Commissioning and Qualification of Biopharmaceutical Cleanrooms
BIOPHARMACEUTICAL INDUSTRY: CURRENT MARKET CONDITIONS IN CLEANROOM CONSTRUCTION
Speed to market is a fundamental goal of all Pharmaceutical and Biotechnology companies in the 21st century. Due to patent life cycles, by the time a suitable drug candidate has been found, developed, and ready for commercial sale, an average of 12.8 years has gone by on the original 20-year patent. Each quarter of missed production due to design, construction, startup, and commissioning and qualification (C&Q) results in less time to capitalize on patent protection.
Not only is there a financial motivation to getting a site up and running, but every day of delay is a day that patients will not receive the lifesaving or life improving medicines that they urgently need. This is especially true for drugs that are on the drug-shortage list, which tracks supply shortages. The list has been growing in recent years and represents direct patient need. Currently the list is at an exceptionally elevated level and is expected to continue growing, due to capacity weaknesses.1
As the pharmaceutical industry continues to follow the trend of prioritizing speed to market, alternative options to traditional cleanrooms have sprung up, such as prefabricated cleanroom products. Prefabricated cleanrooms have the benefit of reducing timelines due to the ability to parallel path construction of the cGMP cleanroom and non-cGMP host facility. There is also a potential for increased quality by purchasing prefabricated cleanrooms from companies with a proven track record and compliant quality system. A prefabricated cleanroom manufacturer will also perform in-house quality and commissioning tests (factory acceptance tests) to confirm quality prior to leaving the factory, which may not be provided by traditional cleanroom contractors.
While there are strong incentives to get a cleanroom facility producing as quickly as possible, quality cannot take a backseat to schedule. A project completed timely but with poor quality will only significantly increase costs and delay project implementation. Therefore, to meet aggressive timelines, proper up-front planning is a must. This paper will provide a guideline of the steps and documentation needed to properly commission and qualify a biopharmaceutical cleanroom.
DEFINING THE DRUG PROCESS
Just as a cleanroom must be physically built on a strong foundation; a strong foundation of risk assessment and design requirements must be established early in the project. Regulatory agencies including FDA, EMA, and others, have increasingly pushed companies toward a risk-based engineering approach by identifying the drug product risks and then determine which risks need to be addressed based on the risk rating. By following the methodology of Quality by Design (QbD), the product’s Critical Quality Attributes (CQA) and Critical Process Parameters (CPP)1 are identified up front. These characteristics are defined as:
Critical Quality Attribute: A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.2 CQAs should be determined based on severity.3
Critical Process Parameters: Independent process parameters most likely to affect the CQAs of an intermediate or finished product and therefore should be monitored or controlled to ensure the process produces the desired quality product.
CQAs and CPPs should be reviewed during an engineering risk assessment with key subject matter experts. In the case of parenteral drug products, a typical cleanroom in an open processing suite would have the following CPPs/ CQAs:
Particulate Levels (impacting purity/identity of the product)
Relative Humidity Percentage (impacting potency of the product),
Temperature (impacting potency of the product).
These CPPs must be monitored and recorded by a GMP compliant Environmental Monitoring System (EMS). Additional CPPs may be determined and further defined based on product requirements identified during the risk assessment, as discussed below.
DETERMINING CLEANROOM REQUIREMENTS
After establishing the CPPs, a User Requirements Specification (URS) document is assembled. This document will allow Subject Matter Experts (SMEs) to provide input on what they require from the system. For prefabricated cleanroom systems, a qualified vendor should be able to provide significant assistance with defining these requirements by leveraging similar designs and applications. In fact, the qualified vendor should be able to provide a completed URS for the system they are providing to ease the burden for the end user.1 Non-prefabricated cleanroom contractors often don’t provide such formative documents as part of their scope of work, leading the end user to have to retain an additional resource to accomplish the same.
There may be many ways to categorize each requirement, and this should be defined by the company’s quality policy. For the Commissioning and Qualification processes, cleanroom requirements can be categorized into either Quality or non-Quality requirements. Quality requirements are any requirements that have potential product impact (by impacting the product CQAs). These requirements must be qualified through design and testing to show that a system is fit for intended use.
Non-Quality requirements also must be met, but do not necessarily impact the product CQAs. For example, in a cleanroom there may be a requirement for a functioning fire alarm and fire suppression system. While not meeting this requirement would not impact the drug products produced in the cleanroom, missing such a requirement would have an impact on the safety of any operators inside of the space.
