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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 (865925)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 of the recalls during the years

    20042011 involved sterile productsvi

    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 m

    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...