WHAT IS CLEANROOM?

The cleanroom is also called an Environmental Controlled Area ECA A cleanroom is a facility ordinarily utilized as a part of specialized industrial production under controlled environmental conditions of cleaning. Cleanrooms are designed to maintain extremely low levels of particulates, such as dust, airborne organisms, or vaporized particles. Cleanrooms typically have a cleanliness level quantified by the number of particles per cubic meter. Cleanrooms are responsible to maintain particulate-free air through the use of either HEPA or ULPA filters employing laminar airflow principles. Laminar or unidirectional, air flow systems direct filtered air downward or in the horizontal direction in a constant stream towards filters located on walls near the cleanroom floor or through raised perforated floor panels to be recirculated. Laminar airflow systems are typically employed across 80% of a cleanroom ceiling to maintain constant air processing. What is a cleanroom At-Rest/Static condition? Cleanroom that is completed and has the production equipment installed and operable, but has no personnel within the cleanroom. What is a cleanroom at Operational or Dynamic conditions? A cleanroom in normal operation, including production equipment and personnel. The most recognized classifications of cleanrooms are defined by the ISO 14644 standard as: How are classified the cleanrooms as per ISO 14644-1? It is the classification level of airborne particulate cleanliness applicable to a cleanroom or clean zone, expressed in terms of an ISO Class. This standard represents the maximum allowable concentrations per volume of air sampled for considered sizes of particles.  According to the ISO 14644-1, the cleanroom classifications number is defined based on the maximum concentration limits for particles per volume equal to and larger than the considered sizes shown below:  (This table also compares the ISO classification number with the legacy standard US FED STD 209D) Equivalence Standards Acceptance Criteria Specifications: Maximum concentration limits of particles/volume ISO 14644 Classification number US FED STD 209D Classification number 0.5 um size particles 1 um size particles 5 um size particles   5   100 3,520  / m3   100 / ft3 832 / m3   —     6   1,000 35,200 / m3   1,000 / ft3 8,320 / m3   293  / m3   7 / ft3   7   10,000 352,000  / m3   10,000 / ft3 83,200 / m3   2,930  / m3   70 / ft3   8   100,000 35,200,000  / m3   100,000 / ft3 832,000 / m3   29,3000  / m3   700 / ft3   TYPES OF CLEANROOMS: Exist two types of cleanrooms, each cleanroom design has advantages and disadvantages in terms of cleanroom air balancing, laminar flow uniformity inside the room, construction, and maintenance. 1. Cleanrooms with plenum Cleanroom with plenum is built to minimize costs, materials, and labor to install ducts for supply and return especially in very restricted areas in which their no space to install ducts. Moreover, once balanced, it brings a high laminarity pattern inside the cleanroom. Due to the big amount of space in the plenum and possible leaks, obtaining the desired differential pressure is very difficult and requires sometimes the installation of motorized HEPA filters to obtain the amount of air velocity inside the cleanroom. 2. Cleanroom with direct supply and return ducts – without plenum. Cleanrooms with the direct duct of supply and return bring some specific benefits during the room air balancing of each HEPA filter. Also, it brings more efficient management of air since leaks can be limited and contained on the ducts. HVAC utility is designed to remove the particle matter in size greater than 0.3 um using the HEPA filters to control the level of viable and non-viable contamination exposure that a drug or medicinal device might receive in addition to regulating temperature and relative humidity conditions. HVAC utility must be qualified to demonstrate operating conditions and effectiveness of the area to comply with the requirements of the ISO 14644 standards. The areas serviced by the HVAC utility are called commonly as “cleanroom” or CEA “Controlled Environmental Area” and they are classified based on viable and non-viable particulate levels during static operating conditions and dynamic operating conditions. Please do not confuse the cleanroom with the AHUs”

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More details on specific FDA expectations for cleanrooms

can be found in the guidance document below.

httpss://www.iso.org/standard/53394.html

For a preview, refer to httpss://www.iso.org/obp/ui/#iso:std:iso:14644:-1:ed-2:v1:en

Three (3) options to create a qualification protocol for a cleanroom.

Option 1. You can create a great protocol, using a template.

You can download a free sample of a validation template in .pdf format. 