CLEANROOM RISK ASSESSMENT
Performed in conjunction with URS development, the Risk Assessment will document all risks to the CQAs of the drug product.2 Key subject matters that are required can include: Quality Assurance, Quality Control, Commissioning/ Validation, Process Engineering, Manufacturing, Safety, Automation, and Project Management. There are many ways of organizing these risk assessments, but a standard process follows the principles of Failure Mode Effects Analysis (FMEA).
FMEA requires that all identified risks to the CQAs must be assigned a risk priority. An example of an identified risk may be ingress/egress from rooms and their potential for allowing elevated particulate levels that could impact the purity of the product. Assignment of risk priority is done through first determining the criticality of the risk, based on the severity (how badly would product quality be affected) and occurrence (how likely is this risk to happen). A standardized score is used to allow comparison of different risks. After the criticality of the risk is determined, the risk assessment team will determine the detection number (how likely is this risk to be detected). After the Risk Priority Number is determined, it is scored as High, Medium, or Low.
Depending on the level of risk that a company’s Quality Assurance team finds acceptable, mitigations may need to be instituted to reduce the High and Medium Risk Priorities. The output from the Risk Assessment meeting will update the User Requirements Specification with any mitigations that are required.
PLANNING FOR COMMISSIONING AND QUALIFICATION
Early in the project lifecycle, the Commissioning process for the cleanroom is defined. A qualified cleanroom provider can lead this process for the end user by providing the end user with a Commissioning and Qualification plan that is reviewed and approved by the end-user’s Quality Assurance team. The Commissioning and Qualification plan is typically specific for the piece of equipment and should align with the overall Validation Master Plan(VMP) for the facility.
The Commissioning and Qualification plan will also set forth the testing activities to be performed by the cleanroom provider. The plan should also detail the philosophy and approach that the company will take on items such as leveraging of vendor executed FAT/SAT protocols, how Change Management should be handled, and what test cases will be performed. The plan will also include a Test Map; a table showing the various requirements and where each requirement will be tested. Here again, a qualified cleanroom vendor with proper Good Documentation Practices and testing standards can lead this effort for the client and, if properly performed, should lead to minimal additional testing outside of the FAT and SAT. Utilizing a cleanroom contractor who does not have this capability can lead to delays and significantly increased costs, especially if these steps are attempted to be completed after the build process has begun.
DESIGN PROCESS AND DOCUMENTATION
After the URS has been completed and approved by key team members and the selected cleanroom vendor, the design process will kick-off. Design documentation is generated to define how the system will be built and how it will operate. Prefabricated cleanrooms generally have an automation system to handle control and monitoring of critical components, so automation design will be defined during this phase. Key design documentation may include:
Basis of Design
Scope of Facility
Sequence of Operations
Bill of Materials
Documentation processes and names may change, depending on company providing the same, but to have a fully qualified design, critical design documents must be reviewed and approved by both Engineering and Quality departments. Design documentation is utilized by the qualified vendor’s manufacturing team to ensure the correct cleanroom is built. The vendor’s commissioning department will then utilize the design documentation in 1) approving vendor provided test cases or 2) generating their own test cases for both the FAT and SAT protocols.
QUALIFICATION OF THE DESIGN AND CHANGE MANAGEMENT
After the cleanroom design has been finalized, a design qualification(DQ) must be performed to ensure that the design has met all the quality requirements specified in the URS. This ensures that the cleanroom, once built, will not have a negative impact on product quality. Proceeding into manufacturing of the cleanroom prior to qualifying the design runs the risk of failing qualification if a quality requirement was missed.
The Design Qualification is performed as a part of the final design review. Typically, the URS is reviewed line by line to ensure that requirements were met in design. A formal protocol may be utilized as well to ensure the design is adequate and that no areas trades/disciplines were overlooked.
Once the design is qualified, the design is considered final. Any changes to the design, whether due to mistakes, build issues, or other items, must be reviewed for potential impact to the Design Qualification. Changes should be reviewed and approved by Subject Matter Experts impacted by the change as well as the Quality team.
During the build, Quality Control inspections will ensure that the cleanroom is matching approved design drawings. In situations where there are significant deviations from the drawings, these items should be escalated through the Engineering Change Management process if they affect the approved design.
