4.0m2.

The dimensions of the grids were defined after considerable debate using the team’s knowledge of the dimensions and scale of the majority of filling lines and Grade B–D cleanroom operations, and successfully testing these in dry-runs.

2.1.1 Grouping grids into functional sectionsDetermining the sampling locations and methods per grid over a large area comprising many grids can be impractical and does not consider interdependencies due to the functions of the process steps in the grids. It is, therefore, recommended that individual grids are grouped into functional sections that cover distinct operational processes, e.g. the filling section of a filling line or the formulation tank with adjacent weighing area and/or process control unit can be functional sections (see Table 2 for examples).

Grade A

(e.g. conventional aseptic filling line,

RABS, isolator)

Grade B

(e.g. background of RABS or UDF cabinet)

Grade C or D

• In-feed

• Filling

• Stoppering

• Out-feed

• Lyo loading

• Unloading of steam sterilizer

• Lyo loading

• Corridor sections leading to different

cleanrooms or filling lines

• Washing area

• Formulation process areas and vessels

• Filtration area

• Documenting area

• Fermentation tanks/vessels

Table 2: Examples which grids can be grouped into functional sections based on process steps



Rating Amenability of equipment and surfaces to cleaning and sanitization (including any mobile equipment stationed in the grid)

Lower (1) Full access for cleaning (e.g. flat stainless steel or glass surfaces)

Intermediate (2) Fully accessible but there are restrictions such as difficult-to-reach corners and/or intricate details (e.g. grooves, holes, moving parts, etc.)

Higher (4) Several restrictions to full access, e.g. hard to reach and intricate, or partly or fully occluded (such as conveyors)

2.2 Factors to assess the risk of contamination

For each grid, a risk level based on the respective process will be determined using these six factors:

1. Amenability of equipment and surfaces to cleaning and sanitization

2. Personnel presence and flow

3. Material flow

4. Proximity to open product or product-contact material

5. The need for interventions/operations by personnel and their complexity

6. The frequency of interventions (only applicable for grade A).

A higher degree of objectivity has been considered in this crucial aspect of the RA method. To assess the impact of each factor on contamination probability, a three-level ordinal scale (1=low, 2=intermediate or 4=high, 1, 4 and 8 for proximity to open product) has been developed for each factor (see below in this section). The absolute contamination probability is markedly lower in grade A filling lines with isolators than, say, in a grade D support room. For ease of use, the same three-level scale and six-factor scoring system are used for all grades and process types. The inherent contamination risk for each of the three levels is different for grade A compared to grades B–D. For example, a lower-risk process situation for grade A concerning material flow is not the same as the lower-risk process situation for grades B–D.

Again, the consensus recommendation is based on current practices that were thoroughly tested in several dry-runs to evaluate if the defined risk factors met expectations in terms of a well-designed EM program, and to determine if factors were missing, redundant or

unclear. The six factors were found to cover the potential mechanisms of contamination introduction into the processing environment.

The frequency of intervention (applicable only to grade A) can be regarded as a weighting factor, but there is no need to not make the distinction between risk factors and weighting factors. These six factors, depending on cleanroom grade, are then applied to each grid. The term ‘interventions’ tends to be applied to grade A filling lines/rooms (including grade A air supply) while the term ‘operations’ is better suited to grade B–D rooms.

The rationale behind the risk factors and how the impact of each factor is rated is explained next. The use of lower, intermediate and higher ratings in the tables is explained in Section 4.3 where the scoring system is also described. Of course, isolators may include difficult-to-sanitize surfaces (e.g. a ‘ring of concern’ on DPTE ports).

2.2.1 Factor 1: Amenability of equipment and surfaces to cleaning and sanitizationThe ability to clean and disinfect surfaces to remove contaminants is an important part of any environmental control program. Surfaces that are not smooth, have sharp corners, are difficult to reach or have intricate details (e.g. grooves or holes) can be difficult to clean and disinfect manually. Consideration must be given to the most inaccessible and difficult-to-clean/sanitize sites as well as those that may contribute to microbial proliferation [6]. As isolators are typically decontaminated using a qualified and automated vaporized hydrogen peroxide system, this ‘cleanability’ factor has relatively less relevance in isolators compared to manual disinfection in RABS [5].



2.2.2 Factor 2: Personnel presence and flowPersonnel is considered the most significant source of contamination in the manufacturing environment [5]. Understanding the movement path and number of personnel in each grid helps identify where personnel are routinely moving and/or performing activities. These locations are more prone to environmental contamination due to the presence of personnel versus locations that see little or no personnel traffic [5]. An estimate of personnel numbers can be derived from the number of people who were present during qualification. If this information is not available, then the numbers can initially be based on the intended design. Personnel flow is the differentiator for barrier systems.

2.2.3 Factor 3: Material flowMovement of material is an important part in the dispersion of contaminants potentially present in manufacturing areas. The assessment of risk from material flow considers the volume of material flow within each grid cell, but not the direction of the flow. Material flow applies to all materials that are moved to and within classified areas (e.g. tools, vessels, raw materials, disinfectants, monitoring materials, instrumentation, etc.).

