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|Who we are and what we do

We are pharmaceutical, quality, compliance and technical consultancies based in Europe and

the USA. With a combined team of 90 consultants, including former EU and FDA Regulatory

Inspectors, we have the infrastructure in place to provide phase-appropriate hands-on

compliance advice and guidance across the entire product lifecycle in the areas of product

development, technology transfer, regulatory approval, manufacture, distribution, post market

(MA Holder) obligations and product discontinuation.

|How we do it

Our consultants work with our clients at a strategic and tactical level providing solutions,

holistic advice and guidance for virtual, operating, and contract manufacturing companies in

the biotechnology, pharmaceutical and medical device sectors.

Our clients range from emerging enterprises to the top multinational corporations. Our team

has the ability and agility to right-size, as appropriate for each client and specific project, to

ensure our clients get the right expertise level, personality and maximum value on each

project. Whether you need a senior-level strategist to write a roadmap for compliance, or

strong mid-level talent to review batch records, close overdue Deviations and CAPAs, or audit

your suppliers, we can find the right person for the project.

|Why we do it

To accelerate and innovate compliant patient care.

We hope you enjoy this White Paper and find it informative. We would welcome your

feedback.

Jonathan Morse Ann McGee

Founder and President Managing Director & Principal Consultant

Complya Consulting Group McGee Pharma International

Following the recent strategic alliance between McGee Pharma International and Complya Consulting Group, we are delighted to present this White Paper entitled ‘Aseptic

Processing – Key differences between the EU and US FDA’. This Paper was born from our desire to add value to you, our colleagues in industry, by imparting practical and

holistic advice to assist with your manufacturing processes.

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|Authors

Ann McGee, Managing Director &

Principal Consultant, McGee Pharma

International

Jilla K. Boulas, Senior Regulatory Affairs

Consultant, Complya Consulting Group

|Background

The need for “sterilization” has its roots in

ancient cultures. Early physicians were

aware of small living organisms that affect

human body and remain invisible to the

eye. Sushruta (Indian physician, 600 B.C.)i

advocated sterilization of wounds. The first

discovery of the use of alcohol as an

antiseptic is contributed to the Iranian

physician Al Rhazi (865–925)i. The

advances in medicine have brought forth

the complex set of requirements that

currently apply to medical practices and to

drug production.

Asepsis may be defined as a state of

control attained by using an aseptic work

area and performing activities in a manner

that precludes microbiological

contamination of the exposed sterile

product.ii In aseptic processing, parts and

components of a drug product are sterilized

and assembled into the finished form under

environmental conditions that maintain the

sterility status.

There are numerous guidance and

regulations addressing different aspects of

aseptic processing: 21CFR210,

21CFR211, 21CFR 600s, FDA Aseptic

Processing guidance document and EU

Directives supported by the EU GMP Guide

(Eudralex Vol. 4, Annexes 1 and 2).ii,iii,iv

Additional guidance is provided by:

International Conference on Harmonization

(ICH), World Health Organization (Good

Manufacturing for Sterile Pharmaceutical

Products), Parenteral Drug Association

technical reports (i.e. Number 1, 22, 36,

62), HTM2010 BS EN 285:1997

Sterilization — Steam sterilizers — Large

sterilizers, Pharmaceutical Inspection

Convention and Pharmaceutical Inspection

Co-operation Scheme (PIC/S) as well as

International Organization for

Standardization (ISO 13408, 14644). It is

pertinent to note that the PIC/S guidelines

are expected to be applied in the EU;

however some level of interpretation may

be applied when properly justified and

documented.

In the US, the sole responsibility of product

approval lies with the FDA. Product

approval by the European Medicinal

Agency (EMA) can be more complex due

to the fact that legislation exists at both an

EU level and also at a national level

(approximately 30 countries). As one

would expect, there are similarities and

differences in the requirements for aseptic

processing between the two regions. Both

regions take a risk-based approach to

evaluation of marketing/manufacturing

authorization applications as well as

inspection of the facilities and processes

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associated with the manufacture of a drug

product.

