submission of comments on revision of ‘annex 1 ...guidance, such as contamination control...

Submission of comments on Revision of ‘Annex 1: Manufacture of

Sterile Medicinal Products’

Comments from:

Name of organisation or individual

Pharmaceutical & Healthcare Sciences Society (Not-For-Profit society): PHSS Annex 1 comment platform:

Comments from Group 1: Pharmaceutical Industry and GMP consultants.

Acknowledgement: The Pharmaceutical & Healthcare Sciences Society: PHSS Annex 1 comment platform includes

contributors from the Pharmaceutical Industry, supporting GMP consultants, Pharmaceutical equipment manufacturers: Barrier

Isolator/RABS technology and Filling process machinery, suppliers: Facility monitoring system and gowning plus academics

with related research and peer reviewed publications as such provides a broad view of international stake holder interest.

The PHSS wish to acknowledge contributions with comments from the following:

PHSS Group 1 comments:

Pharmaceutical Industry: GSK, AstraZeneca, Pfizer, Merck & Co Inc, Ely Lilly France & Italy, Novartis, Allergan Westport,

Fresenius Kabi, Teva-Pliva, Alexion Ireland, Bayer. GMP Consultants: Roland Guinet (France), Gordon Farquharson (UK),

Richard Funnel (UK).

PHSS Group 2 comments:

Pharmaceutical equipment manufacturers: F Ziel GmbH (Barrier Isolator/ RABS Technology), Groninger GmbH & Bausch

Stroebel GmbH (Filling process machines), TSI & Pharmagraph (Facility monitoring systems), DuPont (Cleanroom garbing),

Sterilisation solutions (Alan Heavey), Rapid Micro Biosystems (David Jones) and Academics working in field of Good

manufacturing practice GMP: Professor Bengt Ljungqvist, Associate Professor microbiology Berit Reinmüller, Professor Matts

Ramstorp, Dr Bill Whyte.

Throughout this document, existing text is given in italics where applicable.

Where modifications have been made to existing text these areas are underlined in the proposed text change.

Where large changes have been made such that the text changes significantly there is no underlining.

The most suitable text changes considered by the PHSS are given at the start of each paragraph section.

1. General comments

General comment (1)

This draft revision of Annex 1represents an enormous change from the 2008 version, and includes a great deal of

updated information, current expectations, and focus on current technologies and practices.

However, the Pre Draft issue communication from EU Inspectors Working Group (IWG) indicated that Annex 1

would provide clear guidance to manufacturers with regard to the manufacture of sterile products so Inspectorates and

Manufacturers are not held to unclear expectations. This was understood to be of especial importance to less

technically mature organisations who currently learn via incidents or adverse regulatory inspections.

This document does not meet that expectation nor does it appear to meet current regulatory expectations as

experienced by the industry.

The draft appears to be somewhat immature with tables repeated, has conflicts in many areas with current practice,

and for example doesn’t address the EMA non-distillation WFI Q&A paper that it was supposed to replace.

The document requires improvement and clarification of technical elements, and should be subject to a further editing

process.

The use of terminology such as shall, should and must are not used consistently creating uncertainty over where

expectations are mandatory.

General Comment (2)

Note that some companies are concerned that in contrast to enabling manufacturers to take decisions relating to their

own processes using Quality Risk Management principles, some elaborated new detail is provided in the draft Annex

1 which state specific requirements in general, rather than enabling using individual risk based requirements based on

manufacturing processes.

General Comment (3)

1) The draft Annex is very prescriptive in expectations. There is risk of literal interpretations by inspectors and

industry that will add cost and complexity to sterile manufacturing operations that are not warranted for

sterility assurance. Although QRM principles are included, the statement is such that the controls must meet

or surpass the Annex, which is inconsistent with QRM concepts and subject to interpretation/local

enforcement. Industry experience has been that examples and recommendations are often interpreted by some

authorities as the mandatory requirement.

2) There is an overall emphasis on quality control and testing rather than design, validation and assurance

programs. This will add unnecessary cost and operational complexity with associated risk for burdensome

activities and risk of errors. Focusing on programs that inherently design robust sterility assurance elements

and emphasize risk reduction would provide greater levels of confidence in overall sterility assurance.

3) The draft Annex detailed requirements are based on current technology and the prescriptive methodologies

will impede implementation of new scientific, engineering and analytical methods. Although the Annex

attempts to promote modern technologies, the detailed prescriptive controls do not enable efficient, effective

use of such technology. As a result, manufacturers may be limited in new technology, testing and assurance

options for considerable time.

4) The controls outlined are often universal regardless of the technology (e.g. isolator, RABS) and therefore

manufacturers are limited in operating to maximal efficiency and assurance. Many of the controls involve

taking operations off-line limiting the time available for manufacture of product for supply. In addition, some

of the controls are invasive and may have the unintended consequence of adding risk.

Specific comments on text

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Comment and rationale; proposed changes

(If changes to the wording are suggested, they should be highlighted using 'track changes')

1-4 Comment:

Document Map (Index)

1] The order of the whole document should be improved. For example, Section 5 is the first time that the cleanliness

Grades A-D are defined, yet Section 4 on personnel makes reference to them.

2] Section 8 has equipment items in it. These should be collected together in Section 6.

Proposed change:

Change the order of the sections, and rewrite Section 5 to include the equipment/processes in section 8.

Reduce the size of section 8 by having a separate section on sterilisation.

6-23 Comment:

Scope. To aid the clarity of the document, the scope should be re-written. It should be emphasised that there are two

routes in the manufacture of sterile product namely terminal sterilisation (TS) and aseptic processing. While the

former should be undertaken if feasible, it must be recognised that the growing increase in biopharma products may

increasingly preclude the option for a TS approach. This section should also include references to ICH documents for

QRM.

8-15 Existing Text

The manufacture of sterile medicinal products covers a wide range of product types, (sterile active substance through

to finished dosage form), batch sizes (single unit to multiple units), processes (from highly automated systems to

manual processes), primary packaging materials and technologies (e.g. biotechnology, classical small molecule

manufacturing and closed systems). This Annex provides general guidance that should be used for all sterile

medicinal products and sterile active substances, via adaption, using the principles of Quality Risk Management

(QRM), to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented in the

final product.

Proposed changed text:

Whenever possible products should be terminally sterilised in their primary containers as this provides the highest

level of sterility assurance based on a terminal process of known lethality. Where terminal sterilisation isn’t possible

due to the product being heat labile, the alternative approach of aseptic processing can be used. See also 8.30.

This guidance considers the manufacture of sterile medicinal products manufactured by both terminal sterilisation and

aseptic processing. It covers a wide range of product types, including sterile active ingredients (APIs) and finished

dosage forms for both classic “small molecule” and large molecule biotechnology products. In addition to product

types, guidance is also provided on batch sizes (single unit to multiple units); campaign working (single batches to

campaigns comprising sequential batches); manual processes to highly automated systems; and primary packaging

materials and certain specialised manufacturing technologies. The manufacturing environment is also considered,

including cleanrooms, RABS, and isolators, and their relationship with open and closed process systems. This Annex

provides general guidance that should be used for all sterile medicinal products and sterile active substances, using the

principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogenic contamination

associated with microbes is prevented in the final product, and to ensure more broadly that the products consistently

meet their quality attributes of potency, purity, sterility, and identity.

Comment:

Extended scope to include primary packaging materials and technologies including biotech and closed systems

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17-22 Comment (1):

A definition for the Contamination Control Strategy would be very beneficial.

Existing Text

The intent of the Annex is to provide guidance for sterile medicinal products. However some of the principles and

guidance, such as contamination control strategy, room qualification, classification, monitoring and gowning, may be

used to support the manufacture of other products that are not intended to be sterile (such as certain liquids, creams,

ointments and low bioburden biological intermediates) but where the control of microbial, particulate and pyrogen

contamination, to reduce it as far as possible, is considered important.


Important GMP principles, such as cross-contamination control, are addressed elsewhere in the GMP guidelines. The

intent of this Annex is to provide guidance for sterile medicinal products. However, some of the principles and

guidance, such as contamination control strategy, cleanroom classification, qualification, monitoring and gowning,

may be used to support the manufacture of other products that are not intended to be sterile. Examples include some

liquids, creams, ointments and low bioburden biological intermediates where the control of microbial, particulate and

pyrogenic contamination is considered important.

Comment (2)

Extended scope to include non-sterile products. This statement is too general. It needs to be more specific to eliminate

any lack of clarity. Why pyrogen contamination should be a concern for non-sterile products?

Is this statement on non-sterile products really needed in this guidance?

Proposed change: Suggest delete line 17 to 20.

Comment (3)

The proposed scope includes non-sterile medicinal products and intermediates. This revision will provide

uncertainty as to the specific application of each of the requirements of Annex 1 as they relate to the

manufacture of non-sterile products.

The governing regulatory guidelines for contamination control for the manufacture of non-sterile products

is already provided within the EU Annex 2 regulations. Within that Annex, specific cross reference to

Annex 1 is currently included.

The scope of the guideline should be unambiguous (i.e., sterile medicinal products).

If some of the principles and guidance contained in Annex 1 are to be utilised for non-sterile medicinal

products and intermediates, the relevant guidelines for those products should cross-reference the

applicable requirement in Annex 1.

Comment (4):

Distinction should be made between ‘contamination’ - microorganisms, pyrogens and particulates which represent a

direct hazard and risk to product quality and microorganisms, pyrogens and particulates which are not hazards to

product quality.

Proposed change:

However some of the principles and guidance, such as microbial and particle control strategy, room qualification,

classification, monitoring and gowning, may be used to support the manufacture of other products that are not

intended to be sterile (such as certain liquids, creams, ointments and low bioburden biological intermediates) but

where the control of microorganisms, particulates and pyrogens is considered important.

20-34 2 Principle

General Comment:

It is not clearly indicated that the direct intervention of operators in the critical grade A area should be discouraged, as

indicated by MHRA in many communications on the revision of EU GMP Annex 1.

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This should be indicated also for the manufacturing of all open containers since at point 8.17 for the transfer of

partially stoppered containers two times the requirement is “with physical segregation from operators”.

Thus, point 8.9 is not sufficiently clear and should be “Where possible, the use of… RABS, isolators or closed

systems, should be considered in order to reduce the need for avoid direct interventions into the grade A

environment...”

Comment (1):

Existing Text

a) Facility, equipment and process design must be optimized qualified and validated according to Annex 11

and Annex 15 of EU GMP. The use of appropriate current technologies should be implemented to ensure

protection and control of the product from potential extraneous sources of particulate and microbial

contamination such as personnel, materials and the surrounding environment.


a) Facility, equipment and process design must be optimized qualified and validated according to Annex 11

and Annex 15 of EU GMP. The use of appropriate current technologies according to EU directives 2003/94

Article 5 and 2001/83 Article 23 should be implemented to ensure protection and control of the product

from potential extraneous sources of particulate and microbial contamination such as personnel, materials

and the surrounding environment

Comment (2)

Line 26-28: Distinction should be made between ‘contamination’ - microorganisms, pyrogens and particulates which

represent a direct hazard and risk to product quality and microorganisms, pyrogens and particulates which are not

hazards to product quality.

Alternative proposed text:

The manufacture of sterile products is subject to special requirements in order to minimize risks of a microbiological

(microorganisms and pyrogens), and particulate nature. The following key areas should be considered…

Comment (3)

Line 31-34: Distinction should be made between 'contamination' - microorganisms, pyrogens and particulates which

represent a direct hazard and risk to product quality and microorganisms, pyrogens and particulates which are not

hazards to product quality. Specifically, in this context unless the transfer of microorganisms, particulates is of a

quantity or nature (e.g. pathogenic microorganisms) that exceeds the materials quality attributes at that point (i.e. at a

tolerable level) the microorganisms and particulates are not necessarily contamination.

Alternative proposed text:

The use of appropriate current technologies should be implemented to ensure protection and control of the product

from potential extraneous sources of particulate and microbial hazards such as personnel, materials and the

surrounding environment

36-38 Comment;

As “attitude” is subjective i.e. cannot be reliably measured or evaluated, it is suggested that this term is omitted.

Existing Text

Personnel must have appropriate skills, training and attitudes with a specific focus on the principles involved in the

protection of sterile product during the manufacturing, packaging and distribution processes.


Personnel must have defined skills and training with a specific focus on the principles to ensure the safety, quality and

efficacy of sterile product(s) during the manufacturing, packaging and distribution processes.

40-42 Existing Text

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Processes and monitoring systems for sterile product manufacture must be designed, commissioned, qualified and

monitored by personnel with appropriate process, engineering and microbiological knowledge.


Processes and monitoring systems for sterile product manufacture must be designed, commissioned, qualified and

assessed by personnel with defined process, engineering and microbiological knowledge. These systems must be

defined within the facility contamination control strategy

Comment:

Will this require evidence of qualifications of personnel who designed and commissioned systems?

44-48 Existing text

Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles

that provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Risk

assessments should be used to justify alternative approaches to those specified in this Annex only if these alternative

approaches meet or surpass the intent of this Annex.


Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles

that provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Risk

and impact assessments should be used to identify and justify alternative approaches to those specified in this Annex

only if these alternative approaches meet or surpass the intent of this Annex.

Comment (1):

The basis of quality risk management is to establish controls commensurate with the risk. Requiring that

QRM be used, but then stating that it can only be used if the approaches meet or surpass the intent of the

annex is contradictory in nature. Furthermore, scientific rationale in addition to risk assessment should be

used to justify alternative approaches.

Proposed text change:

Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM

principles that provide a proactive means of identifying, scientifically evaluating and controlling potential

risks to quality. Risk assessments and scientific rationale should be used to justify alternative approaches

to those specified in this Annex. Comment (2):

The draft consistently advocates the use of science based risk assessments to enhance the effectiveness of the

contamination control procedures. However, there is no inclusion that the risk to the patient is dependent on the

chance that an aseptically manufactured product will support microbial growth during the shelf life following

manufacture. For example, a freeze dried product, or one which has a water activity of less than 0.6 will not support

microbial growth and so presents a greatly reduced risk to the patient than a product which does support growth1. The

design of the contamination control devices (e.g. Isolators, RABS or open workstations) and the associated

cleanrooms utilised should reflect this risk

Recommendation:

Information should be added that the risk to a patient is dependent of the likelihood that an aseptically manufactured

product that is contaminated during manufacturing will support microbial growth during the period following

manufacture prior to administration to the patient. The design of the contamination control devices (e.g. Isolators,

RABS or open workstations) and the associated cleanrooms utilised during manufacturing should reflect this risk

50-54 Existing text

Quality Assurance is particularly important, and manufacture of sterile products must strictly follow carefully

established and validated methods of manufacture and control. A contamination control strategy should be

implemented across the facility in order to assess the effectiveness of all the control and monitoring measures

employed. This assessment should lead to corrective and preventative actions being taken as necessary.


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Quality Assurance is particularly important, and manufacture of sterile products must strictly follow carefully

established and validated methods of manufacture and control because sterility of the final product cannot be

definitively measured. A contamination control strategy should be defined and implemented across the facility in

order to assess the effectiveness of all the control and monitoring measures employed. This assessment should lead to

corrective and preventative actions being taken as necessary.

Comment (1):

Line 51: New requirement. The site is required to implement and periodically update a documented holistic

contamination control strategy.

The control strategy defined in 8.7 should be crossed referred here.

Comment (2)

Line 51-53: A single control strategy, and an appropriate strategy term is needed which includes and distinguishes

between the different approaches to controlling microorganisms, pyrogens and particulates which represent direct

hazards to product quality and microorganisms, pyrogens and particulates which do not represent a hazard to product

quality. The control strategy is required to be implemented across the facility, however controls are necessary in

systems and subsystems which may be specific to product (e.g. tests supporting assessment of controls are qualified to

ensure suitability with specific products). Clarification is suggested by changing the text and to include a description

of the term in the glossary.

Alternative proposed changed text:

A microbial and particulate control strategy should be implemented across the facility in order to assess the

effectiveness of all the facility’s control and monitoring measures employed and specific to each product.

56-57 Existing text

The strategy should consider all aspects of contamination control and its life cycle with ongoing and periodic review

and update of the strategy as appropriate.


The strategy should consider all aspects of contamination control throughout the life cycle of the facility with ongoing

and periodic review and update of the strategy as appropriate.

Comment:

Distinction should be made between 'contamination control' of microorganisms, pyrogens and particulates which are

potential hazards to product quality (contaminants) and the control of microorganisms, pyrogens and particulates

which are not hazards to product quality. Specifically tolerable levels of microorganisms in facility areas such as

Grade D or C cleanrooms are not contaminants or contamination as long as they are a quantity and nature which is not

adverse to control or product quality.

Alternative proposed changed text

The strategy should consider all aspects of microbiological (microorganisms and pyrogens), and particulate control

and its life cycle with ongoing and periodic review and update of the strategy as appropriate.

59-62 Existing text

Contamination control and steps taken to minimise the risk of contamination from microbial and particulate sources

are a series of successively linked events or measures. These are typically assessed, controlled and monitored

individually but these many sources should be considered holistically.


Contamination control and the proactive steps taken to minimise the risk of contamination from microbial and

particulate sources and any other extraneous material which may adulterate the product, are a series of linked events

or measures including viable and non-viable particulates counts, airflows, pressure differentials, temperature and

humidity, adherence to procedures etc. These are typically assessed, controlled and monitored individually but these

multiple sources should be considered holistically.

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Comment:

Distinction should be made between 'contamination control' of microorganisms, pyrogens and particulates which are

potential hazards to product quality (contaminants) and the control of microorganisms, pyrogens and particulates

which are not hazards to product quality.


Microbial and particulate control and steps taken to minimise the risks from microbial and particulate sources are a

series of successively linked events or measures. These are typically assessed, controlled and monitored individually

but these many sources should be considered holistically

64-67 Existing text

The development of such strategies requires thorough technical and process knowledge. Potential sources of

contamination are attributable to microbiological and cellular debris (e.g. pyrogens/endotoxins) as well as

particulate matter (glass and other visible and sub-visible particles).


The development of such contamination and control strategies requires thorough technical and process knowledge.

Potential sources of contamination are attributable to microbiological and cellular debris (e.g. pyrogens/endotoxins) as

well as particulate matter (glass and other visible and sub-visible particles).

Comment:

Distinction should be made between "contamination' - microorganisms, pyrogens and particulates which represent a


product quality.


The development of such strategies requires thorough technical and process knowledge. Potential sources of hazards

are attributable to microbiological and cellular debris (e.g. pyrogens/endotoxins) as well as particulate matter (glass

and other visible and sub-visible particles).

69-70 Comment (1):

The list does not include training and qualification program. Suggest add section on training.

Comment (2):

A single control strategy, and an appropriate strategy term is needed which includes and distinguishes between the

different approaches to controlling microorganisms, pyrogens and particulates which represent direct hazards to

product quality and microorganisms, pyrogens and particulates which do not represent a hazard to product quality.


Elements to be considered within such a documented microbial and particulate control strategy should include (but not

be limited to):

93-95 Comment:

Distinction should be made between 'contamination' - microorganisms, pyrogens and particulates which represent a


product quality.

Proposed changed text

Preventative maintenance - maintaining equipment and premises (planned and unplanned maintenance) to a standard

that will not add significant microbial or particulate risk

99-101 Comment:



product quality. Specifically, cleanrooms and environments are expected to and normally contain a micro flora; the

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monitoring systems need to measure this to ensure routine control and also to measure events where genuine

contamination events occur in that levels and nature of the permissible microflora are exceeded.


Monitoring systems - including an assessment of the feasibility of the introduction of scientifically sound, modern

methods that optimize the detection of environmental microbial or particulate risk

69-107 Comment:

The control strategy is suggested to include a number of listed elements. These elements are a mixture of important

and critical items within various systems and subsystems. The wording does not indicate which if any are absolutely

necessary and which are beneficially advantageous but not absolutely necessary. It is recommended that the wording

is amended to reflect systems and subsystems, specific elements therein and if these are mandatory.


Quality systems and respective elements that must he considered within the control strategy are tabulated below

3 Pharmaceutical Quality System (PQS)

General Comments:

- line 131 : “… in chapter 1 of the EU GMP, ...” should be … in chapter 1 of EU GMP Part I,...

- line 135 : “… microbial contamination ...” should be … microbial and other contamination ...

134-136 Comment (1):

No clarity regarding the definition of sterility assurance. Suggest include a definition of “sterility assurance” in the

glossary

Comment (2):



product quality.


There is an effective risk management system integrated into the product life cycle to minimize microbial and

particulate risks to ensure the safety, quality and efficacy of sterile manufactured product, including assurance of

sterility.

138-139 Existing Text

The manufacturer has sufficient knowledge and expertise in relation to the products manufactured and the

manufacturing methods employed.


The manufacturer has defined knowledge and expertise in relation to the products manufactured and the

manufacturing methods employed and the equipment and engineering systems that have a direct impact on product

quality.

Oualitv System System Content (includes but not limited to)

Facility Desinn. traffic flows, utilities, maintenance nrcventative

and repair, cleanine. disinfection, monitorina systems

Manulaclurina Process Desicn. ccniipment. in-nrocess controls, in-process tcsls

Personnel Trainina, certification, garbina.

Procedures Vendor annroval. out sourcinc. risk assessments.

trendina. analysis, investiealional tools. CAPA.

continuous improvement

Product Raw materials, in-nrocess tests, end product tests.

containers, closures

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145 Comment:

New requirement. The site is required to implement and periodically update a documented risk assessment. Should

this risk assessment be incorporated into the contamination control strategy described at line 51?

Proposed change (if any): Eliminate lack of clarity about the difference between the contamination control strategy

document described at line 51 and the risk assessment document described at line 145.

Comment:

There is no guidance regarding the approach to be taken to complete an effective risk assessment that can accurately

quantify the level of product microbial contamination. This requires an understanding of the fundamental risk factors

that are responsible for microbial contamination, associated with airborne deposition, surface contact or liquid

transfer, and how these factors should be combined to provide an accurate assessment of risk

Recommendation:

Include further guidance on the requirement to provide an accurate assessment of risk based upon the fundamental

mechanisms of product contamination by airborne deposition, surface contact or liquid transfer. The guidance should

reference the fundamental risk factors that relate to product (or product contacting surfaces) contamination such as

exposure area and time and the number of contacts with contaminated surfaces

152 Comment:

Chapter 1 of EU GMP vol 4-PQR section 1.10 does not include requirement for QRM. Suggest both documents are

aligned.

154-157 Comment:

Reference to transport of sterile products should be part of GDP. Suggest that this reference is removed. If it remains

then see proposed text below.

Comment:

Is this more of a GDP requirement and is this Annex the right place for this requirement ( i.e. transport)?

Existing Text

Processes associated with the finishing and transport of sterile products should not compromise the finished sterile

product in terms of container integrity or pose a risk of contamination and ensure that medicinal products are stored

and maintained in accordance with registered storage conditions.


Processes associated with the finishing and transport of sterile products should not compromise the finished sterile

product. Aspects that should be considered include:- container integrity, risks of contamination, and avoidance of

degradation by ensuring that medicinal products are stored and maintained in accordance with their registered storage

conditions.


Persons responsible the quality release of sterile medicines should have appropriate access to manufacturing and

quality information and possess adequate knowledge and experience in the manufacture of sterile dosage forms and

their critical quality attributes in order to be able to ascertain that the medicines have been manufactured in

accordance with the registered specification and are of the required safety, quality and efficacy.


Persons responsible for the certification and quality release of sterile medicines should have appropriate access to

manufacturing and quality information and possess defined knowledge and experience in the manufacture of sterile

dosage forms and their critical quality attributes in order to be able to ascertain that the medicines have been

manufactured in accordance with the registered specification and are of the required safety, quality and efficacy.


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3.2 Investigations should be performed into non-conformities, such as sterility test failures or environmental

monitoring excursions or deviations from established procedures, with a specific focus regarding the potential impact

to sterility, to not only the specific batch concerned but also any other potentially impacted batch. The reasons for

including or excluding product from the scope of the investigation should be clearly recorded and justified within the

investigation.


3.2 Investigations must be performed into non-conformities, such as sterility test failures or environmental monitoring

excursions or deviations from established procedures, with a specific focus regarding the potential impact upon

sterility. Investigations must consider not only the specific batch concerned but also any other potentially impacted

batch. The reasons for including or excluding product from the scope of the investigation should be clearly recorded

and justified within the investigation.

4. Personnel

Comment:

Before this section is introduced it would be better to describe the Premises (currently the following section) to define

Grades A-D and the concept of CNC areas. This section also requires revision to clarify and recognise best practise.

The term grade A/B cleanroom is not defined. It may be interpreted by some readers to suggest that it is acceptable for

personnel to fully enter/occupy Grade A zones, which of course is not acceptable.

175-179 Existing text:

4.1 The manufacturer should ensure that there are sufficient appropriate personnel, suitably qualified and

experienced in the manufacture and testing of sterile medicines and any of the specific manufacturing technologies

used in the site's manufacturing operations, to ensure compliance with Good Manufacturing Practice applicable to

the manufacture of sterile medicinal products.

Proposed change:

Removal of the word “appropriate”.

181-186 Existing text

4.2 Only the minimum number of personnel required should be present in cleanrooms. The maximum number of

operators in critical areas should be determined based on QRM principles, documented in the contamination control

strategy, and validated during activities such as initial qualification and aseptic process simulations, so as not to

compromise sterility assurance. This is particularly important during aseptic processing. Inspections and controls

should be conducted outside the clean areas as far as possible.

Comment:

Does this paragraph indicate that staff from the quality function should only conduct audits and inspections from

outside of the aseptic area or is it referring to the inspection of filled containers etc?

Proposed change:

Include the abbreviation (APS) after the “aseptic process simulations”.

Comment:

The document recommends that the maximum number of operators in critical areas should be determined based upon

QRM principles. By the definition of ‘critical’ areas (see Glossary, text line 2104), personnel are unlikely to be within

these areas and it is more appropriate to state that the maximum number of operators in the ‘aseptic processing room’

would be a more appropriate term.

Recommendation:

Change ‘critical area’ to aseptic processing room’


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4.3 All personnel (including those performing cleaning and maintenance) employed in such areas should receive

regular training, qualification (including sampling of the operators bioburden, using methods such as contact plates,

at key locations e.g. hands arms and chest) and assessment in disciplines relevant to the correct manufacture of sterile

products. This training should include reference to 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.

Comment:

Monitoring requirements should be described in the monitoring section.


4.3 All personnel, including those performing cleaning and maintenance employed in such areas should receive

regular training, qualification and assessment in disciplines relevant to the correct manufacture of sterile products.

This training should include reference to 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.

Personnel should be monitored for microbial contamination as described in section 9.