Rating Personnel presence and flow (activity and movement in areas where personnel can actually be present)

Lower (1) Grade A: grid is within a barrier system with any interventions via glove ports

Grades B, C and D: no routine activity or flow is performed in this grid throughout production

Intermediate (2) Grades A, B, C and D: a few* people walk through the grid during production runs and/or a few people stop for activities related to

the process

*‘Few’: In grade A and B this would be less than half of the maximum validated number of people for the process; in grade C to D this

is less than half of the maximum staffing number for the process.

Higher (4) Grades A, B, C and D: many** people walk through the grid during the production runs and/or many* people stop for activities related

to the process

**‘Many’: In grade A and B this would be 50 -100% of the maximum validated number of people; in grade C-D this is half or more of

the maximum staffing number for the process.

Rating Material flow (including mobile equipment)

Lower (1) The area has no routine material traffic or movement is automated (e.g. a corner of a room where there is no reason for material

to be there)

Intermediate (2) Grade A: no direct personnel intervention. Material introduction to the process is routine and through alpha/beta ports or

movement by personnel is via glove ports in closed RABS/isolators

Grades B, C and D: there are occasions when material/equipment is present in the grid momentarily in transit to another location

but is not a grid that is designated for material flow

Higher (4) Grade A: material is manually introduced through openings in the aseptic filling line and requires direct personnel interaction

Grades B, C and D: the area is designated for material traffic and/or material/equipment to be stationed/used in the grid as a routine part

of the process



2.2.4 Factor 4: Proximity to open product or exposed direct product-contact materialThe authors consider this to be the most important factor and a double weighting is applied to it (see page 14). The probability of potential product contamination is much higher when product is exposed or when a direct product-contact material is present, and operations take place close to exposed product and direct product-contact materials. Regardless of other factors, it is important to consider when selecting sampling locations a grid where there is an open product or an exposed direct product-contact material.

Note: To add weight to this factor, ratings of 4 and 8 are used for ‘intermediate’ and ‘higher’ risk situations, respectively.

2.2.5 Factor 5: Interventions/operations and their complexityMore complex ‘interventions’ (grade A) or ‘operations’ (grades B–D) are known to increase the likelihood of contamination (the term ‘operations’ is better suited to activities in grades B–D as the term ‘interventions’ is usually used in a grade A context). Therefore, consideration should be given to assess the potential impact of the interventions or operations. In the three-level scale, consideration is given to the duration, tools used, impact on UDF, accessibility of location, number of movements, numerous actions and the number of hands (one hand, two hands, second person aiding intervention). The more complex and long the interventions/operations, the higher the probability that NVP and viable particles are carried into the process or filling lines, which ultimately constitutes a risk to the product.

Rating Proximity to open product or exposed direct product-contact material (including bulk product in grade B–D areas)

Lower (1) More than 60cm between grid activity and product or exposed direct-contact material

Intermediate (2) Between 30–60cm between grid activity and product or exposed direct-contact material

Higher (4) Less than 30cm from grid activity and product or exposed direct-contact material

Rating Interventions/operations and their complexity (all grade A interventions validated through process simulations shall be considered. In

grades B, C and D it is the interaction with the process that results from the activity)

Lower (1) Very simple activities or interventions (e.g. simple storage room, unloading an autoclave, etc.). Also includes aseptic connections

using closed single-use systems and upstream processes that are in closed systems but not aseptic

Intermediate (2) Grade A: interventions

• Can be completed by using sterile tools

• Are performed in areas easily accessible with no impact to air flow

• Require minimal steps and duration to complete, e.g. removal of a fallen vial on turntable edge

Grades B, C and D: operations

• Process steps are performed using partially closed systems, minimizing the introduction of contamination into the environment

through exposure of product or non-sterile components and materials.

Example: sterile compounding using single-use systems or fixed piping and vessels

Higher (4) Grade A: intervention requires one or more of the following conditions:

• Extended reach requiring personnel’s body/head to enter the grade A zone

• Direct contact with the product path by personnel’s gloves

• Number of steps and/or duration leads to an increase in complexity

• Reach requires obstruction of first air above open or exposed primary packaging

Examples: set up of filling line, aseptic connections, adjustment of vial guides, removal of vials from the center of the turntable,

adjustment of filling needles, etc.

Grades B, C and D: processes in the area include exposure of ‘to be cleaned’ equipment, non-sterile components or materials, or

‘wet’ operations. Examples include: the equipment wash area, compounding area where powders are weighed, the location where

product-contact parts are stored or handled before cleaning



2.2.6 Factor 6: Frequency of interventions/process operations The expected number of interventions should be considered for scoring. The number of interventions in the grade A grid cell can be determined from aseptic process simulation data where all known interventions need to be part of the simulation. For new processes, this can be based on process knowledge and may be updated over time when more routine data becomes available.

