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Production & Cleanroom

Pharmaceutical production poses unique challenges that differ from non-sterile manufacturing processes. Considering that many drugs will interact directly with patients and potentially pose a high risk to patient safety and treatment outcomes, their production, storage, and distribution are highly regulated. The products are susceptible to environmental conditions and contamination due to microbes, requiring strict environmental control as specified in the current good manufacturing practice (cGMP) guidelines.

01 What environmental conditions are monitored?

Microbes can change the drug chemistry or alter the pharmacology of the product. Consequently, the breaking down of active ingredients can cause a decline in drug efficacy and can render more sensitive products useless. Additionally, the drug's toxicity may increase because of the chemical breakdown of active components into toxic byproducts. These can be harmful to patients in terms of morbidity and mortality. They may also contribute to the development of chronic diseases or the decline of patient response to treatment.

Protocols to measure and ascertain drug, biological product, and medical device quality are meant to protect public health.

For these reasons and more, pharmaceutical production requires stringent environmental control. Humidity, temperature, and pressure differentials must be controlled and monitored to ensure the conditions are suitable. Here is where cleanrooms come into play.

What is a cleanroom?

A cleanroom is a room or suite where the environment is controlled to avoid pollutants like dust, airborne microbes, aerosol particles, and chemical vapors. Unlike regular production rooms, cleanrooms require high efficiency particulate air (HEPA) filters or ultra low particulate air (ULPA) filters to trap particles and reduce product contamination. While microbial testing can check for the presence of microbes, testing alone cannot provide total assurance or microbial control. A cleanroom is the best way to go because microbial control is built into the process from the beginning to the end.

What is the purpose of a cleanroom?

The primary purpose of a cleanroom is to control the introduction of contaminants into the manufacturing or testing environment. The environment remains at a constant level of cleanliness suitable for product viability. Environmental conditions are required to be monitored to prove compliance to the relevant standards. Moreover, air quality monitoring plays a critical role. Adherence to cleanroom protocols demonstrates microbial quality of the facility space and assures the client of the product’s sterility.

Monitored Environmental Conditions

  • Humidity

  • Temperature

  • CO2

  • Pressure and Pressure Differential

  • Particles

  • Door opening

Slight variations in humidity, for example, can be detrimental in the pharmaceutical industry. Ingredients in powder form begin to absorb moisture, leading to the clogging of production lines. In addition to altering the ingredients' chemical composition, the introduction of moisture in the production process will affect temperature control, production time, and efficacy, resulting in an inferior quality product. To avoid dust and bacteria entering the room, the entire clean room chamber is set under over-pressure. Therefore the monitoring of pressure inside the chamber and the monitoring of the pressure difference in the access doors is crucial. Inside the clean rooms the contamination levels are monitored using particle counters. Often also the access doors are monitored by door opening sensors in order to have a clear access log. Cleanrooms are constructed in such a way to maintain these parameters.

Cleanroom Monitoring Compliance

The design, implementation, and operation of a cleanroom are crucial in pharmaceutical production. A cleanroom will help you establish product security and ensure patient safety throughout the entire production process. However, cleanrooms can be burdensome because of the numerous compliance requirements. There are requirements for the room's design, the room’s materials, and specifications for operations. Monitoring requirements prove adherence to the relevant guidance documents and protocols.

Why do we need requirements?

Requirements provide a basis upon which regulatory authorities can evaluate a cleanroom. If the room meets the threshold, they can issue a compliance certification to the company. If not, remedial action must take place before retesting and confirmation.

Requirements help establish global uniformity.

Despite the varying capacities of different national regulatory bodies, there are international standards. Through cleanroom classification, the same grade cleanroom in different countries will have exact parameters. That means the distribution of drugs can be smooth and efficient since cleanrooms at the destination match the standard of cleanrooms at the port of departure.

Requirements for cleanrooms help ensure product quality.

Pharmaceutical products are sensitive to the presence of microbes and variations in environmental conditions. There must be requirements to stipulate the necessary ambient conditions of temperature, humidity, and pressure to ensure consistent product quality. The requirements must state the acceptable air particulate concentration for different applications of the cleanroom. Maintaining product quality protects the patient from damaged and harmful products. Additionally, there will be improved patient outcomes, a better treatment response, and a decrease in the global disease burden.


Who publishes requirements for cleanrooms?