4.4 The personnel working in a grade A/B cleanroom should be trained for aseptic gowning and aseptic practices.

Compliance with aseptic gowning procedures should be assessed and confirmed and this should be periodically

reassessed at least annually and should involve both visual and microbiological assessment (using additional

locations such as arms and chest). Only trained personnel who have passed the gowning assessment and have

participated in a successful aseptic process simulation (APS) test, during which they performed their normal duties,

should be authorized to enter any grade A/B area, in which aseptic operations will be conducted, or are being

conducted, whilst unsupervised. The microbial monitoring of personnel in the grade A/B area should be performed to

assess their aseptic behaviour. This monitoring should take place immediately after completion of a critical

intervention and upon each exit from the cleanroom. It should be noted that there should also be an ongoing

continuous monitoring program for personnel including some consideration of periodic monitoring under the

supervision of the quality unit.

Comment:

Use of grade A/B again. There seems to be an expectation that cleaning staff who will not be directly involved in

aseptic processing need to participate in a successful APS. This requirement has been omitted in the proposed text

below.


4.4 As far as possible personnel should be excluded from entering Grade A zones. The personnel working in a Grade

B cleanroom and especially those supporting Grade A zones, must be trained for aseptic gowning and aseptic

practices. Compliance with aseptic gowning procedures should be assessed and confirmed and this should be

periodically reassessed at least annually and should involve both visual and microbiological assessment. Only trained

personnel who have passed the gowning assessment should be authorized to enter any grade B area, in which aseptic

operations will be conducted, or are being conducted, whilst unsupervised. Only trained personnel who have

participated in a successful aseptic process simulation (APS) test, during which they performed their normal duties,

should be authorized to undertake aseptic processing. The microbial monitoring of personnel in the grade B area

should be performed to assess their aseptic behaviour. This monitoring should take place immediately after

completion of a critical intervention and upon each exit from the cleanroom. It should be noted that there should also

be an ongoing monitoring program for personnel which will include periodic monitoring under the supervision of the

quality unit.

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Comment (1): Note some companies believe that the personnel monitoring frequency should be based upon the

activity that personnel are engaged in and should not necessarily be required on each exit.

Comment (2)

Line 199: Requalification should include visual and microbiological assessment

Proposed change (if any): suggest adding visual and microbiological assessment

Comment (3):

Line 205-206: EM on each exit of the cleanroom may be excessive. One company monitors at the end of a shift or at

the end of a campaign, at least once on each operator.

Proposed change (if any): recommend EM at each end of shift or campaign -

Define critical intervention in the glossary

Comment (4):

Line 208-208: What is the difference between critical and significant intervention?

The term “continuous monitoring” for personnel is confusing. “Routine” should be used.

-Is also gown monitoring required after a critical intervention? To be clarified. Only glove monitoring should be

required after a critical intervention, supported by risk assessment

Proposed change (if any): -Routine” should be used. Clarify if only glove monitoring is acceptable after completion of

a critical intervention, supported by risk assessment

Comment (5):

The Grade A/B cleanroom is a part of the aseptic manufacturing area in which there may be separate rooms which are

only Grade B status (contain no Grade A zones). Aseptic processing room (definition included in the Glossary) would

be a more appropriate term

Recommendation:

Change ‘Grade A/B cleanroom’ to aseptic processing room’ throughout the document.

Comment (6):

Line 200: Personnel who are validated and authorised to enter into the aseptic processing room may not perform direct

manufacturing activities e.g. to perform peripheral cleaning and disinfectant or supervisory activities, and

consequently would have no requirement to participate in a successful aseptic process simulation test.

Recommendation:

Remove the requirement for all personnel who enter into the aseptic processing room to have participated in a

successful aseptic process simulation test and specify that the requirement is specific to those personnel who have

direct manufacturing activities.

Comment (7)

Line 205: ‘Critical intervention’ is defined in the Glossary section (text line 2154) as ‘Intervention (an aseptic

manipulation or activity that occurs at the critical area)’ so the term critical is not required

There are interventions that will have been assessed to be aseptically secure, included in aseptic process simulations

and are an inherent part of the process in order for the operation to continue (e.g. replenishment of the container

closures). In these cases, it would not be appropriate to perform personnel microbial monitoring. Any such monitoring

needs to be considered for, and specific to, corrective interventions that are not included in aseptic process simulations

Recommendation:

Change ‘critical area’ to aseptic processing area

Change ‘after completion of a critical intervention’ to ‘after completion of a non validated intervention’.

Comment: (8)

Line 206: Personnel may leave the cleanroom in which the manufacturing activities are located to retrieve

consumables or related items for use during the manufacturing operation. For these activities, personnel microbial

monitoring would not be expected as personnel are returning to the cleanroom. However, when the personnel

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subsequently leave the aseptic processing area/aseptic manufacturing area, and discard their cleanroom attire,

monitoring would be appropriate

Recommendation

Change ‘upon each exit from the cleanroom’ to ‘upon each exit from the aseptic manufacturing area’

Comment (9):

Line 205-206: Does this refer to finger sample only monitoring or gown monitoring. Gown monitoring would be

unachievable as operators would have to leave the area to re-gown mid process to avoid agar contamination from their

sterile suit.

Proposed change:

Finger sample monitoring should take place…


4.5 There should be systems in place for disqualification of personnel from entry into cleanrooms, based on aspects

including ongoing assessment and/or the identification of an adverse trend from the personnel monitoring program.

Once disqualified, retraining and requalification is required before permitting the operator to have any further

involvement in aseptic practices. This should include consideration of participation in a successful Aseptic Process

Simulation (APS).


4.5 There should be systems in place for disqualification of personnel from entry into cleanrooms, based on aspects

including ongoing assessment and/or the identification of an adverse trend from the personnel monitoring program.

Once disqualified, retraining and requalification is required before permitting the operator to have any further

involvement in aseptic practices. This should include participation in a successful Aseptic Process Simulation (APS)

depending upon the reasons for disqualification and its impact.


4.6 Manufacturers should establish written procedures outlining the process by which outside staff who have not

received such training (e.g. building or maintenance contractors) need to be brought into grade A/B areas. Access by

these persons should only be given in exceptional circumstances, evaluated and recorded in accordance with the PQS.


4.6 Manufacturers should establish written procedures outlining the process by which outside staff who have not

received such training (e.g. building or maintenance contractors) need to be brought into Grade B areas or access

Grade A zones. Access by these persons should only be given in exceptional circumstances, evaluated and recorded in

accordance with the PQS.

225-226 Comment:

“periodic health checks for such conditions should be performed.” This sentence is not clear. Who should perform the

check? Is self-assessment acceptable?

Proposed change (if any): Clarify the meaning of “periodic”.


Actions to be taken with regard to personnel who could be introducing an undue microbiological hazard should be

described in procedures decided by a designated competent person.

Comment:

What actions can be taken/how to avoid a breach in confidentiality of personnel medical information.

227 Comment:

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Definition required for “Undue microbiological hazards”

232 Comment:

Is it problematic for Biological Quality personnel who work in the core to also work in the lab without a “rigorous,

clearly defined and effective entry procedures have been followed”?

Not clear how far you need to go to investigate this. You cannot check personal activities? What about part time

butchers, farmers? Concern? Our gowning and Cleaning and disinfection SOPs should be effective?

Proposed change (if any): More clarification of what entails a “rigorous, clearly defined entry procedure” is…

233 Comment:

The term ‘sterile product areas’ is not defined and is a new term, not used throughout the document

Proposed change:

Change ‘sterile product areas’ to ‘aseptic processing area/aseptic manufacturing area’


4.9 Wristwatches, make-up and jewellery and other personal items such as mobile phones should not be allowed in

clean areas.

Comment (1):

Is this referring to classified clean areas only OR CNC areas also?

Comment (2):

The definition of clean areas is not included in the glossary

The requirement to not use mobile phones in all Grades of clean rooms is too stringent.

Proposed change (if any): Include a definition of clean areas in the glossary.

Reword as follows: “Wristwatches, make-up and jewelry should not be allowed in clean areas. Other personal items

and electronic devices (e.g. mobile phones) should be allowed in clean areas, where needed, only if adequately

decontaminated and fit for purpose.

Comment (3):

More guidance on make-up is needed to suit modern culture. Make-up can now be semi-permanent, for example lip

staining.

Recommendation:

Change make up to non-permanent make-up


4.10 Changing and hand washing should follow a written procedure designed to minimize contamination of clean

area clothing or carry-through of contaminants to the clean areas. Garments should be visually checked for

cleanliness and integrity prior to entry to the clean room. For sterilized garments, particular attention should be

taken to ensure that garments and eye coverings have been sterilized and that their packaging is integral before use.

Reusable garments should be replaced based at a set frequency determined by qualification or if damage is

identified.


4.10 Garment changing and hand washing should follow a written procedure designed to minimize contamination of

cleanroom clothing or transfer of contaminants to the cleanrooms. Garments should be visually checked for

cleanliness and integrity prior to entry to the cleanroom. For sterilized garments, particular attention should be taken

to ensure that garments and eye coverings have been sterilized and that their packaging is integral before use.

Reusable garments should be replaced based upon a set frequency determined by qualification or when damage is

identified.

Comment:

Line 242-243: The gowning components include the garments and all other items required to complete full personnel

enclosure (e.g. garment, hood, overboots, gloves, masks, eye coverings) and all components should be confirmed to

have been sterilised with integral packaging prior to use.

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Recommendation:

Change ’particular attention should be taken to ensure that garments and eye coverings have been sterilised and that

their packaging is integral before use’ to ’particular attention should be taken to ensure that all garment components

have been sterilised and that their packaging is integral before use’

253 Comment:

‘Disinfected Shoes’ – this should not be a requirement but the type of microbial /particulate control for shoes in Grade

D should be based on the risk of contamination entering into the next stage of cleanroom.

254-260 Comment:

Disinfection of dedicated Grade D shoes should not be required. Suggest to use either overshoes or dedicated shoes

Proposed change (if any): re-word as follows: “A general protective suit and either area dedicated shoes or overshoes

should be worn.”

258-261 Comment:

The objective is to ensure appropriate measures in order not to bring contamination inside clean areas. Entry into

Grade C areas with facility dedicated shoes does not pose a risk of undue contamination. Furthermore, the

requirement for non -particle shedding garments in Grade C areas is not consistent with the non-viable particulate

limits (Grade C level classification) present in those areas. It is also not consistent with QRM principles since in those

areas there is no direct exposure of product or sterile product contact surfaces


b) Grade C: Hair, beards and moustaches should be covered. A single or two-piece trouser suit gathered at the wrists

and with high neck and appropriately disinfected or facility dedicated shoes or overshoes should be worn.


c) Grade A/B: Sterile headgear should totally enclose hair and facial hair; it should be tucked into the neck of the

sterile suit; a sterile face mask and sterile eye coverings should be worn to cover all facial skin and prevent the

shedding of droplets and particles. Appropriate sterilized, non-powdered rubber or plastic gloves and sterilized

footwear should be worn. Trouser-legs should be tucked inside the footwear and garment sleeves into the gloves. The

protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body.

Garments should be packed and folded in such a way as to allow operators to change into the garments with contact

to the outer surfaces of the garment reduced to a minimum.

Comment:

There is no mention of the use of gowning gloves nor under-suits which are essential in contamination control and are

used fairly ubiquitously.


b) Grade B: A dedicated single or two-piece under-suit should be worn. Sterilised outer garments (non-

shedding) must be donned for the manufacture of aseptically processed products. The single trouser suit,

gathered at the wrists and with a high neck, must provide total body coverage, such that the headgear must

fully enclose the hair and be tucked into the neck of the suit. Full face cover and eye protection must be

used to prevent the shedding of droplets. Eye protection equipment e.g. goggles, integral helmets and

glasses must be sterilised by suitable procedures. Sterilised non-powdered rubber gloves and sterilised

footwear must be worn with trouser legs tucked inside the footwear and garment sleeves into the outer

gloves (see below). The garments must be handled and donned, using a pair of sterilised gowning gloves,

such that they do not gather additional contamination and must shed virtually no fibres or particulate matter,

retaining particles shed from the body. Following gowning an additional pair of sterilised (outer) gloves

must be worn over the gowning gloves. Garments should be packed and folded in such a way as to allow

operators to change into the garments without contact to the outer surfaces of the garment and to help

prevent the garment touching the floor or other surfaces.

Comment (2)

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Line 270-272

“… with contact to the outer surfaces of the garment reduced to a minimum.” should be without contact to the outer

surfaces of the garment.

Comment (3):

Line 263: Headgear for consistency to be referred to as headwear and (as for other items of protective attire similarly

referenced throughout) it is more appropriate to refer to as being ‘sterilised’ and not as ‘sterile’ as any such sterilised

headwear is unlikely to have remained sterile during the donning process

Recommendation:

Change ‘sterile headgear’ to ‘sterilised headwear’

Comment (4):

Line 264: Data is available that confirms disinfection to be an effective process to reduce the surface concentration on

cleanroom goggles to very low levels and that the subsequent higher surface microbial concentrations recovered

during gowning qualification and on exit monitoring (from the aseptic processing area), occurs during the donning

process. Although sterilised goggles will have less surface microbial contamination than disinfected goggles, the

donning procedure will transfer more microbes than are residual on the goggles, regardless of whether they are

sterilised or disinfected. The air velocities present in cleanrooms are insufficient to remove such microbe-carrying

particles from the surface of goggles and so product contamination would only occur if product, or product contacting

surfaces, contacted the goggles. This is extremely unlikely and the risk of product contamination from microbes

present on the surface of goggles is extremely unlikely. Consequently, disinfection (with appropriate controls and

monitoring) should be considered as an acceptable method for to control surface microbial contamination on eye

coverings worn in grade A/B areas.

Recommendation

Change ‘sterile eye coverings’ to ‘sterilised or appropriately disinfected and controlled eye coverings:

Comment (5):

Line 265: The document states that face masks and eye coverings (like the other components of the gowning) should

be worn to prevent the shedding of droplets and particles. Shedding of droplets and particles will occur regardless of

the use of face masks and eye coverings but the function of these items is to control (but will not fully prevent) the

subsequent dispersal of such contaminants into the environment.

Proposed change:

Change ‘cover all facial skin and prevent the shedding of droplets and particles’ to ‘cover all facial skin and control

the dispersal of droplets and particles’.

Comment (6):

Line 266: Double gloving has been confirmed to be an effective control method to minimise the risk of product

contamination resulting from ruptured gloves. The use of double gloving should be suggested in the text.

Proposed change: Add ‘double gloving should be considered to minimise the risk of product contamination resulting

from ruptured gloves’.

275 Comment:

Dedicated socks is an excessive requirement and it would not improve contamination control.

276-279 Comment (1):

“Outdoor clothing” requires clarification as it will change depending upon the time of year.

Comment (2):

Clarification required on the purpose of the change room if cannot be used for outdoor clothing.

Comment (3):

Clarification on the use of socks e.g. what is the purpose of these and in what type room should these be donned.

Comment (4):

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Line 277: There are numerous methods that can be utilised in order to adequately control contamination in

changerooms leading to Grade B and C cleanrooms. If socks remain covered (e.g. by the use of dedicated shoes) in

such changerooms, the need for dedicated socks may not be appropriate.

Proposed change:

Change ‘It is recommended that facility suits, including dedicated socks, are worn before entry to change rooms for

Grade C and B’ to ‘It is recommended that facility suits (with consideration for dedicated socks where appropriate),

are worn before entry to change rooms for that access into Grade B and C cleanrooms’

281-284

Existing text:

4.14 For every worker in a grade A/B area, clean sterilized protective garments (including eye coverings and masks)

of an appropriate size should be provided at each work session. Gloves should be regularly disinfected during

operations. Garments and gloves should be changed at least for every working session.


4.14 For every worker in a grade B area, clean sterilized protective garments (including eye coverings and masks) of

an appropriate size as well as under garments should be provided at each work session. Gloves should be regularly

disinfected during operations. Garments and gloves should be changed at least for every working session.


4.15 Clean area clothing should be cleaned, handled and worn in such a way that it does not gather additional

contaminants which can later be shed. These operations should follow written procedures. Separate laundry facilities

for such clothing are desirable. Inappropriate treatment of clothing will damage fibres and may increase the risk of

shedding of particles. After washing and before sterilization, garments should be checked for integrity.


4.15 Clean area clothing should be cleaned, handled and worn in such a way that it does not gather additional

contaminants which can later be shed. These operations should follow written procedures. Separate laundry facilities

for such clothing are required. Inappropriate treatment of clothing will damage fibres and may increase the risk of

shedding of particles. After washing and before sterilization, garments should be visually checked for wear and

damage.


4.16 Activities in clean areas, especially when aseptic operations are in progress, should be kept to a minimum and

movement of personnel should be controlled and methodical to avoid excessive shedding of particles and organisms

due to over-vigorous activity. Operators performing aseptic operations should adhere to strict aseptic technique at all

times. To prevent changes in air currents that introduce lower quality air, movement adjacent to the critical area

should be restricted and the obstruction of the path of the unidirectional airflow must be avoided. The ambient

temperature and humidity should be set to prevent shedding due to operators becoming too cold (leading to excessive

movement) or too hot.


4.16 Activities in clean areas, especially when aseptic operations are in progress, should be kept to a minimum and

movement of personnel should be controlled and methodical to avoid excessive shedding of particles and micro-

organisms owing to over-vigorous activity. Operators performing aseptic operations should adhere to strict aseptic

technique at all times. To prevent adverse air currents that could introduce lower quality air into an adjacent critical

area, movement adjacent to the critical area should be restricted. The obstruction of the path of the unidirectional

airflow within Grade A zones must be avoided. The ambient temperature and relevant humidity should be specified,

maintained and monitored either to meet specific product requirements or to ensure operator comfort. Poor operator

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comfort can lead to increased contamination dissemination and an inability of personnel to concentrate on critical

tasks.

Comment:

Line 299-300: If stated that being too cold causes excessive movement, then it should also be stated that being too hot

may increase sweating and breach of gowning

Proposed change (if any):

Suggested to change the sentence as follows “The ambient temperature and humidity should be set to prevent

shedding due to operators not being comfortable”.

5. Premises

Comment:

This section should be earlier in the document as it defines Grades A-D. The section requires modification to improve

clarity, use correct and consistent terminology, and to correct errors.

Airlocks for personnel should also be referred to as gowning rooms.


5.2 The various operations of component preparation, product preparation and filling should be carried out with

appropriate technical and operational separation measures within the clean area.


5.2 The various operations of component preparation, product preparation and filling should be carried out with

appropriate technical and operational separation measures within the clean area to prevent mix-up and cross-

contamination.


5.3 For the manufacture of sterile medicinal products 4 grades of clean room can be distinguished.

General Comment:

Here and throughout the document the term “clean room” is used. Note cleanroom is a single word.


5.3 For the manufacture of sterile medicinal products 4 grades of classified clean areas are defined in this guidance.


Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making

aseptic connections. Normally, such conditions are provided by a localised air flow protection, such as laminar air

flow work stations or isolators. Unidirectional air flow systems should provide a homogeneous air speed in a range of

0.36 - 0.54 m/s (guidance value), the point at which the air speed measurement is taken should be clearly justified in

the protocol. During initial qualification and requalification air speeds may be measured either close to the terminal

air filter face or at the working height, Where ever the measurement is taken it is important to note that the key

objective is to ensure that air visualization studies should correlate with the airspeed measurement to demonstrate air

movement that supports protection of the product and open components with unidirectional air at the working height,

where high risk operations and product and components are exposed. The maintenance of unidirectional airflow

should be demonstrated and validated across the whole of the grade A area. Entry into the grade A area by operators

should be minimized by facility, process and procedural design.


Grade A: The local zone for high risk operations, e.g. filling zone, stopper hopper and feeder bowls, open ampoules

and vials, and making aseptic connections. Normally, such conditions are provided by localised unidirectional air flow

protection, such as an uni-directional air-flow work station, RABS or isolator. Unidirectional air flow systems should

provide a homogeneous air velocity across the plane perpendicular to the airflow direction. The typical air velocity in

a traditional uni-directional airflow clean zone is an average of 0.45 m/s+/- 20%. Lower average velocities may be

advantageous in isolators and closed RABS. In some isolator applications Grade A conditions can be maintained with

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non-unidirectional airflow. The plane at which the air velocity measurement is taken should be clearly justified in the

protocol. During initial qualification and requalification air velocities may be measured either close to the terminal air

filter face or at a defined test level. Where ever the measurement is taken it is important to note that the objective is to

ensure that air visualization studies should correlate with the air velocity measurement at a defined test plane level and

clearly demonstrate air movement that provides protection of the product and open components with unidirectional air

at the working height, where high risk operations and product and components are exposed. The maintenance of

unidirectional airflow should be demonstrated and qualified across the whole of the Grade A clean zone. Operators

must not enter the Grade A zone. Intervention access into the Grade A zone by operators should be minimized by

facility, process and procedural design

Comment (1)

Line 318: “Grade A : The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and

vials, making aseptic connections.” should be e.g. filling zone, stopper bowls, open primary containers (ampoules,

vials, syringes, cartridges…)....

Comment (2):

Line 321: The measurement of the unidirectional airflow (UDAF) velocity needs to be completed at a location that

when measured in the same manner will provide a consistent value that can be used to determine if there has been any

change. The UDAF passes round objects located in the working zone and creates an area that has little air movement

and so the velocity in these zones (near to product) is very low impractical to measure. Users may incorrectly specify

a higher velocity close to the exposed product which are not necessary to provide the required airflow and present

issues with airflow uniformity and increased energy costs. A distance of 15cm to 30cm from the filter face is

suggested in ISO 14644-3 (Test methods).

Alternative Proposed text change:

Unidirectional airflow should be provided in the critical area. During qualification and re-qualification the airflow

velocity should be measured at several locations to demonstrate a uniform velocity across the filter face and should be

measured 15 to 30cm from the filter face. Airflow visualisation should also be completed to demonstrate that air

movement is unidirectional.

Comment (3):

Line 330-331: Entire Grade A area must be studied with airflow visualization studies.

Clarify the meaning of …across the whole of the Grade A area”

Proposed change (if any): delete ‘whole.

Comment (4):

Line 331 & 815, 839: ‘Entry into grade A area by operators…’Regulatory authority guidance has previously

stated that the zone cannot be considered to be Grade A if personnel are present within the zone.

Alternative Proposed Change: Clarification is needed on terminology, e.g. Grade A zones that operators

enter to be termed localised unidirectional airflow (L-UDAF) or appropriate similar term.

General comment:

Throughout the document the term “laminar flow” is used. The definition of laminar airflow is provided in the

Glossary section (line 2177). According to this definition, the airflow moves in a single direction and in parallel layers

at constant velocity to the end of a straight line vector. This is not possible and the term unidirectional flow (UDAF) is

more accurate.

Proposed change: Change ‘laminar air flow’ to ‘unidirectional airflow (UDAF)’


Lower grades can be considered where isolator technology is used (refer to clause 5.19-5.20).

Comment:

This lacks clarity, please define precisely which background grades should be used.


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5.4 In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to minimize the

shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agents,

and disinfectants, where used.


5.4 In classified cleanroom areas and clean zones, all exposed surfaces should be smooth, impervious and unbroken in

order to minimize the shedding or accumulation of particles and micro-organisms and to permit the repeated

application of cleaning agents, and disinfectants, where used.

Comment:

Line 345: No description or glossary entry to explain the difference between cleaning agent and disinfectant.

Alternative Proposed Change: Include additional definitions in glossary for; Cleaning Agent (Chemical solution used

for the removal of fat based particulates), Disinfectant (Chemical agent used for the destruction of microorganisms)


5.5 To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum

of projecting ledges, shelves, cupboards and equipment. Doors should be designed to avoid uncleanable recesses.


5.5 To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum

of projecting ledges, shelves, cupboards and equipment. Doors should be designed to avoid uncleanable recesses,

open only to the higher grade and be mechanically self closing.


5.8 Sinks and drains should be prohibited in grade A/B areas. In other areas air breaks should be fitted between the

machine or sink and the drains. Floor drains in lower grade rooms should be fitted with traps or water seals to

prevent back flow and should be regularly cleaned and disinfected.


5.8 Sinks and drains are prohibited in Grade A and B areas. In other areas air breaks should be fitted between the

machine or sink and the drains. Drains in lower grade rooms should be fitted with water traps to prevent back flow

and should be regularly cleaned and disinfected.

361-367 Comment:

Definition needed for ‘flushed’, does this mean to remove the area from particulate?

Existing text:

5.9 Airlocks should be designed and used to provide physical separation and to minimize microbial and particulate

contamination of the different areas, and should be present for material and personnel moving from different grades,

typically airlocks used for personnel movement are separate to those used for material movement. They should be

flushed effectively with filtered air. The final stage of the airlock should, in the at-rest state, be the same grade as the

area into which it leads. The use of separate changing rooms for entering and leaving clean areas is generally

desirable.


5.9 Airlocks should be designed and used to provide physical separation between areas of different Grade, to maintain

pressure differentials and to minimize microbial and particulate contamination transfer between different areas.

Personnel airlocks (PAL or gowning room) should be separate from those used for material transfer. They should be

flushed effectively with filtered air. The final stage of the airlock should, in the at-rest state, be the same grade as the

higher graded area with which it interfaces. By first intent separate changing rooms should be used for entering and

leaving clean areas. Where this is not possible the removal of gowns must not take place in the same area where fresh

sterile gowns are put on.

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Clarification required on cascade from D to C; this sentence details that this ‘should’ be performed; recommend that

the sentence clarifies if this is or is not required. The cascade and use of Grades should form part of site cross

contamination RA and the selected design of area should be justified.

Proposed change (if any): Recommendation is that the Eg as per section b, part iii below (lines 390-392).

Existing text:

a) Personnel airlocks. A cascade concept should be followed for personnel (e.g. from grade D to grade C to grade B).

In general hand washing facilities should be provided only in the first stage of the changing rooms.


a) Personnel airlocks. A cascade concept should be followed for personnel ( from Grade D to Grade C to Grade B). In

general hand washing facilities should be provided only in the first stage of changing rooms. Hand washing facilities

incorporating water should not be installed within Grade B PALs. Topical disinfection of gloved hands should be

used in Grade C and B PALs.

Comment:

Line 369: Jumping of grades in personnel airlock cascades seems to be not allowed

Proposed change (if any): recommend add ‘generally a cascade concept should be followed’


i. Pass through hatches without active filtered air supply should be avoided. If necessary, provisions and procedures

should be in place to avoid any risk of contamination (e.g. by the incoming material or by entering air).