2.3 The scoring system

The scoring of operational activities is inherently subjective, and, at best, an ordinal scale can be used to increase objectivity. In the RA process, each grid is assessed against the six factors described in 4.2. For each of the factors, a rating is assigned (see Table 3):

• Rating of 1 for lower-level impact of the factor

• Rating of 2 for moderate-level impact of the factor (rating of 4 for the proximity to open product or exposed direct product-contact material factor)

• Rating of 4 for higher-level impact of the factor (rating of 8 for the proximity to open product or exposed direct product-contact material factor)

So, each grid is assigned up to six scores (one for each of the six factors). These ratings are multiplied to derive a risk score for the grid. Multiplication of the ratings helps make more prominent grids with high scores 4 (or 8) for any of the six factors and thus requiring particular focus. The scoring system is illustrated in Table 4. The minimum and maximum risk score for a grid are also shown.

In total, there are 14 possible risk scores (see Table 4). These are ranked 1 to 14 and are used to assign a risk level to each grid:

• The lowest five scores indicate a ‘lower-risk grid’

• The middle four scores indicate an ‘intermediate-risk grid’

• The highest five scores indicate a ‘higher-risk grid’.

For grade B, C and D classified cleanrooms and barrier technologies, such as isolators (grade A), it is expected that a lower-risk score than conventional filling lines or open RABS is obtained based on the design of the system/processes. In the absence of scores in the highest ranking, consideration should be given to the locations that score the highest for performing EM.

The scoring system was tested and refined during dry-runs. Judgment will be required when using these scores as they are an indication of contamination probability. However, lower-risk grids can be considered for monitoring as part of a holistic program (e.g. where there are many lower-risk grids in one functional area).

Rating Frequency of interventions/process operations

Lower (1) No or minimal interventions (on average <=1 per batch or shift*)

*Per shift is more suitable in some areas such as washing areas where ‘per batch’ would not be a relevant period

Intermediate (2) Occasional interventions (on average >1 but <=5 per batch or shift*)

Higher (4) Multiple interventions (on average >5 per batch) especially in the most critical areas of the filling line (e.g. the filling and stoppering area)



2.4 Additional considerations

In addition to the determined ranking and the resulting risk score, the following aspects need to be considered to refine the final EM sampling locations. This additional information may not be available grid-by-grid but can still be considered during the scoring of each category:

• Evaluations of the smoke studies

• The HVAC operations qualification data that shows areas of higher NVP counts and historical EM alerts/action level excursions

• Existing controls in the grid that have been put in place to reduce the risk of contamination (e.g. automatic decontamination, using barrier systems, cleaning hidden surfaces, etc.)

• Historical data: for example, any ‘low’ and ‘intermediate’ risk areas that showed limit excursions in EM (for filling line/cleanrooms already in use)

• During routine monitoring, EM criteria applied for the background of grade A air supply needs to be applied at a minimum. Depending on whether human intervention is required, or appropriate technology to prevent contact with the vials is installed, additional EM is recommended.

Table 3: Six ratings are assigned to each grid and multiplied for a risk score. The minimum and maximum risk score scenarios are shown

Table 4: Possible risk scores, their ranks and interpretation

Amenability

of equipment

and surfaces

to cleaning and

sanitization

Personnel

presence and

flow

Material flow Proximity of

open product or

product-contact

materials

Interventions/

operations by

personnel and

their complexity

Frequency of

interventions

Risk score

(product)

Lower (1) 1 1 1 1 1 1 1

Intermediate (2) 2 2 2 4 2 2 128

Higher (4) 4 4 4 8 4 4 8192

Risk score (product of six ratings) Number of combinations of ratings

that give this score

Rank of score Interpretation

1 1 1 Lower-risk grid

2 5 2

4 16 3

8 36 4

16 65 5

32 96 6 Intermediate-risk grid

64 120 7

128 126 8

256 111 9

512 80 10 Higher-risk grid

1024 46 11

2048 20 12

4096 6 13



2.5 Recommendations on frequency of sampling and methods of sampling

Based on the assessment against the six factors and additional considerations, each grid will then be assessed for the potential monitoring locations based on activity in the area and the risk associated within the grid. Some general principles are set out next before recommendations are provided on sampling method frequency in different grades in Table 5.

2.5.1 Sampling methods

Viable and non-viable air sampling Active viable air sampling devices, such as impaction and filtration samplers, can be used to achieve quantitative results for viable counts. Non-destructive rapid microbiological methods may be considered as an alternative to conventional viable particles and NVP methods [7].

Active viable air sampling methods should be preferred at locations where human activities take place with a high probability of creating local air turbulence by movement (e.g. human interventions, equipment movement, personnel movement, robotics, etc.).

The application of active air monitoring in aseptic areas is recommended in areas near critical process steps, such as filling and stoppering, and in areas with complex interventions according to the respective RA for this area.

Passive viable air sampling using settle plates can be considered as a qualitative or semi-quantitative method for continuous surveillance of potential product impact due to local turbulences.

The application of passive viable air monitoring in aseptic areas is recommended in locations where product-contact parts or primary packing material are exposed to the environment for a longer time (e.g. stopper hopper, vibrating bowl, turntable, etc.). Furthermore, it is recommended for areas with change of air cleanliness, such as mouseholes, in-feed of isolator or RABS grade A areas.

Non-viable air sampling can be conducted either by using a fixed particle counter, mainly used in isolator, RABS or mobile sampling equipment. This method is recommended for use at positions near product critical location and critical manipulations, such as stoppering and filling. In all grade A areas, aseptic processes should be monitored using continuous non-viable air monitoring with fixed particle counters.