Although several organizations take part in the publication of requirements for cleanrooms, the outstanding ones include the ISO 14644, the EU Annexes 1, FDA, and the WHO. These documents contain principles and parameters for cleanroom design, construction, operation, and monitoring. Here are a few of the recognized guidance documents that cover the controls needed for cleanrooms:

International Organization for Standardization (ISO)

The ISO 14644 is among the most used documents in the pharmaceutical industry. ISO 14644-1 gives details on obtaining certification for compliance, while ISO 14644-2 explains how to conduct monitoring in cleanroom environments. In addition to observance of cleanroom classification requirements, the document emphasizes adopting a monitoring strategy based on the risk assessment conducted for the cleanroom’s intended use. The ISO documentation classifies monitoring into three categories: continuous, sequential, and periodic. Sequential monitoring is not acceptable for pharmaceuticals, while continuous monitoring provides immediate analysis for unseen contamination events. Part of the document also highlights the appropriate location for particle counter probes, instrument selection, and conducting a risk assessment.

EU GMP Annex 1

The EU GMP Annex 1 is a governing document within the European Union that stipulates the controls necessary to produce sterile pharmaceutical products. Together with the FDA requirements, the cGMP forms the bulk of guidance material for sterile pharmaceutical manufacturing. The purpose of this guidance is to provide instructions on how to minimize microbial, particulate, and pyrogen contamination in sterile drug manufacturing. The documentation covers critical areas such as personnel training and equipment qualification. You will also find detailed guidance on cleanroom environmental monitoring to ensure safe drug production and distribution. Any company manufacturing within the European Union or importing into the region must comply and prove adherence with the EU GMP Annex 1.

Federal Drug Association (FDA)

The FDA has a guidance document that outlines protocols for sterile drug products manufactured through aseptic processing. This is found in CFR Title 21 Parts 210 and 211. The aseptic process is comprehensive and entails more variables than terminal sterilization. Since there is no provision for sterilizing the product in its final container, filling and sealing must occur in high-quality environments. Additionally, individual parts that constitute the final product must undergo separate sterilization with an appropriate technique depending on their composite material. You will find that each of these sterilization modalities and manufacturing techniques require control and validation. The FDA guidance document gives all the required procedures for process control.

CFR 21 Part 11 discusses requirements for electronic records. These requirements are relevant to data monitoring in cleanrooms.

World Health Organization (WHO)

The WHO provides regulatory insight into cleanroom environmental monitoring. The document covers human vaccine manufacturing facilities since the WHO is the vaccine depositary for all UN agencies. In chapter three, you will find guidance on cleanroom classification and environmental monitoring. The section defines each classification based on their maximum permitted airborne particulate concentration. It also provides the standards for the vaccine prequalification process. Other topics include particulate sampling methods, routing particulate monitoring, and data analysis after monitoring.

Air, temperature, and humidity are among the most important environmental conditions in a cleanroom. The environmental conditions in a cleanroom must be within a stipulated range to ensure the products are not damaged. These acceptable ranges will vary depending on the sensitivity of the product and the sterile requirements for the production process.

Cleanrooms classification is specified by the particulate concentration per air grade. The particulate filters can employ laminar or turbulent airflow to eliminate up to 99.9% of micro-particles. By using HEPA or ULPA filters, you can control the number of particles in the cleanroom. These filters are tested to ensure proper operation. After attaining the right air quality, the bulk of the remaining work is to maintain that standard. Additionally, pressure differentials should be measured to determine the adequate pressure to maintain the desired direction of airflow. The goal is to sweep contaminants away from work surface areas.

For larger cleanrooms, a key cGMP requirement is temperature and humidity mapping. The study will identify the areas of the room with the most drastic conditions. This is where you should set up your permanent sensors.

Continuous temperature monitoring is performed by data loggers and transmitters. Previously, data loggers did not have connectivity, so data retrieval was manual, tiring, and costly. Now, there are a variety of options. Modern loggers have inbuilt connectivity, and you can access the data from any internet-enabled device. Depending on your unique requirements, on-premises monitoring systems as well as cloud systems are available with wireless or wired sensors.

Apart from temperature excursions, out-of-range humidity values are the next most prominent cause of pharmaceutical product damage. High humidity interferes with potency and product effectiveness by allowing contents to absorb moisture. The moisture content can cause bacterial growth and makes products extra sticky, leading to machine clogs and hiccups in the production process. Different products will require different humidity levels, but in general, the WHO recommends an optimal relative humidity of less than or equal to 60 percent.