In the case of prefabricated cleanrooms, the commissioning process includes a Factory Acceptance Test (FAT) before the cleanroom leaves the manufacturing premises and a Site Acceptance Test (SAT) at the final site. For traditional built facilities, most if not all testing would be performed at the final location. Testing protocols may be broken down in different protocols/nomenclature, but a typical protocol is an Installation Qualification and Operational Qualification(IQOQ). The purpose of the IQOQ is to ensure all Quality requirements set forth in the URS are tested and met.
For a typical cleanroom IQOQ with a dedicated Human-Machine Interface (HMI) controlling the HVAC and Door Interlocking systems, testing is generally broken into several different segments:
Cleanroom Fit/Finish Verification
CLEANROOM FIT/FINISH VERIFICATION
The goal of cleanroom fit/finish verification is to ensure that the cleanroom has been built correctly and that there are no potential issues with the cleanroom’s ability to maintain cleanliness. Below are example tests that are typically performed:
Visual Inspection verifies that the cleanroom is easily cleanable, free from debris/damage, and that there are no open penetrations that break the cleanroom envelope and allow outside air/particulates in. A testing example would be visually inspecting a wall for damage. A scratch found during testing may have the potential for microorganism growth so would need to be addressed prior to completion. At that time, a work order would be opened, completed, and inspected prior to completion of the FAT.
Door Interlock Testing verifies that all doors are functioning correctly and interlocking is working correctly. Typically interlocking prevents more than 1 door per room to be opened at a time but could be related to pressure or time delay as well.
Additional testing typically performed under this section may also include:
Lighting Level and Uniformity
Sound Level Verification
Calibrated Components Verification
Engineering Turnover Package Review
The goal of the HVAC testing portion is to ensure that the HVAC system is operating correctly, per design, and maintaining temperature, humidity, and pressure targets. Below are example tests that are typically performed:
Testing, Adjusting and Balancing (TAB) is verification that airflows and room pressures meet design. Testing will first verify each terminal filter has the correct airflow entering the cleanroom and then pressures are balanced to ensure there is a proper pressure cascade, typically with a higher pressure in the cleanest space and decreasing from there. During testing, a Quality/Commissioning Engineer may adjust a return damper to increase room pressure and ensures that the new pressure is above the regulatory requirement for pressure differentials between rooms.
Cleanroom Performance Testing is Verification that the cleanroom meets regulatory standards for room particulate levels and there are no leaks in terminal filters. For an FDA regulated cleanroom, testing should follow the ISO 14644 standard. The ISO 14644 standard also underpins the EU Cleanroom Grade system, with differences introduced for at-rest and in-operation conditions. A typical execution of cleanroom performance testing would include checking HEPA Filters for leaks by introducing aerosol particulates upstream of the filter and then scanning the entire filter face.
Additional testing typically performed under this section may also include:
HVAC Sequence of Operation
PID Loop Tuning
12/24 Hour Temperature, Humidity, and Pressure Control
The goal of automation testing is to test all components of the automation system to ensure that the system is properly functioning. (The testing discussed herein does not consider the full testing required for an Environmental Monitoring System(EMS), though there are many ways of incorporating an EMS into the automation system controlling the clean space equipment.) Below are example tests that are typically performed:
Inputs/Outputs Loop Testing verifies that all points that monitor/control the cleanroom are properly working. Testing equipment is used on inputs to ensure that there are no issues from the sensor to the HMI. For outputs, the output value is simulated to mimic the condition and verify that the expected result occurs in the field. During typical testing, a Quality/Commissioning Engineer places a calibrated temperature gauge next to a monitored temperature sensor. After increasing the temperature, the Engineer verifies that the reading on the calibrated gauge matches the results displayed on the HMI.
HMI Screen Verification verifies that all HMI screens are functioning properly. All screen elements and buttons are tested for functionality. On a standard cleanroom HMI, navigating to the Room Overview screen and selecting a specific temperature transmitter will show key information for the sensor. A Quality/ Commissioning engineer will ensure that this pop-up shows the correct information pertaining to trending, maintenance actions, and alarm limits, if applicable.