Surface monitoring For grade A: product-critical positions, surfaces difficult to disinfection (manual disinfection), barriers to grade B and isolator/RABS gloves.

For grade B: floors, walls and ceilings

Surface sampling can be performed to detect the growth of aerobic or anaerobic organisms using contact plates that support the growth of the different organisms. A further method to detect microbial growth on surfaces is sampling using swabs.

Glove monitoring Is recommended for all gloves used in all higher-risk grids.

2.5.2 Principles for selecting sampling methods and locations1. To have a common approach, intermediate- and

higher-risk grids must be accounted for with sampling during the EMPQ

2. The sampling frequency and number of locations for routine monitoring can be optimized by focusing on grids with higher-risk scores and any intermediate-risk grids with observable EM findings (that might be of concern)

3. Critical sites may not be selected for monitoring if there is a low probability of contamination during production/filling, e.g. sterilized surfaces that are not manipulated [6]

4. For EMPQ, it is recommended that samples from low-, intermediate- and higher-risk grids are included. Not all low-risk grids would require a sampling point and judgment must be used as to which low-risk grids will provide the best data regarding the facility-cleaning program

5. The probability of contamination varies depending on its classification, design and operation, and has to be assessed for each room and each filling line. A general distinction, however, can be made between barrier technologies and a conventional filling line. In isolators, the contamination risk of sterilized material within the isolator and its environment is reduced to a minimum, as barrier technology isolates and separates the operator and the surrounding environment (usually grade C or D) from the critical aseptic processing core. See also ISO 13408-1 [1] “Isolator: enclosure capable of preventing ingress of contaminants by means of physical interior/exterior separation, and capable of being subject to reproducible interior bio-decontamination”. More stringent monitoring should, therefore, be applied in grade A areas without barrier technology, whereas less monitoring is an option when using isolator technology. This distinction is reflected in the recommended rating scales

6. Monitoring for viable and NVP in grade A areas shall occur within 30cm of the work site in accordance with the FDA’s Aseptic Processing guide [2]



7. The sampling scheme above should also be extended to within 30cm (in line with point 6. above) of the areas identified as potential entry points of contamination using contact plates as a minimum, e.g. glove ports, doors, in-feed/out-feed ports, rapid transfer ports in isolators, pass-through between different functional section classifications, etc.)

8. Personnel monitoring using contact plates according to grade A limits should be performed after every intervention into a grade A area during filling or bulk manufacturing in open RABS and after filling line set up

9. Surface sampling must be performed at the end of the manufacturing campaign or batch, unless scientifically justified

10. For the grids that have intermediate-risk scores, the reduction of the EM sampling plan (post-qualification) should be based on collected historical or EMPQ data (qualitative and quantitative)

11. Following successful EMPQ cycle and cleanroom validation, the EM program will switch to routine monitoring. A determination must be made as to which sample locations will remain for the routine program. It is recommended to maintain sampling locations in higher-risk grids. There may have been cases within the EMPQ where more locations were added to a grid than would be needed to adequately monitor a grid in routine operations, so specific locations may be able to be removed, or the frequency of monitoring may be reduced, based on an assessment of the obtained EMPQ data and RA outcome. Consideration can also be given to surrounding grids to create sections that are captured by individual samples, as applicable

12. Depending on how much data is collected during an EMPQ, the locations in intermediate risk grids can continue to be monitored. Some moderate grid locations can be maintained for the routine program and others can be removed if justified

13. Lower-risk grid locations typically do not need to be monitored during the routine monitoring program. The sampling regime matrix for EMPQ and EM is summarized in Table 7

14. Caveats to the above points include that if locations monitored during the EMPQ recover counts above what is expected in any of the grids, or have action-level excursions, then those locations should continue to be monitored regardless of their risk factor. Also, a controlled area that only has low-risk grids will need to have some locations to demonstrate the effectiveness of the cleaning program and maintenance of the cleanroom classification

15. Finally, the RA is a living document and the risk factors and subsequent sampling regime should be checked on a regular basis, but especially in the course of a change control process to determine if the RA needs to be adapted and if the RA is still verifying the correct aseptic practices through monitoring at the right locations.

2.5.3 Recommendations for minimum sampling standardsConsidering the principles set out in Sections 4.5.1 and 4.5.2, minimum sampling standards are recommended in Table 5.



Table 5: Minimum monitoring method and frequency recommendations by grade

Grade A

• Non-viable air monitoring should be undertaken for the full duration of

critical activities, e.g. filling (including equipment assembly)

• Viable air monitoring should be performed during critical processing

steps, including equipment assembly. But with the availability of new,

continuous, viable air monitoring techniques, new rapid and alternative

methods should be considered

• Note that an option is becoming feasible for using rapid micro methods

in grade A settings. For example, biofluorescent particle counting for

air monitoring [7]

• To determine if passive and/or active air monitoring is to be used, the

respective risks of the cleanroom concept should be considered

(i.e. isolator, RABS, UDF cabinet)

• As the handling of agar plates within grade A areas during activities for

surface or glove monitoring might introduce a risk of contamination

due to potential residual agar in the grade A area, it is expected to

perform surface monitoring at minimum at the end of a manufacturing

campaign. If there is no campaign, surface monitoring should be

performed at the end of each batch.

