Science & Technology Article

Risk & Science-Based Validation Of Cleanroom Garments

Authors: Milenko Pavičić and Thierry Wagner
*Originally Published on IVT Network GXP Volume 23, Issue 4 – July 2019

ABSTRACT

Important quality attributes of cleanroom garments that will be worn during the manufacture of sterile medicines include: cleanliness; sterility; particle and microbial filtration efficiency; durability; usability; and comfort. Important risk factors related to cleanroom garment systems include gowning processes and related activities, such as laundering, packing, sterilization, repairs, storage, handling and logistics, as well as change management. Because many factors contribute to the overall quality, adequacy and suitability of cleanroom garment systems, a thorough and focused validation of cleanroom garments is critically important.

After providing a review of current and emerging regulations and standards, this article proposes a risk- and science-based quality-by-design approach for the development, implementation and validation of sterile cleanroom garment systems.

With this approach, more effort is spent at the front-end during the design phase as well as during design qualification. This will lead to designed-in risk reductions; enhanced scientific knowledge on selected technical solutions; and better

awareness of limitations and residual risks. As a result, there should be fewer issues during cleanroom qualifications and process validations, leading to more effective routine operations as well as improved patient safety. The proposed approach, if implemented correctly, is not only the correct strategy to effectively control contamination risks related to people, but also an adequate response to the latest regulatory requirements.

Introduction

Parenteral medicines are administered through injection, infusion or implantation, and must be sterile and pure to assure product safety. Therefore, the manufacture of parenteral medicines requires a controlled and validated clean production final packaging, resulting in a sterility assurance level (SAL) of at least 10⁻⁶. If terminal sterilization of the final product is not possible, aseptic manufacturing is the only alternative. In aseptic production, exposure of the sterile product to the using sterile ingredients to filling the product in its final container). In Europe, exposure of sterile products to the environment is only allowed in EU-GMP grade A zones placed in a grade B cleanroom or in an isolator¹.

Aseptic manufacturing of sterile products requires a high level of contamination control. Figure 1 shows the important elements that must be addressed in a contamination control strategy to assure purity of the products, sterility of sterile products and good microbiological quality of non-sterile products.

According to current Good Manufacturing Practices (GMP) guidelines, (EU², US³, Japan⁴, WHO⁵,⁶),processes, equipment, facilities and manufacturing activities should be managed in accordance with

Figure 1. Important elements of a contamination control strategy for sterile manufacturing.

Quality Risk Management (QRM) principles⁷ that provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. A quality-by-design approach⁸, combined with effective risk management, should be applied to ensure the safety, quality and efficacy of sterile products. This comes from the belief that quality cannot be tested into the product, it can only be built into the design of products and the processes used to produce them. Risk assessments must be performed to identify, assess, eliminate and control contamination risks from the design phase of an aseptic process; to monitor and detect contamination; and to establish process requirements and acceptance criteria for all elements of a sterile manufacturing process. Risk assessments should be documented as well as maintained and should include the rationale for decisions taken in relation to mitigating risks, discounting of potential risks and residual risk.

An important risk factor in sterile manufacturing is personnel. People can cause contamination of the production

environment and products in many ways⁹. Contamination from people mainly consists of hair, skin cells, skin flakes,

saliva, sebaceous matter, sweat, particles from clothing and many different exogenous particles and substances picked up in the environment. These contamination sources mostly contain different endogenous (i.e., commensal) and exogenous microorganisms present in numbers which vary from a few (e.g., skin cell) to thousands (e.g., sweat) or even millions e.g., saliva). Therefore, it is important that people working in an environment, where sterile products are manufactured, wear adequate cleanroom garments.

Contamination control related to people starts with good personal hygiene based on adequate hygienic procedures, such

as hand washing and hand disinfection; aseptic behavior; aseptic skills; and a good working discipline. Adequate

cleanroom garments, as well as undergarments¹⁰ are critically important to minimize the risk of contaminating the

environment or products with contamination generated by people. Cleanroom undergarments serve as a first barrier

against contamination from people. The cleanroom garments must form a very robust barrier between the person and the environment.

Additional protective measures, such as adequate cleanroom footwear, cleanroom socks, head coverings, face masks, eye coverings and (sterile) gloves, may be necessary or required from a regulatory point of view, to minimize the

contamination risk.