This paper focuses on some of the

differences between Food and Drug

Administration (FDA) and EU/ European

Medicines Agency (EMA) requirements for

aseptic processing. The goal is not to

provide a comprehensive list of differences,

rather a discussion of four key factors

(equipment, process and facility design; air;

water and testing/controls); based on the

experience of the authors.

|Product and Dosage Form The need for sterility is influenced by both

the product and route of administration. All

injectable products, as well as ophthalmic,

and aqueous oral inhalation products are

required to be sterile in the US market as

per 21CFR200.50 and 21CFR200.51

respectively. Sterility is a state defined

where the probability of a single spore

surviving (after the sterilization process) is

one in a million (10-6). This state may be

achieved through filtration, heat (dry or

steam), chemical, radiation, etc. Many

biologics cannot undergo final sterilization

due to the potential for denaturation of the

product. Hence the state of ‘sterility’ must

be achieved by control of production

activities through the final packaging of the

sterile drug product.

Terminal sterilization is the preferred

method and should be chosen unless the

product cannot be terminally sterilized, for

example, heat sensitive products (iii). The

EMA provides a decision tree for

determination of when aseptic processing

may be performed where terminal

sterilization is not an optionv. Emphasis is

placed on packaging not being an

acceptable factor in determining the need

for aseptic processing. Once the need for

sterility has been identified, a decision has

to be made regarding terminal sterilization

or aseptic processing based on the product

formulation and characteristics.

According to the EU GMP Guide Annex 1,

“the manufacture of sterile products is

subject to special requirements in order to

minimize risks of microbiological

contamination, and of particulate and

pyrogen contamination. Much depends on

the skill, training and attitudes of the

personnel involved.” Lack of sterility plays

a big role in product recalls in the US,

“Over ¾ of the recalls during the years

2004–2011 involved sterile products”vi

many of which were related to failure to

maintain state of sterility.

Once the product dosage form is identified,

a stepwise approach to aseptic design may

be taken. The manufacturing process may

involve automated systems, the traditional

manual process or a combination of both.

This in turn will impact the design of facility

and equipment followed by specifics

regarding clean utilities (air, water, etc.). It

is noted that the principles of aseptic

processing and core GMP considerations

apply equally for the traditional manual

processes and the advanced automated

processes. The approach to achieving

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those requirements may vary with differing

levels of technology, reflective of the level

of risk that applies for contamination of the

manufacturing system and the drug

product.

|Equipment, Process and Facility

Design It is estimated that personnel account for

80% of contamination into a cleanroom

environment, equipment for 15% and the

environment for 5%vii. Hence, manual

operations, by their nature, pose the

biggest risk of contamination to the

product. Advances towards automation of

processes through use of isolators/barriers

and blow fill seal systems can reduce risks

associated with activities carried out in

traditional aseptic processingviii. A well-

designed facility allows for maximum

control, maintenance of equipment and

monitoring of facility, equipment, personnel

as well as the process to ensure sterility of

the final product. Factors to be taken into

account include flow of air, personnel,

materials, equipment; appropriate

segregation of activities; appropriate

dedication of rooms and equipment;

alignment of utilities and equipment

operational requirements and the level of

automation. The system has to be

validated and FDA recommends the use of

smoke studies for qualification of the critical

areas (ii). Smoke studies are not directly

referenced in Annex 1; however,

visualization studies are expected to be

performed per ISO 14644; Part 3ix .

To allow for proper segregation, a

classification scheme is applied to areas

with different levels of cleanliness. Some

differences exist between the naming

system for area classification used by FDA

versus that of EU (see Table 1). While the

ultimate intent of both the FDA and

EMA/EU regulators is to ensure

appropriate conditions for aseptic

processing, some GMP requirements are

defined specifically by one agency and not

the other. This can result in some

differences in areas of focus during

regulatory inspections and interpretation of

minimum requirements by US and EMA/EU

Inspectors. For example, in the EU GMP

Guide, Annex 1, gowning requirements are

specified for each grade of area A to D. In

addition, in the EU, it is expected that

changing rooms are designed as airlocks

and that the final stage of the changing

room should, in the at-rest state, be the

same grade as the area into which it leads.

The design of the process and whether it is

manual or automated affects the

requirements for classification of the

neighboring or background areas. In a

traditional aseptic process design, most

often the entire aseptic filling room is

maintained at Class 100 (ISO 5); however,

the background environment for isolators

may be Grade C or D classification (or ISO

equivalent). The controls required to

support aseptic processing in an isolator

located in a Grade C versus a Grade D

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environment are different and the handling

of adverse conditions or events needs to

reflect the level of protection offered by the

background environment.

Equipment used to achieve sterility of parts

and components, namely

sterilizers/autoclaves play an important role

in design considerations. While there are

various methods of sterilization, heat

sterilization is the preferred method by

EMA/EU and considered the most widely

used method by the FDA (ii). Sterilization

processes must be validated and

monitored through a combination of

mechanical, chemical, physical and

biological techniques.