Grade A air supply

The proposed definition in the revised Annex 1 [4] is “Air which is passed

through a filter qualified as capable of producing grade A non-viable

quality air, but where there is no requirement to continuously perform

non-viable monitoring or meet grade A viable monitoring limits.” A

grade A air supply is used for areas where capping of sterile products is

conducted outside the aseptic core (as per Annex 1 [4]).

There is variation in practices in the industry and the authors plan

to work on this in future versions of this guide. In the meantime, a

minimum standard is proposed to facilitate discussion:

• The objective of EM of a grade A air supply is to confirm the quality of

the air immediately after the HEPA filtration. This needs to be ensured

on a regular basis, as a minimum during requalification and periodically

during routine operations.

• Additional operation-specific monitoring (e.g. surface monitoring)

should be established considering the operation(s) performed and the

classification of the area supplied with the grade A air.

Grade B

• Viable and non-viable air monitoring in grade B background

areas for grade A areas should be performed at least on a

daily basis when grade A activities occur

• Surface monitoring should be performed at the end of a

batch/campaign

• If no grade A activity occurs, the frequency should be defined based

on the criticality of the activity, with a minimum of once per week

• Grade B areas adjacent to grade A rooms (e.g. corridors, storage

rooms, air locks, etc.) need to be monitored at least weekly.

Grade C

• Viable air monitoring should be done on a weekly basis for rooms with

open product handling (e.g. formulation, weighing, etc.) and cleanrooms

where product-contact parts are prepared (such as clean storage rooms)

• Scheduling of EM should preferably be when handling the product occurs

(e.g. compounding)

• For rooms with other activities (e.g. corridors, material air locks, personal

air locks, storage rooms, etc.), weekly sampling can be performed on a

rotation basis per room, or sampling can be extended to at least monthly

for each cleanroom.

Grade D

• Grade D areas should be monitored on a monthly basis as a minimum.

Anaerobic testing

• Anaerobic testing should be considered, based on production activities and according to local procedure.



2.5.4 Practical limitationsSome practical limitations may occur, which should be explained and noted in the RA documentation, for example:

• Physical space limits

• Potential to add more risk of contamination through interventions (e.g. reaching over a hopper). No monitoring should risk product contamination

• Sampling locations should not disrupt the manufacturing process, including its airflow.

2.5.5 Mimimum monitoring principleEach functional section should include a selected combination, but not necessarily all, of the following monitoring methods:

• Non-viable particles

• Viable particles active

• Viable particles passive

• Viable surface particles.

Generally, there should be at least one viable (active and/or passive) and one non-viable air monitoring, and at least one viable surface sample, within each functional section.

Lower-risk grid For EMPQ and routine EM sampling: sampling is not required in these grids because of the low-risk categorization (but it is

optional in the context of an overall EMPQ monitoring plan)

Intermediate-risk grid For EMPQ sampling: the minimum sampling in this grid is required. Place in this grid at least one from the list below:

1. Non-viable

2. Viable-active

3. Viable-passive

4. Viable surface.

For routine EM sampling: this depends on the results from the EMPQ (in practice, there would usually be less monitoring than

that performed during the EMPQ). Compare the number of excursion results during respective EMPQ and, if above the pre-

set limit, then routine monitoring is recommended in this grid.

Higher-risk grid For EMPQ and routine EM sampling: the minimum sampling in this grid is required. Place in this grid at least one from the list below:

• Non-viable

• Viable-active

• Viable-passive

• Viable surface.

Unless the minimum required is covered by sampling in an adjacent grid, which is in the same functional section, the sampling

location can be between the two adjacent higher-risk grids.

It is recommended that sections that have grids with high scores have viable and non-viable monitoring defined for initial

qualification. They should also be considered for inclusion in the routine EM program if the identified risk factors are not minimized

through the introduction of control measures.

The type of sampling selected depends on the nature of the activity in this grid and the line configuration.

Designation of risk level EMPQ sampling Routine EM sampling

Lower Optional No sampling unless there are significant recoveries in historical data or EMPQ

Intermediate Sample Optional

Higher Sample Sample

Table 6: Minimum monitoring principles by relative probability of contamination based on the scoring system

Table 7: Summary of sampling recommendations for each grid



3.0 Practical steps with illustrative example

To consolidate the recommendations into a useable format and add some essential details, the RA process is described in a step-by-step guide showing how the above principles and recommendations are brought to life in an illustrative example.

The case study is based on a company in the collaboration. It is a conventional filling line within a grade B room and a grade A filling line. With room dimensions of 55m² for the grade B room and 19m² for the grade A filling line.

Step 1: Build a multidisciplinary team

A multidisciplinary approach is required to ensure that all aspects of the process and the facility are understood. Participation from the following disciplines is recommended:

• Sterility assurance or an SME with a microbiology background

• Quality assurance

• Validation

• Production

• Quality control

• Engineering.

All people involved in the process should be trained in the RA tool. The flow diagram shown in Figure 1 can be used to align the team with the purpose of the exercise.