Important quality attributes of cleanroom garments are cleanliness (free from chemicals, particles, pyrogens, fibers);

sterility; particulate and microbial filtration efficiency; durability (tear, puncture, seam strength, abrasion); and comfort.

Personal protection against chemical or biological agents may also be a relevant quality attribute. A quality-by-design

approach⁸ combined with effective risk management⁷, should also be applied to the design, selection and implementation of adequate cleanroom garments.

With the quality-by-design approach, more effort is spent at the front-end, in the design phase as well as in the design

qualification, leading to designed-in risk reductions; better understanding of key aspects, limitations and residual risks;

and fewer issues during final simulation runs and routine operations. This approach also creates the basis for proper root

cause analysis (in case of issues) and adequate change management.

Other important risk factors related to cleanroom garments include gowning procedures and processes and activities

related to cleanroom garments, such as laundering, packing, sterilization, repairs, storage, handling and logistics. Because many factors contribute to the overall quality, adequacy and suitability of cleanroom garment systems, a risk- and science-based validation of cleanroom garment systems is very important.

This article provides an overview of the various qualification, validation and monitoring aspects of cleanroom garments.


Current Regulatory Guidance For Validation Of Cleanroom Garments

Depending on the jurisdiction, aseptic production of sterile medicines must meet various regulatory requirements such as those set out in Annex 1 of the EU Guidelines to Good Manufacturing Practice¹ or in the U. S. Food and Drug Administration (FDA) Guidance for Industry on sterile drug production³.

The FDA guidance outlines various recommendations for gowns, such as proper gown control; no unreasonable contamination risk to the gown; providing a barrier between the body and exposed sterilized materials; and preventing contamination from particles generated by, and microorganisms shed from the body. Gowns should be sterilized and

non-shedding. Methods used to don each gown component in an aseptic manner should be detailed. Manufacturers should implement an aseptic gowning qualification program to assess the ability of a cleanroom operator to maintain the quality of the gown after performance of gowning procedures, including periodic requalification and

microbiological monitoring of strategically selected locations on the gown.

The current EU-GMP guidelines require sterile (sterilized or adequately sanitized) garments to be provided for grade A/B areas and changing and washing to follow a written procedure designed to minimize contamination of clean area clothing or carry-through of contaminants to the clean areas. It further requires that clothing and its quality be “appropriate” without defining what would be considered appropriate. It also requires clothing to “be worn in such a way as to protect the product from contamination.” In terms of attributes, “protective clothing should shed virtually no

fibers or particulate matter and retain particles shed by the body”. Reusable garments are required to be cleaned and handled in such a way that the garment does not gather additional contaminants that can be shed later.

The current EU-GMP Annex 1 for the Manufacture of Sterile Medicinal Products¹¹ includes little guidance on cleanroom garment qualification except that it needs to be “appropriate”.



The new draft EU-GMP Annex 1 ¹² published for consultation in December 2017 explicitly introduces the application of QRM principles and provides more details on gowning, including the requirement that gowning is part of a holistic contamination control strategy. It further requires that:

• Personnel are trained on gowning practices, which must be assessed

• Personnel are qualified through a successful aseptic process simulation test

• Microbial monitoring of personnel is performed


In addition, this new draft EU-GMP Annex 1 ¹² requires that garments are visually checked for cleanliness and integrity. It also provides several new requirements regarding clothing of grade A/B; body parts that should be covered; the surfaces ofthe garment reduced to a minimum”.

A key addition is the requirement that “reusable garments should be replaced based at a set frequency determined by qualification or if damage is identified”. This requires manufacturers to produce data regarding the effect of However, there is little guidance on how to qualify those garments other than stating in subclause 4.11 that “clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way The Japanese Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing⁴, developed by a task force of Japanese experts, is an extensive document covering all areas of aseptic processing. It includes recommendations on gowning, operations, monitoring and controls that are comparable to other standards. It provides some interesting design recommendations on gowning and de-gowning areas and highlights the need to establish appropriate control procedures, including visual inspection. It also defines maximum allowable frequency of steam sterilization for reusable materials, such as aseptic gowns, to “ensure maintenance of specifications, safety, and intended functions after repeated exposure to steam at its maximum intensity”.


ISO 14644-5¹³ includes an informative annex B on cleanroom clothing requirements that provides some useful guidance on aspects to consider during qualification of such clothing. It provides guidance on barrier properties; evaluation of electrostatic properties; some guidance on fit and function; and helpful guidance on construction, finishing of seams and general design criteria that can be used to establish URS. It proposes use ofthe dispersal chamber or body box¹⁴ as a simulation procedure to evaluate performance; recommends that shelf life of sterile packaging be determined; and includes considerations on thermal comfort and some guidance on cleaning, referring to IEST-RP-CC003.4¹⁴ .