Material airlocks and pass through hatches must be configured to prevent transfer of contamination from the less clean

to the cleaner area. The use of active filtered air supply should be considered. Provisions and procedures should be in

place to prevent contamination transfer on materials or in the air.


ii. For airlocks leading to grade A and B areas, only materials and equipment that have been included as part of the

qualification list should be allowed to be transferred into the grade A/B area via the air lock or pass through; the

continuity of grade A should be maintained in the aseptic core when the materials have to be transferred from grade B

to grade A areas, consideration should be given to listing these items on an authorized list. Any unapproved items that

require transfer should be an exception. Appropriate risk evaluation and mitigation strategies should be applied and

recorded as per the manufacturer's contamination control strategy and should include a specific sanitisation and

monitoring regime approved by quality assurance.


ii .For airlocks leading to Grade A and B areas, only materials and equipment that have been included on a

qualification list should be allowed to be transferred into the Grade A clean zones or Grade B cleanrooms area via an

air lock or pass through hatch. The continuity of grade A should be maintained in the Grade A aseptic core when the

materials are in transit through the Grade B cleanroom to the grade A zone. Any unapproved items that require

transfer should be an exception. Appropriate risk assessment and mitigation measures should be applied and recorded

as per the manufacturer's contamination control strategy and should include a specific sanitisation and monitoring

regime approved by quality assurance.

Comment (1):

The continuity of Grade A is an important aspect of aseptic control and is often required by regulators. This is the only

area of the entire document in which it is mentioned. It also doesn’t appear in the glossary.

Comment (2):

Line 383: “… transferred from grade B to grade A areas, ...” should be … transferred from lower grades to grade A

areas, …

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Line 388: There is no definition of ‘sanitisation’ provided in the Glossary section (line 2177) and

disinfection is a more appropriate term that is included in the Glossary section.

Proposed change:

Change ‘sanitisation’ to ‘disinfection’.


iii. The movement of material from clean not classified (CNC) to grade C should be based on QRM principles, with

cleaning and disinfection commensurate with the risk.


iii. The movement of material from clean not classified (CNC) to Grade C cleanrooms should be based on QRM

principles, with cleaning and disinfection applied commensurate with the risk.

Comment:

Line 390: CNC is defined by the International Society for Pharmaceutical Engineering (ISPE) as ‘controlled not

classified’. To use the same abbreviation (CNC) to define an area that is ‘clean not classified’ will be confusing. It

would be more appropriate to utilise the current ISPE definition of CNC (a cGMP manufacturing area designed to

produce a consistent and controlled environment but not necessarily monitored to a given environmental

classification) or use an alternative acronym for an area that is to be defined as clean not classified.

Proposed change:

Change ‘CNC’ to controlled not classified and include the ISPE definition of CNC in the Glossary section (line 2076).


5.10 Both airlock doors should not be opened simultaneously. The opening of more than one door at a time should be

prevented, for airlocks leading to grade A and B an interlocking system should usually be used; for airlocks leading to

grade C and D at least a visual and/or audible warning system should be operated. Where required to maintain zone

segregation, a time delay between the closing and opening of interlocked doors should be established.

Comment (1):

Replace wording “grade C and D” with Grade C and D cleanrooms. Also remove word “usually” on Line 396.

Comment (2):

Line 397: The airborne cleanliness levels within airlocks is directly related to the rate of volume air supply into the

airlock and the rate of dispersal of contamination within the airlock. If the rate of volume air supply is sufficiently

high and the dispersal is well controlled, the operational airborne cleanliness levels will be maintained at sufficiently

low levels that may not require a time delay to prevent the transfer of contamination into the zone of highest

cleanliness.

Proposed change:

Change ‘When required to maintain zone segregation, a time delay between the closing and opening of interlocked

doors should be established’ to ‘When required to maintain zone segregation, adequate airborne cleanliness levels

should be maintained throughout operation or a time delay between the closing and opening of interlocked doors

should be established’


5.11 A HEPA or ULPA filtered air supply should maintain a positive pressure and an air flow relative to surrounding

areas of a lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of

different grades should have a pressure differential of 10 - 15 Pascals (guidance values). Particular attention should

be paid to the protection of the zone of greatest risk, that is, the immediate environment to which a product and

cleaned components which contact the product are exposed. The recommendations regarding air supplies and

pressure differentials may need to be modified where it becomes necessary to contain some materials, e.g. pathogenic,

highly toxic, radioactive or live viral or bacterial materials or products. Decontamination of facilities, e.g. the clean

rooms and HVAC, and the treatment of air leaving a clean area may be necessary for some operations.

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5.11 A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower

grade under all operational conditions and should flush the area effectively. Terminal HEPA filters should be used for

Grade A clean zones, Grade B and C cleanrooms and should as a minimum be H14 filters to EN1822. Terminal filters

used in Grade A, B, and C areas should be periodically in-situ leak tested in accordance with ISO 14644-3. Adjacent

cleanrooms of different grades should have a pressure differential of 10 - 15 Pascals (guidance values). Particular

attention should be paid to the protection of the zone of greatest risk, that is, the immediate environment to which a

product and cleaned and sterilised components which contact the product are exposed. The recommendations

regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some

materials, e.g. pathogenic, highly toxic, radioactive, live viral or bacterial materials or products. Decontamination of

facilities, e.g. the cleanrooms and HVAC, and the treatment of air leaving a clean area may be necessary for some

operations.

Comment:

Line 400: HEPA filters at 95 % efficiency will remove all microbe-carrying particles from supply air and a HEPA

filter (H14, reference to EN 1822, 2005) will remove all particles ≥0.5µm and so unless there is a particular

requirement, ULPA filters will achieve no extra reduction in the concentration of airborne contamination in the air

supplied to a cleanroom or workstation. ULPA filters require a much higher differential pressure, with more energy

consumption and noise and more frequent replacement.


Add ‘Unless there is a need to remove particles from the supply air that are smaller than ≥0.5µm, HEPA filters are

sufficient to remove all airborne contamination from the air supply, and the use of ULPA filters is not necessary.


5.12 It should be demonstrated that air-flow patterns do not present a contamination risk, e.g. care should be taken to

ensure that air flows do not distribute particles from a particle- generating person, operation or machine to a zone of

higher product risk. Air flow patterns should be visualised in grade A/B areas to evaluate if airflow is unidirectional.

Where unidirectional air flow is not demonstrated, corrective actions, such as design improvements, should be

implemented. In the other areas, the need to demonstrate the air flow patterns should be based on a risk assessment.

Air flow pattern studies should be performed under dynamic conditions. Video recordings of the airflow patterns are

recommended. The outcome of the air visualisation studies should be considered when establishing the facility's

environmental monitoring program.

Comment (1):

Line 415 : Change “A/B” to “Grades A and B” and change “evaluate” to “confirm”. Airflow patterns should be

carried out in both the static and dynamic condition and must include operator interventions. Video recordings must

be carried out and retained.

Comment (2):

Note some companies do not think it is possible to perform dynamic airflow visualisation studies in CRABS or

isolator lines.

Comment (3):

Line 415: “Air flow patterns should be visualised in grade A/B areas to evaluate if airflow is unidirectional...” should

include in operation including environmental monitoring such as volumetric air sampling.

Comment (4):

Line 415-418: There is no requirement to have unidirectional airflow in Grade B.

Need of risk assessment for other areas (C/D) in order not to perform smoke studies.


The requirement of unidirectional airflow should be for Grade A only.

Comment (5):

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Line 412-421: Not all grade A and B areas should require airflow pattern testing (as not all those areas

possess unidirectional airflow). As written the requirement would restrict the use of suitable alternatives in

the case where airflow pattern test is not physically possible (e.g. depyrogenation tunnel).


5.12 It should be demonstrated that air-flow patterns do not present a contamination risk, e.g. care should

be taken to ensure that air flows do not distribute particles from a particle generating person, operation or

machine to a zone of higher product risk. Air flow patterns should be visualised in all unidirectional

airflow areas and at the interface with areas directly adjacent to these (e.g. in critical Grade A/B

processing areas). Where unidirectional air flow is not demonstrated, corrective actions, such as design

improvements, should be implemented. In the other areas, the need to demonstrate the air flow patterns

should be based on a risk assessment. Air flow pattern studies should be performed under dynamic

conditions. Video recordings of the airflow patterns are recommended. Alternatively, simulations may be

used to demonstrate adequate airflow. The outcome of the air visualisation studies should be considered

when establishing the facility's environmental monitoring program. Comment (6):

Line 415: Grade B areas are unlikely to have unidirectional airflow and therefore assessment of unidirectional airflow

in Grade B areas is an unlikely scenario. Not all Grade A zones may have unidirectional airflow (consider a closed

isolator where non UDAF air supply can be acceptable). Proposed Change:

The evaluation of unidirectional airflow should be visualised in those zones that are supplied with unidirectional

airflow.


5.13 A warning system should be provided to indicate failure in the air supply and reduction of pressure differentials

below set limits. Indicators of pressure differences should be fitted between areas, based on QRM principles. These

pressure differences should be recorded regularly or otherwise documented.

Comment:

A warning system MUST be provided. Pressure differences must be monitored continuously and documented.


5.14 Consideration should be given to designing facilities that permit observation of activities from outside the clean

areas, e.g. through the provision of windows or remote camera access with a complete view of the area and processes

to allow observation and supervision without entry.


Facilities should be designed to permit observation of activities from outside the clean areas, e.g. through the

provision of windows or remote camera vision with a complete view of the area and processes to allow observation

and supervision without entry

434 Barrier Technologies

General comment:

Prefer the use of “bio-decontamination” rather than “disinfection”.

Comment:

The following text should be added BEFORE Line 435

Proposed text

By first intent barrier technology such as Isolators and Restricted Access Barrier Systems (RABS) should be

employed to ensure adequate separation of the Grade A zone from both operators and the surrounding environment.

This is to reduce the need for interventions into the grade A environment and to minimize the risk of contamination.

Automation of processes should also be considered to remove the risk of contamination by interventions (e.g. dry heat

tunnel, automated lyophilizer loading, SIP). The absence of such technology may be acceptable in exceptional

circumstances provided there is sufficient control and evidence of the maintenance of Grade A integrity and that the

general principles for RABS are applied

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438-439 Comment:

“… and therefore the entry of additional materials following sterilisation should be minimized” Does that mean that

only sterilized materials can be introduced inside the RABS or isolator? This is not in accordance with filling

technologies using tubs of RTU syringes or vials since 5 to 10 tubs are introduced every minute, most of the time

without any individual integrity check of the packaging.


5.17 The critical zone of the RABS or isolator used for aseptic processes should meet grade A with unidirectional air

flow. Under certain circumstances turbulent airflow may be justified in a closed isolator when proven to have no

negative impact on the product. The design of the RABS and open isolators should ensure a positive airflow from the

critical zones to the surrounding areas; negative pressure isolators should only be used when containment of the

product is considered essential.

Comment (1):

The critical zone comment should cross reference section 5.3. Note that turbulent flow may be necessary for effective

fumigation of closed isolators.

Comment (2):

Line 450: Unidirectional and non-unidirectional airflow are both turbulent airflows and the term non-

UDAF is the correct term referenced in the ISO 14644 series of standards. Proposed change (if any):

Replace (throughout) ‘turbulent airflow’ with ‘non-unidirectional airflow’ (non-UDAF).


5.18 For RABS, the background environment should meet grade B. For open RABS, or where doors may be very

rarely opened during processing, and studies should be performed to demonstrate the absence of air ingress.

Proposed text:

5.18 For RABS, the background environment must be a minimum of Grade B. For open RABS, or where doors may

be very rarely opened during processing, airflow studies should be performed to demonstrate the absence of air

ingress.

Comment:

“For open RABS, or when doors may be very rarely open during processing” what is very rarely? The doors of RABS

must never be open during processing, all interventions should be performed through the gloves of the RABS

otherwise this not a barrier technology.


5.19 For open, positive pressure isolators or closed isolators with decontamination by a sporicidal agent, the

surrounding area should correspond to a minimum of grade D. The disinfection regime should be included as a key

consideration when performing the risk assessment to design the contamination control strategy for an isolator.

Comment:

Minimum background for isolators should be Grade C.


5.20 For isolators, the required background environment can vary depending on the design of the isolator, its

application and the methods used to achieve bio-decontamination. The decision as to the supporting background

environment should be documented in a risk assessment where additional risks are identified, such as for negative

pressure isolators. Where items are introduced to the isolator after disinfection then a higher grade of background

should be considered.

Comment (1):

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Regulatory expectation should be clearly given here as to the required grade for isolators to ensure consistency of

approach. Note that for isolators used for filling operations, fresh sterilised stoppers are frequently added AFTER bio-

decontamination using RTPs.

Comment (2):

Definition required for higher grade of background.

Comment (3):

Line 465: How does this statement match the statement at paragraph 5.19 which states that “ For open, positive

pressure isolators or closed isolators with decontamination by a sporicidal agent, the surrounding area should

correspond to a minimum of grade D”?

Proposed change (if any): Ensure consistency of the 5.19 and 5.20 requirements.

Comment (4):

Line 466: Definition for bio-decontamination is required in the glossary.


5.21 Glove systems, as well as other parts of an isolator, are constructed of various materials that can be prone to

puncture and leakage. The materials used shall be demonstrated to have good mechanical and chemical resistance.

Integrity testing of the barrier systems and leak testing of the isolator and the glove system should be performed using

visual, mechanical and physical methods. They should be performed at defined periods, at a minimum of the

beginning and end of each batch, and following any intervention that may affect the integrity of the unit.

Proposed text change




visual, mechanical and physical methods. They should be performed at defined periods, at a minimum of the

beginning and end of each batch, unless otherwise justified as in campaign processing and following any intervention

that may affect the integrity of the unit. Glove systems for RABS should be subject to visual checks to confirm their

integrity

Comment (1):

Is the leak testing at the beginning and end of processing to be applied just to gloves OR both gloves and isolator?

Comment (2):

The testing per batch should not be an absolute requirement – instead this should be based on risk to the process and

to ensure that the testing encompass all batches impacted.

Comment (3):

Line 472: Glove testing using physical methods, performed at the beginning and end of each batch, is not the common

Industry practice. Frequency be based on a risk assessment.

The difference between mechanical and physical methods is not clear. Should three checks (visual, mechanical,

physical) be performed each time?

Allow to establish the frequency of glove testing based on a risk assessment.

Clarify the difference between mechanical and physical methods and if three checks (visual, mechanical, physical)

should be performed each time

Comment (4):

There are several designs for RABS and Isolators, and while integrity testing using mechanical, physical and visual

methods is appropriate, they should not be required at the same frequency. QRM should be used to justify the

frequency for each.





visual, mechanical or physical methods. They should be performed at defined periods, as determined by a quality risk

assessment of the process. A visual check should be performed at the beginning and end of each batch, and following

any intervention that may affect the integrity of the unit.

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Comment (5):

Line 476: Integrity testing of the gloves systems should confirm the integrity of batches pre and post manufacture but

the frequency of the integrity testing should be established from operational performance. This may indicate that

testing at the beginning and end of each batch may not be required with the derived testing frequency utilised to

confirm the gloves systems integrity for a number of batches.

Proposed change:

Change ‘They should be performed at defined periods, at a minimum of the beginning and end of each batch, and

following any intervention that may affect the integrity of the unit’ to


5.24 Clean rooms and clean air devices should be qualified in accordance with Annex 15 of EU GMP. Reference for

the classification of the clean rooms and clean air devices can be found in the ISO 14644 series of standards.


5.24 Clean rooms and clean air devices should be qualified in accordance with Annex 15 of EU GMP. Reference for

the classification of the clean rooms and clean air devices can be found in the ISO 14644 series of standards. This

standard provides the basis for determining the minimum number of sampling locations (evenly distributed), the

minimum air sample size at each location, and the method for evaluating the data. It assumes simple areas without

complexities of processes, equipment, and personnel. In order to accommodate the infinite variety of operational

cleanrooms and clean zones, the standard allows additional risk-based locations to be added.

501 Comment (1):

5µm removed for classification purposes, but left in for monitoring. From a practical perspective, it would not seem

sensible to leave it out of classification activities when it is required for routine monitoring.

Comment (2):

Line 501 & 1653: For routine monitoring, airborne particle concentrations at both >0.5μm and >5μm particle sizes is

required. The ratios of ≥0.5μm and ≥5μm particles to microbe carrying particles (MCPs) have been established by

experiment and has demonstrated that if the requirement for ≥0.5μm particles and airborne microbial counts should be

complied with, the limit required for particles ≥5μm is too low and for each cleanroom grade, the limit for ≥5μm

particles should be increased by a factor of 10. Consequently, particle generating events in cleanroom areas will

produce particle counts that, although compliant with the class limits for ≥0.5μm particles and MCPs, may exceed the

class limit for ≥5μm particles. Therefore, for classification, airborne particle concentrations at both >0.5μm and >5μm

particle sizes should be undertaken.


If the requirement to monitor particles at >5µm is to remain (see 1653 and 1705), replace the existing with ‘For

classification, the airborne particles equal to or greater than 0.5µm and 5µm should be measured’

505 Comment (1):

Table 1: Maximum permitted airborne particle concentration during classification, indicates that classification should

be undertaken in the “in operation” state. Clarification is needed as classification is usually performed “at rest” and

monitoring is performed “in operation”

Comment (2):

Typo in Table I: The last column header should be “ISO classification at rest/in operation” instead of “ISO

classification in operation/at rest”

Comment (3):

The recommended maximum limits for particles is not harmonised with the limits defined in the reference document

EN ISO 14644-1(2015).

Proposed change:

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Harmonise the recommended maximum limits for particles defined in Table 1 with the limits defined in EN ISO

14644-1(2015)

.

510-517 Existing Text:

5.26 For initial classification the minimum number of sampling locations can be found in ISO 14644 Part 1. However,

a higher number of samples and sample volume is typically required for the aseptic processing room and the

immediately adjacent environment (grade A/B) to include consideration of all critical processing locations such as

point of fill stopper bowls. With the exception of the aseptic processing room, the sampling locations should be

distributed evenly throughout the area of the clean room. For later stages of qualification and classification, such as

performance qualification, locations should be based on a documented risk assessment and knowledge of the process

and operations to be performed in the area.


5.26 For basic cleanroom and clean zone classification, the minimum number of sampling locations can be found in

ISO 14644 Part 1. In Grade B aseptic processing rooms, and critical Grade A zones, a higher number of sampling

locations is typically required to assess critical processing locations. For Grade B aseptic processing rooms an

example of an additional sampling location is the region immediately adjacent to open door intervention access into

Grade A clean zones or RABS; and for the critical Grade A zone the point of loading stopper hoppers, where stoppers

or other sterilised components are exposed in feeding systems, the point of fill of containers, and stopper placement

station. For other Grades of cleanroom, the sampling locations should be distributed evenly throughout the area of the

cleanroom as described in ISO 14644-1. For later stages of qualification and classification, such as performance

qualification, locations should be based on a documented risk assessment and knowledge of the process and

operations to be performed in the area


b) The definition of "at rest" is the room complete with all HVAC systems, utilities functioning and with

manufacturing equipment installed as specified but without personnel in the facility and the manufacturing equipment

is static.

Comment:

Add the following, “The “at rest” state provides an important performance reference datum for cleanrooms and clean

air devices”.

Comment:

Line 522-527: Add definitions of at rest and in operation to glossary section.


e) The particle limits given in Table 1 above for the "at rest" state should be achieved after a "clean up" period on

completion of operations. The "clean up" period should be determined during the initial classification of the rooms.


e) The particle limits given in Table 1 above for the “at rest” state should be achieved after a “clean-up” period of 10-

15 minutes (guidance value) on completion of operations. The "clean-up" period should be determined during the

qualification of the cleanrooms, and is an essential mechanism for determining the ventilation effectiveness of the

cleanroom HVAC system. ISO 14644-3, ISO 14644-4 and ISO 14644-16 contain information, guidance and test

methods on air change rate effectiveness, recovery time and its measurement.

Comment (1):

Line 534: 5.26 e) The method for the determination of the “clean up” period should be indicated such as following

ISO 14644-3 B12.

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Comment (2):

The "clean up" period should be initially determined during the initial classification of the rooms and modified as

necessary under worst case conditions

Proposed change (if any): Include a definition of “clean up period” in the glossary.

Comment (3):

Line 533 & 1655: The most appropriate scientific method to determine the ‘clean up’ rate is defined in ISO 14644-3:

2005 as the ‘Recovery Test’ (section B12.3). Further detail on the correct application of this method for EU GMP

cleanrooms has been published, including measurement at the >0.5μm particle size. No time is specified in order to

achieve clean up and so poor ventilation effectiveness is acceptable as long as the poor results are repeatable. A

minimum time must be included in the ‘clean up’ test if the test has any relevance.

Proposed change:

Include ‘An appropriate test method can be found in ISO 14644 Part 3’. A guidance time similar to the existing annex

(15 to 20 minutes) to be added


f) In order to meet "in operation" conditions these areas should be designed to reach certain specified air-cleanliness

levels in the "at rest" occupancy state.

Comment:

[Note: This is an error! Just meeting the “at rest” level doesn’t mean that the “in operation” will be achieved. The

ability to meet the “in operation’ level of cleanliness is determined by the ability of the unidirectional or non-

unidirectional airflow system to displace or dilute the contamination source].

[Note could “at rest occupancy state” be defined? Is it the same as “at rest”, but with people present?]


f) In order to meet “in operation” conditions these areas should be designed to reach certain specified air-cleanliness

levels in the “at rest” occupancy state, and for the unidirectional or non-unidirectional airflow system to displace or

dilute the contamination source effectively.

540 Comment:

5.27 Should be “The microbial load of the clean rooms should be determined as part of the clean room qualification

considering both environmental and human origins of micro-organisms.

544 Existing text:

Table 2: Recommended limits for microbial contamination in operation.

Comment:

Replace “limits” with “levels”.

For Grade A the value should be <1 in the table for note (b) to be valid.

The table is reproduced, more comprehensively in section 9. Suggest having full table here. The table could then be

referenced in section 9. This would also negate the need for Lines 552 to 553.

Comment:

Table 2 and line 1746 Table 6. Action limits instead of recommended maximum limits and maintain <1 instead of 1

for grade A. Add swab to contact plates and cfu/plate or swab.

- It should be indicated that the viable monitoring incubation programme should be justified as for APS in lines 1928-

1930

Comment:

Only contact plates are mentioned for qualification of microbial contamination of surfaces. It is not clear how limits

should be calculated when swabs are used.

Comment: More clarification on Table II. Do we need settle plates in the Grade D?

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Proposed change (if any): ensure consistency between 5.27 and table II. Does this refer to qualification or in

operation?


(a) Individual settle plates may be exposed for less than 4 hours. Where settle plates are exposed for less than 4 hours

the limits in the table should still be used, no recalculation is necessary. Settle plates should be exposed for the

duration of critical operations and changed as required after 4 hours.

Comment:

Note (a) should only apply to Grade A plates.

Comment:

Sentence asks for 4 hours but for high air change systems, plate change may be less than 4 hours but the annex does

not address this.

548 &1751 Comment:

The principles section of the draft Annex 1 encourages companies to use modern methods and apply QRM principles.

It also states that for environmental monitoring ISO14644 should be looked to for method guidance. It is therefore

inconsistent to cite a single methodology as the only appropriate solution. Furthermore, the alternative methodologies

may not be able to express results in the exact same units as cited in the Annex.

Proposed Change:

Add a note to Tables 2 and 6 in the Annex to state that “Alternative methods for sampling are acceptable, as long as

validated for the intended use and appropriate limits can be applied”.

552 Comment:

For gown qualification is it A or B limits that should be applied


5.29 Clean rooms should be requalified periodically and after changes to equipment, facility or processes based on

the principles of QRM. For grade A and B zones, the maximum time interval for requalification is 6 months. For

grades C and D, the maximum time interval for requalification is 12 months.

Comment (1)

The scope of the requalification testing should be clearly defined. Does it refer to cleanroom and clean zone particle

counting or standard 6 or 12 monthly filter integrity checks, air velocities and pressure differential checks?

Note these intervals may be extended, subject to comprehensive risk assessment, when system performance and

environmental monitoring systems, and historical qualification data indicate frequencies are excessive.

Comment (2)

Cleanrooms should be operated and maintained relating to process and products’ risks; the design and operation of the

cleanrooms including e.g. HVAC, cleanliness grade, maximum occupancy states, cleaning/disinfection/sanitization

regimens etc. should be covered by the contamination control strategy. Since cleanrooms are under continuous control

with data obtained from environmental monitoring programs (viable and non-viable monitoring data) and

building/facility monitoring systems (e.g. differential pressures, temperature and humidity), reliable data is already

available to ensure proper function and compliance of the cleanrooms during their operational conditions. Any changes

to the cleanrooms and processes (as e.g. introduction of new equipment) would require a re-evaluation of the cleanroom

processes per the current Quality Risk Management systems, and most often include requalification activities. When

there are no changes to the qualified status and operations in a cleanroom, compilation and trending of data is sufficient

to detect issues related to the hygienic standards and no specific requalification should be required other than the regular

integrity testing of HEPA-filters.

Many cleanrooms are uninterrupted operational, including monitoring and control. Re-qualifying the cleanrooms in

accordance to the ISO standards ‘at rest’ conditions, would not only be providing no additional insight into the status

of the cleanroom, but also lead to not justified production interruptions.


Clean rooms should be requalified after changes to equipment, facility or processes, based upon the principles of QRM.

In addition, all data obtained from continuous and regular monitoring of manufacturing cleanrooms should be

periodically compiled and trended, on a minimum of an annual basis, to provide ongoing evidence of the intended

cleanliness status.

Comment (3)

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This section is unclear as to what is meant by clean room requalification. The section deals with both HVAC

qualification as well as cleanroom classification and the requirement is located just below the area classification

section. Clarify the sentence to indicate that it is HVAC system requalification that is intended. As the frequency of

monitoring in grade A and B is high, an additional EMPQ every six months will not provide significant additional

data for the investment required. Furthermore, Annex 1 should avoid citing a specific frequency and rely on the ISO

standard as it has in several previous sections.

Proposed Change:

5.29 Clean rooms HVAC systems should be requalified periodically and after changes to equipment, facility or

processes based on the principles of QRM and ISO14644. The rationale for the frequency of requalification should be

documented.

Comment (4):

Line 558: The tests needed to qualify and requalify a cleanroom need to be specified. In addition to classification, the

minimum tests needed to ensure that a cleanroom or workstation functions correctly are the measurements of rate of air

supply or UDAF velocity, filter system integrity and pressure differentials which should be specified.


Add ‘as a minimum, the following tests should be carried out: particle concentration (classification), rate of air supply

or UDAF velocity, filter system integrity and pressure differentials.