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Option 2. We can bring you a formal training on how to create your own validation protocols using our template(s).

This option is recommended if you want to learn more about how to build a robust validation protocol. One of our expert(s) will provide online step-by-step training to your team (unlimited assistance) on how to build a reliable validation protocol using a template. You can improve your corporate validation procedures and policies incorporating our template sections.  It includes the template, an exam, and a training certificate for each assistant.  Request a quote now.

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STATUTORY AND REGULATORY REQUIREMENTS

for Cleanrooms

Validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)), which states the following:

“… a drug (including a drug contained in a medicated feed) shall be deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirement of the act as to the safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.”

Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)), which states the following:

FDA regulations describing current good manufacturing practice (CGMP) for finished pharmaceuticals are provided in 21 CFR parts 210 and 211.

The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process material and the finished product meet predetermined quality requirements and do so consistently and reliably.

Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and 211. The foundation for process validation is provided in § 211.100(a), which states that “[t]here shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess…” (emphasis added). This regulation requires manufacturers to design a process, including operations and controls, which results in a product meeting these attributes.

Other CGMP regulations define the various aspects of validation. For example, § 211.110(a), Sampling and testing of in-process materials and drug products, requires that control procedures “. . . be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product” (emphasis added).

Under this regulation, even well-designed processes must include in-process control procedures to assure final product quality. In addition, the CGMP regulations regarding sampling set forth a number of requirements for validation:

Samples must represent the batch under analysis (§ 211.160(b)(3)); the sampling plan must result in statistical confidence (§ 211.165(c) and (d)); and the batch must meet its predetermined specifications (§ 211.165(a)).

In addition to sampling requirements, the CGMP regulations also provide norms for establishing in-process specifications as an aspect of process validation. Section 211.110(b) establishes two principles to follow when establishing in-process specifications. The first principle is that

“. . . in-process specifications for such characteristics [of in-process material and the drug product] shall be consistent with drug product final specifications . . . .”

Accordingly, in-process material should be controlled to assure that the final drug product will meet its quality requirements. The second principle in this regulation further requires that in-process specifications “. . . shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate.”

This requirement, in part, establishes the need for manufacturers to analyze process performance and control batch-to-batch variability.

The CGMP regulations also describe and define activities connected with process design, development, and maintenance. Section 211.180(e) requires that information and data about product quality and manufacturing experience be periodically reviewed to determine whether any changes to the established process are warranted. Ongoing feedback about product quality and process performance is an essential feature of process maintenance.

In addition, the CGMP regulations require that facilities in which drugs are manufactured be of suitable size, construction, and location to facilitate proper operations (§ 211.42). Equipment must be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use (§ 211.63). Automated, mechanical, and electronic equipment must be calibrated, inspected, or checked according to a written program designed to assure proper performance (§ 211.68).

References

httpss://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=225.1

https://www.imdrf.org/docs/ghtf/final/sg3/technical-docs/ghtf-sg3-n99-10-2004-qms-process-guidance-04010.pdf

httpss://www.fda.gov/media/94074/download

httpss://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=225.1

httpss://www.fda.gov/regulatory-information/search-fda-guidance-documents/part-11-electronic-records-electronic-signatures-scope-and-application

httpss://ispe.org/publications/guidance-documents/gamp-5

https://www.imdrf.org/docs/ghtf/final/sg3/technical-docs/ghtf-sg3-n99-10-2004-qms-process-guidance-04010.pdf

httpss://www.fda.gov/media/94074/download

https://www.imdrf.org/docs/ghtf/final/sg3/technical-docs/ghtf-sg3-n99-10-2004-qms-process-guidance-04010.pdf

httpss://www.fda.gov/media/94074/download

httpss://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=225.1

httpss://www.fda.gov/regulatory-information/search-fda-guidance-documents/part-11-electronic-records-electronic-signatures-scope-and-application

httpss://ispe.org/publications/guidance-documents/gamp-5

Related topics and resources:

Validation Plan, Installation Qualification, Operational Qualification, Performance Qualifications, Component Qualification, Traceability Matrix, Ppk, Control Charts, Cpk, User Requirements, Functional Requirement Specifications, GAMP5, risk assessment