Step 2: Divide the room into grids and describe the process activities occurring in each grid in detail

Use the scale drawings of the room to draw grids of appropriate sizes:

• Grade A: a grid size of 0.5m² is recommended

• Grades B, C and D: a grid size of 4m² is recommended.

The grid cell size/locations may be adjusted slightly to avoid cutting through a process step (e.g. where a grid

that does not cover a full glove or a whole surface is better covered by a full grid). For consistency, grid sizes close to those stated above are recommended. In exceptional circumstances with atypical dimensions and constrained by issues such as large fillers tanks, a combination of grid sizes could be used; but for the benefits of harmonization, grid sizes close to those stated above are, again, strongly recommended.

Assign identification numbers to the grids and describe the activities that take place in each one (see Table 8).

Make a note of any specific and existing bioburden controls in the grid that have been put in place to reduce the risk of contamination (e.g. hidden surfaces in isolators that are disinfected manually before being decontaminated with vaporized hydrogen peroxide).

Step 3: Map the process steps

A clear understanding of the manufacturing process for the room to be assessed is essential to have operational knowledge of the layout, process steps and activities (see Figure 2 and accompanying table).

The team should walk the process on paper and, if possible, on the shop floor with a focus on, for example, access for cleaning, personnel flow, material flow, exposure to open product, activities in the room (i.e. interventions/process steps), etc.

The drawings of the room layout must be up-to-date and fit-for-purpose.

Note that for the illustrative example used below, it was not possible to go ‘live’ to the filling line because the filling line was running and therefore no visitors were allowed. Information from standard operating procedures for the set up and those for aseptic interventions was used by the team, e.g. smoke studies, photos of the different compartments of the filling line and walking lines of the operators in the filling room.



Table 8: Description of process activities in the grids in the in-feed functional section

Grid Process activities (in-feed functional section)

1 Depyrogenated glass is entering the filling line, turntable.

1. Moistening turntable performed with closed doors, when the turntable is empty, at least once per batch. Silicon wipes are

transferred to the grid. Silicon wipe is transferred to grade B through the grid

2. Manipulation of a container performed with closed doors, forceps (part of set up). If you reach over other containers, you need to

remove the containers

3. During set up: placing forceps (open doors)

4. Adjustments of format parts with one open door (not frequent intervention; empty compartment grids 1–8).

Note: silicon wiping only during set up.

2 No interventions

3 Depyrogenated glass is entering the filling line, turntable.




3. Adjustments of format parts with open doors (not frequent intervention) (one door), empty compartment grids 1–8).

4 Glass is transported.


remove the containers.

2. Adjustment of format parts with closed doors (not frequent intervention) (empty compartment grids 1–8). A tool is used if necessary.




2. Adjustment of format parts with closed doors interventions (empty compartment grids 1–8). A tool is used if necessary.







2. During set up: bringing tweezers in (open door).




2. Adjusting format part with closed doors (not frequent intervention).


4. Removing broken vials with closed doors with tweezers (not frequent intervention).

Step 4: group the grids into functional sections

• Grids should be grouped into functional sections before performing scoring based on adjacency and similarity of activity for practical reasons (see Figure 2)

• However, in some small rooms grouping into functional sections may not be possible because the room is small enough to make it necessary to consider sampling as a whole

• Functional sections also apply in isolators and RABS-like in-feed, filling, stoppering, etc., as this helps to determine where to put viable and non-viable air sampling points. See Table 5 below.



Figure 2: Room layout with overlaid grids, process step description and functional sections

LYO outfeed

Outfeed

Loading FD trolleys

Tray loadingFilling

In-feed (comprising

grids 1-8)Transfer of

semi-stoppered vials

Stoppering

Grade B filling room; pass through for stopper bags and IPC; set-up of filling pumps stopper station trolley;

Placing and picking up trolley

2

3

1

5

6

4

8

7



Step 5: Score each grid using the six factors

This process is illustrated in Table 9 a spreadsheet template is also available with the algorithm of the scoring system built in.

Table 9: Rating each grid against six factors and calculating risk score

Amenability

of equipment

and surfaces

to cleaning and

sanitization

Personnel

presence and

flow

Material flow Proximity of

open product or

product-contact

materials

Interventions/

operations by

personnel and

their complexity

The frequency

of interventions/

operations

Risk score Rank

of risk

score

Rating 1 4 4 8 4 4 2048 12

Grid 1 Depyrogenated glass entering filling line, turntable.

1. Moistening turntable performed with closed doors, when the turntable is empty, at least 1/batch. Silicon wipes are transferred to the grid. Silicon

wipe is transferred to grade B through the grid

2. Manipulation of a container performed with closed doors, forceps (part of set up). If reach over other containers, need to remove the containers


4. Adjustments of format parts with open doors (not frequent intervention) (one door), empty compartment grids 1–8.

Note: silicon wiping only during set up.

1 1 1 8 1 1 8 4

Grid 2 No interventions

1 4 4 8 4 4 2048 12

Grid 3 Depyrogenated glass enters filling line, turntable.