Cleanroom Environmental Monitoring Regulations

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02 Validation and Qualification

Cleanroom validation and qualification are essential to ensure your research is credible. Validation serves several functions like ensuring the facility design and the intended purpose are congruent. Validation confirms that the room, equipment, and environment satisfies the user requirements and that good manufacturing practices are observed. Depending on the cleanroom grade identified in ISO regulations, the validation requirements and strictness will vary.

Validation Includes Qualification

Validation includes a four-stage approach in a qualification process.

  • Design Qualification (DQ)

  • Installation Qualification (IQ)

  • Operational Qualification (OQ)

  • Performance Qualification (PQ)

The design qualification comes first to prove the design of the facility, the systems, and the equipment will be suitable for their intended purpose.

Installation qualification can only commence after the approval of the design qualification. It is a documented process that verifies the HVAC; the HEPA filters; and other critical equipment, software, and tools have been delivered, correctly installed, and/or configured according to the associated standards. Their installation is according to the user and design requirements. This includes the calibration status for equipment, an analysis of the standard operating procedures, and site acceptance tests.

In the operational qualification stage, the tests focus on the operation of the cleanroom under worst-case scenarios. It should include testing under maximum and minimum temperature and humidity limits. After establishing these limits, the resulting airflow patterns, alarm operation, personnel contamination, and differential pressure reports will determine the cleanroom's performance.

Performance qualification forms the tail end of the process, giving assurance that the cleanroom processes will always produce the desired outcomes under normal operating conditions. The tests verify the system’s ability to perform under simulated real-world conditions.

Qualifications for Monitoring Environmental Conditions

Cleanroom environmental monitoring is necessary to establish that all parameters are within acceptable limits. Alarms are programmed to alert the user when conditions are beginning to deviate, allowing time for remedial processes to be performed. The equipment, including the software and hardware, must be qualified to prove they are carrying out the expected outcomes. The software validation requirements include record retention, an audit trail, system access, and system security. Data integrity is crucial, especially in GMP compliance. It assures the client that it is impossible to manipulate the data. You can prove data integrity through adherence of the electronic signatures guidance documents (CFR Title 21 Part 11, EU Annex 11).

Cleanroom Qualifications

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03 User Requirement Specification for a Cleanroom Monitoring System

Before commissioning any design for a cleanroom, the first process is to draft a user requirement specification (URS). The URS defines the design, implementation, and operation of the cleanroom.

What is a URS?

A URS is a document detailing the users' requirements and business needs for a system, equipment, and/or a cleanroom. The document details the design and construction of the cleanroom. Every cleanroom project begins and ends with the user requirements. In the beginning, it forms the basis for building the project, and at the end, it forms the evaluation criteria for the project's success. The user does not give technical insight, but their process knowledge will help shape the cleanroom structure. It is the work of the design engineers to translate all user requirements into technical specifications that will inform the design plans.

A URS document should rely on knowledge of good manufacturing practice standards.

Every cleanroom will be subject to standards and compliance. Therefore, it is expedient to ensure that from the beginning, the project starts with these standards. That will ensure that both the structural components and operational procedures fall within acceptable limits.

What Components are in the Cleanroom URS?

Each cleanroom will have equipment relevant to its intended purpose. The client should describe the requirements of equipment needed for the cleanroom. Additionally, the consideration of the equipment must be in tandem with the good manufacturing practice standards, making sure that it introduces minimal particulate into the cleanroom environment.

The capacity of the cleanroom is another consideration in the URS. The capacity considers the optimal cleanroom operation, looking at the personnel and equipment it can accommodate without compromising the air quality. You must also consider the personnel interactions with one another, the equipment, and the outside environment. The capacity will inform the design layout, workflow arrangement, and material distribution to ensure minimal contamination.

Cleaning requirements form part of the URS. They cover the personnel, equipment, and surfaces. Proper gowning and facility access protocols can prevent the personnel from spreading contaminants in the cleanroom. For equipment, you need to know the correct cleaning protocols and substances that will not damage the appliances or introduce unwanted particulates.

In any pharmaceutical business, the cleanroom is a vital component for success. It helps ensure product quality and patient safety. However, the cleanroom must be under regular validation and qualification to ensure adherence to the prevailing standards. The equipment, personnel, and surfaces are the main components of a cleanroom that require validation. Validation is described in the URS.

Cleanroom Monitoring URS

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