Comment (5):

Line 559: The frequency of cleanroom requalification should be risk based. Where the installation is equipped with

instrumentation for continuous or frequent monitoring (e.g. airborne particle concentrations, unidirectional airflow

velocity, room air change rate, differential pressure etc.) and operational monitoring (e.g. microbial air sampling, settle

plates, surface sampling etc.) is completed and other key test parameters (e.g. air supply velocities, room air change

rate, extract velocities, airflow visualisation etc.) are frequently measured or verified by independent testing companies,

the maximum time intervals for requalification can be extended. Guidance on testing frequencies is available in BS EN

ISO 14644 Part 2.

Proposed change:

Change ‘For grade A and B zones, the maximum time interval for requalification is 6 months. For grades C and D, the

maximum time interval for requalification is 12 months’ to ‘The frequency of requalification should consider the level

of continuous or frequent monitoring, the level of operational monitoring and other scheduled measurement of key

contamination control parameters’


5.30 Other characteristics, such as temperature and relative humidity, depend on the product and nature of the

operations carried out. These parameters should not interfere with the defined cleanliness standard.

Comment:

Suggest that recommended ranges for temperature and humidity are given e.g. 19+/-2°C and 45 to 50% r.h.

567 Comment:

Change title of section to “Cleaning and Disinfection”.

569-578 Comment (1):

The proposed revision clarifies that a minimum of two agents are required, and that one needs to be a

sporicidal agent – original sentence could be misconstrued as indicating 2 disinfecting agents plus a third

sporicidal agent.

Proposed Change:

5.31 The disinfection of clean areas is particularly important. They should be cleaned and disinfected

thoroughly in accordance with a written programme (for disinfection to be effective, cleaning to remove

surface contamination must be performed first)., More than one type of disinfecting agent should be

employed, one of which being a sporicidal agent to be used periodically. Disinfectants should be shown to

be effective for the duration of their in-use shelf-life taking into consideration appropriate contact time and

the manner in and surfaces on which they are utilized. Monitoring should be undertaken regularly in order

to show the effectiveness of the disinfection program and to detect the development of resistant and/or

spore forming strains. Cleaning programs should be effective in the removal of disinfectant residues.

Comment (2)

Line 572: The need to utilise more than one type of disinfectant, if a sporicidal agent is periodically used, is dependent

upon the mode of action of the disinfectant. If the mode of action is completed by bacterial cell wall/membrane, and

not by passive diffusion, resistance is unlikely.

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Proposed change:

Change ‘More than one type of disinfecting agent should be employed’ to ‘depending on the mode of action of the

disinfectant agent, more than one type of disinfection agent should be considered’

Comment (3):

Line 575: Organisms do not develop resistance to disinfectants like they do to antibiotics. The application and

chemical agent may not be effective vs this spore former.

Proposed change (if any): Recommend change “…development of resistant…” to “…Detect the appearance of new or

spore forming strains”

580 Comment:

Clarify if it is intended only for in house dilutions, not for ready to use disinfectants with a defined expiration date.

Recommended change: “Non-sterile Disinfectants and detergents used for C and D areas should be monitored for

microbial contamination…An in- use period should be determined.”


5.33 Disinfectants should be shown to be effective when used on the specific facilities, equipment and processes that

they are used in.

Comment:

More detail on regulatory expectation is required here.


5.34 Fumigation or vapour disinfection of clean areas such as Vapour Hydrogen Peroxide (VHP) may be useful for

reducing microbiological contamination in inaccessible places.

Comment:

This text seems to underplay the importance of these agents in the validated, automated decontamination of properly

prepared, cleaned Grade A Isolator environments. The text may prompt readers to abandon this type of proven

technology and adopt manual processes which by their nature cannot be reliably validated. Also VHP is described as

useful for reducing microbiological contamination in accessible places - need clarification as later in the annex VHP

is described as bio-decontaminant (Conflicting definitions) bio-decontamination not referenced in the glossary

6 Equipment

General Comment:

Consider integrating equipment from other sections into this.

General improvements and clarification are required in this section.

Many will believe this relates to unitary equipment, when actually it related also to bespoke process systems

592 Comment:

The following should be added:- “In this section, the term equipment is intended to include both items of unitary

equipment, pre-engineered skid mounted systems, and in-situ assembled and build processing systems”.


6.1 A written, detailed description of the equipment design should be produced (including diagrams as appropriate)

and kept up to date. It should describe the product and other critical gas and fluid pathways and controls in place


6.1 A written, detailed description of the equipment design shall be produced (including diagrams as appropriate) and

kept up to date throughout the life-cycle of the equipment. It should describe the product and other critical gas and

fluid pathways and their controls.


6.2 Equipment monitoring requirements should be determined during qualification. Process alarm events should be

reviewed and approved and evaluated for trends


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6.2 Equipment monitoring requirements should be defined during the design, and the operation and performance

confirmed during qualification. Process alarm events should be reviewed, and appropriate actions taken. They should

also be evaluated for trends.


6.3 As far as practicable equipment, fittings and services should be designed and installed so that operations,

maintenance, and repairs can be carried out outside the clean area, if maintenance has to be performed in the clean

area then precautions such as additional disinfection and additional environmental monitoring should be considered.

If sterilization is required, it should be carried out, wherever possible, after complete reassembly.


6.3 As far as practicable equipment, fittings and services should be designed and installed so that operations,

maintenance, and repairs can be carried out outside the clean area, if maintenance has to be performed in the clean

area then precautions such as issuing permits to work, clearly defined method statements, additional cleaning and

disinfection, and additional environmental monitoring should be considered. If sterilization or bio-decontamination is

required, it should be carried out, wherever possible, after complete reassembly of the equipment.


a) Can remove any residues that would otherwise create a barrier between the sterilizing agent and the equipment

surfaces.


a) Can remove any residues that would otherwise create a barrier between the disinfecting, bio-decontamination or

sterilizing agent and the product contact equipment surfaces.


b) Prevents chemical and particulate contamination of the product during the process and prior to disinfection.


c) Prevents chemical and particulate contamination of the product during the process and prior to disinfection

or bio-decontamination.

Comment:

Definition required for particulate contamination.

619 Existing text:

6.6 All critical surfaces that come into direct contact with sterile materials should be sterile.

Comment:

Change “should” for “must”.


6.7 All equipment such as sterilizers, air handling and filtration systems, water treatment, generation, storage and

distribution systems should be subject to qualification, monitoring and planned maintenance; their return to use

should be approved.


6.7 All equipment such as sterilizers; air handling systems (including air filtration); water treatment systems

(including water purification, storage and distribution elements) should be subject to qualification, monitoring and

planned maintenance. Upon completion of maintenance, their return to use shall be approved

Comment:

Line 621: Qualification is a typo.

There may be ambiguity on who will be approving the return to use. Approval should be by the Quality Unit.

Proposed change (if any): Correct typo.

Recommended change: “their return to use should be approved by the Quality Unit.” .

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6.8 A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower

air cleanliness, unless the belt itself is continually sterilized (e.g. in a sterilizing tunnel).


6.8 A conveyor belt must not pass through a partition between a Grade A clean zone or a Grade B cleanroom and a

processing area of lower air cleanliness, unless the belt itself is continually sterilized (e.g. in a sterilizing tunnel).


6.9 Particle counters should be qualified (including sampling tubing). Portable particle counters with a short length

of sample tubing should be used for qualification purposes. Isokinetic sample heads shall be used in unidirectional

airflow systems.

Comment:

Line 629: Portable particle counters is a new requirement. What is the definition of “short” length of tubing?

Proposed change (if any): delete ‘should’ and replace by ‘can’ in line 630


6.9 Real-time particle monitoring systems using light scattering airborne particle counters (LSAPC) should be

qualified (including the sampling tubing). Portable particle counters with a short length (NMT 3 metres) of sample

tubing should be used for qualification purposes. Isokinetic sample heads shall be used in unidirectional airflow

systems. ISO 14644-2 provides guidance on real-time airborne particle monitoring.


6.10 Where unplanned maintenance of equipment critical to the sterility of the product is to be carried out, an

assessment of the potential impact to the sterility of the product should be performed and recorded.


6.10 Where unplanned maintenance of equipment critical to the sterility of the product is to be carried out, an

assessment of the potential impact to the sterility of the product should be performed, recorded, and evaluated as part

of the product release.

Section 7 Utilities

General Comment:

This section requires improvement, editing, and correction of errors and poor practice.

If this section is intended to replace the EMA non-Distillation WFI Q&A Paper, it is inadequate. If this paper is to be

retained, then some of the guidance is useful. The comments below are made assuming the Q&A will still apply to

EMA jurisdictions.

The WFI source water requirements are incorrect. They are dependent upon the production method.

The WFI sampling guidance is impractical, and doesn’t follow current practice.


7.1 The nature and amount of controls associated with utilities should be commensurate with the risk associated with

the utility determined via risk assessment.


7.1 The nature and extent of controls applied to utility systems should be commensurate with the risk to product

quality associated with the utility. The impact should be determined via a documented risk assessment.

644 Existing text:

a) Directly contact product e.g. compressed gases.


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a) Directly contact product or product contact surfaces. e.g. water for washing and rinsing, compressed gases,

and steam for sterilisation.

646 Existing text:

a) Contact materials that ultimately will become part of the product.


b) Materials that ultimately will become part of the product.

648 Comment:

Omit line 648 as this is covered in line 644 with text change (see above)


7.3 Utilities should be installed, operated and maintained in a manner to ensure the utility functions as expected.


7.3 Utilities should be installed, operated, monitored and maintained in a manner so as to ensure the utility functions

as expected.


7.4 Results for critical parameters of the high risk utility should be subject to regular trend analysis to ensure that

system capabilities remain appropriate.


7.4 Critical performance parameters of direct impact critical utilities should be monitored, and subject to regular trend

analysis to ensure that system capabilities remain appropriate.

Comment

“regular” requires definition.


7.5 Current drawings should be available that identify critical system attributes such as: pipeline flow, pipeline

slopes, pipeline diameter and length, tanks, valves, filters, drains and sampling points.


7.5 Records of the utility installation shall be maintained throughout the system life-cycle. Such records should

include current drawings and schematic diagrams, component lists and specifications. Typical important information

includes attributes such as: pipeline flow direction, slopes, diameter and length; tank and vessel details; and valves,

filters, drains and sampling points.

Water Systems

General Comment:

The requirements for water systems are complex and detailed descriptions should be removed and reference to the

European Pharmacopoeia, or other appropriate documentation, for water systems should instead be included.

Proposed change:

Remove the requirements for water systems and refer to the European Pharmacopoeia or other specialist

documentation

670 Comment:

Replace “relevant Pharmacopoeia” with “European Pharmacopoeia”


7.8 Water for injections (WFI) should be produced from purified water, stored and distributed in a manner which

prevents microbial growth, for example by constant circulation at a temperature above 70oC. Where the WFI is

produced by methods other than distillation further techniques post Reverse osmosis (RO) membrane should be

considered such as nanofiltration, and ultra-filtration.

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7.8 When Water for Injection (s) (WFI) is produced using distillation as the final purification step, the feed water to

the still shall be appropriate for the distillation method used. When multi-effect distillation is used, the water quality is

commonly purified water, and when vapour compression distillation is used, deionised water is suitable. Once

generated, WFI shall be stored and distributed in a manner which prevents microbial growth, for example by constant

circulation at a temperature above 70°C. When WFI is produced by non-distillation methods, the pharmacopoeias

define the required feed water quality, and provide guidance on the preferred sequence of purification steps post

reverse osmosis membrane (RO), including deionisation and ultra-filtration.

Comment:

Line 672: Specifically calls for WFI to be produced by Purified Water (i.e. final processing using PW as feed-water).

This is too restrictive.

Proposed change (if any): Suggest that it does not specify the source of the water, providing that the WFI

requirements are met once WFI is produced.


7.9 Water systems should be validated to maintain the appropriate levels of physical, chemical and microbial control,

taking seasonal variation into account.

Proposed text:

7.9 Water systems should be validated to demonstrate the ability to maintain the appropriate levels of physical,

chemical and microbial control, taking into account seasonal variations in raw water quality and environmental

conditions.

681 Existing text:

7.10 Water flow should remain turbulent through the pipes to prevent microbial adhesion.

Comment:

No requirement to measure flow velocity?


7.11 The water system should be configured to prevent the proliferation of microorganisms, e.g. sloping of piping to

provide complete drainage and the avoidance of dead legs. Where filters are included in the system, special attention

should be taken with regards to the monitoring and maintenance of these filters.

Proposed text:

7.11 The water system should be configured to prevent the proliferation of microorganisms. Techniques that should be

considered include maintenance of turbulent flow in pipelines to inhibit proliferation of microorganisms, avoidance of

dead-legs, sloping of piping to allow drainage of systems. Where filters are included in the system, special attention

should be taken with regards to the monitoring and maintenance of these filters. Sterilising grade, dead-end filters

shall not be used in purification and distribution systems as they can conceal systemic microbiological contamination.


7.12 Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters the filters should be

sterilized, and the integrity of the filter tested before and after use.

Comment (1):

Should the filter be sanitised and heated?

Comment (2):

Even if generally free from microorganisms, water for injection (WFI) is not expected to be a sterile media since for

example, the European Pharmacopoeia requirements for this water quality is to contain less than 10 CFU/100ml for

microbial count, and bacterial endotoxin levels less than 0.25 IU/ml. The storage tanks, distribution systems (water

piping, loops) and points of use (taps or connections to equipment) for the WFI need to be designed, maintained,

controlled and monitored relating to the requirements for the manufacturing operations – and storage tank filters for

WFI would not need mandatory sterilization and/or integrity testing. The benefit therefore is not clear for the handling

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of vent filters for a non-sterile medium that is continuously prepared and distributed with the same requirements as

sterilizing filters for aseptically produced product.

Proposed text change: Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters the

filters may be sterilized, and the integrity of the filter tested before and after use, based upon Quality Risk

Management principles.

Comment (3):

Does this apply to water other than WFI?

Proposed change (if any): Applicable to both Purified Water and WFI systems regarding vent filter types.

Comment (4):

For water systems that are continuously maintained at >70oC, and with a high frequency of sampling (as indicated by

the Annex), it is unnecessary to sterilize and routinely integrity test vent filters. There are several other much more

effective and real time measures to ensure proper operation of the system (such as temperature, pressure, flow rate,

TOC and conductivity measurements of the loop), along with the routine microbial monitoring. Integrity testing

should be performed at installation and prior to removal but this was unclear in the draft Annex.

Proposed Change:

7.12 Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters the filters should be

integrity tested after installation and prior to removal.


7.13 To prevent the formation of biofilms, sterilization or disinfection or regeneration of water systems should be

carried out according to a predetermined schedule and also when microbial counts exceed action and alert limits.

Disinfection of a water system with chemicals should be followed by a validated rinsing procedure. Water should be

analyzed after disinfection/regeneration; results should be approved before the start of use of the water system.


7.13 Biofilms can form in ambient temperature water purification trains, and storage and distribution systems. To

prevent the formation of biofilms, sanitisation, disinfection or regeneration of water systems should be carried out

according to a predetermined schedule, and also when microbial counts exceed action levels. Disinfection of a water

system with chemicals should be followed by a validated rinsing or inactivation procedure. Water should be

monitored after disinfection, and results should be approved before the start of use of the water system.

Comment (1):

Some companies believe it is not possible to prevent the formation of biofilms and regeneration of water system

should only be undertaken in extreme cases.

Comment (2):

(Relating to Lines 691-693):

The operation of manufacturing water systems should be covered by the contamination control strategy. Since the water

systems are under continuous control related to data obtained from e.g. bioburden and bacterial endotoxin testing and

commonly in-line monitoring systems (e.g. TOC and conductivity); reliable data is available to ensure proper function

of the water systems during their operational conditions. When there are no changes to the qualified status and operations

of the water system, compilation and trending of data is sufficient to detect issues related to the hygienic standards.

Single events (i.e. exceeded alert or action limits) should not automatically render sterilization, disinfection or

regeneration of the full water system since the excursion could relate to a single point of use and not be a systemic issue

in the water system. The actions taken upon single exceeded limits from water samples should rather correlate to the

process risks, and risks of usage of water, in the manufacturing processes. Also, considerations should be given that hot

WFI water loops as such are having a self-sanitizing effect, making a predetermined schedule for disinfection obsolete.


To prevent the formation of biofilms, sterilization or disinfection or regeneration of water systems should be carried

out based upon Quality Risk Management principles or when microbial counts or other monitoring data show a

negative trend.

Comment (3):

Line 691: Why exceeding an alert limit should require a sanitization/sterilization of the system?

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Add “routine flushing” to prevent biofilms.

Add “repeated alert limits excursions”

Proposed change (if any): Replace exceed action and alert with trending data

Comment (4)

Each of the techniques described in this section describes a way to treat biofilms when they occur. Heat is very

effective at killing biofilms, but sterilization is not required. Hot water sanitization above 65C is effective to kill

biofilms. More extreme actions such as sterilization or chemical disinfection should only be taken for-cause if

indicated by routine monitoring data and not on a routine schedule.

Proposed Change:

Replace entire section 7.13 text. Proposed wording: Periodic sanitization (thermal or chemical) of water systems

should be carried out to mitigate the formation of biofilms if the system is not kept in a continuously sanitizing

condition (temperature greater than 65oC). Other actions, such as disinfection of distribution piping or re-generation,

may also be used in response to adverse trends in the routine monitoring data. The use of chemicals for this purpose

should be followed by sampling or the use of online monitoring to ensure their removal before the start of use of the

water system


7.14 A suitable sampling schedule should be in place to ensure that representative water samples are obtained for

analysis on a regular basis.

Comment:

Sampling schedule should in place for both on-line and off-line testing.

Regulatory expectation for sampling schedules for purified and WFI water systems would be helpful here.


7.15 Regular ongoing chemical and microbial monitoring of water systems should be performed with alert limits

based on the qualification that will identify an adverse trend in the performance of the systems. Sampling should

include all outlets and user points at a specified interval. A sample from the worst case sample point, e.g. the end of

the distribution loop return, should be included each time the water is used for manufacturing and manufacturing

processes. A breach of an alert limit should trigger review and follow-up, which might include investigation and

corrective action. Any breach of an action limit should lead to a root cause investigation and risk assessment.

Comment (1):

(Lines 701-706)

The operation of manufacturing water systems should be covered by the contamination control strategy. In the strategy,

the reasoning behind sampling locations and frequencies should be established based on Quality Risk Management

principles, taking into account as a minimum, the water quality, the water system design and the use of the water in the

manufacturing process and/or in product preparation such as monitored during the water system qualification. The

requirement to sample at worst case locations at one part of a loop, whenever water is used for manufacturing processes

at other parts of the loop, needs to be clarified. On bigger WFI loop systems this sample point might be several 100metres

after the point of use, not providing any insight for the quality of water taken for the manufacturing operations.

Proposed text change (1):

Regular ongoing chemical and microbial monitoring of water systems should be performed with alert limits, sample

locations and sampling frequencies based upon the qualification that will identify an adverse trend in the performance

of the systems. Sampling should include all outlets and user points at a specified interval. A sample from the worst

case sample point, e.g. the end of the distribution loop return, should be included on a daily basis.

Alternative Proposed Text change (2):

(Lines 701-708)

7.15 Regular on-going chemical and microbial monitoring of water systems should be performed with alert levels

based on the qualification that will identify an adverse trend in the performance of the systems before action levels are

reached. Sampling should include all sample points and points-of-use at specified intervals. For WFI systems, at least

one point-of-use and the end of the distribution loop (prior to re-entry into the distribution tank) should be sampled

daily, ensuring all are sampled over a defined period of time. A breach of an alert level should initiate a review and

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follow-up, which might include investigation and corrective action. Any breach of an action level should lead to a root

cause investigation and risk assessment.

Comment (3):

Specific sampling guidance is now included such as requiring sampling from a worst case point on the water system

each time it is used for manufacturing purposes (an example given is the return distribution header from the system).

Action limit excursions should include an assessment on the risks posed to processes that used the water.

More clarification is needed to describe the purpose of a risk assessment when an action level is reached such as

impact on process/products that used the water.

Comment (4):

The term ‘points of use’ should be used in lieu of ‘outlets’. Water systems typically have quite a number of other

“outlets” in technical areas that are used for complete system drainage or other non-processing reasons, and these

“outlets” do not typically require sampling. Also, the end of the loop may not be the worst case location. A complex

point of use will often be a worse condition than the loop return in the case of microbiological contaminants, which

are unlikely to be uniformly distributed. Clarification or rewording should also be provided about the intent of

sampling this worst case point “each time the water is used” Additionally, the terms alert and action limits are used in

this section, but the terms alert and action levels are defined in the glossary. The requirements for breach of an action

limit/level in this section are different than those imposed by the definition n lines 2023-2024 – they should be

aligned. Alert levels are initially calculated based on the qualification, but should be revised based on more recent

ongoing monitoring data. Clarification between risk assessment (done prospectively) and impact assessment

(performed after an event in order to determine impact).

Proposed Change:

7.15 Regular ongoing chemical and microbial monitoring of water systems should be performed with alert levels

based on historical results such that an adverse trend in the performance of the system would be identified. Sampling

should include all points of use at a specified interval. Risk assessment should be used to determine potential worst

case sampling locations and an appropriate sampling frequency. An exceeded alert level should trigger review and

follow-up, which might include investigation and corrective action. Any exceeded action level should lead to a root

cause investigation and impact assessment.


7.16 WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and

conductivity.


7.16 WFI systems shall be continuously monitored on-line for Total Organic Carbon (TOC), conductivity,

temperature and flow rate

Comment (1):

Continuous monitoring of TOC is a new requirement.

Interestingly only specifies WFI grade water for continuous TOC monitoring with a preference to online over offline

monitoring; other similar guidance documents such as ISPE Baseline Guide for Water & Pure/Clean Steam and USP

General Chapter <1231> still allow for either offline or online monitoring of these properties.

Proposed alternative suggestion: Offline monitoring for TOC is still an acceptable monitoring practice.

Comment (2):

The Annex should not mandate on-line continuous monitoring for TOC and Conductivity as it is not scientifically

necessary. While desirable for any newly installed systems, retrofitting of older systems would involve a very invasive

process, with high cost and high complexity and can lead to inadvertent contamination of the systems.

Proposed change:

Remove Section 7.16

Steam used for sterilization


7.17 Purified water, with a low level of endotoxin, should be used as the minimum quality feed water for the pure

steam generator.


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7.17 Purified water, with a low level of endotoxin, shall be used as the minimum quality feed water for a pure steam

generator equipped with droplet and particle elimination. If a simple heat exchanger is used, the feed water shall be

WFI.

Comment (1):

Regulatory guidance on the expectation for low level of endotoxin would be helpful.

Comment (2):

Feed water for a pure steam generator could be derived from water that is of different quality than purified water, e.g.

from water treated with reverse osmosis. Also, the particular mention of “low level of endotoxin” does not seem to be

justified since the steam generators as such significantly reduces endotoxin levels. The quality of feed water should be

related to the performance of clean steam generator.


Suitably treated water, should be used as the minimum quality feed water for the pure steam generator.”

Comment (3):

Clarify what low endotoxin in feed water for pure steam generation is.

Proposed change (if any): Clarify what low endotoxin in feed water for pure steam generation is or suggest the

following wording “Pure Steam Generation systems using purified water should be qualified using water of defined

endotoxin content to ensure that the pure steam generated does not add endotoxin risk”.

Comment (4):

The statement around low level of endotoxin is subjective, and does not conform to the European Pharmacopeial

specification for Purified Water. Furthermore, well designed clean steam generators do not have an issue in handling

removal of endotoxins.

Proposed Change:

7.17 Purified water should be used as the minimum quality feed water for the pure steam generator.


7.18 Steam used for sterilization processes should be of suitable quality and should not contain additives at a level

which could cause contamination of product or equipment. The quality of steam used for sterilization of porous loads

and for Steam-In-Place (SIP) should be assessed periodically against validated parameters. These parameters should

include consideration of the following examples: non-condensable gases, dryness value (dryness fraction), superheat

and steam condensate quality.


7.18 Steam used for sterilization processes shall be of suitable quality and should not contain additives at a level

which could cause contamination of product or equipment. When condensed, the condensate shall meet the WFI

specification. Additionally, the quality of steam used for sterilization of porous loads and for Steam-In-Place (SIP)

should be assessed periodically and whenever there is an interruption in the steam supply, against validated

parameters. These parameters include non-condensable gases, dryness value (dryness fraction), and superheat.

Reference EN285.

Comment:

Added clarification for testing the physical attributes of steam as noted within EN 285 (as well as HTM-0101). Need

clarification of what steam condensate quality is.

Proposed change (if any): Clarify that steam condensate must meet WFI compendial requirements for chemical and

endotoxin quality and should be free of microbial contamination

Comment:

Line 720: Is this necessary also for SIP systems?

Line 723: Need to clarify the expectation of steam condensate quality.

Compressed gases and vacuum systems

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7.19 Compressed gases that come in direct contact with the product/container primary surfaces should be of

appropriate chemical, particulate and microbiological purity, free from oil with the correct dew point specification

and, where applicable, comply with appropriate pharmacopoeial monographs. Compressed gases must be filtered

through a sterilizing filter (with a nominal pore size of a maximum of 0.22pm) at the point of use. Where used for

aseptic manufacturing, confirmation of the integrity of the final sterilization gas filter should be considered as part of

the batch release process.


7.19 Compressed gases that come in direct contact with the product, product contact surfaces, or product primary

containers shall be of appropriate chemical, particulate and microbiological purity, free from oil and hydrocarbons,

with an appropriate dew point specification, and comply with appropriate pharmacopoeial monographs where

applicable. Compressed gases must be filtered through a sterilizing filter (with a nominal pore size of a maximum of

0.2μm) at the point of use. Where used for aseptic processing, confirmation of the integrity of the final sterilization

gas filter should be considered as part of the product batch release process.

Comment:

The frequency for testing the integrity of gas filter should be based upon risk assessment.

Comment:

Line 731-733: Should integrity test of gas filters be performed on a per batch basis or is a periodic testing based on

RA acceptable? If integrity testing of the gas filter is performed on a defined frequency and not by batch, what would

the batch release process requirement be?


7.20 There should be prevention of backflow when any vacuum or pressure system is shut off.


7.20 There should be prevention of backflow when any vacuum or pressure system is shut off or activated.

738 Cooling Systems

Comment:

Change title of section to Energy utility systems


7.21 Major items of equipment associated with hydraulic and cooling systems should, where possible, be located

outside the filling room. Where they are located inside the filling room there should be appropriate controls to

contain any spillage and/or cross contamination associated with the hydraulics of cooling system fluids.