The validation of sterilization processes is

looked at in considerable technical detail

during EU/EMA regulatory inspections.

Two elements require consideration:

equipment qualification and process

validation. EU regulators inspect against

the EN 285 standardx and with reference to

the HTM 2010 Sterilization Standardxi for

autoclave qualification. Inspectors are

likely to review the qualification data in

detail, for example, load thermometric

testing and autoclave performance tests. In

relation to the validation and re-validation

of sterilization cycles, expectations are

broadly aligned between the agencies.

Validation is expected to include heat

penetration and load configuration testing

with the use of Biological Indicators.

Consistent performance of the sterilization

process is expected; HTM 2010 defines

very specific performance criteria for

interpretation of thermometric

measurements, including equilibration

time. In terms of monitoring in routine use,

the expectation for routine monitoring of

‘cold spots’ reflecting the outcome of the

validation studies is also aligned. For

routine use of autoclaves, a test is required

to be performed each day the equipment is

used, to confirm the continued validated

status of the autoclave e.g. Bowie Dick test

or equivalent.

Capping equipment maintenance,

operating parameters and the quality of air

supply for the capping process are subject

to inspection. Capping seals the stoppered

vials and protects the stopper from

damage. The FDA does not specify the

environmental requirements for capping

operations but recommends on-line

detection of “improperly seated stoppers”

(viii). This is also an expectation of the

EU/EMA. The environmental requirements

of the capping area have been the subject

of much debate in the EU and hence also

for companies operating in the USA that

export product to the EU. The EU/EMA

considers that a vial is not closed until the

seal is in place; therefore, the potential for

contamination exists until that point. Two

options for a capping environment include

the capping station within the aseptic core

or one outside the core. According to the

EU Guide Annex 1 “vials should be

protected by Grade A conditions up to the

point of leaving the aseptic processing

area, and thereafter stoppered vials should

be protected with a Grade A air supply until

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the cap has been crimped.” Where vial

capping is carried out within the aseptic

core, sterile components are required to

minimize the risk of contamination of the

area. Unfortunately, in reality, significant

challenges exist as a result of the

interpretation of minimum requirements in

the EU. A revision of Annex 1 is expected

to be published in Q2 2016 which will

hopefully provide additional clarity in

relation to this topic.

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|Table 1 Differences in Equipment, Process and Facility Design (EU vs. FDA) Factor Topic Differences Comments

Design Validation/Qualification EU/EMA – Smoke studies not directly mentioned but are expectediii,ix FDA - reference to the use of smoke studiesii EU/EMA – Annex 1 defines laminarity for laminar air flow stations; low turbulence unidirectional flow is sometimes accepted FDA – requirement is for unidirectional airflow in critical areas;

Both agencies expect the air flow pattern not to cause contamination.

Room Classification Subtle differences between the classification of areas per Annex 1 and FDA.

See Table 2 for Class A requirements for particles of 5 µm

Area Segregation - Isolator background environment

EU/EMA – Does not define the allowed level of particulates in Class D areas during operations. FDA – Defines the maximum number of microbiological particles in air and plate samples

Requirements for the background environment for Isolators is harmonized between the EU and the US.

Area Segregation – Changing Room

EU/EMA – “the final stage of a change area/room is required to be the same grade as the area into which it leads” iii FDA – No specific classification for the final gowning stage (see Air section below); inspections are risk based, focusing on those operations that require employees to enter the critical areas of the processing line

Equipment Sterilizer/Autoclave EU/EMA – Bowie Dick test is spe-cifically referenced for heat pene-tration studies. However, an ap-propriate alternative test is likely to be considered acceptable. Inspections against the detail of the EN 285 & HTM 2010 stand-ards. FDA – Expectations are aligned; however, not as specifically de-fined in regulations or guidance documents.

Both regulatory bodies will study the Sponsor’s challenge studies for validation of the sterilizers. USP <1211>. Expectations are aligned for monitoring ‘cold spots’ routinely.

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|Air The classification of a clean area is based

on the quality of air as determined by the

number of particles per unit volume, the

size of the particles and their

microbiological properties. Class 100 (US

designation, 3520 particles per ft3 of 0.5µm

size) is analogous to the EU Class A in

respect of 0.5µm particle limits. In the EU,

class A standards are based on monitoring

of both 0.5µm and 5.0µm particulates while

the US requirements relate to 0.5µm

particles only (see Table 2 for details). The

EU GMP Guide, Annex 1 defines the

requirement for measurement of the

number of 0.5µm and 5.0µm particles for

area classification and routine monitoring.