ISO 13408-1 ¹⁵ on general requirements of aseptic processing includes some general requirements on cleanroom garments but does not provide much guidance on cleanroom garment system qualifications.

IEST-RP-CC003.4 “Garment Systems Considerations for Cleanrooms and Other Controlled Environments” ¹⁴ provides guidance on design, selection, specification, maintenance and testing of garment systems. It includes useful guidance on material qualification attributes, considerations on processing (cleaning, re-sterilization, etc.), gowning system specifications and quality management. Appendix B proposes various tests for assessments of particle penetration and garment cleanliness, which includes the well-known and very useful body box test¹⁶,¹⁷ that allows simulation of the actual use of the garment, as well as the Helmke drum test¹⁸ . Overall, IEST-RP-CC003.4¹⁴ is the most useful document to support qualifications of cleanroom garment systems.


The EU general guidance on validation (GMP Annex 15¹⁹) provides the general framework that we will apply to the qualification of cleanroom garment systems.


Validation Approach For Cleanroom Garments

The main stages of validation of equipment, facilities, utilities or systems are:

• Definition of User Requirements Specification (URS)

• Design Qualification (DQ)

• Installation Qualification (IQ)

• Operational Qualification (OQ)

• Performance Qualification (PQ)


This approach is also appropriate for cleanroom garments. Some stages of the validation can focus mainly on the quality of the cleanroom garment itself, but in other stages, the other items of the cleanroom clothing system (i.e., cleanroom undergarments, footwear, socks, head coverings, face masks, eye coverings, gloves and other accessories) must be included. The packaging (sterile and non-sterile barriers) of the cleanroom garments should be part of the validation. An overview of the different validation stages and validation items for cleanroom garments is given in Figure 2. Each validation stage must be formally finalized before progressing to the next stage.


The GMP (EU, US, Japan) guidelines state that QRM⁷ should be used for qualification and validation activities. If

changes occur during the project phase or during commercial production (e.g., change of garment design, fabric, zipper

type, packaging, laundering process or sterilization process), the risk assessments must be repeated to determine if

additional validation must be performed. The way in which risk assessments are used to support qualification and

validation activities should be clearly documented.


For critical goods and materials, such as cleanroom garments, it is also important to qualify the supplier. This

qualification should provide an appropriate level of confidence that the supplier is able to supply cleanroom garments

with consistent quality and acts in compliance with regulatory requirements. A supplier qualification should also

include qualification of subcontractors, suppliers of base materials (e.g., fabric and garment accessories) and outsourced service providers (e.g., laundries and sterilization facilities).


User Requirements Specification (URS)

The specification for cleanroom garments should be defined in a User Requirements Specification (URS). The URS is a

document that specifies requirements necessary and sufficient to create a feasible design, meeting the intended purpose of the material, equipment, utility or system. The URS may also include additional requirements, such as protection of people against chemical and/or biological agents. An example of a URS for cleanroom garments is given in Table I.


Cleanroom garments for use in EU-GMP grade A/B cleanrooms should adequately protect the environment and products against contamination from people. A trained and qualified operator, wearing a nonwoven polypropylene head cover, clean polyester two-piece undergarment, clean dedicated socks, double sterile gloves, a sterile face mask and sterile goggles, must be able to work at least three hours in the same set of cleanroom garments without causing unacceptable (cGMP) levels of contamination of the garments and the aseptic working environment.


Design Qualification (DQ)

During DQ, compliance of the cleanroom garment design with cGMP must be demonstrated and documented, and the

requirements of the URS must be verified. The purpose of the DQ is to confirm that the selected cleanroom garment is

qualified for the intended use. Therefore, it should also include tests to simulate the intended use. The DQ must be

executed and authorized by suitably qualified persons who are knowledgeable enough to challenge the proposed design and its performance.


Following the model of design validations of sterile barrier systems described in ISO 11607-1²⁰ , it is recommended to

split the DQ into four key areas: material qualification, performance testing, stability testing and usability evaluation. For

reusable garments, reprocessing should be the subject of a separate DQ by the manufacturer and IQ-OQ-PQ by the

supplier.