7.21 Major items of equipment such as those associated with vacuum, hydraulic, cooling and heating systems shall be

located outside the filling room. Where components of these systems are located inside the filling room, there should

be appropriate controls to contain any spillage and prevent cross-contamination.


7.22 Any leaks from the cooling system must be detectable (i.e. an indication system for leakage). In addition, there

must be adequate cooling flow within the system.


7.22 Any leaks from the energy utility system must be detectable (i.e. an indication system for leakage). In addition,

there must be adequate cooling flow within the system.


7.23 The cooling circuit should be subject to leak testing both periodically and following any maintenance.


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7.23 Cooling and heating circuits should be subject to leak testing both periodically and following any maintenance.


7.24 There should be periodic cleaning/disinfection of both the vacuum system and cooling systems

Proposed text

7.24 There should be periodic cleaning/disinfection of vacuum systems.

Comment:

Add periodic “preventive maintenance”

Proposed change (if any): Cooling systems should be included in PM program.

There should be periodic preventive maintenance and cleaning/disinfection of both the vacuum system and cooling

systems.

754 8 Production and Specific Technologies

General Comment (1):

Consider moving specific equipment guidance to Section 6 and create an additional section on sterilisation. Just keep

technologies here. Many improvements to the language and clarity must be made, particularly for non-native English

speakers. Reference to relevant EN and ISO sterilisation standards must be made to ensure readers clearly understand

regulatory expectations. Some of the sterilisation lecture material is repetitive, and should be re-organised or removed.

General Comment (2):

There is no mention of vaporized hydrogen peroxide (VHP) as a sterilitant (e.g of certain isolator critical surfaces).

This is inconsistent with the position of the European Pharmacopeia. 5.1.1 Methods of Preparation of Sterile

Products, section on Gas Sterilisation (Vapor Phase Sterilisation)

Proposed Change:

Text should be added to define an acceptable approach for the use of VHP as a sterilant.


8.2 Filling of products for terminal sterilization should be carried out in at least a grade C environment.


8.2 Filling of products for terminal sterilization should be carried out in at least a Grade C environment, with a local

Grade A air supply protecting the processing zone

769-775 Comment:

This paragraph is not required following the proposed change above for line 766 to 767.

Comment (2)

The meaning of “wide necked” is not clear. Vials are wide necked compared with ampoules. Should filling of vials

require a Grade A environment?


8.4 Processing of the bulk solution should include a filtration step to reduce bioburden levels and particulates prior to

filling into the final product containers.

Comment:

Process design should be handled and maintained in relation to process and product risks; the design and operations

(including any filtration steps) of processes should be based on Quality Risk Management principles and the

requirements for the specific product. Some bulk solutions as e.g. fat emulsions or suspensions cannot be filtered through

bacterial retention filters due to the physical product characteristics. Bioburden levels must be thoroughly controlled

during the process since bioburden levels cannot be reduced with the applied 10 – 20 µm pore size filters typically used

for those types of emulsion products.

Proposed text change (1)

8.4 Processing of the bulk solution should include a filtration step, employing a 0.2 micron filter where possible, to

reduce bioburden levels and particulates prior to filling into the final product containers.

Alternative text change (2)

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Processing of the bulk solution should include a filtration step to reduce bioburden levels and particulates prior to filling

into the final product containers, wherever product characteristics allow.”

785 Aseptic Preparation


8.6 Aseptic processing is the handling of sterile product, containers and/or devices in a controlled environment, in

which the air supply, materials and personnel are regulated to prevent microbial contamination. Additional

requirements apply to Restricted Access Barrier Systems (RABS) and isolators (refer clauses 5.15-5.22).


8.6 Aseptic processing is the handling of sterile product, containers and/or devices in a controlled environment, in

which the air supply, materials and personnel are regulated to prevent microbial contamination. By first intent barrier

technology such as Isolators and Restricted Access Barrier Systems (RABS) should be employed to ensure adequate

separation of the Grade A zone from both operators and the surrounding environment. This is to reduce the need for

interventions into the grade A environment and to minimize the risk of contamination. Automation of processes

should also be considered to remove the risk of contamination by interventions (e.g. dry heat tunnel, automated

lyophilizer loading, SIP). The absence of such technology may be acceptable in exceptional circumstances provided

there is sufficient control and evidence of the maintenance of Grade A integrity.

Comment:

Note this paragraph has also been included by PHSS in Section 5 Premises under Barrier Technologies

792-797 Comment:

-Change “justifed” to “mitigated and not result in unnecessary risk to product/process’.

- Requirement for discrete aseptic process risk assessment as part of contamination control strategy

Proposed change (if any): Residual risk cannot pose unnecessary risk. Residual risks should be mitigated and

supported by a risk assessment.

805-809 Comment:

This paragraph is no longer required following proposed text change to line 787 to 790.

815 Comment (1):

The table should be modified to include under Grade A, “ Removal and cooling of unwrapped items from steriliser.

The removal of wrapped items from the sterilizer should be protected by a local Grade A air supply within the Grade

B area. There should also be a provision for a protective local Grade A air supply within the Grade D cleanroom for

the handling of components, equipment and accessories after washing prior to being sterilised.

Comment (2):

The current wording in the draft Annex 1 is (on examples of operations to be performed in grade B) “Removal of sealed

product from the grade A zone.” The mentioned example is not a good one. When product has been sealed in grade A

it can be automatically transferred under clean air (i.e. grade A air supply) into different cleanroom zones, as e.g. a grade

C zone. The product in its’ sealed container would be of no risk of being contaminated by this process design and

cleanroom grades.

Suggest that the text in Table 4: “Removal of sealed product from the Grade A zone” is omitted.

Comment (3)

Table 4 section B “Removal of sealed product from the grade A zone” is not clear since it could mean that for a vial

after capping a grade B area is required for the removal of the sealed vial.

Comment (4):

Grade A should not be required for packaged items (see also Grade B example of operations in the same table and

clause 8.41)

Proposed change (if any): Change the sentence as follows: “Grade A: Removal and cooling of unprotected (e.g.

unpackaged) items from heat sterilizers”.

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Comment (5):

Additional clarification requested to the examples in Table 4 as several of the examples can be present in several

configurations, not all of which place them in the Grade A classification category and thus can lead to confusion and

misinterpretation. Also suggest moving the requirements around aseptic connections (should be sterilized by steam in

place whenever feasible) to a more prominent section of the document. Having it placed within a table of examples

means it can easily be missed or disregarded.

Proposed change:

Table 4: Examples of operations and which grades they should be performed in

A Critical processing zone.

Aseptic assembly of filling equipment.

Aseptic connections

Aseptic compounding and mixing.

Replenishment of sterile product, containers and closures.

Removal and cooling of items from heat sterilizers (unless appropriately protected).

Staging and conveying of sterile primary packaging components (unless appropriately protected).

Aseptic filling, sealing, transfer of open or partially stoppered vials,

including interventions.

Loading and unloading (of unsealed containers) of a lyophilizer

Comment (6):

(see also 331 & 839) A Grade A environment is specified for the removal and cooling of items from heat sterilisers

and for the loading and unloading of a lyophiliser. These activities can be adequately undertaken in zones supplied

with unidirectional airflow where personnel may be present. Regulatory authority guidance has previously stated that

the zone cannot be considered to be Grade A if personnel are present within the zone.

Proposed Change:

Clarification is needed on terminology, e.g. Grade A zones that operators enter to be termed localised unidirectional

airflow (L-UDAF) or appropriate similar term

Comment (7):

Lines 839/1479 (see also 331 & 815) The document states that the transfer of partially closed containers to a

lyophilizer should be done under Grade A conditions and then clarifies this environment to be HEPA filtered positive

pressure. This activity can be adequately undertaken in zones supplied with unidirectional airflow where personnel

may be present. Regulatory authority guidance has previously stated that the zone cannot be considered to be Grade A

if personnel are present within the zone.

Proposed Change:

Clarification is needed on terminology, e.g. Grade A zones that operators enter to be termed localised unidirectional

airflow (L-UDAF) or appropriate similar term


Note; If Isolators are used then a risk assessment should determine the necessary background environment grade; at

least a minimum of grade D should be used. Refer clauses 5.19-5.20.

Comment:

This may indicate to the reader that Isolators are a less secure option than open processing.


8.11 Where the product is not subsequently sterile filtered, the preparation of equipment, components and ancillary

items and products should be done in a grade A environment with a grade B background.

8.12 Preparation and filling of sterile products such as ointments, creams, suspensions and emulsions should be

performed in a grade A environment, with a grade B background, when the product and components are exposed and

the product is not subsequently filtered or sterilized.


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Where the product is not subsequently sterile filtered, the preparation of equipment, components and ancillary items

and products should be undertaken in a Grade A environment with a Grade B background, unless Isolator technology

is used. This includes the preparation and filling of sterile products such as ointments, creams, suspensions and

emulsions should be performed in a Grade A environment, with a Grade B background, when the product and

components are exposed and the product is not subsequently filtered or sterilized.


8.14 The transfer of partially closed containers to a lyophilizer, should be done under grade A conditions (e.g. HEPA

filtered positive pressure) at all times and, where possible, without operator intervention. Portable transfer systems

(e.g. transfer carts, portable Laminar Flow Work Stations, etc.) should ensure that the integrity of transfer system is

maintained and the process of transfer should minimize the risk of contamination.


8.14 The transfer of partially closed containers to a lyophilizer, shall be undertaken under Grade A conditions at all

times, without direct operator intervention in order to minimise the risk of contamination. Technologies such as

conveyor systems, portable transfer systems (e.g. clean air transfer carts, portable unidirectional airflow workstations

should ensure that the integrity of transfer system is maintained.


8.15 Aseptic manipulations (including non-intrinsic aseptic connections) should be minimized using engineering

solutions such as the use of preassembled and sterilized equipment. Whenever feasible, product contact piping and

equipment should be preassembled, then cleaned and sterilized in place. The final sterile filtration should be carried

out as close as possible to the filling point and downstream of aseptic connections wherever possible


8.15 Aseptic manipulations (including non-intrinsic aseptic connections) should be minimized using engineering

solutions such as the use of preassembled and sterilized equipment. Whenever feasible, product contact piping and

equipment should be preassembled, then cleaned and sterilized in place. The final sterile filtration should be carried

out as close as possible to the filling point and downstream of aseptic connections wherever possible unless the

integrity of the sterile product pathway downstream of the filter can be confirmed e.g. using integral stainless steel

piping which is subject to a SIP process and an integrity test.


a) Time between equipment, component, and container cleaning, drying and sterilization.


The period between washing and depyrogenation of components and also their use when supplied to filling lines via

integrated depyrogenation tunnels must be limited and justified.


c) The time between the start of the preparation of a solution and its sterilization or filtration through a micro-

organism-retaining filter. There should be a set maximum permissible time for each product that takes into account its

composition and the prescribed method of storage.


c) The time between the start of the preparation of a solution and its sterilization or filtration through a micro-

organism-retaining filter. There should be a set maximum permissible time for each product that takes into account its

composition, its susceptibility to microbial proliferation, chemical stability and the prescribed method of storage.


g) Maximum exposure time of sterilized containers and closures in the critical processing zone (including filling)

prior to closure.

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Note filling needles, stopper bowls etc may be exposed for days within the processing zone when campaign filling is

undertaken.

875 Finishing of sterile products


8.17 Partially stoppered vials or prefilled syringes should be maintained under grade A conditions (e.g. use of

isolator technology, grade A with B background, with physical segregation from operators) or grade A LAF carts

(with suitable grade B background environment and physical segregation from operators) at all times until the

stopper is fully inserted.

Comment (1):

If the expectation is that a minimum of RABS should be employed, then this should be stated here.

Comment (2):

Since physical segregation from operators is required 2 times for partially stoppered containers this should be also

clearly indicate for open containers not partially stoppered.


8.18 Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. Form-Fill-

Seal Small Volume Parenteral (SVP) & Large Volume Parenteral (LVP) bags, glass or plastic ampoules, should be

subject to 100% integrity testing. Samples of other containers should be checked for integrity utilising validated

methods and in accordance with QRM, the frequency of testing should be based on the knowledge and experience of

the container and closure systems being used. A statistically valid sampling plan should be utilized. It should be noted

that visual inspection alone is not considered as an acceptable integrity test method,

Comment: (1)

Further clarification should be given on what are defined as acceptable integrity test methods i.e. microbiological or

chemical?). This should align to defined CCI methodologies given in USP1027 or state other acceptable tests.

The document should give more guidance on sampling frequencies (e.g. batch by batch testing, random batch testing)

and references to acceptable CCI tests as these vary vastly in sensitivity.

Further clarification is required on application of risk assessment as this could lead to vastly different approaches. For

example, visual inspection of a vial is limited due to occluded area under cap so this could be considered high risk in

which case 100% detection would seem appropriate. Conversely for the same container the QRM could highlight this

as a perceived low risk in which case no sampling may be required. The current position is ambiguous and could lead

to vastly different approaches.

Suggest adding 100% CCI technology should be employed when possible where there is a risk of non-detection of

defects using visual inspection processes such as in blind spots and difficult to inspect locations.

Comment (2):

LVP plastic-bags (one chamber bags and multi chamber bags), as physiochemical welded/bonded components, differ

in criticality from typically fused LVP containers (e.g. bottles produced as Blow Fill Seal from e.g. PE/PP plastic

granulates). Automated and highly controlled welding processes, together with utilising validated methods and sampling

plans for integrity testing, deliver a high assurance of package integrity for physiochemical welded/bonded plastic bags.

Welded bags can be tested in-line with vacuum/pressure in the empty bag stage rather than as filled products (after

mechanical capping), where no standardized 100% integrity tests are available. Furthermore, those bags are often

sterilized in an additional barrier over-pouch, which furthermore decreases the risk.


Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. Small Volume

Parenteral (SVP) & Large Volume Parenteral (LVP) manufactured from granulates, glass or plastic ampoules, should

be subjected to 100% integrity testing. Samples of other containers (including LVP plastic bags as physiochemical

welded/bonded components) should be checked for integrity utilising validated methods and in accordance with

QRM, the frequency of testing should be based on the knowledge and experience of the container and closure systems

being used. A statistically valid sampling plan should be utilized. It should be noted that visual inspection alone is not

considered as an acceptable integrity test method.”

Comment (3):

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Container closure integrity should be ensured by a robust control strategy and should leverage a series of checks and

controls throughout the process, and, as acknowledged in this section, it is this control strategy that dictates the

frequency of testing and the appropriate sample size. Sample set should always be representative of the batch.

Proposed change:

8.18 Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. Form-Fill-Seal

Small Volume Parenteral (SVP) & Large Volume Parenteral (LVP) bags, glass or plastic ampoules, should be subject

to 100% integrity testing. Samples of other containers should be checked for integrity utilising validated methods and

in accordance with QRM, the frequency of testing should be based on the knowledge and experience of the container

and closure systems being used. The sample set should be representative of the batch. It should be noted that visual

inspection alone is not considered as an acceptable integrity test method.


8.19 Containers sealed under vacuum should be tested for maintenance of vacuum after an appropriate, pre-

determined period and during shelf life.

Comment

Clarification is needed to confirm if this requirement is product stability (e.g. moisture ingress) or micro ingress

related – if this is specifically in products where loss of vacuum could lead to product degradation then this should be

specified.

Note - there is a concern that although vacuum levels may be lost over shelf life, this may not permit microbial or

moisture ingress. This requirement should align to the Maximum Allowable Leakage concept stated in USP1027 or

define other acceptable methodologies.


8.20 The container closure integrity validation should take into consideration any transportation or shipping

requirements.

Comment:

It is not clear in the document if this is CCI of primary pack after transportation and shipping (within its finished

pack) or other stages (e.g. bulk intermediate shipping) therefore further clarification should be added. Note that this

document does not actually mention requirements for the core CCI validation of the primary pack at early stages in

life cycle e.g packaging development, manufacturing and sterilisation processes.


8.23 In the case where capping is conducted as a clean process with grade A air supply protection, vials with missing

or displaced stoppers should be rejected prior to capping. Appropriately validated, automated methods for stopper

height detection should be in place. Microbial ingress studies (or alternative methods) should be utilized to determine

the acceptable stopper height displacement.

Comment (1):

The document should clarify that vials with missing or displaced stoppers can be inspected prior to capping but they

can be physically rejected after crimping. We assume that laser height is suitable, as well as vision, if appropriately

validated?

Suggest to reword rejection position as vials identified with displaced stoppers can be physically rejected after

capping.

This only covers micro ingress but does not consider the potential for loss of gas headspace (where critical). This

should align to the Maximum Allowable Leakage concept stated in USP1027.

Comment (2):

Line 911-913

Whenever capping is conducted as a clean process under Grade A air supply, included automated systems for missing

or displaced stopper detection, there should be no additional risk for microbial contamination, especially if in addition

the Grade A air is protected by RABS systems. Microbial ingress studies (or equivalent) would normally be performed

during container closure integrity testing (CCIT) of completely sealed finished product containers to ensure their

integrity during transport and shelf life. Performing CCIT studies of unsealed vials with different inserted stopper

heights and then setting limits based on that for a stopper positioning sensor will not add additional sterility assurance

to the product. Limits should be set conservatively and be based on full insertion.


Appropriately validated, automated methods for stopper height detection should be in place.

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Comment (3):

Should indicate “For a clean capping process where human intervention is required at the capping station...”


8.25 RABS and isolators may be beneficial in assuring the required conditions and minimising direct human

interventions into the capping operation.

Comment:

The statement regarding RABS/Isolators for capping should be assessed based on QRM, e.g. if the product is

sealed/closed under vacuum this may not be needed.


8.26 All filled containers of parenteral products should be inspected individually for extraneous contamination or

other defects. QRM principles should be used for determination of defect classification and criticality. Factors to

consider include, but are not limited, to the potential impact to the patient of the defect and the route of

administration. Different defect types should be categorized and batch performance analysed. Batches with unusual

levels of defects, when compared to routine defect levels for the process, should lead to investigation and

consideration of partial or the whole rejection of the batch concerned. A defect library should be generated and

maintained which captures all known defects. The defect library can be used as a training tool for production and

quality assurance personnel. Critical defects should not be identified during any subsequent sampling of acceptable

containers as it indicates a failure of the original inspection process.

Comment:

Line 923 to 925: Does the requirement to use QRM to assess defect criticality apply to all defect types or just

particles. Need further clarification on risk factors as this is vague.

Line 927 to 929: Need clarification on which defects types should be categorised. Typically, all critical/major should

be assessed but this is not necessary for minor cosmetic defects – a risk approach should be permissible.

Line 931 to 932: There should be a reference to applicable sampling plans (e.g. ISO2859). Additional sampling for

difficult to inspect products is not included (ref: USP790).


8.27 When inspection is done manually, it should be done under suitable and controlled conditions of illumination

and background. Inspection rates should be appropriately validated. Operators performing the inspection should

undergo robust visual inspection qualification (whilst wearing corrective lenses, if these are normally worn) at least

annually. The qualification should be undertaken using appropriate sample sets and taking into consideration worst

case scenarios (e.g. inspection time, line speed (where the product is transferred to the operator by a conveyor

system), component size or fatigue at the end of shift) and should include consideration of eyesight checks. Operator

distractions should be removed and frequent breaks of appropriate duration from inspection should be taken.

Comment:

Line 934 to 937: Ref: to EP 2.9.20 / USP790 manual inspection setup and method should be made for particles

inspection. Reference to the number of test set runs / passes should be made (e.g. 3 consecutive passes are required for

operator qualification).

Line 938 to 942: There are no requirements for criteria to be applied for the qualification or categories (e.g. such as

100% rejection of critical defects). Expectation would that this would be included and risk based on criticality of the

defect. Does not state any additional requirements for difficult to inspect products (e.g. change of conditions to

enhance process to inspect to extent possible).


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8.28 Where automated methods of inspection are used, the process should be validated to detect known defects with

sensitivity equal to or better than manual inspection methods and the performance of the equipment checked prior to

start up and at regular intervals.

Comment:

Clarification is required at to which defects this applies to. If this covers all defects, then a comparison to manual can

lead to reduced performance for critical defects (as increased detection on minor defects can also mask poor detection

on more critical defects)..

Typically, ‘better than or equal to criteria’ is usually required for particulate defects. This draft document infers that

comparison to manual can be used for all defects (critical, major, minor). Using manual process as a baseline for all

defects can lead to a lesser standard for a poorly applied manual process. Further clarification on application of the

requirement should be made.

Additional specific criteria should apply for automated systems linking to AQL classifications e.g. 100% rejection

required for critical defects.

Clarification is also required if criteria (i.e. comparison to manual) is applicable to semi-automated inspection – this is

the typical industry requirement.

Clarification is required as to what regular means in terms of equipment checks as this is ambiguous.

No reference given to requirements for validation of re-inspection (ejects) – as USP1790 requirement “If a two-stage

inspection strategy is used, it must be validated as intended for use. Defective containers with less than a 100% PoD

will have the PoD reduced further with each stage of inspection, thus the PoD should be determined after inspection

through both stages to ensure acceptable sensitivity is maintained”.

Comment (2)

“For automated methods of inspection …the performance of the equipment checked prior to start up and at regular

intervals for a single batch” should be indicated


8.29 Results of the inspection should be recorded and defect types and levels trended. Reject rates for the various

defect types should also be trended. Investigations should be performed as appropriate to address adverse trends or

discovery of new defect types. Impact to product on the market should be assessed as part of this investigation.

Comment:

The requirement for analysis of batch performance is already stated in Line 926 therefore there appears to be some

duplication. Further clarification is needed on this.

953 Sterilization

Comment:

Is this section intended for product or equipment or both?

955-960 Comment (1):

Should this paragraph actually reference the EMEA document on filing new products as it is in this document that

details on how to choose the sterilization method is provided?

Comment (2):

Line 959: Pasteurisation relates to treatments for food and drink and there is no associated definition included in the

Glossary section.

Proposed change:

Remove the word ‘Pasteurisation’

Existing text:

8.30 Where possible, finished product should be terminally sterilized using a validated and controlled sterilization

process as this provides a greater assurance of sterility than a validated and controlled sterilizing filtration process

and/or aseptic processing. Where it is not possible for a product to undergo a sterilisation, consideration should be

given to using terminal bioburden reduction steps, such as heat treatments (pasteurization), combined with aseptic

processing to give improved sterility assurance.


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8.30 Where possible, finished product should be terminally sterilized using a validated and controlled sterilization

process as this provides a greater assurance of sterility than a validated and controlled sterilizing filtration process

and/or aseptic processing. Where it is not possible for a product to undergo a sterilisation, consideration should be

given to using terminal bioburden reduction steps, such as heat treatments, combined with sterile filtration and aseptic

processing to give improved sterility assurance.

967-968 Comment:

Clarification of what is considered an “atypical” sterilization cycle is required.

Please define atypical sterilization cycle in the glossary.


8.33 All sterilization processes should be validated. Particular attention should be given when the adopted

sterilization method is not described in the current edition of the Pharmacopoeia, or when it is used for a product

which is not a simple aqueous solution. Where possible, heat sterilization is the method of choice. Regardless, the

sterilization process must be in accordance with the registered marketing and manufacturing specifications.


8.33 All sterilization processes must be validated (product and equipment, components etc). However for product

sterilisation, particular attention should be given when the adopted sterilization method is not described in the current

edition of the Pharmacopoeia, or when it is used for a product which is not a simple aqueous solution. Where possible,

heat sterilization is the method of choice. Regardless, the sterilization process must be in accordance with the

registered marketing and manufacturing specifications.


8.34 Before any sterilization process is adopted, its suitability for the product and equipment and its efficacy in

achieving the desired sterilizing conditions in all parts of each type of load to be processed should be demonstrated by

physical measurements and by biological indicators where appropriate.

Comment:

Include the word “also” in front of “by biological indicators”

982-985 Comment :

Clarification required on what is considered a ‘process’ e.g. does this mean the sterilization process for sterile

product?


8.36 For effective sterilization, the whole of the material and equipment must be subjected to the required treatment

and the process should be designed to ensure that this is achieved.


8.36 For effective sterilization, the whole of the product, components, material and equipment must be subjected to

the required treatment and the process should be designed to ensure that this is achieved.


8.38 Suitable biological indicators (Bis) placed at appropriate locations may be considered as an additional method

for monitoring the sterilization. Bis should be stored and used according to the manufacturer's instructions. Prior to

use of a new batch/lot of Bis, the quality of the batch/lot should be verified by confirming the viable spore count and

identity. Where Bis are used to validate and/or monitor a sterilization process (e.g. for Ethylene Oxide), positive

controls should be tested for each sterilization cycle, with strict precautions in place to avoid transferring microbial

contamination from Bis, including preventing positive control Bis from contaminating Bis exposed to the sterilization

cycle. If biological indicators are used, strict precautions should be taken to avoid transferring microbial

contamination to the manufacturing or other testing processes.

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BIs should be incubated for a minimum of 7 days.


Each basket, tray or other carrier of products, items of equipment or components should be clearly labelled with the

material name, its batch number and an indication of whether or not it has been sterilized. Indicators such as

autoclave tape, or irradiation indicators may be used, where appropriate, to indicate whether or not a batch (or sub-

batch) has passed through a sterilization process.

Comment:

There are other options rather than physically and individually labelling baskets, trays or other carriers of products,

equipment and components that have been sterilized to differentiate them from others which have not been sterilized.

For a double door autoclave/sterilizer that separates a fully automated pre-sterilization loading area from a fully

automated post-sterilization unloading area, there are electronic systems in place to ensure full tracking of separate

sterilizer loads; and where material names, batch numbers and sterilization records for the sterilized materials are

integrated in the validated data system.


Each basket, tray or other carrier of products, items of equipment or components should be clearly labelled or

electronically traceable with the material name, its batch number and an indication of whether or not it has been

sterilized. Indicators such as autoclave tape, or irradiation indicators may be used, where appropriate, to indicate

whether or not a batch (or sub-batch) has passed through a sterilization process.

1017-1026 Comment (1):

Suggest that this paragraph is headed with “Staging and Transfer of Sterilised Items into the Grade A zone” and re-

worded as below

Existing text:

8.41 Where possible, materials, equipment and components should be sterilized by validated methods appropriate to

the specific material. Suitable protection after sterilization should be provided to prevent recontamination. If items

sterilized "in house" are not used immediately after sterilization, these should be stored, using appropriately sealed

packaging, in at least a grade B environment, a maximum hold period should also be established. Components that

have been packaged with multiple sterile packaging layers need not be stored in grade B (where justified) if the

integrity and configuration (e.g. multiple sterile coverings that can be removed at each transfer from lower to higher

grade) of the sterile pack allows the items to be readily disinfected during transfer into the grade A zone. Where

protection is achieved by containment in sealed packaging this process should be undertaken prior to sterilisation.