The limits defined for 5.0um particles mean

that Grade A areas need to meet ISO 4.8

and Grade B ISO 5. US based companies

that wish to market their products in the EU

need to meet the requirements of Annex 1

in this regard.

Both FDA and EU/EMA regulators

recommend the use of air handling

systems capable of achieving a minimum

of 20 air changes per hour, air flow speed

of 0.36-0.54m/s (EU Annex 1) or 0.45m/s

(±20%, FDA) in the critical areas. The air

handling units must be equipped with High

Efficiency Air Particulate (HEPA) filters of

99.97% efficiency for removal of

particulates, as small as 0.3µm in diameter.

As noted above, design considerations

must segregate the air in the critical areas

from contamination by the air from the

lower classification of the neighboring

rooms. Such design factors should include

a positive pressure differential whereby

typically, the air flows from the critical clean

area to area of lower cleanliness

classification. Depending on the

classification of the adjacent room, a

pressure differential of 10-15 Pascals (Pa)

is expected for traditional aseptic

processing areas. It is noted that pressure

differential requirements for isolators may

be quite different. Monitoring of the

pressure differential is often a component

of the building alarm system which must be

validated; system alarms must be defined,

qualified and any event activating an alarm

must be properly investigated and

documented while restoring aseptic

conditions.

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|Table 2 Differences in Air Quality Requirements (EU vs. FDA) Factor Topic Differences Comments

Air quality

Classification naming system

EMA/EU – Grade A; FDA – Class 100 etc. EMA/EU – Class A must meet ISO classification of 4.8 for particles of 5µm EMA/EU – operates to m3 measurements FDA – operates to ft3 measurement;

See guidance documents for specifics

EN ISO 14644-1 ix provides for intermediate classifications

Particulates – Type, size, and number/m³

EU – distinction between critical area particulates while “at rest” and “in-operation”

FDA – particulates at “dynamic” conditions (i.e. in-operation).

See Table 4 for more details

HEPA filters

Air exchange rate not specified by either agency

EU – HEPA filters are discussed in the context of air that has passed through filters of an appropriate efficiency & the ability to meet clean room classification standards as defined in ISO 14644iii

FDA – Provides additional guidance on efficacy, leak and challenge testing;

FDA – HEPA filters are leak-tested twice a year and require periodic monitoring

The FDA requirements for filter leak testing and periodic monitoring applies equally in the EU and is defined by the ISO 14644 standard.

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|Water Water for injection (WFI) is required for

aseptic processing to minimize the risk of

contamination. Historically, there have

been differences between the two

regulatory agencies in relation to

acceptable methods of production. The

FDA accepts reverse osmosis and

distillation (per USP) as methods for

production of WFI; WFI produced by

ultrafiltration (not listed in USP)xii may also

be acceptable. In the EU, it is currently a

requirement for WFI to be produced by

distillation; reverse osmosis is not

considered acceptable. However, it is

pertinent to note that a new draft of the

European Pharmacopeia monograph

allows for non-distillation methods for

producing WFI but does not define GMP

controls for the generation system; this

update is being coordinated and aligned

with a revision to EU GMP Guide Annex 1.

Constant circulation of the WFI at “high”

temperature is a common expectation; the

EU references temperature of >70°C (Per

EU Annex 1, paragraph 59) while FDA

refers to “…a temperature of 65°C – 80°C

is commonly used and is acceptable”(xii).

Agencies in both jurisdictions expect a risk

based approach to defining the sampling

points in the water distribution systems;

and EU/EMA expects this risk assessment

to be formal, documented and reviewed

annually for improvement and assessment

of potential changes to the sampling

program. Inspections by both agencies will

include water system sampling frequency

as justified by the system validation and

performance data and must cover critical

areasxiii and the point-of-use (where water

is delivered to the process). “Action or alert

limits must be based upon validation data

and must be set low enough to signal

significant changes from normal operating

conditionsxiv”. Meaningful alert and action

limits that reflect the capability of the

system will ensure detection of a shift or

emerging trend in compliance with both

agencies expectations.

Clean Steam is used in autoclaves or

sterilization in place (SIP) cycles for

equipment, tanks and surfaces. Steam

condensate is expected to meet WFI

standard and it should be tested

accordingly in line with a defined program.