Additional testing typically performed under this section may also include:
Software Installation Verification
HMI Security Access Verification
Audit Trail Verification
COMMISSIONING AND QUALIFICATION CLOSEOUT
After completion and post-approval of testing protocols, a final report is generated to accumulate the data. This report provides a post-action summary of the results of the testing, including any key discrepancies/deviations from the testing. An explanation of the discrepancy/deviation should include the original issue, the path forward to correct, and the results of the path forward. Also included in the final summary report is a Requirements Traceability Matrix (RTM). The focus of the RTM is to show that each Quality requirement from the URS was captured in design documents and was tested in the Commissioning protocols. This gives traceability in the case of future Non-Conformances and allows for a faster root cause investigation by the Quality Assurance team.
For a properly engineered and qualified solution, it is imperative that all C&Q activities are accounted for and/or performed. When a company is performing upfront options analysis, it is important to note that there may be many differing solutions at different price points, with some vendors not performing anything outside of “building a box.” A company utilizing a cleanroom contractor based on lowest price per square foot will likely be missing many key engineering and commissioning activities that are needed for a fully qualified facility. This has the potential to cause delays and cost increases at the end of the qualification process.
Cleanrooms are a critical quality component of biopharmaceutical manufacturing. As they require a large upfront capital expenditure and have a long lead time (typically 1-2 years for a traditional built facility), it is critical to devote time and resources to properly planning the effort. Proper planning prior to the build of the cleanroom and testing to ensure the cleanroom meets the design standards should be a primary consideration to ensure that the therapeutic is manufactured safely, on time and within budget.
Along with proper planning, the cleanroom construction method and vendor selection play an enormous role in assuring a successful project. With prefabricated cleanrooms, the equipment acquisition and commissioning process can more easily fit into a standard framework that will be followed for all critical quality equipment. And a qualified cleanroom vendor can really lead the way in this effort, reducing the burden on the end user while ensuring that the process driven approach leads to more consistent results. With onsite built approaches, the ad hoc methods generally employed do not allow for such a systematic approach even if the vendor provides commissioning within their scope of work. End users should be well aware of the same even in the early stages of the project, as a well-built project with an insufficient quality approach will not meet GMP standards and trying to meet these standards after the fact is extremely challenging, time consuming and expensive.
Hanan Shaban, PharmD(2018, January) Impact of Drug Shortages on Patient Safety and Pharmacy Operation Costs.(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248141/)
ICH Pharmaceutical Development Q8(R2) (2009, May) Page 15
Lawrence X. Yu, et al. Understanding Pharmaceutical Quality by Design (AAPS Journal: 2014, May) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070262/
How to Identify Critical Quality Attributes and Critical Process Parameters http://pqri.org/wp-content/uploads/2015/10/01-How-to-identify-CQA-CPP-CMA-Final.pdf
This document typically contains the following sections: a system description, definitions, abbreviations, and the list of requirements by area such as electrical, structural, automation, etc.
ICH Q9 (2006, June)
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About the Author
Thomas Ronat is the Sr. Director of Quality and oversees the Quality Control, Quality Assurance, Commissioning, and Service departments at G-CON. Prior to his role at G-CON, he served as a GMP Project Manager and C&Q Manager. Thomas has over 8 years of quality experience, focusing primarily on GMP compliance for automated systems and equipment throughout the pharmaceutical equipment lifecycle.
Sid Backstrom is the Vice President, Business Management for G-CON Manufacturing, Inc. He functions in multiple areas overseeing Human Resources, Information Technology, Quality and Commissioning, Intellectual Property, and other areas including contract negotiations, partnerships, risk and insurance, regulatory, sales and marketing, management, company policies and procedures, etc. He has authored two book chapters and several papers related to the cleanroom industry. He is a Board Member and Secretary for the Texas Parenteral Drug Association. Backstrom has also provided consulting services to Gradalis, Inc., Strike Bio, Inc. the Mary Crowley Cancer Research Center, and several other related entities. He has sat on the Business Advisory board to Path4 venture capital firm based in Austin, TX, a firm that specialized in the Life Sciences musculoskeletal sector with a focus on early-intervention orthopedic solutions. Sid has a B.S. in Finance from Louisiana State University and a J.D. also from Louisiana State University.
Defining the Drug Process
Determining Cleanroom Requirements
Cleanroom Risk Assessment
Planning for Commissioning and Qualification
Design Process and Documentation
Qualification of the Design and Change Management
Commissioning and Qualification Closeout