8.41 Materials, equipment and components must be sterilized by validated methods appropriate to the specific

material. Suitable protection after sterilization should be provided to prevent recontamination. If items sterilized "in

house", in the absence of any packaging are not used immediately after sterilization, these should be staged under

Grade A conditions using barrier technology. Items sterilised "in house" within appropriate sealed packaging, unless

utilised within Grade A isolators, should be staged within the sealed packaging and protected by a Grade A supply

located in at least a grade B environment. Where packaged items are sterilised "in house" via autoclaving for use in

Grade A isolators, the items should be staged within the sealed packaging and protected by a Grade A supply located

in at least a grade C environment. The packaging must be suitable to permit decontamination of its outer surface prior

to the exposure and removal of the sterilised contents within the Grade A environment. A maximum staging period

should be established. Components that have been packaged with multiple sterile packaging layers such as those

supplied irradiation or ethylene oxide sterilised need not be stored in grade B (where justified) if the integrity and

configuration (e.g. multiple sterile coverings that can be removed at each transfer from lower to higher grade) of the

sterile pack allows the items to be readily disinfected during transfer into the grade A zone. Where protection is

achieved by containment in sealed packaging this process should be undertaken prior to sterilisation.

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Comment (2):

Line 1019-1026

In-house sterilized items to be used for terminally sterilized products would not need to be stored in grade B, even if

only a single layer protective packaging be used. In most terminally sterilized manufacturing facilities grade B areas are

not available, although a grade A LAF-zone may be used for the filling operations in grade C, before terminal

sterilization takes place. It should be clearly stated that the requirement as mentioned in the revised Annex 1 is only

intended for aseptically produced products.


If items to be used in aseptic processing and sterilized “in house” are not used immediately after sterilization, these

should be stored, using appropriately sealed packaging, in at least a grade B environment, a maximum hold period

should also be established. Components that have been packaged with multiple sterile packaging layers need not be

stored in grade B (where justified) if the integrity and configuration (e.g. multiple sterile coverings that can be removed

at each transfer from lower to higher grade) of the sterile pack allows the items to be readily disinfected during transfer

into the grade A zone. Where protection is achieved by containment in sealed packaging this process should be

undertaken prior to sterilisation.

Comment:

Line 1022-1025: It is unclear if items must be autoclaved with multiple packaging or if it is acceptable for them to be

disinfected.

Proposed change (if any): “…need not be stored in grade B if items are packaged in multiple sterile packs or the

sterile pack allows the items to be readily disinfected during transfer…”


8.42 Transfer of materials, equipment, and components into an aseptic processing area should be via a unidirectional

process (e.g. through a double-door autoclave, a depyrogenation oven, effective transfer disinfection, or, for gaseous

or liquid materials, a bacteria-retentive filter).

Comment:

Include the words “depyrogenation tunnel”


8.44 Where materials, equipment, components and ancillary items are sterilized in sealed packaging or containers,

the integrity of the sterile protective barrier should be qualified for the maximum hold time, and the process should

include inspection of each sterile item prior to its use to ensure that the sterile protective measures have remained

integral.

Comment:

Excessive handling during inspection of each item may result in an increased contamination risk.

Comment:

Please confirm whether “qualified” refers to media fill or some other type of test e.g. physical test.


8.45 For materials, equipment, components and ancillary items that are necessary for aseptic processing but cannot

be sterilized, an effective and validated disinfection and transfer process should be in place. These items once

disinfected should be protected to prevent recontamination. These items, and others representing potential routes of

contamination, should be included in the environmental monitoring program.

Comment:

This paragraph is in the sterilisation section, yet refers to validated disinfection and transfer process?


8.46 When a depyrogenation process is used for any components or product contact equipment, validation studies

should be performed to demonstrate that the process will result in a minimum 3 log reduction in endotoxin. There is

no additional requirement to demonstrate sterilization in these cases


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8.46 When a thermal depyrogenation process is used for any components or product contact equipment, validation

studies should be performed to demonstrate that the process will provide a suitable Fh value and result in a minimum

3 log reduction in endotoxin. There is no additional requirement to demonstrate sterilization in these cases


8.48 In those cases where parametric release has been authorized, a robust system should be applied to the product

lifecycle validation and the routine monitoring of the manufacturing process. This system should be periodically

reviewed.

Comment:

Periodically requires defining.


8.49 Each heat sterilization cycle should be recorded on a time/temperature chart with a sufficiently large scale or by

other appropriate equipment with suitable accuracy and precision. Monitoring and recording systems should be

independent of the controlling system.

Comment (1):

Clarification is required here. Are independent systems required for both temperature and pressure for moist heat

sterilisation as Line 1100 to 1104 states “Time, temperature and pressure should be used to monitor the process”. Also

what is the regulatory definition of independent?

Comment (2):

Line 1078-1079: The controlling system is usually integrated with the recording systems.

Proposed change (if any): suggest a broader statement, by replacing ‘should’ with ‘can’

Comment (3):

This statement appears to have been written with much older technologies in mind. In modern facilities the equipment

utilized for sterilization is controlled by an automation system and a record of the cycle is downloaded into a historian.

With use of this kind of automation, which provides real time and much more accurate control, it is not necessary to

have separate systems for monitoring and control – only one set of instrumentation is capable of performing both tasks

accurately.

Proposed change:

8.49 Each heat sterilization cycle should be recorded by appropriate equipment with suitable accuracy and precision


8.50 The position of the temperature probes used for controlling and/or recording should have been determined

during the validation (which should include heat distribution and penetration studies), and, where applicable, also

checked against a second independent temperature probe located at the same position.


8.50 The position of the temperature probes used for controlling and/or recording should have been determined during

the sterilisation cycle validation (which should include heat distribution and penetration studies). The thermometric

studies should be undertaken using independent multi-point calibrated thermocouples


8.53 After the high temperature phase of a heat sterilization cycle, precautions should be taken against contamination

of a sterilized load during cooling. Any cooling fluid or gas in contact with the product should be sterilized unless it

can be shown that any leaking container would not be approved for use.

Comment:

It is recommended that air flow visualisation studies are conducted to identify and assist in the elimination of any

adverse contaminating convection currents.

1098 Moist heat sterilization

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Comment:

Suggested additional text for clarity and guidance “Autoclaves should be controlled and maintained in accordance

with EN285. Typical sterilisation conditions within a given load are 121°C for 15 minutes and 134°C for 3.5 minutes.

Other temperatures and times may be justified when supported by scientific rationale”.


8.54 Time, temperature and pressure should be used to monitor the process. Each item sterilized should be inspected

for damage, seal and packaging material integrity and moisture on removal from the autoclave. Seal and packaging

integrity should also be inspected immediately prior to use. Any items found not to be fit for purpose should be

removed from the manufacturing area and an investigation performed.

Comment (1):

Examination of every item may lead to excessive handling and a potential for contamination

Comment (2):

Line 1102-1104: A packaged and sterilized item not passing the seal and package integrity inspection prior to use should

not automatically require a full investigation. The sterilized item would only be used in manufacturing if the sterile

package is integral, and as such a damaged package would not pose a hygienic risk to the operations and would not need

to be investigated, unless an adverse trend of defect packages is obvious.


Seal and packaging integrity should also be inspected immediately prior to use. Any items found not to be fit for

purpose should be removed from the manufacturing area


8.57 Validation should include a consideration of equilibration time, exposure time, correlation of pressure and

temperature and maximum temperature range during exposure for porous cycles and temperature, time and F0 for

fluid cycles. These critical parameters should be subject to defined limits (including appropriate tolerances) and be

confirmed as part of sterilization validation and routine cycle acceptance criteria. Revalidation should be performed

annually.

Comment:

Validation must include equilibration time, exposure time, correlation of pressure and temperature and maximum

temperature range during exposure for porous cycles and temperature, time and F0 for fluid cycles. For steam

sterilisers, guidance on equilibration time and other aspects of cycle validation can be found in EN 285 and ISO

17666-1.

Comment:

Suggest revalidation or rather requalification is directed towards worse case load as determined by QRM.


8.59 When the sterilization process includes air purging (e.g. porous autoclave loads, lyophilizer chambers) there

should be adequate assurance of air removal prior to and during sterilization. Loads to be sterilized should be

designed to support effective air removal and be free draining to prevent the build-up of condensate.


8.59 When the sterilization process includes air purging (e.g. porous autoclave loads, lyophilizer chambers) there

should be adequate assurance of air removal prior to and during sterilization. Loads to be sterilized should be designed

to support effective air removal and be free draining to prevent the build-up of condensate. The fitting of an air

detector to porous load sterilisers is recommended.


8.60 The items to be sterilized, other than products in sealed containers, should be dry, wrapped in a material which

allows removal of air and penetration of steam but which prevents recontamination after sterilization. All load items

should be dry upon removal from the sterilizer. Load dryness should be confirmed as a part of sterilization process

acceptance.

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8.60 The items to be sterilized, other than products in sealed containers, should be dry, wrapped in a material (unless

maintained under Grade A conditions post sterilisation) which allows removal of air and penetration of steam and

condensate removal but which prevents recontamination after sterilization. All load items should be dry upon removal

from the sterilizer. Load dryness should be confirmed as a part of sterilization process acceptance.


8.62 Care should be taken to ensure that materials or equipment are not contaminated after the sterilization exposure

phase of the cycle due to the introduction of non-sterile air into the chamber during subsequent phases; typically only

sterile filtered air would be introduced into the chamber during these phases.


8.62 Care should be taken to ensure that materials or equipment are not contaminated after the sterilization exposure

phase of the cycle due to the introduction of non-sterile air into the chamber during subsequent phases; typically only

sterile filtered air would be introduced into the chamber during these phases. Moist heat sterilisers employing porous

cycles must be fitted with 0.2 micron vent filters which are capable of being sterilised and integrity tested in situ.


8.63 Where Sterilization in place (SIP) systems are used, (for example, for fixed pipework, vessels and lyophilizer

chambers), the system should be appropriately designed and validated to assure all parts of the system are subjected

to the required treatment. The system should be monitored for temperature, pressure and time at appropriate critical

locations during routine use, this is to ensure all areas are effectively and reproducibly sterilized; these critical

locations should be demonstrated as being representative, and correlated with, the slowest to heat locations during

initial and routine validation. Once a system has been sterilized by SIP it should remain integral prior to use, the

maximum duration of the hold time should be qualified.

Comment(1):

Add the following to the end of this paragraph: “Validation and requalification of SIP systems requires the use of BIs

as well as independent thermometric devices”.

There is no mention of over-pressure requirements or defined leak rate acceptance criterion?

Comment (2):

Line 1145: SIP has previously been used in the document to refer to Steam in Place, which is the correct term (not

Sterilisation in Place).

Proposed change:

Change ‘Sterilisation in Place’ to ‘Steam in Place’

1155 Dry Heat sterilization.

Comment:

Suggested additional text for clarity and guidance “Typical sterilisation conditions are 160°C for 120 minutes; Typical

depyrogenation conditions provide an Fh value equivalent to 250°C for 30 minutes. Other temperatures and times may

be justified when supported by scientific rationale”.


8.65 Dry heat sterilization or depyrogenation tunnels are typically employed to prepare components for aseptic filling

operations but may be used for other processes. Tunnels should be configured to ensure that airflow patterns protect

the integrity and performance of the sterilizing zone, by maintaining a stable pressure differential and airflow pattern

through the tunnel from the higher grade area to the lower grade area. All air supplied to the tunnel should pass

through a HEPA filter; periodic tests should be performed to demonstrate filter integrity. Any tunnel parts that come

into contact with sterilized components should be appropriately sterilized or disinfected. Critical process parameters

that should be considered during validation and/or routine processing should include, but may not be limited to:

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Comment:

It is desirable for the cooling zone to be capable of automated disinfection or sterilisation. Where located outside of

the aseptic area, the pressure differential between the cooling zone and the surrounding environment must be set at a

defined minimum value.

A HEPA filter is defined in the glossary as 99.97% efficient. Can hot air filters be reliably manufactured to this

standard?

Comment:

Line 1169: validation of depyrogenation tunnel should include a maximum exposure time in order to avoid any

damage of the filled product if the container is not sufficiently cooled down.


8.67 Dry heat ovens are typically employed to sterilize or depyrogenate primary packaging components, finished

materials or APIs but may be used for other processes. They should be maintained at a positive pressure to lower

grade areas. All air entering the oven should pass through a HEPA filter. Critical process parameters that should be

considered in validation qualification and/or routine processing should include, but may not be limited to::

Comment:

Other processes include the sterilization of oil based excipients.

Periodic tests should be performed to demonstrate filter integrity.

1195 Existing text:

c) Chamber pressure.

Comment:

Also include airflow and or fan velocity

1206 Existing text:

Sterilization by radiation

Comment:

Suggested additional text for clarity and guidance “Typical sterilisation dose is 25kGy delivered over a pre-

determined time. Other doses may be justified when supported by bioburden studies and a scientific rationale”.

Reference could also be given to ISO11137.

1220 Existing text:

Sterilization with Ethylene Oxide

Comment:

Reference could be given to ISO11135.


8.72 This method should only be used when no other method is practicable. During process validation it should be

shown that there is no damaging effect on the product and that the conditions and time allowed for degassing to

reduce any residual ethylene oxide (EO) gas and reaction products to defined acceptable limits for the type of product

or material.


8.72 This method should only be used when no other method is practicable. During process validation it should be

shown that there is no damaging effect on the product and that the conditions and time allowed for degassing are

sufficient to reduce any residual ethylene oxide (EO) gas and reaction products to defined acceptable limits for the

type of product or material.

Comment:

Line 1222: “8.72 This method should only be used when no other method is practicable.” This should be clarified

since many suppliers of syringes and vials in tubs and nets use this EO sterilization method.


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8.75 Each sterilization cycle should be monitored with suitable biological indicators, using the appropriate number of

test pieces distributed throughout the load unless parametric release has been authorized by the National Competent

Authority.

Comment:

Is parametric release actually being considered for EtO sterilisation? That is BIs and sterility test not required for

articles processed by this method?


8.76 Critical process variables that should be considered as part of sterilization process validation and routine

monitoring include, but are not limited to: EO gas concentration, relative humidity, temperature and EO gas pressure

and exposure time.


8.76 Critical process variables that should be considered as part of sterilization process validation and routine

monitoring include, but are not limited to: EO gas quality, EO gas quantity or concentration, relative humidity,

vacuum, temperature and EO gas pressure and exposure time.

1249 Filtration of medicinal products which cannot be sterilized in their final container


8.78 If a liquid product cannot be terminally sterilized by a microbiocidal process, it should be sterilized by filtration

through a sterile, sterilizing grade filter (with nominal pore size of 0.22 micron (or less) or with at least equivalent

micro-organism retaining properties), and subsequently aseptically filled into a previously sterilized container, the

selection of the filter used should ensure that it is compatible with the product, see 8.119.. Suitable bioburden

reduction and/or sterilizing grade filters may be used at multiple points during the manufacturing process to ensure a

low and controlled bioburden of the liquid prior to the primary sterilizing grade filter. Due to the potential additional

risks of a sterilizing filtration process as compared to other sterilization processes, a second filtration through a

sterile, sterilising grade filter (positioned as per clause 8.15), immediately prior to filling, is advisable


8.78 If a liquid product cannot be terminally sterilized by a microbiocidal process, it should be sterilized by filtration

through a sterile, sterilizing grade filter (with nominal pore size of 0.22 micron (or less) or with at least equivalent

micro-organism retaining properties), and subsequently aseptically filled into a previously sterilized container, the

selection of the filter used should ensure that it is compatible with the product, see 8.119.. Suitable bioburden

reduction and/or sterilizing grade filters may be used at multiple points during the manufacturing process to ensure a

low and controlled bioburden of the liquid prior to the primary sterilizing grade filter. Due to the potential additional

risks of a sterilizing filtration process as compared to other sterilization processes, a second filtration through a sterile,

sterilising grade filter (positioned as per clause 8.15), immediately prior to filling, is advisable unless the sterile

product pathway down-stream of the filter can be demonstrated to be fully integral e.g. hard-piped stainless steel

system subject to SIP and held under positive pressure. In exceptional circumstances it may not be possible to

undertake a second sterilising filtration where process/product considerations prevent this.

Comment:

Line 1252: There are non-filterable formulations. Some biologicals such as vaccines with adjuvants cannot be

filtered, and are aseptically processed without a filtration step.

Proposed change (if any): Add it should be sterilized by filtration “when possible”


e) Allow sterilization procedures, including SIP, to be conducted as necessary. The sterilization procedures should be

validated to ensure achievement of a target sterilization assurance level (SAL) of 10"6 or better (e.g. 10 7).

Comment:

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Not sure why SAL for SIP is mentioned here OR if referring to the validation of the filtration process per se should it

read as “e) Allow sterilization procedures, including SIP, to be conducted as necessary. The sterilization by filtration

procedures should be validated to ensure achievement of a target titre reduction of 107 per cm2 or better when

challenged with a suitable test micro-organism such as B.diminuta.


f) Permit in-place integrity testing, preferably as a closed system, prior to filtration as necessary. In-place integrity

testing methods should be selected to avoid any adverse impact on the quality of the product.

Comment:

Can it be clarified if this section is for new design or does it also apply to previously designed processes where the

design did not include in line integrity testing?


8.82 Wherever possible, the product to be filtered should be used for bacterial retention testing. Where the product to

be filtered is not suitable for use in bacterial retention testing, a suitable surrogate product should be justified for use

in the test. The challenge organism used in the bacterial retention test should be justified.


8.82 Wherever possible, the product to be filtered should be used for bacterial retention testing. Where the product to

be filtered is not suitable for use in bacterial retention testing e.g. as it has inherent anti-microbial properties, a suitable

surrogate product should be justified for use in the test. The challenge organism used in the bacterial retention test

should be justified.

1301-1305 Comment:

Water can be used to flush and integrity test a filter, and in this case, as long as the filter is completely dried by

filtered air, there is no need to add a product flush.

Proposed change:

8.83 Filtration parameters that should be considered in validation and routine processing should include but are not

limited to: a) If the system is flushed or integrity tested in-situ with a fluid other than the product, then flushing with

the product should be part of the process unless this fluid is WFI and the filter can be fully dried prior to use.

1311 Comment:

8.83 c) Filtration process conditions: vii indicates time taken for a know volume and pressure difference as in the

current Annex 1 but already indicated in this point 8.83 c) alineas iii, iv and v.

1328 Comment:

8.83 c) vii “ Results of these checks should be included in the batch record” should be applied to all parameters of

8.83 c) Filtration process conditions.


8.84 The integrity of the sterilized filter assembly should be verified by testing before use, in case of damage and loss

of integrity caused by processing, and should be verified by on line testing immediately after use by an appropriate

method such as a bubble point, diffusive flow, water intrusion or pressure hold test. It is recognised that for small

batch sizes, this may not be possible; in these cases an alternative approach may be taken as long as a formal risk

assessment has been performed and compliance is achieved. There should be written integrity test methods, including

acceptance criteria, and failure investigation procedures and justified conditions under which the filter integrity test

can be repeated. Results of the integrity tests (including failed and repeated tests) should be included in the batch

record.

Comment (1):

Single use system gamma irradiated filters cannot always be integrity tested prior to use. This is seen by much of

industry as a key issue. Some companies incorrectly remove filter from housing for testing, therefore is this

requirement clear enough? Note it is for product filtration only NOT air, vents, compressed gases etc.

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Comment (2)

Also there is no reference to the use of off-line testing?

Comment (3)

8.84 “It is recognised that for small batch sizes...” It should be indicated what is considered as a small batch size.:

Comment (4):

Line 131: This sentence is not clear: in case of damage and loss of integrity caused by processing,

Proposed change (if any): Delete or clarify the highlighted sentence.

Comment (5):

While in situ testing post use is useful, it should not be mandated as this may lead to much greater increased

complexity of the system and can lead to additional risk to the process. The use of off line testing will not impact the

accuracy of the filter integrity test results. Additionally, propose the removal of the examples for appropriate filter

integrity testing methods as these may evolve over time, and as long as a test is appropriate for and validated for its

intended use, the actual methodology should not be prescribed.


8.84 The integrity of the sterilized filter assembly should be verified by testing before use, in case of damage and loss

of integrity caused by processing, and should be verified immediately after use by an appropriate method. It is

recognised that for small batch sizes, this may not be possible; in these cases an alternative approach may be taken as

long as a formal risk assessment has been performed and compliance is achieved. There should be written integrity

test methods, including acceptance criteria, and failure investigation procedures and justified conditions under which

the filter integrity test can be repeated. Results of the integrity tests (including failed and repeated tests) should be

included in the batch record


8.85 The integrity of critical sterile gas and air vent filters in the filter assembly should be verified by testing after use.

The integrity of non-critical air or gas vent filters should be confirmed and recorded at appropriate intervals.

Comment:

Definition required for “after use”

Comment:

Line 1341: This requires post-use integrity testing of all critical sterile gas and vent filters.

Proposed change (if any): The term ‘critical filter’ should be defined


8.86 For gas filtration, the avoidance of unintended moistening or wetting of the filter or filter equipment is

important. This can be achieved by the use of hydrophobic filters.


8.86 For gas filtration, the avoidance of unintended moistening or wetting of the filter or filter equipment is important.

For this reason, by first intent hydrophobic filters should be used.

1349 Comment:

8.87 Serial filtration: it should be indicated that the sample for bioburden must be taken before the last sterilizing filter

and the specification NMT 10 CFU/100 ml for bioburden should be indicated.

Comment:

Line 1349 &1354: Need clarification on “serial filtration” versus “redundant filter”


8.88 Where a redundant sterilizing filter is used, the additional filter does not require post- integrity testing unless the

primary sterilizing filter fails, in which case the redundant filter must then satisfactorily pass post-use integrity

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testing. Bioburden samples should be taken prior to the first filter and the sterilizing filter, systems for taking samples

should be designed so as not to introduce contamination.

Comment:(1)

Omit wording “ the first filter and” or state that if a bioburden sample is taken prior to the first filter then it is not

necessary to take an additional sample prior to the sterilizing filter.

The meaning of redundant can vary in different parts of the world. Can the word be defined for filtration?

Comment (2)

Line 1356-1358: The requirements for product bioburden testing should be based on Quality Risk Management

principles and relate to the design of the manufacturing operations (including holding times) and product characteristics

(including growth promoting abilities). It is agreed that for aseptic manufacture a bioburden sample always should be

taken prior to the sterilizing filter, but any samples taken prior to the first filter should depend on above mentioned

aspects and can be validated. The design of the bioburden sampling regimen should be included in the overall

contamination control strategy.


Bioburden samples should be taken prior to the sterilizing filter and unless otherwise validated, before the first filter.

Systems for taking samples should be designed so as not to introduce contamination.

Comment (3):

Line 1354: 8.88 “Where a redundant sterilizing filter is used, the additional filter does not require post-integrity

testing unless...” Does that mean that the redundant filter should be tested for integrity before use even if the first filter

passed the pre-use integrity test? “Bioburden samples should be taken prior to the first filter and the sterilizing

filter...” In redundant sterilizing filtration all filters are sterilizing filters and thus bioburden should be taken only

before one sterilizing filter, the last one or the first one as explained in PICS interpretation PI 032-2 in January 2010.

The specification NMT 10 CFU/100 ml for bioburden should be indicated.

Comment (4):

Pre-filtration bioburden testing is utilized to verify the microbial load just prior to the final sterilizing filter to ensure it

is appropriate to the process. Based on the process and the product, a bioburden control strategy may suggest

additional testing at other points upstream, but that will be product and process related and should be determined by

the control strategy.


8.88 Where a redundant sterilizing filter is used, the additional filter does not require post integrity testing unless the

primary sterilizing filter fails, in which case the redundant filter must then satisfactorily pass post-use integrity testing.

Bioburden samples should be taken prior to the sterilizing filter, systems for taking samples should be designed so as

not to introduce contamination.


8.89 Liquid sterilizing filters should be discarded after the processing of a single lot. The same filter should not be

used for more than one working day unless such use has been validated.


8.89 Liquid sterilizing filters should be discarded after the processing of a single lot unless they are designed to be

used for multiple lots and are validated for such purposes e.g. Large scale cartridge filters for use in API manufacture

which are designed for repeated sterilisations. In all other cases the same filter should not be used for more than one

working day unless such use has been validated.

Comment (1):

Filter exchange can pose a risk to aseptic processes since closed systems need to be opened and critical areas exposed

for this operation. Exchanging the filter after every single lot would add an avoidable risk to campaign production,

where several lots of the same product are produced in a validated sequence.

The maximum usage duration, total filtration volume, number of in-line cleaning and sterilization cycles for sterilizing

filters should rather be based on a validated process and Quality Risk Management principles. The liquid sterilizing

filter should be validated related to e.g. filter conditioning, filtration time, flow rate, filtration volume, bacterial retention

testing, extractables/leachables and sterilization procedures for the filter. In-line integrity testing of the sterilizing filter

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should be included in the validation, as well as any cleaning, flushing, drying, hold-times, etc. of the filter in-between

batches and/or after certain periods of use. The validation outcome would include provision for the maximum use of

the sterilizing filter which would be part of a standard operating procedure and/or manufacturing method. Filtration

parameters set during validation for products and/or product groups would subsequently be monitored to ensure proper

functioning of the filter during regular use.

Alternative Proposed text change (2)

Liquid sterilizing filters should be discarded after a defined and validated maximum use period.

Comment (3)

This requirement would prohibit the use of continuous manufacturing and back to back manufacturing systems from

being implemented by the industry. It is clear that filters should not be intended for re-use.


8.89 Liquid sterilizing filters should be discarded after the processing of a single lot unless such use has been

validated and is supported by the process risk assessment.

1364 Form-Fill-Seal

1366-1373 Line 1366 to 1373

Existing text:

8.90 Form-Fill-Seal (FFS) units include blow moulding from thermoplastic granulate and thermoforming from

thermoplastic film typically known as Blow-Fill-Seal (BFS) and Vertical-Form-Fill-Seal (VFFS) respectively. VFFS

process is an automated filling process, typically for terminally sterilized processes, that may utilize a single or dual

web system which constructs the primary container out of a flat roll of thermoplastic film while simultaneously filling

the formed bags with product and sealing the filled bags in a continuous process. All such containers are considered

to be sealed by fusion and, as such, fall under the requirement to perform 100% integrity testing.