Factors such as pressure of the steam,

contact surface/ material of construction

and risks of condensate formation are

referenced in the FDA inspection manualxv.

The utility system used to generate and

deliver WFI or clean steam must be

validated/qualified for its intended use.

Such studies need to include biological kill

at the ‘cold spot(s)’ and achievement of the

required level of sterility assurance.

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|Table 3 Differences in Water and Clean Steam Requirements (EU vs. FDA) Factor Topic Differences Comments

Water WFI required for parenteral products

EU/EMA – Per Ph. Eur.; distillation is currently the only acceptable methodxvi

FDA – Per USP reverse osmosis & distillation are acceptable methods; ultrafiltration may be accepted

Ph. Eur. revision recommended by European Directorate for the Quality of Medicines (EDQM) regarding acceptable methods for production of feed water quality

WFI must meet compendia specifications.

EU/EMA - Constant circulation at a temperature above 70°C

FDA – Constant circulation at a temperature range of 65°C – 80°C.

Specific inspection guidance applies.

Rinse Water - for parenteral products, final rinse water should meet the specifications of WFI.

FDA – Critical areas identified during validation must be sampled at the point of use

EU Annex 15: Qualification and Validation

USP <1231>

Clean Steam Quality and use

EU – Discussed in the context of autoclave use

FDA – Discussed in the context of autoclave and SIP

System validation & verification of the quality of the steam is important to both agencies for all relevant uses of clean steam.

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|Testing and Controls In addition to the regular environmental

monitoring of the classified areas, testing

plans must be in place for maintaining

aseptic conditions while manufacturing

processes are in progress during all shifts.

All components of aseptic processing

discussed above (equipment, area, air,

water, personnel) require proper routine

and in-process monitoring. Specific testing

requirements are applicable per US

Pharmacopeia (USP), European

Pharmacopeia (Ph. Eur.). The

Pharmacopeial Discussion Group (PDG)

has worked diligently to harmonize several

pharmacopeia topics, resulting in

harmonization of methods such as

microbial endotoxin test method (ICH

Q4B). However, while test methods may

be harmonized, there are some differences

in sample collection requirements (see

Table 4).

When establishing a monitoring program,

requirements such as sample size/volume;

frequency of sampling; location and time of

sampling; appropriateness of sample

collection technique and test methods must

be taken into account (21 CFR 211.84,

211.160(b)). Both regulatory agencies

expect scientifically sound methodology

and provide examples of acceptable

monitoring methods. These comprise,

active air sampling; settle plating; contact

plating and personnel finger dabs.

The preferred air sampling method in both

the US and EU is active air, using active air

samplers. In the EU, it is expected that all

methodologies are used routinely and it is

our experience that settle plating is used

more extensively in the EU during routine

production than it is by companies in the

USA. Samples must be collected from

sites that allow the highest potential for

detection of contaminants,xvii such as the

gown of operators, fingers (5 fingers, iii) or

areas where complex manipulations are

performed. Samples must represent the

entire process (beginning, middle and end)

and results are evaluated against

appropriate limits. Microbiological

samples, limits and method of collection

are not harmonized (see Table 4).

However, both EU/EMA and FDA require

identification of contaminants when

positive results are obtained. EU/EMA

requires a formal risk assessment to

support the EM program (iii). Annual

review of the risk assessment, and

potential revision of the program is

expected with reference to data generated.

The agencies in both jurisdictions expect

the review of environmental monitoring

data to include evaluation of the

effectiveness of the cleaning procedures,

potential presence of resistant strains of

micro-organisms (iii) and/or adverse trends

(ii).

Simulation/media fill studies are an

important element of validation and re-

validation of the aseptic manufacturing

process. Media fill studies are simulations

of the production process using growth

medium, instead of the product, known to

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promote microbiological growth. They

must be conducted per approved protocol

and appropriately documented. There is

much agreement between the two

agencies regarding the frequency of such

studies. An apparent difference relates to

the recommended microbiological action

limits for Grade A; in the EU the action limit

is less than 1 whereas in the US, the action

limit is listed as 1. However, there is a

caveat that “samples from Class 100 (ISO

5) environments should normally yield no

microbiological contaminants”. Therefore,

in effect, to meet expectations of both

regulatory agencies, there should be no

microbial growth.