The material qualification includes the qualification of key characteristics and key properties of the materials and fabrics used, the cleanroom garments and the packaging.


Performance testing includes testing of the cleanroom garments and the packaging under simulated and standardized

conditions using standardized test methods.


Stability testing must be performed to assure that key material characteristics and properties remain sufficiently stable

during the life cycle. Characteristics and properties that change over time (e.g., deterioration of filtration efficiency of

garments due to repeated laundering and sterilization; wear of the garments due to multiple use; and changes to the

integrity of the sterile packaging during storage due to long-term effects of gamma irradiation) should be validated under worst-case conditions. Information for material qualification, performance testing and stability testing normally should be provided by the supplier. It is important to verify that the data has been generated using validated and sound scientific methods.


The purpose of the usability evaluation is to assure that the cleanroom garments can be used with acceptable remaining contamination and safety risks due to the design of the garments and the established gowning, working and de-gowning

procedures. The usability evaluation is typically done by the end-user however, suppliers can also evaluate their garments for the intended use and supply that data to users for verification and further mitigation of identified risks during gowning and operations. The concept of usability engineering and testing has developed into a well-accepted way to successfully reduce use-related risks by reviewing these risks during the design phase and systematically reviewing the design and use of the product against those identified risks (see also IEC 62366-1 on usability engineering of medical devices²¹).



Relevant items to be covered for each of the four areas are presented in Table II. A summary is given in Figure 2.


Reusable Versus Single-Use Cleanroom Garments. The validation of reusable cleanroom garments is more complex and more extensive compared to single-use cleanroom garments. Repeated laundering, repeated sterilization, multiple use and repairs influence the quality of reusable cleanroom garments. This also means that the influence of these factors must be validated throughout the entire life cycle in the frame of the stability testing and the performance testing at the end of the life cycle. In addition, not only the supplier of the garments but also the cleanroom laundry, sterilization facilities and repair service must be qualified. Reprocessing should be the subject of a separate DQ by the manufacturer and IQ-OQ-PQ by the supplier.


Installation Qualification (IQ)

The IQ for cleanroom garments is a formal check to verify if all required elements of the cleanroom gowning system are present. These include the gowning and de-gowning facilities; certificates of conformance and/or analysis; implementation of instructions from the supplier; standard operating procedures for gowning and de-gowning; logistical processes for the cleanroom garments and related accessories; and the operator training and qualification plan.

Risk assessments that were executed as part of the DQ of the cleanroom garments should be finalized and risk controls should be implemented.

In addition, it is important to verify that the correct materials have been received for performing the OQ and PQ (i.e., the correct cleanroom garments, correctly folded, in the correct packaging and correctly labeled). A summary of items to be included in the IQ is given in Figure 2.


Operational Qualification (OQ)

During the OQ, the objective is to qualify the gowning and de-gowning concept. For this purpose, all relevant steps of the gowning and de-gowning process, including logistics, should be qualified. In addition, the aseptic presentation of the garments should be qualified. To validate the aseptic gowning procedure, at least three independent, consecutive, successful visual and microbiological assessments for at least one person who is trained for aseptic gowning should be performed. The OQ should also include a formal assessment to verify that different work tasks can be executed properly from a practical point of view (e.g., moving, bending, stretching and lifting). It is recommended to perform this assessment with all available sizes of the cleanroom garments and with people of different body shapes. A summary of items to be included in the OQ is given in Figure 2.


Performance Qualification (PQ)

During PQ, the objective is to validate the performance of the cleanroom garment system when it is actually in use. The requirements specified in the URS must be complied with fully.


The PQ of cleanroom garments consists of two stages. In the first stage of the PQ, compliance with aseptic gowning procedures should be assessed and confirmed. This gowning qualification must involve both a visual and microbiological assessment. The visual assessment is to qualify that people don the cleanroom garments in a correct and aseptic manner, which shall be described in detail in a gowning procedure. After gowning, the microbiological quality shall be assessed by taking surface samples from several locations on the cleanroom garments, gloves, goggles and face mask. Locations must be determined based on a risk assessment.


Each person accessing an EU-GMP grade A/B environment must perform a gowning qualification. For the PQ, it is important to determine how many gowning qualifications are required to demonstrate compliance with the requirements. Typically, initial gowning qualification is performed three times for each person. It is important that adequately trained, qualified and experienced persons execute the PQ to exclude failures due to causes other than quality issues with the cleanroom garments.