3. Adjustments of format parts with open doors (not frequent intervention) (one door), empty compartment grids 1–8.

1 1 1 8 1 2 16 5

Grid 4 Glass is transported.


2. Adjustment of format parts with closed doors (not for every batch), empty compartment grids 1–8. A tool is used if necessary.

1 1 1 8 1 4 32 6



2. Adjustment of format parts with closed doors (not frequent intervention) (empty compartment grids 1–8). A tool is used if necessary.

2 2 2 4 2 2 2048 6


1. Manipulation of a container performed with closed doors, forceps (part of set up). If reach over other containers, need to remove the containers.

1 4 4 8 1 4 512 10




1 4 1 8 1 2 64 7



2. Adjusting format part with closed doors (not frequent intervention)

3. During set up: bringing tweezers in (open door)

4. Removing broken vials with closed doors with tweezers (not frequent intervention).



Figure 3: Example of ratings against the six factors and applying the scoring system to each grid to create a heat map of relative probability of

contamination (Note the functional sections in the filling line encased in blue edging)

LYO outfeed

Outfeed

Loading FD trolleys

Tray loadingFilling

In-feed

Transfer of semi-stoppering

vials

Stoppering

Grade B filling room; pass through for stopper bags and IPC; Set-up of filling pumps stopper station trolley;

placing and picking up trolley

1

43

44

45

47

46

18

48

51

3

2

4

68

41

42

40

39

38

37

36

35

34

33

32

28

29

30

10

50

7

13

26

27

9

14

25

10

15

24

22

11

16

23

21

12

17

19 20

5



Grade A filling room with grade B background

Am

enab

ility

of e

quip

men

t an

d

surf

aces

to

clea

ning

and

san

itiz

atio

n

Per

sonn

el p

rese

nce

and

flow

Mat

eria

l flow

Pro

xim

ity

of o

pen

prod

uct

or

prod

uct-

cont

act

mat

eria

ls

Inte

rven

tion

s/op

erat

ions

by

pers

onne

l and

the

ir c

ompl

exit

y

The

freq

uenc

y of

inte

rven

tion

s/

oper

atio

ns

Ris

k sc

ore

Ran

k of

ris

k sc

ore

Gri

d

Sect

ion Process Step Description (activities in this grid) Existing

controls In

this grid

1

In-f

eed

Depyrogenated glass is entering the filling line - turntable.

1. Moistening turntable performed with closed doors - when the

turntable is empty - at least 1/batch. Silicon wipes are transferred

to the grid. Silicon wipe is transferred to grade B through the

grid. 2. Manipulation of a container performed with closed doors,

forceps (part of set up). If you reach over other containers, you

need to remove the containers. 3. During set up: placing forceps

(open doors). 4. Adjustments of format parts with open doors (Not

frequent intervention) (1 door) - empty compartment grid 1-8).

We assumed silicon wiping only during set-up

5. extra

ECO

monitoring

- not to

consider

1 4 4 8 4 4 2048 12

2 No interventions 1 1 1 8 1 1 8 4

3 Depyrogenated glass is entering the filling line - turntable.

1. Manipulation of a container performed with closed doors,

forceps (part of set up). If you reach over other containers,

you need to remove the containers. 2. During set up: placing

forceps (open doors). 3. Adjustments of format parts with open

doors (Not frequent intervention) (1 door) - empty compartment

grid 1-8)

1 4 4 8 4 4 2048 12

4 Glass is transported. 1. Manipulation of a container performed with

closed doors, forceps (part Glass is transported. 1. Manipulation of

a container performed with closed doors, forceps (part of set up).

If reach over other containers, need to remove the containers.

2. Adjustment of format parts with closed doors (not for every

batch). Empty compartment grid 1-8). A tool is used if necessary.

1 1 1 8 1 2 16 5

5 Glass is transported. 1. Manipulation of a container performed

with closed doors, forceps (part of set up). If you reach over other

containers, you need to remove the containers. 2. Adjustment of

format parts with closed doors (NSI) - (empty compartment grid

1-8). A tool is used if necessary

1 1 1 8 1 4 32 6



containers, you need to remove the containers.

1 1 1 8 1 4 32 6



containers, you need to remove the containers. 2. during set up:

bringing tweezers in (open door)

1 4 4 8 1 4 512 10



containers, you need to remove the containers. 2. Adjusting format

part with closed doors (Not frequent intervention). 3. During set

up: bringing tweezers in (open door). 4. Removing broken vials with

closed doors with tweezers (Not frequent intervention)

1 4 1 8 1 2 64 7



Table 10: Description of process activities in the grids in the in-feed functional section

General considerations (focusing on higher-risk grids)

1. As grids 1, 3 and 7 are a higher risk, they should be covered with monitoring of viable and/or NVP in PQ and routine EM

2. Grids 2 and 4 should not be monitored as they are low risk

3. Evaluate fixed probes as they are part of the line design. Fixed probes should be placed in high-risk grids to be sure they will be covered in

PQ and routine.