In relation to sterile filtration of products,

both agencies have an expectation for

Filter Integrity Testing (FIT) of product

sterilizing filters pre and post use. The

requirement is for the pre-use FIT to be

performed on the sterilized filter (iii). This is

presenting challenges to some

manufacturers where the design of their

manufacturing lines may not enable this to

be done in a manner that minimizes the

potential for contamination of the sterilized

filter while performing the test. Where the

PUPS (pre-use, post sterilization) FIT

expectation cannot be met, we would

recommend that manufacturers perform a

formal risk assessment on their FIT

arrangements and engage with their

regulators to agree an acceptable

approach.

Both regulatory agencies require the use of

all materials within their validated shelf

lives. This extends also to the use of

equipment. While the core requirements

are similar, in our experience, there is a

particular focus in EU/EMA inspections on

the following:

1) Paragraphs 77–80 of the EU GMP

Guide, Annex 1 define specific ex-

pectations for acceptable time inter-

vals between washing and drying;

between drying and the sterilization

of components, containers and

equipment and between steriliza-

tion and use. Typically, compliance

with these requirements is reviewed

and it is expected that appropriate

records are available to demon-

strate actual time intervals for rou-

tine processing.

2) Paragraph 80 of Annex 1, EU GMP

Guide, defines a requirement to

minimize the time between the start

of preparation of a solution and its

sterilization or filtration through a

micro-organism retaining filter. Typ-

ically, this is also inspected quite

rigorously by EU/EMA Inspectors. It

is expected that actual times are

documented on a batch basis and

that compliance with the process

validation in relation to time and

also critical filtration parameters

(e.g. pressure) is evaluated as part

of the batch review process.

3) Paragraph 80 of Annex 1, EU GMP

Guide, requires bioburden monitor-

ing of the bulk solution before steri-

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lization. Once again, EU/EMA reg-

ulators require this to be performed

for every batch and for the results to

be considered as part of the batch

review process.

4) Paragraph 62 of Annex 1, EU GMP

Guide states that disinfectants and

detergents should be monitored for

microbial contamination. The ex-

pectation for solutions of this nature

to have appropriate shelf lives is

common across the agencies and

most companies will perform valida-

tion studies to support shelf lives.

However, this is a topic of discus-

sion for some companies with their

EMA/EU Inspectors who also ex-

pect that these solutions should be

monitored routinely for microbial

contamination.

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|Table 4 Differences in Tests and Controls (EU vs. FDA) Factor Topic Differences Comments

Air Samples -Routine Monitoring

Frequency EU/EMA – Particles are monitored for the duration of critical activities

FDA – Must be representative of the entire lot and processing conditions

Requirements across the agencies are essentially similar.

Type and Size EU/EMA – Sample size & frequency for Grade A & B areas should be sufficient to ensure that all interventions, transient events and any system deterioration will be captured and alarms triggered if alert limits are exceeded

FDA – Sample volume should be sufficient to optimize detection of contaminants

Requirements for monitoring across the agencies are essentially similar.

Air, surface and personnel (contact plates/swabs) samples are expected by both agencies.

For classification of Grade A, EU requires a minimum sample volume of 1m3.

Location EU/EMA – Locations identified through “a formal risk analysis “

FDAii – Not more than 1 ft. from the work site for classification purposes. Must include samples from sites with the highest potential for contamination.

Requirements across the agencies are essentially similar.

Some critical areas (such as fill line) may be sampled upon completion of the processing.

Method EU/EMA – All methods to be used routinely (active air, settle plates, contact plates, personnel monitoring) as part of a risk based approach.

FDA – Methods to reflect a scientific approach by the manufacturer

In our experience, the extent of settle plating is greater in EU monitoring programs; approach to using other methods is similar across the two jurisdictions.

EU provides additional testing option: contact plates

(diameter 55 mm) cfu/plate.

In-process EM samples

Location EU/EMA – specify that 5-finger touch plates are expected. Expectation that the face (typically for forehead), chest and both arms are sampled.

Both jurisdictions have expectation that several locations are routinely sampledii,iii.

Sampling has to be representative of each production session

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Factor Topic Differences Comments

FDA – several sampling locations include fingers, facemask, etc.

reflecting the movement of people

Specification EU/EMA – <1 cfu/glove or settle plates (diameter 90 mm) cfu/4 hours

FDA – 1 cfu/4 hours (Microbiological Settling Plates Action Levels (diam. 90mm)). Caveat that “samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants”ii

Essentially similar expectations by both agencies

Simulation Initial validation EU/EMA – Three consecutive tests per shift

FDA – Three consecutive successful runs per processing line

While this appears as a difference, both agencies expect the simulation runs to represent the normal production as well as worst-case activities (maximum personnel, increased manual interventions).