The second stage of the PQ focuses on the validation of the microbiological quality of the gowned personnel with the garments and other accessories (e.g., gloves, face mask, goggles) during the actual work (e.g., aseptic compounding, aseptic filling, cleaning and disinfection, and other activities).


The second stage of the PQ also includes validation of the microbiological and particulate quality of the environment people are working in and the execution of aseptic process validations (i.e., media simulations or media fills). The number of runs for these validations must be determined based on a risk assessment. Typically, these validations are performed three times. To exclude failures due to causes other than quality issues with the cleanroom garments, it is important that adequately trained, qualified and experienced personnel execute the PQ in areas with an excellent quality

history.


The PQ is typically done under worst-case conditions. These worst-case conditions must be determined based on a risk assessment. Also, the actions that should be taken if established criteria are not met during the PQ, must be defined before executing the PQ. Only after a successful PQ can the cleanroom clothing system be formally implemented. A summary of items to be included in the PQ is given in Figure 2.

Revalidation And Change Management

The cleanroom clothing system should be evaluated at an appropriate frequency (e.g., annually or biennially) to confirm

that it remains in a state of control. Gowning qualifications shall be repeated at least annually and even more frequently

in cases where there is doubt about the quality of the aseptic gowning process or aseptic gowning skills of specific

persons. The cleanroom clothing system is included in validations which must be performed periodically (i.e., cleanroom qualifications under dynamic conditions and aseptic process validations).

Changes must be reviewed critically and may lead to revalidations that are more or less extensive, depending on the type of change. Properly and well documented DQs, as well as IQ-OQ-PQ, are the basis for successful change management.


Monitoring

Personnel monitoring must be part of the environmental monitoring program¹,³,²². The microbiological quality of

cleanroom garments for persons working in a grade A/B environment must comply with the EU-GMP¹ grade B limit for

surface samples (i.e., the action limit is 5 CFU/contact plate). Alert limits are usually lower (e.g., 2 or 3 CFU/contact

plate). Cleanroom garments, face masks, goggles and gloves are typically sampled at the conclusion of activities in a

grade A/B area, but just before leaving the area. For this “exit monitoring,” contact samples are taken from different

locations. Sample locations must be determined based on a risk assessment. Commonly selected locations for exit

monitoring are shown in Figure 3. After sampling, the person must leave the area to prevent spreading contamination due to medium residues present on the cleanroom garments.


Gloves should be sampled after performing activities in a grade A environment to verify the quality of the aseptic

conditions and aseptic handling. Gloves of operators working in a grade B environment should also be monitored during each work shift. Gloves are typically sampled with a frequency ranging from once to multiple times per work shift.


In addition to personnel monitoring, samples from several locations in the cleanroom should be taken to determine if the production environment and processes are in control. Sampling is typically performed during (passive and active

microbiological air sampling and particle counting) or at the conclusion (surface sampling) of operations but may also be performed under static conditions (i.e., in the at-rest state of an area), to verify cleanliness.


In the case of non-conformities, assessments must be done to determine root causes. The cleanroom clothing system as

a potential root cause should be included in these assessments.


It is also recommended to assess if gowning procedures, cleanroom behavior guidelines and aseptic procedures are

followed correctly. These visual assessments should be done on a regular basis.


Conclusion

A science- and risk-based quality-by-design approach for the development, implementation and validation of sterile

garment systems for EU-GMP grade A/B aseptic processing areas is not only the correct approach to effectively control

contamination risks related to people, but also an adequate response to the latest regulatory requirements. The new EUGMP Annex 1 draft is based on QRM principles and introduces the concept of a holistic contamination control strategy that considers all aspects of contamination control over the entire life cycle based on thorough technical knowledge and sound process know-how. Considerable efforts will be required by manufacturers to update their technical files, with cleanroom garments being just one of the many aspects.


With a risk-based quality-by-design approach applied to cleanroom garment systems, more effort is spent at the frontend, in the design phase, as well as in the design qualification. This will lead to designed-in risk reductions; better

scientific knowledge of key aspects, attributes, limitations and residual risks of the selected technical solutions; and

fewer issues during cleanroom qualifications, process validations and routine operations. In case of failures, it can be

difficult to determine the root cause or the elements that have failed. That’s why a quality-by-design approach, with

focused and extensive design qualifications for each element, is the only way to successfully and systematically reduce

the risk of failure. This approach also creates the foundation for adequate and risk-based change management.

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