Sampling method considerations for higher-risk grids

1. In the example, a fixed non-viable particulate monitoring would be positioned in grid 1 to perform the continuous NVP monitoring in the

worst-case place (regarding activities performed in this functional section). Note: air flow-visualization study results indicate grid 3 would

be covered by monitoring in grids 1 and 7

2. There is no short intervention in this part of the filling line, only long-time exposure of empty vials, so active viable air monitoring in this

functional section is not recommended

3. As the activities performed in grid 3 are similar to grid 1, continuous monitoring methods can be combined across the two grids (i.e. a non-

viable probe in grid 1 and settle plate in grid 3 are adequate for both grids 1 and 3)

4. There are also interventions in grid 7, a settle plate is recommended in grid 7

5. Note: there are no gloves in grid 1 as interventions performed in there are actually done with the gloves in grid 4. Therefore, glove testing

at the end of the batch/campaign in grid 4 is recommended. This is a situation where glove testing is performed in a lower-risk grid

6. To complete the higher-risk grid monitoring, a contact plate should be performed in grid 1 at the end of the batch/campaign.

PQ monitoring considerations

1. Include grids 5, 6 and 8 in PQ but optional for routine EM

2. As intervention in grids 5, 6 and 8 are performed with gloves, they should be tested at the end of the batch/campaign (gloves used are from

grids 4, 7 and 8)

3. Monitoring of grid 5, 6 and 8 should be performed with a contact plate at the end of the batch/campaign.

Routine monitoring consideration

1. Include grids 5, 6 and 8 in PQ, optional for routine

2. Depending on the PQ results, the gloves test in grids 4 and 8 can be stopped

3. The same consideration should be applied to contact plates in grids 5, 6 and 8.

Step 6: Assemble information on other relevant factors that could impact the assessment

Smoke studies conducted during the evaluation showed the line has a good historical performance.

Step 7: Review the information on each grid and each functional section grid-by-grid and section-by-section to decide on sampling locations and sampling methods

The recommendations and principles in Section 2.5 are brought together to determine an EMPQ and routine sampling plan. These are shown in Table 10 and Figure 4.



For PQ and routine

Non-viable monitoring

Contact plates

Settle plates

Glove test

For PQ, optional for routine

Contact plates

Glove test

Figure 4: Example sampling plan for the in-feed functional section

Key

1

3

7

2

4

5

6

8



Term Description

EM Environmental monitoring

EMPQ Environmental performance qualification

FDA US Food and Drug Administration

FMEA Failure mode and effects analysis

HACCP Hazard analysis and critical control points

UDF Uni-directional air flow

NVP Non-viable particles

PQ Performance qualification

RA Risk assessment

RABS Restricted access barrier system

SME Subject matter expert

Acronyms/abbreviations



References1 FDA, “Guidance for industy: Sterile drug products produced by aseptic processing,” Current.

2 PDA, “TR13 Vol. 5 (revised): Fundamentals of an environmental monitoring program,” 2014.

3 ISO, “14644-4: Cleanrooms and associated controlled environments Part 4: Design, construction and start-up.,” 2015.

4 European Commission, “EU guidelines to good manufacturing practice of medicinal products for human and veterinary use: Annex 1 manufacture of sterile medicinal products,” https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2008_11_25_gmp-an1_en.pdf, 2008.

5 BioPhorum ARMM workstream, “Continuous Microbiological Environmental Monitoring for Process Understanding and Reduced Interventions in Aseptic Manufacturing.,” To be published in j PDA in 2019.

6 USP, “<1116> Vol. 1: Microbiological control and monitoring of aseptic processing environments.,” Baltimore MD, 2012, pp. 697-707.

7 ISO, “14644-2: Cleanrooms and associated controlled environments - Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration,” 2015.

8 ISO, “13408-1: Aseptic processing of health care products – Part 1: General requirements.,” 2008.

Other key references (uncited)

• CFR - Code of Federal Regulations Title 21: Part 210, Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs; general, 2017, www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=210&showFR=1

• CFR - Code of Federal Regulations Title 21: Part 211, Current good manufacturing practice for finished pharmaceuticals, 2017, www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211&showFR=1

• ICH guideline Q9 on quality risk management, Committee for Human Medicinal Products, 2015, EMA/CHMP/ICH/24235/2006, www.ema.europa.eu/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-3.pdf

• ISO 14971:2007 Medical devices – Application of risk management to medical devices, www.iso.org/standard/38193.html

• Recommendation on the Validation of Aseptic Processes, Pharmaceutical Inspection Convention, PIC/S, 2011, PI 007-6, page 10 of 16, https://www.gmp-compliance.org/guidelines/gmp-guideline/pic-s-validation-of-aseptic-processing-pi-007-6-20118 ISO, “13408-1: Aseptic processing of health care products – Part 1: General requirements.,” 2008.



Permission to useThe contents of this report may be used unaltered as long as the copyright is acknowledged appropriately with correct source citation, as follows “Entity, Author(s), Editor, Title, Location: Year”

DisclaimerThis document represents a consensus view based on current data good practices, and as such it does not represent fully the internal policies of the contributing companies.

The recommendations in the guidance should be considered alongside appropriate regulatory guidance and expectations. Neither BioPhorum nor any of the contributing companies accept any liability to any person arising from their use of this document.

environmental monitoring in modern biopharmaceutical drug product … · 2019. 12. 15. · and usp ...

Documents