Re-validation EU/EMA – Repeated twice a year per shift and process.

FDA – Semi-annual test per processing line.

Both agencies expect re-validation of the process routinely and after implementation of changes to the system.

Batch size EU/EMA - Recommended batch size doesn’t include provisions for processing using high volume isolator technology lines.

EU/EMA – PIC/S guidance (PI007-6, Validation of Aseptic Processes) – offers guidance for when filling takes place over extended time (greater than 24 hours)

FDA – Adequate batch size to mimic commercial batch sizes. Accepts simulation of smaller batch sizes for isolators

Criteria for acceptable number of contaminated units per batch are the same for both agencies.

Speed/Duration of run

FDA – One media fill run per line speed EU/EMA – PIC/S guidance (PI007-6, Validation of Aseptic Processes) – refers to the use of appropriate combinations of container size and opening and line speed and testing at the extreme

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|Conclusion The complexity of aseptic processing

justifies the number of guidance

documents written to make the

interpretation of regulatory rules and

expectations clearer. There are several

dimensions to aseptic processing all of

which are important. Therefore the focus

of this paper was limited to address only 4

factors, namely, equipment, process and

facility design; air; water and testing/

controls.

The dosage form determines the need for

sterility, product characteristics must rule

out the possibility of terminal sterilization. It

is only then that aseptic processing can be

justified. Manufacturing process and

facility design must suit the product quality

requirements. Automated processes are

ideal as they reduce human interventions,

the main source of microbiological

contamination.

The building design is a complex body

made of parts such as air, water/steam,

gas, temperature and humidity, equipment,

direction of flow/movement, etc., all of

which must be synchronized to achieve

one goal: appropriate environmental

classification. This is one area where there

is lack of harmonization.

Once the building and its utilities are

validated to provide aseptic conditions, the

operations may begin and evidence of

asepsis is collected through continuous

environmental and operational monitoring

plans. Details of sampling, frequency,

location, and test methods may be

documented in a formal risk assessment

and justified based on validation activities

and data. In order to ensure a state of

control and also for the purposes of

identifying improvement opportunities,

evidence of aseptic status is reviewed

ensuring compliance with quality standards

and/or early identification of a potential

adverse trend.

This article aimed at pointing out some of

the differences between the FDA and the

EU/EMA with respect to requirements of

aseptic processing. Risk assessment is an

expectation shared by both agencies which

should be the first step in the development

of a product and design of the process to

ensure the product is safe and effective.

Consideration of aseptic processing step is

a critical part of a well-documented risk

management plan. It must be scientifically

robust, and continuously improving based

on meaningful interpretation of product-

specific data.

While there are significant areas of

harmonization of requirements, continued

compliance with the multitude of complex

aseptic processing requirements across

the regulatory jurisdictions worldwide still

remains a significant challenge for the

industry. The array of aseptic processing

requirements necessitates analysis and

interpretation of the regulatory

requirements and guidelines by relevant

Subject Matter Experts (SMEs), and a level

| 19

of interpretative variability is somewhat

inevitable.

The regulators and the industry have a

common goal: patient care. The regulatory

agencies are actively engaging with one

another with a view to optimizing the

regulatory environment in the interests of

accelerating product development for the

benefit of the patient. It is likely that

harmonization initiatives through, for

example, the International Conference on

Harmonisation of Technical Requirements

for Registration of Pharmaceuticals for

Human Use (ICH), will continue. These

initiatives are complex and multi-faceted

and as a result, take time to achieve. In

parallel, regulatory requirements continue

to grow and change reflecting

developments in technology and

experiences in providing patient care. The

agencies, through their current co-

operation initiatives are building trust and

working relationships that undoubtedly will

be beneficial to the ongoing harmonization

of guidance for the industry.