8.90 Form-Fill-Seal (FFS) units include blow moulding from thermoplastic granulate and thermoforming from

thermoplastic film typically known as Blow-Fill-Seal (BFS) and Vertical-Form-Fill-Seal (VFFS) respectively. VFFS

process is an automated forming/filling process, typically for terminally sterilized products, that may utilize a single or

dual web system which constructs the primary container out of a flat roll of thermoplastic film while simultaneously

filling the formed bags with product and sealing the filled bags in a continuous process. All such containers are

considered to be sealed by fusion and, as such, fall under the requirement to perform 100% integrity testing.

Comment:

Line 1372: 8.90 VFFS containers are considered to be sealed by fusion. Does that mean that BFS containers are not

considered to be sealed by fusion?


a) Determination of the "critical zone" that should be protected from contamination, and its control.

Comment:

This is open to interpretation. Please can it be stated clearly what is meant? Is it the parison forming and moulding

zone, the filling zone or the shuttle area between both?


8.95 Shuttle and Rotary-type equipment used for aseptic production which is fitted with an effective grade A air

shower should be installed in at least a grade C environment, provided that grade A/B clothing is used.

Comment:

Avoid use of term A/B. Grade B clothing should be worn.


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8.97 For Rotary-type equipment the environment should comply with the viable and nonviable limits "at rest". It is

not normally possible to perform environmental monitoring within the parison during operation" Monitoring of the

background environment should be performed in accordance with risk management principles


8.97 For Rotary-type equipment the environment should comply with the viable and nonviable limits "at rest". It is

not possible to perform environmental monitoring within the parison during operation". Controls should be in place to

assure the integrity of the parison e.g. breaches in the parison should not go undetected. Monitoring of the

background environment should be performed in accordance with risk management principles


8.99 In addition, for Shuttle-type designs, the area between parison cutting and mould sealing should be covered by a

flow of HEPA filtered or sterile air of appropriate quality to provide grade A at the critical zone.

Comment:

The sterility of formed containers in the shuttle zone is maintained by the protective heated air currents associated

with the process. Feeding this area with HEPA filtered air may well adversely impact the sterility of the process.


8.101 External particle and microbial contamination of the polymer should be prevented by appropriate design,

control, and maintenance of the polymer storage and distribution systems.

Comment:

More definition is required on the scope or minimum expectation in respect to contamination control.


8.103 Process validation should take into consideration critical operating parameters and variables of the equipment

that impact on the quality of the product, e.g. filling speed, extrusion temperature, filling times.


8.103 Process validation should take into consideration critical operating parameters and variables of the equipment

that impact on the quality of the product, e.g. filling speed, extrusion temperature, mould vacuum, air supply to

mould, filling times.

1450 Lyophilisation

Comment:

The section contains no guidance for bulk lyophilisation processes as used for some API manufacturing.


8.106 The lyophilizer should be sterilized before each load. The lyophilizer should be protected from contamination

after sterilization.


8.106 Unless Grade A continuity has been maintained following sterilization, the lyophilizer should be cleaned and

sterilized before each load. The frequency for CIP and SIP should be determined by risk assessment.

Comment (2)

Line 1460: The sterilization processes and manufacturing equipment should be handled and maintained relating to

process and product risks; the design and operations of processes should be based on Quality Risk Management

principles. The lyophilizer use, and the characteristics and risk for the product operated in the lyophilizer, should form

the basis for control and monitoring of the lyophilizer, specifically under consideration of producing sterile APIs.

The following should be considered:

• The frequency for lyophilizer sterilization should be challenged during the regular media fills (aseptic

processing simulation) using worst case considerations.

• Historical and continuous monitoring data from the environment

• Automated loading mechanisms that minimize the risk of contamination versus manual loading mechanisms.

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• The nature of the items to be lyophilized (e.g. finished product versus API lyophilization as Cephalosporin

and Penicillin).

• The effect on other manufacturing steps, giving the possibility for validated campaign production.

Alternative Proposed text change (2)

The lyophilizer should be sterilized in a defined and validated frequency that is challenged during aseptic process

simulations.


8.110 The integrity of the system should be monitored periodically along with consideration of the leak rate test.


8.110 The integrity of the system should be monitored periodically along with the leak rate test.

1478-1479 b) Transport to the lyophilizer and loading of filled product, or other equipment into the lyophilizer should take place

under a grade A environment.


c) Transport to the lyophilizer and loading of filled product, or other equipment into the lyophilizer should take

place under a grade A environment. By first intent automated systems in the absence of human intervention

should be used. Otherwise these operations should be protected by mobile Grade A RABS incorporating

glove ports to prevent direct human intervention.

Comment:

Line 1479: 8.111 b) It should be added after “… place under grade A environment.” “with physical segregation from

operators” to be in compliance with point 8.17.


c) Airflow patterns should not be adversely affected by transport devices and venting of the loading zone. Unsealed

containers should be maintained under grade A environment.


c) Airflow patterns should not be adversely affected by transport devices and venting of the loading zone. Unsealed

containers should be maintained under grade A environment separated from operators by the use of barrier

technology.

1492 Closed Systems

1499 Comment:

Add physical contamination

Proposed change (if any):Contamination may be microbiological, chemical or physical


8.114 It is critical to ensure the sterility of product contact surfaces of closed systems used for aseptic processing. The

design and selection of any closed system used for aseptic processing must ensure maintenance of sterility.

Tubing/pipework that is not assembled prior to sterilization should be designed to be connected aseptically, e.g. by

intrinsic aseptic connectors or fusion systems.


8.114 It is critical to ensure the sterility of all product contact surfaces used for aseptic processing, including those of

closed systems. The design and selection of any closed system used for aseptic processing must ensure maintenance of

sterility. Tubing/pipework that is not assembled prior to sterilization should be designed to be connected aseptically,

e.g. by intrinsic aseptic connectors or fusion systems.


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8.116 The background in which closed systems are located will vary. If there is a high risk that the system will not

remain integral during processing it should be located in a grade A environment. If the system can be shown to

remain integral at every usage then lower grades, including grade D, can be considered.

Comment:

This is confusing, as it seems to suggest that you can accept a sterile system not maintaining its integrity. Surfaces in

Grade A may not be sterile, therefore if a liquid bridge occurs, there will still be a risk to contaminate the product.

While it is appreciated that the risk will be lower, this does not appear to be sound GMP.

1517 Single use Systems


i)Assessment of suppliers of disposable systems (including sterilization of these disposable systems.


i) Assessment of suppliers of disposable systems, including the sterilization of the equipment. Note these systems may

consist of parts supplied from different manufacturers but received as sterilised assemblies. It is important to ensure

that the manufacturing and change control procedures are adequate and enforced.


8.119 The compatibility of materials used for product contact surfaces with the products should be ensured under the

process conditions by evaluating e.g. adsorption and reactivity to the product.

Comment:

Also need to take into account the physical dimensions of tubing etc. Non-uniform thickness of tubing may lead to

excessive wear and damage when using peristaltic pumps leading to leakage.

1580 Section 9 Viable and non-viable environmental & process monitoring:

General comment:

Overall this section is very light on detail of what regulatory expectations are. For more information and clarity it

should draw from existing peer reviewed guidance literature. As a whole the ordering of the section is a little confused

and requires re-editing.

1584 Comment:

More clarification is required for “process monitoring”.


9.3 These key elements provide information with regards to the process and facility capabilities with respect to the

maintenance of sterility assurance. The information from these systems should be used for routine batch release and

for periodic assessment during process review or investigations.


9.3 These key elements as well as pressure differential, airflow, temperature and humidity data provide information

with regards to the process and facility capabilities with respect to the maintenance of sterility assurance. The

information from these systems should be used for routine batch release and for periodic assessment during process

review or investigations.

1599 Environmental monitoring


9.4 In order to establish a robust environmental monitoring program, i.e. locations, frequency of monitoring and

incubation conditions (e.g. time, temperature(s) and aerobic and or anaerobic), appropriate risk assessments should

be conducted based on detailed knowledge of the process inputs, the facility, equipment, specific processes,

operations involved and knowledge of the typical microbial flora found, consideration of other aspects such as air

visualization studies should also be included. These risk assessments should be re-evaluated at defined intervals in

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order to confirm the effectiveness of the site's environmental monitoring program, and they should be considered in

the overall context of the trend analysis and the contamination control strategy for the site.

Comment:

A lot of this section seems to be about viable monitoring…not general monitoring requirements. Incubation

temperature is mentioned but there is no guidance regarding the possibility of selecting different temperature for

different grades.


9.5 Routine monitoring for clean rooms, clean air devices and personnel should be performed "in operation"

throughout all critical stages, including equipment set up. The locations, frequency, volume and duration of

monitoring should be determined based on the risk assessment and the results obtained during the qualification.

Comment:

This paragraph is very much open to interpretation. Routine monitoring within Grade A zones, using viable surface

sampling must only be carried out upon completion of activities. It would be useful to reference the requirements in

standards such as ISO 14644-2.


9.7 For grade A monitoring, it is important that sampling should be performed at locations posing the highest risk of

contamination to the sterile equipment surfaces, container-closures and product in order to evaluate maintenance of

aseptic conditions during critical operations.

Comment:

There is insufficient detail to determine the placement of non-viable monitoring probes. Should they be at a maximum

of 30cm from the point of interest at working height or could they be placed just under the HEPA filters because “they

would otherwise hinder routine activities”?


The monitoring of Grade A clean zones should be adequate to demonstrate the maintenance of aseptic processing

conditions during critical operations. Monitoring should be performed at locations posing the highest risk of

contamination to the sterile equipment surfaces, container-closures and product. The selection of monitoring locations

and the orientation and positioning of sampling devices should be justified and appropriate to obtain data from the

critical zones.


9.8 Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring.

Alert levels should be established based on results of Performance Qualification (PQ) tests or trend data and should

be subject to periodic review.

Comment:

Should alert and action limits or alert and action levels be applied? The glossary only refers to levels.

It is unclear how non-viable alert and action levels would be set i.e. against counts per cubic foot or per cubic metre.

Could the word periodic be defined i.e. is the expectation to trend data continuously, weekly, monthly or annually etc?


9.9 The alert limits for grade B, c and D should be set based on the area performance, with the aim to have limits

lower than those specified as action limits, in order to minimise risks associated and identify potential changes that

may be detrimental to the process.

Comment:

What about non-viable alert levels in Grade A?

Comment:

Line 1629: c not in capital letter, please correct.


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9.10 If action limits are exceeded operating procedures should prescribe a root-cause investigation followed by

corrective and preventive action. If alert limits are exceeded, operating procedures should prescribe scrutiny and

follow-up, which might include investigation and corrective action.

Comment (1):

The actions taken for both alert and action levels look almost identical and will be in most cases of Grade B viable

excursions.

Comment (2):

Line 1634: 9.10 The requirement “if alert limits are exceeded...which might include investigation...” should comply

with the point 6.9 part I of EU GMP, indicating that ” Any out of trend or out of specification data should be

addressed and subject to investigation.”


9.11 Surfaces and personnel should be monitored after critical operations. Results from monitoring should be

considered when reviewing batch documentation for finished product release.

Comment:

Again this paragraph appears to be describing viable monitoring..but it is in the general section.

1642 Non-viable monitoring

General comment:

This section would be better located within section 5 to avoid repetition and confusion. It is understood that it was

placed here to differentiate classification from monitoring, but the overall effect is not helpful.


Table 5: Recommended limits for airborne particle concentration for the monitoring of non-viable contamination

Comment (1):

The table is similar to that in section 5, Premises, but now includes at rest and in operation for 5 micron particles or

greater and reorders the limit columns i.e. “in operation” is listed before “at rest” in this table. To avoid confusion, it

would be more appropriate to have one table within the Premises section and cross refer to it from this section. The

maintenance of the 5 micron particle for monitoring is sensible.

Comment (2):

The Annex refers to ISO14644 for sampling methodology guidance and applies the ISO limits for all cases except for

the 5 micron particulates for Grade A area. There is no scientific rationale for this single discrepancy. ISO limits

should be applied in Table 5.

Proposed change:

Table 5: Recommended limits for airborne particle concentration for the monitoring of non-viable

contamination

Grade Recommended maximum limits Recommended maximum limits

for particles ≧ 0.5 μm/m3 for particles ≧ 5 μm/m3

in operation at rest in operation at rest

A 3 520 3 520 29 29

Comment (3):

Line 1653: Particle counters, which utilise laser light technology, are known to be unable to record absolute numbers

and sizes of particles and trying to count low levels of particles at ≥5μm, is subject to a high degree of uncertainty.

This is reflected in the EN ISO 14644-1(2015) standard where the monitoring of ≥5μm particles for ISO Class 5 is

excluded. It is more appropriate to record particle concentrations at one size only, specifically at the accompanying

≥0.5μm size, where the total allowable number of particles is sufficiently high to negate the inaccuracies of the

particle detection methodology.

The ratios of ≥0.5μm and ≥5μm particles to microbe carrying particles (MCPs) have been established by experiment

and has demonstrated that if the requirement for ≥0.5μm particles and airborne microbial counts (Table 6) should be

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complied with, the limit required for particles ≥5μm is too low and for each cleanroom grade, the limit for ≥5μm

particles should be increased by a factor of 10. Consequently, particle generating events in cleanroom areas will

produce particle counts that, although compliant with the class limits for ≥0.5μm particles and MCPs, may exceed the

class limit for ≥5μm particles.

Real time monitoring, particularly within EU Grade A zones, is the most useful approach for managing excursions2.

Most particle counters operate at a flow rate of 1ft3/min where the proportioned per ft3 limit for ≥5μm particles is <1.

This anomaly causes considerable difficulties in setting a meaningful operational limit for particles ≥5μm but there are

no such issues if the single particle size of ≥0.5μm is utilised. This would also further harmonise the European

guidelines with those of the United States Food and Drug Administration. It should also be noted that the

recommended maximum limits for particles is not harmonised with the limits defined in the reference document EN

ISO 14644-1(2015).

Proposed change:

1. Measure airborne particle concentrations only at the ≥0.5μm size;

2. Harmonise the recommended maximum limits for particles defined in Table 5 with the limits defined in EN ISO

14644-1(2015);

3. If the document retains the recommendation to also monitor at the ≥5μm size, the per m3 limit for Grade A, B and C

areas should be increased to 200, 20 000 and 200 000 respectively


Note 1: The particle limits given in the table for the "at rest" state should be achieved after a short "clean up" period

defined during qualification in an unmanned state after the completion of operations (see 5.26e).

Comment:

This sentence is almost a repeat from Lines 533 to 535. Please refer to the earlier comment regarding a guidance time

to achieve clean up.

1659-1662 Existing Text:

Note 2: With regards to the monitoring of 5.0 µm, the limit of 20 is selected due to the limitations of monitoring

equipment. It should be noted that alert limits should also be set based on historical and qualification data, such that

frequent sustained recoveries below the action limit should also trigger an investigation.


Note 2: With regards to the monitoring of >=5.0 μm, the limit of 20 is selected owing to the sensitivity limitations of

the light scattering airborne particle counter (LSAPC) instrumentation. It should be noted that alert limits should also

be set based on historical and qualification data, such that frequent sustained particle counts, below the action limit

should also trigger an investigation.

Comment:

Note 2 should be “With regards of the monitoring of ≥5.0 μm ...”

Line 1661: It should be indicated what is considered as “frequent sustained recoveries” such as every batch or every

working session.


9.15 The grade A zone should be monitored continuously and with a suitable sample size (at least 28 litres (a cubic

foot) per minute) so that all interventions, transient events and any system deterioration would be captured and

alarms triggered if alert limits are exceeded.

Comment:

Some guidance is needed to understand regulatory expectations for assessing counts. Should it be against cubic foot

limits or per cubic metre limits? This is important to know as the use of the latter would clearly dilute temporarily

high counts (lasting 1 to 5 minutes for example) which would exceed cubic foot limits.

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Comment:

Line 1667: 9.15 should be “...with a suitable sample size (at least 28 litres (a cubic foot) per minute or less) so that all

interventions...”


9.16 It is recommended that a similar system be used for grade B zones although the sample frequency may be

decreased. The design of the monitoring system should be based on risk assessment and be commensurate with the

risk of the process to the product sterility assurance. The grade B zone should be monitored at such a frequency and

with suitable sample sizes that the programme captures any change in levels of contamination and system

deterioration. If alert limits are exceeded, alarms should be triggered.

Comment:

Does the wording "similar system" rule out the use of sequential monitoring devices? The wording “any change in

levels of contamination” may indicate that falls in contamination levels may warrant investigation.

1678-1681 Comments:

Table 5 gives recommended levels, however 9.17 leaves it up to the manufacturer. Please correct ambiguity.


9.19 In the case where contaminants present due to the processes involved would damage the particle counter or

present a hazard, e.g. live organisms and radiological hazards, the frequency and strategy employed should be such

as to assure the environment classification both prior to and post exposure to the risk. Additionally, monitoring

should be performed during simulated operations. Such operations should be performed at appropriately defined

intervals. The approach should be defined in the contamination control strategy.

Comment:

Can the regulatory expectation for the term “appropriately defined intervals” be more accurately defined?


9.21 The sample sizes taken for monitoring purposes using automated systems will usually be a function of the

sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal

qualification of clean rooms and clean air devices.

Comment:

More clarity on regulatory expectation is required as different readers will interpret differently.


9.22 Although monitoring of ^ 5.0 pm particles are not required for room qualification and classification purposes, it

is required for routine monitoring purposes as they are an important diagnostic tool for early detection of machine,

equipment and HVAC failure.


9.22 Although monitoring of ≧ 5.0 μm particles are not required for room qualification and classification purposes, it

is required for routine monitoring purposes as they are considered to provide some evidence of potential microbial

contamination events; for detection of machine, equipment and HVAC deterioration; and may be indicative of poor

practice during machine set-up and routine operation.

Comment:

Line 1705: It is stated that monitoring of particles ≥5µm is ‘an important diagnostic tool for early detection of

machine equipment and HVAC failure’ This is not correct and the monitoring of particles ≥5µm provides no benefits

to the control of contamination in cleanrooms but causes numerous issues.

Proposed change:

Remove Section 9.22.


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9.23 The occasional indication of macro particle counts, especially ^ 5.0 pm, may be considered false counts due to

electronic noise, stray light, coincidence, etc. However, consecutive or regular counting of low levels may be

indicative of a possible contamination event and should be investigated. Such events may indicate early failure of the

room air supply filtration (HVAC) system, filling equipment failure, or may also be diagnostic of poor practices

during machine set-up and routine operation.


9.23 The occasional indication of macro particle counts, (≧ 5.0 μm), may be considered false counts owing to

electronic noise, stray light, and accumulated particles shed from the sampling system. However, consecutive or

regular counting of low counts may be indicative of a possible contamination event and should be investigated.


9.24 Monitoring conditions such as frequency, sampling volume or duration, alert and action limits and corrective

action including investigation should be established in each manufacturing area based on risk assessment.

Comment:

There is an absence of guidance regarding location or orientation of sampling sensors, tube length, the avoidance of

kinks and radii requirements in tubing etc. see earlier comment re Lines 1621 to 1623.

1718 Viable monitoring:

Comment:

There are scientific papers available proving that impaction volumetric air samplers can vary markedly in their capture

efficiency depending upon their d50 value, yet there is no mention of this attribute in this document.


9.25 Where aseptic operations are performed, microbiological monitoring should be frequent using a combination of

methods such as settle plates, volumetric air, glove print and surface sampling (e.g. swabs and contact plates).

Comment (1):

The term frequent will be open to interpretation. It is suggested that reference is made to a guidance document for

more clarity.

Comment (2):

Line 1721: “...using a combination of methods such as...” should be in accordance with the PICS interpretation PI032-

2 ...using the methods indicated for each grade in Table 6

Comment (3):

This section of the Annex is specifically listing out and limiting sampling methods, whereas in lines 112-116 it

specifically stated that it did not wish to give detailed guidance on sampling methodology. Suggest making slightly

more general to ensure appropriate type of sampling is performed, without being prescriptive on the specific method

to be used.


9.25 Where aseptic operations are performed, microbiological monitoring should be frequent using a combination of

methods such as passive air, volumetric air, glove print and surface sampling.


9.26 Monitoring should include sampling of personnel at periodic intervals during the process. Particular

consideration should be given to monitoring personnel following involvement in critical interventions and on exit

from the grade A/B processing area.


9.26 Monitoring of personnel should follow a defined schedule with particular consideration given following

involvement in critical interventions within the Grade A zone and on exit from the Grade B processing area. For

gowned operators working within Grade B cleanrooms locations such as gloves, arms, goggles, hood and chest must

be sampled using contact plates and/or swabs.

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9.27 Continuous monitoring in grade A and B areas should be undertaken for the full duration of critical processing,

including equipment (aseptic set up) assembly and filling operations (i.e., an understanding of function and

interactions of each clean area). The monitoring should be performed in such a way that all interventions, transient

events and any system deterioration would be captured and any risk caused by interventions of the monitoring

operations is avoided.

Comment (1):

What is the expectation for continuous Grade B monitoring? Should it be performed using passive or active air

sampling or both? Should it be performed throughout the aseptic area (not just the processing room)? For facilities

which run campaign processing this may mean a significant increase in monitoring with areas being effectively

monitoring for 12 to 24 hours a day.

Note: no viable monitoring program is capable of capturing all risks from transient events, system deterioration etc.

Comment (2):

Line 1728-1730

Viable monitoring, as part of the environmental monitoring program should be based on Quality Risk Management

principles and included in the overall contamination control strategy. It is agreed that for aseptic production operations

viable and non-viable (total airborne) particles should be continuously monitored in critical processing areas in grade A

(with the exception of powder filling operations for which total airborne particles cannot be determined during filling

operations) – whereas the frequency of monitoring in grade B (as well as for grade C and D) should be based on a risk

assessment and product/process requirements - and be aligned with any air-visualisation/smoke studies in the aseptic

manufacturing area. Where and when a grade B area surrounding the critical processing area (grade A) poses a risk of

adding contamination into the critical area - such as during an intervention - monitoring during operations should take

place.


Continuous monitoring in the Grade A area should be undertaken for the full duration of critical processing, including

equipment (aseptic set up) assembly and filling operations (i.e., an understanding of function and interactions of each

clean area), wherever product characteristics allow.

Comment (3):

There is currently not a requirement for continuous monitoring in Grade B areas., nor is active viable air continuously

sampled in Grade A, only passive air. We recommend to be able to continue current practices.

Proposed change (if any): Reword as follows: “Continuous monitoring in Grade A area should be undertaken, and

Grade B at intervals determined by risk assessment.

Comment (4):

If the design of the areas includes critical operations or interventions with possible impact on product quality to be

performed in grade B, then its viable monitoring should be equivalent to A. Where B is only the class surrounding

class A, with no critical interventions, then there is no need for the same frequency of monitoring, since the risk and

impact are not the same. Additionally, clarify that continuous monitoring applies to passive air sampling (not

volumetric air).


9.27 Continuous passive air monitoring in grade A areas should be undertaken for the full duration of critical

processing, including equipment (aseptic set up) assembly and filling operations (i.e., an understanding of function

and interactions of each clean area). The monitoring should be performed in such a way that all interventions,

transient events and any system deterioration would be captured and any risk caused by interventions of the

monitoring operations is avoided. This could also apply to Grade B areas if surrounding critical operations or

protecting interventions, as determined by the risk assessment.

Comment (5):

Line 1728 & 1751: It is unclear what continuous (viable) monitoring in grade A and B areas relates to. It is not

feasible to continuously monitor surfaces. It is subsequently stated (line 1751) that settle plates should be exposed for

the duration of critical operations. Does exposure of settle plates throughout with supplementary air sampling meet the

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recommendations for continuous monitoring. If a periodic volumetric air sample is taken, then particle and settle

plate sampling is more than sufficient to demonstrate that microbial contamination is under control.

Proposed change:

Define the expected approach, for settle plates and air sampling to meet the recommendations for continuous (viable)

monitoring in grade A and B areas.


9.28 Rapid microbial monitoring methods may be adopted after validation as long as they are demonstrated to be at

least equivalent to the established methodology.

Comment:

This is the only one of two references to RMMs and may indicate regulatory loss of confidence in these emerging

technologies. This absence of positive promotion will probably encourage companies to continue to use traditional

methodologies.


9.29 Sampling methods should not pose a risk of contamination to the manufacturing operations.

Comment:

Where the only intervention into the Grade zone A is to perform monitoring, can a reduced schedule be adopted to

reduce the risk of contamination? Or if continuous particle counting is carried out, and other checks and controls are

in place (validated airflows, differential pressures monitored) can viable monitoring in such areas be halted?


9.30 Additional microbiological monitoring should also be performed outside production operations, e.g. after

validation of systems, cleaning and disinfection.

Comment:

Does this apply to Grades A and B or all Grades?


Table 6: Recommended maximum limits for microbial contamination

Comment:

This table is repeated from section 5 premises but now includes gloves. Recommend that it appears in a completed

form in one section only. The same comments apply to the values and notes as per section 5. i.e. Replace “limits” with

“levels”. For Grade A the value should be <1 in the table for note (b) to be valid.

Comment (2):

Table 6 “action limits” instead of “recommended maximum limits” and for grade A <1 instead of 1 as in the previous

Annex 1. Table 6 should indicate also and swabs in the head with contact plates such as: Contact plates (diam 55

mm), Swabs, cfu/plate or swab.

As for microbiological qualification, it should be indicated that the viable monitoring incubation programme should

be justified as for APS in lines 1928-1930.- It should be indicated that after sampling the incubation should start as

soon as possible and in a delay not exceeding 4 hours. - Line 1746 Table 6 Add chest and arms with Glove print

following the requirements line 189 point 4.3 and line 199 point 4.4.

Comment (3):

Limits for gown monitoring in Grades A and B are not included

Proposed change (if any): Include limits for gown monitoring in table 6.

Comment (4):

Recommend consistent use of the word limit or level. Are they interchangeable? If so, based on the glossary

definition, recommend adding a <1 for the limits/levels to Grade A.

Proposed change (if any): Glossary definition: Action Level - An established microbial or airborne particle level that,

when exceeded, should trigger appropriate investigation and corrective action based on the investigation.

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Comment (5):

Line 1747: The deposition velocity of airborne microbe-carrying particles (MCPs) falling towards surfaces was

obtained experimentally in operating theatres and cleanrooms. The airborne concentrations of

MCPs, and their deposition rate onto surfaces, are related by the deposition velocity. The deposition velocity of MCPs

was found to vary with the airborne concentration, with higher deposition rates occurring at lower airborne

concentrations1. The relationship of airborne concentration and settle plate counts of MCPs shown in Table 6 to

specify grades of pharmaceutical cleanrooms were derived from data originally published by the Parenteral Society2

and based on a single deposition velocity of 0.46cm/s. Using the set of more accurate deposition velocities, the

maximum concentrations can be recalculated to provide more accurate settle plate counts limits.