This industry can play its part through

engagement with the regulatory process to

support the continued development of

harmonized guidance and through

consistent implementation of appropriate

standards to ensure patient care.

| 20

|References

i History of Clinical Research – A merging of Diverse Cultures, John L Gallin M.D, October 2014;

Accessed November 2015:

https://ippcr.nihtraining.com/handouts/2014/Gallin_John-10-14-14-Slides_with_Notes-Color.pdf

ii Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Man-

ufacturing Practice, FDA September, 2004

iii EU GMP Guide, Annex 1 Manufacture of Sterile Medicinal Products, 2008

iv EU GMP Guide, Annex 2 Biological Manufacture of Biological Active Substances and Medicinal

Products for Human use, 2012

v Decision Trees for The Selection of Sterilization Methods (CPMP/QWP/054/98) Annex to Note for

Guidance On Development Pharmaceutics (CPMP/QWP/155/96)

vi A Review of Reported Recalls Involving Microbiological Control 2004-2011 with Emphasis on FDA

Considerations of “Objectionable Organisms” Scott Sutton and Luis Jimenez , American Pharmaceuti-

cal Review, January/February 2012 Volume 15,

Accessed November 2015:

http://www.americanpharmaceuticalreview.com/Featured-Articles/38382-A-Review-of-Reported-Re-

calls-Involving-Microbiological-Control-2004-2011-with-Emphasis-on-FDA-Considerations-of-Objec-

tionable-Organisms/

vii Prevention or Cure. What are the Risks”, Alan Fisher, Contamination Control Specialist, 23 April

2013 http://www.interphex.com/RNA/RNA_Interphex_V2/documents/2013/speaker-presenta-

tions/Manufacturing-Alan-Fisher.pdf?v=635012077524560891

viii STERILE DRUG PROCESS INSPECTIONS, FOOD AND DRUG ADMINISTRATION

COMPLIANCE PROGRAM GUIDANCE MANUAL, 7356.002A, September 11, 2015

ix ISO 14644-1:2015en - Cleanrooms and associated controlled environment

x BS EN 285:2015 Sterilisation – Steam Sterilisers – Large Sterilisers

xi Health Technical Memorandum 2010, Part 3 (Including Amendment 1): Validation and Verification,

Sterilization

McGee Pharma International

McGee Pharma International (MPI) provides the pharmaceutical, biopharmaceutical, medical device and healthcare sectors with expert EU Regulatory Affairs, Quality and Compliance advice, across all stages of the product lifecycle. Our team of over 30 consultants and technical

specialists, with extensive expertise across all GxPs, includes a numbf former EU Regulatory Inspectors. This ensures that the service we provide our clients is in line with current international regulatory requirements.

Services

McGee Pharma International’s Quality, Compliance,

Regulatory Affairs and Technical services include:

Quality Management System (QMS) Design

Process Mapping

System Development

SOP writing

Inspection readiness / mock regulatory audits and

remediation support

Quality Risk Management, in compliance with ICH Q9

Marketing Authorisation support

MAH compliance, ensuring all activities are

conducted in accordance with the holder’s obligations

Pharmacovigilance services including EU QPPV

Virtual Quality Assurance (VQA), including

developments and updates of Technical / Quality

agreements

Qualified Person (QP) services

Responsible Person (RP) services

Technical support services

Tailored training

| 21

xii FDA GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS 7/93

Accessed November 2015:

http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074905.htm

xiii USP <1231> Water for Pharmaceutical Purposes

xiv : FDA WATER FOR PHARMACEUTICAL USE 12/31/86 Number: 46

Accessed November 2015: http://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTech-

nicalGuides/ucm072925.htm

xv : FDA GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS, Sterile

Drug Substance Manufacturers (7/94)

Accessed November 2015

http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074930.htm

xvi EMA Note for Guidance on quality of water used for pharmaceutical use, May 2002

Accessed November 2015: http://www.ema.europa.eu/docs/en_GB/document_library/Scien-

tific_guideline/2009/09/WC500003394.pdf

xvii Eudralex Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Hu-

man and Veterinary Use Part 1/ Chapter 6: Quality Control Brussels, 28 March 2014

your partner in compliance

| 22

McGee Pharma International

McGee Pharma International (MPI) provides the pharmaceutical, biopharmaceutical, medical device and healthcare sectors with expert EU

Regulatory Affairs, Quality and Compliance advice, across all stages of the product lifecycle.

Our team of over 30 consultants and technical specialists, with extensive expertise across all GxPs, includes a number of former EU Regulators. This ensure that the service we provide our

clients is in line with current international regulatory requirements.

Complya Consulting

Complya Consulting is a global Quality As-surance and Regulatory Affairs consulting firm. Complya works closely with compa-nies in the pharmaceutical, medical device and biotechnology industries that require consulting support for GxP compliance, FDA filings and submissions, audits, warn-ing letter remediation and clinical trial oversight.

Complya’s PEARL Matching process for matching individual consultants with spe-cific project needs differentiates Complya as a go-to company for a broad spectrum of complex strategic and ‘day to day’ tactical consulting services.

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