Proposed change:

Correct the current limits in Table 6 to the following;


9.33 If microorganisms are detected in a grade A or B zone, they should be identified to species level and the impact

of such microorganisms on product quality (for each batch implicated) and state of control should be evaluated.

Consideration may also be given to the identification of grade C and D contaminants and the requirements should be

defined in the contamination control strategy.

Comment:

The identification to species level of Grade A and B isolates for EM conflicts with the requirements for positive vials

in APS studies where identification to genus level is described as adequate (reference Lines 1925 to 1930). Is the

regulatory expectation to identify to species level all isolates from all Grade B cleanrooms or just the processing

areas? Would it be better to identify all Grade B recoveries exceeding alert or action levels in Grade B areas?

Comment (2):

Line 1770: 9.33 The point should include after “and state of control should be evaluated.” When the same species is

identified in a product or APS container and an environmental monitoring sample for the manufacturing of the same

batch, the identification to the strain level should be considered.

Comment (3):

Grade B areas do not pose the same risk or impact as Grade A areas (by definition of the activities which occur in

each classification) and therefore should not be treated as equivalent. Suggest clarifying that only critical adjacent

Grade B are to be treated similarly to Grade A, both for identification purposes as well as potential batch impact.


9.33 If microorganisms are detected in a grade A or critical surrounding Grade B zone, they should be identified to

species level and the impact of such microorganisms on product quality (for each batch implicated) and state of

control should be evaluated. Other Grade B areas should have representative colonies identified to the species level to

support ongoing evaluation of microbial control in the aseptic area. Consideration may also be given to the

identification of grade C and D contaminants and the requirements should be defined in the contamination control

strategy

Grade Air Sample

(cfu/m3)

Settle Plates

(diam. 90mm)

cfu/4 hours

Current limits

Settle Plates

(diam. 90mm)

cfu/4 hours

Corrected

limits

A 1 1 1

B 10 5 7

C 100 50 30

D 200 100 48

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1774 Aseptic process simulation (APS)1

Comment:

There is an absence of guidance for bulk manufacturing aseptic processes such as API manufacture


9.34 Periodic verification of the effectiveness of the controls in place for aseptic processing should include a process

simulation test using a sterile nutrient media and/or placebo. Selection of an appropriate nutrient media should be

made based on the ability of the media to imitate product characteristics at all processing stages. Where processing

stages may indirectly impact the viability of any introduced microbial contamination, (e.g. sterile aseptically

produced semi-solids, powders, solid materials, microspheres, liposomes and other formulations where product is

cooled or heated or lyophilized, etc.), alternative surrogate procedures that represent the operations as closely as

possible can be developed and justified. Where surrogate materials, such as buffers, are used in parts of the process

simulation, the surrogate material should not inhibit the growth of any potential contamination.

Comment (1):

The last sentence needs clarification. It is recommended that only the open stages of a bulk process should be subject

to an APS. As written there could be an expectation to seed API closed systems with media.

Comment (2)

Line 1777: and/or placebo should be deleted since it not further explained how a microbial growth can be expected

with this placebo and this is not indicated in PICS PI007, PDA TR22 or ISO 13408-1.

Comment (3):

The requirement that the media mimic product characteristics at all processing stages can be misconstrued to mean

that it should imitate characteristics such as pH, viscosity, density and others, which could make it unsuitable for the

recovery of microorganisms. Suggest clarification of the intent.


9.34 Periodic verification of the effectiveness of the controls in place for aseptic processing should include a process

simulation test using a sterile nutrient media and/or placebo. Selection of an appropriate nutrient media should be

made based on the ability of the media to recover microbiological contaminants potentially present in the processing

environment. Where processing stages may indirectly impact the viability of any introduced microbial contamination,

(e.g. sterile aseptically produced semi-solids, powders, solid materials, microspheres, liposomes and

other formulations where product is cooled or heated or lyophilized, etc.), alternative surrogate procedures that

represent the operations as closely as possible can be developed and justified. Where surrogate materials, such as

buffers, are used in parts of the process simulation, the surrogate material should not inhibit the growth of any

potential contamination.


a) Process simulation tests should assess all aseptic operations performed subsequent to the sterilisation of materials

utilised in the process.

Comment:

Same comment as above for lines 1776 to 1786.

1794 Comment

9.35 b) Should be “For non-filterable formulations or products, or after the last sterile filtration, any additional aseptic

steps should be assessed.


c) Aseptic manufacturing performed in a strict anaerobic environment should be evaluated with an anaerobic media

in addition to aerobic evaluation.

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Comment :

Processes conducted under a nitrogen atmosphere to minimise the risk of contamination will now require two media

fills: aerobic and anaerobic. This is contrary to all conventional approaches which require only an aerobic media fill.


d) Processes requiring the addition of sterile powders should employ an acceptable surrogate material in containers

identical to those utilised in the process being evaluated.


Unless closed systems are employed for transfer, processes requiring the addition of sterile powders should employ an

acceptable surrogate material in containers identical to those utilised in the process being evaluated.


e) Processes involving blending, milling and subdivision of a sterile powder require similar attention.


e) Processes involving open blending, open milling and open subdivision of a sterile powder, by which the powder is

exposed to the processing environment, require similar attention.

1805

footnote

Existing text:

1 For further details on the validation of aseptic processing, please refer to the PIC/S Recommendation on the Validation of Aseptic

Processing (PI 007) For PICS version only

Comment:

It is noted that this document and ISO14644 are the only guidance documents referenced in this revision.


The process simulation should duplicate the lyophilization process, with the exception of freezing and sublimation,

including partial vacuum and cycle duration and parameters as appropriate for the media.

Comment (1):

Use of the word “duplicate” could cause confusion, especially with using the term “cycle duration” in the same

sentence. The step of applying partial vacuum and vacuum release might be performed in duplicate, since those steps

are generally considered the most critical process steps in regard to possible microbial ingress. However, it must be

clear that the length of the simulated freezing and sublimation phase should be reasonable and not exceed a few hours.

The wording as currently proposed might suggest that the length of those process steps (that for some products take

several days) are to be simulated as long as the partial vacuum does not affect the media.


The process simulation should correspond as closely as possible to the regular lyophilization process, with the

exception of freezing and sublimation, using partial vacuum and parameters as appropriate for the media, and with the

exception of the total cycle duration, which may be reduced. Certain critical process steps, such as the application and

release of vacuum might be instead duplicated during the simulation.

Comment (2):

9.35 f) “...including partial vacuum and cycle duration...” cycle duration should be deleted since some lyophilization

cycles can take more than one day and there is no risk of microbial contamination inside the chamber if all the

accepted steps are simulated.


b) Corrective interventions in representative number and with the highest degree of intrusion acceptable.


This should not be interpreted as validating poor practise i.e. undertaking an excessive number of intrusions in the

APS to justify the same in routine production. Passing an APS is not the same as confirming sterility, this point needs

to be made.

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9.37 There should be an approved list of allowed interventions, both inherent and corrective, which may occur during

production and in the APS. The procedures listing the types of inherent and corrective interventions, and how to

perform them, should be updated, as necessary, to ensure consistency with the actual manufacturing activities.

Comment:

The approved list should be supported by risk assessment (FMEA) which provides confidence in the acceptability of

the intervention.

1827-1828 Comment:

Please clarify where it states “risk principles should be used” is this requiring a risk assessment?

1830-1832 Comment:

Please define “variables”.

1835 Comment:

“Bracketing or a matrix approach can be considered for initial validation of the same container/closure configuration.”

This approach could also be used for different container/closure configuration if justified.


c) The volume filled per container, which should be sufficient to ensure that the media contacts all equipment and

component surfaces that may directly contaminate the sterile product.


c) The volume filled per container, which should be sufficient to ensure that the media contacts all equipment and

component surfaces that may directly contaminate the sterile product and permit the detection of growth.

1845 Existing text:

e) Ensuring that any contamination is detectable.

Comment:

No APS can ensure all contamination is detectable.

Comment:

This sentence is too general.

Proposed change (if any): Reword as follows:

“Ensuring that any contamination is detectable by performing Growth Promotion Test on the filled containers at the

APS


f) The requirement for substitution of any inert gas used in the routine aseptic manufacturing process by air, unless

anaerobic simulation is intended.

Comment:

Does this line contradict lines 1796 to 1797?


g) The duration of the process simulation filling run to ensure it is conducted over the maximum permitted filling time.

If this is not possible, then the run should be of sufficient duration to challenge the process, the operators that perform

interventions, and the capability of the processing environment to provide appropriate conditions for the manufacture

of a sterile product.

Comment:

More clarity is required. Is the regulatory expectation to carry out APS studies for the full duration of processing or be

of sufficient time to permit all interventions and critical operations to be performed?


h) Simulating normal aseptic manufacturing interruptions where the process is idle. In these cases, environmental

monitoring should be conducted to ensure that grade A conditions have been maintained.

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Comment:

Does this simply mean carry out Grade A monitoring throughout the APS study, including when the process has

temporarily stopped? If so does this include continuous Grade A monitoring for campaign processing that are halted

over-night?

Comment:

Does continuous particulate monitoring and settle plates fulfill this requirement??

1860 Existing text:

i) The special requirements and considerations for manually intensive operations.

Comment (1):

Please clarify what is meant by the “special requirements and considerations”?

Comment (2):

“The special requirements and considerations for manually intensive operations.” Manually intensive operations

should not be considered as an acceptable aseptic process if not performed with a barrier technology.


j) Where campaign manufacturing occurs, such as in the use of barrier technologies or manufacture of sterile active

substances, consideration should be given to designing and performing the process simulation so that it simulates the

risks associated with both the beginning and the end of the campaign and demonstrating that the campaign duration

does not pose any risk. If end of production campaign APS are used, then it should be demonstrated that any residual

product does not negatively impact the recovery of any potential microbiological contamination.


Where closed systems and/or barrier technologies such as Isolators and RABS are employed then it is possible to

carry out aseptic campaign manufacturing. In such cases consideration should be given to designing and performing

the process simulation so that it simulates the risks associated with both the beginning and the end of the campaign

and demonstrating that the campaign duration does not pose any risk. If end of production campaign APS are used,

then it should be demonstrated that any residual product does not negatively impact the recovery of any potential

microbiological contamination.

Comment:

Does line 1862 to 1868 contradict lines 1850 to 1854 in that full duration of APS is not necessarily required.


k) Where barrier technologies (RABS, isolators, BPS, etc.) are used in the routine aseptic manufacturing process, the

relative risk and unique aspects of these technologies should be taken into consideration when assessing the design of

aseptic process simulation tests.


k) Where barrier technologies (RABS, isolators, BPS, etc.) are used in the routine aseptic manufacturing process, the

relative reduced risk and unique aspects of these technologies, compared with open processing, should be taken into

consideration when assessing the design of aseptic process simulation tests.


9.39 For sterile active substances, batch sizes should be large enough to represent routine operation, simulate

intervention operation at the worst case, and cover potential contact surfaces. In addition, all the simulated materials

(surrogates of growth medium) should be subjected to microbiological evaluation. The recovery rate from simulation

materials should be sufficient to satisfy the evaluation of the process being simulated and should not compromise the

recovery of micro-organisms.

Comment:

Where closed systems are used which are subject to SIP and protected by integral filters, it should not be desirable to

contact these sterile surfaces with growth media.

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9.40 Process simulation tests should be performed as initial validation, generally with three consecutive satisfactory

simulation tests per shift, and after any significant modification to the HVAC system, equipment, major facility shut

down, process and number of shifts, etc. Normally process simulation tests (periodic revalidation) should be repeated

twice a year (approximately every six months) for each aseptic process and filling line, and at least annually for each

operator. Consideration should be given to performing an APS after the last batch prior to shut down, before long

periods of inactivity or before decommissioning or relocation of a line.

Comment:

Could the regulatory definition of a shift be provided? Is it a group of persons or a period of time within a day?

Agree with performing an APS before long periods of inactivity or before decommissioning or relocation of a line, but

not prior to a planned shut-down.


9.41 Where manual filling occurs, each product, container closure, equipment train and operator should be

revalidated approximately every 6 months. The APS batch size should mimic that used in the routine aseptic

manufacturing process. An aseptic process or filling should be subject to a repeat of the initial validation when:

Comment:

There is no mention of bulk operations which involve tray drying and with manual handling and transfers.


9.42 The number of units processed (filled) for process simulation tests should be sufficient to effectively simulate all

activities that are representative of the aseptic manufacturing process; justification for the number of units to be filled

should be clearly captured in the PQS. For small batches, e.g. those under 5,000 units filled, the number of containers

for media fills should at least equal the size of the production batch.

Comment:

The minimum number of units to be filled for a valid trial is not mentioned anymore. Although specifying the

minimum and maximum number may not be totally science-based, it is helpful to align everyone to regulatory

expectations. Both regulators and manufacturers need to be clear on this important aspect.

1911-1918 Comment:

Line 1914 states the number of APS repeats should be determined using QRM principles however line 1916 states 3

successful repeats would be expected.


9.44 Filled APS units should be agitated, swirled or inverted before incubation to ensure contact of the media with all

interior surfaces in the container. Cosmetic defects, non- destructive weight checks and all other units should be

identified and incubated with the other units. Units discarded during the process simulation and not incubated should

be comparable to units discarded during a routine fill.

Comment:

There is no requirement to incubate in an inverted orientation such that the media is in contact with the container

closure. This may be unacceptable for heat sealed ampoules owing to the fragile nature of the fusion closure, but

should be possible with other dosage form presentations.

Comment (2):

Line 1924: It could be indicated that the same number of units incubated must be read at the end of the incubation.


9.45 Filled APS units should be incubated in a clear container to ensure visual detection of microbial growth.

Microorganisms isolated from contaminated units should be identified to at least the genus, and to the species level

when practical, to assist in the determination of the likely source of the contaminant. The selection of the incubation

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duration and temperature should be justified and appropriate for the process being simulated and the selected growth

medium.


9.45 Filled APS secondary units should be incubated in a clear container to ensure visual detection of microbial

growth. It is recognised that this may not be possible for bulk API containers which will therefore require opening and

sampling at the completion of incubation to allow for the detection of growth. Microorganisms isolated from

contaminated units and containers must be identified to the species level, to assist in the determination of the likely

source of the contaminant as part of the APS investigation. The selection of the incubation duration and temperature

should be justified and appropriate for the process being simulated and the selected growth medium.

Comment:

Opaque containers are not addressed. Please include clear and/or opaque.

1952 10 Quality Control (QC)


10.2 The bioburden assay should be performed on each batch for both aseptically filled product and terminally

sterilized products and the results considered as part of the final batch review. There should be working limits on

contamination immediately before sterilization, which are related to the efficiency of the method to be used.

Comment (1):

Clarity is required here. Does the bioburden assay for an aseptically filled product refer to the pre sterile filtration

value? Also should the bioburden assay sample for a terminally sterilised product be taken immediately prior to

sterilisation or, if cold chained and controlled with adequate monitoring records, at an appropriate justified time? This

would be applicable to items sterilised by third party contractors. If the prefiltration bioburden limit is expected to be

NMT10cfu/100ml, this should be stated for clarity.

Comment (2):

Line 1958: 10.2. “The bioburden assay should be performed on each batch for both….” Does that mean that the

bioburden should be evaluated even if the product cannot be sterile filtered?


10.6 The sterility test should be performed under aseptic conditions, which are at least consistent with the standard of

clean room required for the aseptic manufacture of pharmaceutical products.

Comment:

The background environment for isolator sterility testing cabinets will be required to meet Grade C or Grade D if it is

required to be commensurate with the manufacturing environment. Please confirm if the wording,” the sterility testing

environment should be suitable to minimise the contamination risk to the test” is more acceptable?.

Comment:

Clarification is needed to ensure that Sterility testing isolators are not required to be installed in a Grade D

background environment. All material loaded into a sterility testing isolator is fully sealed and often contains

additional protection, and as a result does not require the protection of a Grade D background environment.


10.6 The sterility test should be performed under aseptic conditions, which are at least consistent with the standard of

clean room required for the aseptic manufacture of pharmaceutical products. When sterility testing isolators are used,

they can be located in an unclassified area.


10.7 Samples taken for sterility testing should be representative of the whole of the batch, but should in particular

include samples taken from parts of the batch considered to be most at risk of contamination, for example:

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a) Products which have been filled aseptically, samples should include containers filled at the beginning and end of

the batch and after any significant intervention.

Comment:

If the sampling plan should represent the entire batch and processing conditions in the absence of intervention and

other anomalies, shouldn’t samples also be required from the middle of processing? Regulatory guidance is required

on numbers of samples or a justification for these numbers to be taken following interventions.


b) For products which have been heat sterilized in their final containers, consideration should be given to taking

samples should be taken from the potentially coolest part of the load.


b) For products which have been heat sterilized in their final containers, samples should be taken from the potentially

coolest part of the load.


c) Each sterilized load should be considered as different batches and require a separate sterility test.

Comment (1)

Detailed requirements for finished product testing should be based on Quality Risk Management principles. Requiring

separate sterility tests for all sterilizer loads, regardless of type of sterilization process and/or controls in place, would

lead to significantly more sterility testing for certain terminally sterilized products compared to aseptically processed

products, which does not reflect the sterility assurance risks associated with the different processes types.

As an example: For certain flexible multi-chamber Large Volume Parenterals (LVP) bags for Total Parenteral Nutrition

(TPN), containing up to 2.5 litres in volume, the regular sterilization operations can require more than 20 individual

autoclave/sterilizer loads for a single set of preparation vessels, which are filled in less than 24 hours. The European

Pharmacopoeia’s requirement for sterility testing of LVP, i.e. units of more than 100ml container size, sets the

requirement of a minimum of 10 units per batch being tested for sterility. This will lead to 200 LVP bags part of 20

individual sterility tests for one lot of product.

Having a mandatory separate sterility test per sterilized load for terminally sterilized products would be unreasonably

more units tested compared to purely aseptically performed manufacturing processes (which are generally recognized

being higher risk processes in regard to sterility assurance).

It is agreed that each individual sterilized load must be represented in a sterility test, but the way of sampling and

whether individual or pooled sterility tests are performed should be based on control measures implemented, as e.g.:

• Appropriate design of the sterilization area with usage of double-door autoclaves that separate a (fully

automated) pre-sterilization loading area from a (fully automated) post-sterilization unloading area.

• Appropriate physical (temperature distribution and heat penetration) and microbiological validation of the

sterilization cycles for well-defined loading patterns.

• Appropriate cycle controls including independently monitoring.

• Appropriate pre-sterilization bioburden controls, including separate screening for the presence of spore

forming microorganisms (heat resistance test) where required.

Wherever a sterilization process and its control mechanisms are well established and re-validation data show consistent

and uniform heat penetration throughout autoclave loads (into all individual product units) an individual sterility test

per sterilized load does not add to the sterility assurance of the finished product.


Each sterilized load should be appropriately represented in the test for sterility.

Comment (2):

It is assumed that this only applies to TS products (which are not approved for parametric release) and not for example

vial stopper loads to be utilised in aseptic processing. There is no guidance provided for campaign filling where a

single batch may be aseptically filled over two days: Does this require a minimum of 20 units (if sufficient fill

volume/mass) to be sampled and tested per day?

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Note: Where sterilization or lyophilization leads to separate sterility tests, consideration of performing separate

testing for other finished product tests should also be given.

Comment:

This is too prescriptive and should be part of the overall company process qualification.


10.9Media used for environmental monitoring and APS should be tested for its growth promotion capability, in

accordance with a formal written program.

Comment (1):

Guidance required for when this should be performed. Prior to use only or post use also

Comment (2):

Line 2000: It should be indicated that for settle plates used in grade A the growth promotion test should be performed

after a 4 hours exposure under grade unidirectional airflow and at the end of the incubation.

2002-2005 Comment:

Grade B areas do not pose the same risk or impact as Grade A areas (by definition of the activities which

occur in each classification) and therefore should not be treated as equivalent. Suggest clarifying that only

critical adjacent Grade B are to be treated similarly to Grade A with regards to batch review. Furthermore,

the Annex does not prescribe environmental monitoring specifications, only the recommended maximum

limits – need to maintain consistent terminology.


10.10 Environmental monitoring data generated in critical processing areas (Grade A and critical adjacent Grade B)

should be reviewed

as part of product batch release. A written plan should be available that describes the actions to be taken when data

from environmental monitoring are found out of trend or exceeding the maximum recommended limits.


10.11 The use of rapid microbial methods can also be considered. These methods should be validated for the

product(s) or processes concerned and be approved in the registered product testing specification.

Comment (1):

Only the second short reference to RMMs.

Comment (2):

It should be indicated that for sterile products with short shelf-life and used before the end of the sterility test, a rapid

microbial method must be used if possible.

Glossary Comment (1):

The glossary is very limited and requires a broad edit.

Examples:-

Action Limits are referred to throughout the document, but are called Action Levels in this section.

An intervention is described as a manipulation or activity that occurs at the critical area, but this can be less of a risk if

performed through glove ports as opposed to via an open barrier door etc. Both types of intervention require defining.

HEPA filter – should be defined as:-A High efficiency particulate air filter. An H14 filter in accordance with EN 1822

has an integral collection efficiency of 99.995%, and a local collection efficiency of 99.975% at the most penetrating

particle size (MPPS). It should be defined as per EN 1822.

Isokinetic sampling head –should be defined as:- A sampling head designed to disturb the air as little as possible by

ensuring that the air velocity entering the probe is equal to the velocity of undisturbed air at the same point.

Isolator -should be described as:- A bio-decontaminated enclosed environment supplied with Grade A (ISO 5) or

higher air quality that provides uncompromised, continuous isolation of its interior from the external environment

(e.g., surrounding cleanroom air and personnel).

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ULPA filter should be described as:- ULPA filter - Ultra-low penetration air filter. An U15 filter in accordance with

EN 1822 has an integral collection efficiency of 99.9995%, and a local collection efficiency of 99.9975% at the most

penetrating particle size (MPPS).

Pass through hatch should be described as:- A small airlock into which only small goods can be placed.

Comment:

Line 2040:

The concentration is intended as CFU/cm2 of filter surface.

Proposed change (if any): Correct the definition, replace CFU/ ml by CFU/cm2

Comment (2):

The cleaning and EM in a CNC area should be defined by the company’s QRM principles where appropriate.

Line 2040-2042

Comment (3)

Correction: the microbial challenge should be expressed as a concentration per cm2 of the filter membrane

and not per volume to be filtered as all filter validations are performed to scale and not at actual filling

volumes.


Bacterial retention testing – This test is performed to validate that a filter can remove bacteria from a gas

or solution. The test is usually performed using a standard organism, such as Brevundimonas diminuta at a

minimum concentration of 107 Colony Forming Units/cm2.

Line 2076-2084

Existing text:

Clean Non Classified (CNC) area - An area that does not meet any of the formal predetermined grades of cleanliness

included in the Annex, i.e. grades A to D, but where a manufacturer defined level of microbial control is still required.

The area should be subject to a formal cleaning/disinfection regime and formal environmental monitoring program to

achieve the defined level of control. The level, type and frequency of both the cleaning program and the environmental

monitoring program (including contamination limits) should be based on a formal risk assessment (captured within the

wider contamination control.

strategy) and should be commensurate with the specific risks to the processes and product performed manufactured

within each CNC area.

Comment (1):

Areas not classified within the A, B, C or D grades as defined in the Annex 1 do not specifically require environmental

monitoring programs and/or limits for microbial or particulate contamination levels, which is the reason they are

controlled but not classified. The controls in place for these areas could range from temperature and/or humidity to

certain gowning requirements such as shoe covers, protective coats or safety glasses. The definition of appropriate

control measures of any CNC area should be under the responsibilities of the manufacturer and need to be aligned with

the overall contamination control strategy.


Controlled Non Classified (CNC) area - An area that does not meet any of the formal predetermined grades of cleanliness

included in the Annex, i.e. grades A to D, but where a manufacturer defined level of control is still required. The area

should be subject to a formal cleaning/disinfection regime and hygienic requirements as applicable (e.g. related to

gowning requirements) to achieve the defined level of control. The level, type and frequency of the cleaning program

and any monitoring programs (e.g. temperature, humidity) should be based on a formal risk assessment (captured within

the wider contamination control strategy) and should be commensurate with the specific risks to the processes and

product manufactured within each CNC area.”

Note: ch. 5.9 b iii in the draft Annex 1 would need to be revised with the same CNC definition, based on the proposed

change above.

Comment (2):

CNC areas should have procedures in place to control gowning, sanisation and personnel and material flow in order to

ensure the any potential contamination carried into the classified areas is minimized. It is excessive however to require

that these areas be periodically monitored to non-specific arbitrary levels. The environmental monitoring results for

the adjacent Grade D and C areas is the best indication of the effectiveness of the controls in place and are much more

frequent and reliable. Additionally, suggest rewording last sentence as there are normally no manufacturing processes

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which take place within the CNC classified areas. Also suggest that the requirements contained within this definition

also be cited within the text of the document to ensure it is consistently applied (possibly between section 5.14 and

5.15).


Clean Non Classified (CNC) area - An area that does not meet any of the formal pre determined grades of cleanliness

included in the Annex, i.e. grades A to D, but where a level of environmental control is still required. The area should

be subject to a formal cleaning/disinfection regime and formal gowning and access control program to achieve the

defined level of control. The level, type and frequency of the cleaning program should

be based on a formal risk assessment (captured within the wider contamination control strategy) and should be

commensurate with the specific risks to the processes and product manufactured

Line 2079

Comment:

Instruction for environmental monitoring programme requirements in CNC areas where required should be included

in section 9, not the glossary

Line 2145-2147

Comment:

Suggest that the requirements contained within this definition also be cited within the text of the document to ensure it

is consistently applied (possibly between section 8.22 and 8.23).

Line 2177-2178

Comment:

The term “Laminar flow” should be removed from this document in favour of “Unidirectional flow” as it reflects the

current ISO 14644 terminology.

Proposed change:

Delete the definition and replace throughout the document

Line 2217-2220

Existing text

Sterile Product - For purposes of this guidance, sterile product refers to one or more of the elements exposed to aseptic

conditions and ultimately making up the sterile finished drug product. These elements include the containers, closures,

and components of the finished drug product.

Comment:

Sterile products can be manufactured via terminal sterilization processes of the finished product in its sealed containers.

In processing terminal sterilized products there would be no need of aseptic processing conditions.


Sterile Product - For purposes of this guidance, sterile product refers to one or more of the elements ultimately making

up the sterile finished drug product. These elements include the containers, closures, and components of the finished

drug product.

submission of comments on revision of ‘annex 1 ...guidance, such as contamination control...

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