Applying Quality by Design to Sterile Manufacturing Processes

May 1, 2009
Warren Charlton

Warren Charlton is a consultant at WHC Bio Pharma Technical Services, PO Box 20309, Greenville, NC 27858, tel. 252.327.4733, fax 252.756.4733.

Pharmaceutical Technology, Pharmaceutical Technology-05-01-2009, Volume 2009 Supplement, Issue 2

The author reviews the draft guidance on process validation, its QbD applications, and its potential impact on sterile manufacturing operations.

In November 2008, the US Food and Drug Administration issued a much needed document titled, Draft Guidance for Industry on Process Validation: General Principles and Practices. The draft guidance clarifies the quality-by-design (QbD) approach to processing human and veterinary drugs, including biologics, active pharmaceutical ingredients (APIs), and medical devices. Although the document may have been better titled "process design," it has addressed many industry concerns regarding how to take a life-cycle approach and how to meet regulatory expectations with regard to validation. Many questions still remain, however, and industry must grasp and integrate the proposed guidance concepts along with the International Conference on Harmonization's guidelines Q8 Pharmaceutical Development and Q9 Quality Risk Management (1, 2).

Individuals working in pharmaceutical sterile development and manufacturing will undoubtedly be the most affected by regulations associated with QbD because of the unique associated technologies, processes, and products currently in use and development (see sidebar, "Quality-by-Design Overview"). Many of these technologies require new manufacturing processes that support existing traditional fill-finish operations. Many facilities, utilities, processes, and equipment may need to be modified (e.g., improving controls to reduce variability). This article provides an overview of FDA's draft guidance on process validation and QbD's impact on sterile manufacturing operations.

Quality-by-Design overview

Manufacturing process

The following sections discuss how the draft guidance may influence the manufacturing process and product development. Processes addressed include manufacturing, aseptic manufacturing, lyophilization (freeze drying), and others that depend on multiple-unit operations (see Figure 1).


Process design is typically the biggest challenge for a company's process development team and has tremendous impact on the success of the product. Sterile manufacturing has become increasingly more complex because of the increase in the number of poorly stable compounds, new technologies, unit operations, and controls. Numerous biotechnology companies, for example, use unique freeze–thaw systems to support dispensing and bulk-drug storage at temperatures often ≤ –80 °C that provide complete control of bulk-drug thawing, dispensing , freezing, and storage.

FDA's draft guidance suggests that the process development team design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its critical quality attributes (CQAs). The team's objectives are to: understand the sources of variation, detect presence and degree of variations, understand the impact of variation on the process and product attributes, and control variation in a manner that is commensurate and proportionate to the risks presented to the process and product. FDA further recommends an integrated team approach, with members representing multiple disciplines. The team should have solid project-management skills and archiving capabilities, be able to capture scientific knowledge and maintain project plans, and have full senior-management support. The latter may involve regular reports or presentations to senior management (3, 4).

In addition, the draft guidance calls for process decisions and justifications of control to be documented, internally reviewed, and preserved for later use in the product life cycle. Verification and mapping of the process design through to commercial documentation is required and planned changes should be documented and justified. Finally, after the performance qualification (PQ), a report documenting and cross-referencing results, data, issues, nonconformances, corrective actions, and overall conclusions regarding whether the process is in an adequate state of control must undergo management review and approval.

Design of experiment and risk analysis. Design of experiment (DOE) and risk analysis are recommended in the draft guidance to provide data that support process design. The emphasis should be to reveal relationships between variable inputs (e.g., component characteristics, processing parameters) and resulting outputs (e.g., in-process material, intermediates, or the final product).

Early-stage product assurance. The draft guidance states "early process design experiments do not need to be performed under CGMP conditions." Emphasis during early stage development are verification rather than validation. "Decisions and justifications of the controls should be sufficiently documented and internally reviewed," according to the draft guidance. Some examples of early-stage product assurance are outlined below (4, 5).

  • Viral and impurity clearance studies are required because they have a direct impact on product quality

  • Cleaning verification would replace validation during the early stages of development

  • Sterility must be ensured but may not be completely validated (e.g., if performing sterile filtration on a water-based product, a filter integrity test may be performed using water-for-injection to demonstrate that the filter still meets its manufacturer's integrity test value)

  • Preliminary specifications, tests, acceptance criteria, and limits should be operational.

Overall, the further along a company is in its product development, the more verification and validation are expected. Process controls that address variability can help to ensure the product's quality.

Models. "It is important to understand the degree to which models represent the commercial process including differences that may exist," states the guidance (4). The significance of understanding the process increases with a model that properly reflects all the variants of the process and product. A good model can be used as a tool for process and equipment design, process control development, estimating variablity, and training personnel.

Process analytical technology and qualification. Process analytical technology (PAT) "uses timely analysis and control loops to adjust processing conditions so that the output remains constant," states the guidance (4). As a result, there is a higher degree of process control. It is unclear, however, whether maintaining the process within the design space using PAT reduces process-validation testing. The draft guidance places added emphasis on design (qualification = design plus verification). There are requirements, for example, to challenge the process under load, to test interventions, and to test stoppage and start-up routines as expected for production.

The common industry practice of testing three batches for PQ may no longer apply. Specific requirements regarding when batches can be released and the information needed to begin commercial distribution are included in the draft guidance. PQ must have a higher level of sampling, testing, and scrutiny of process performance to confirm the product's quality during batch processing.

According to the draft guidance, "In the case of PAT strategy, the approach to process qualification will be different from that for other process designs," but the agency did not explain how the process will be different (4). This difference is important because additional use of PAT leads to additional validation to verify the technology's capability. Industy will assume this means an easier validation approach because conformation of control would be readily available, but there are no examples provided in the draft guidance.

With regard to continued process verification, the goal is to ensure the process remains in a state of control during commercial operations (3, 4). The draft guidance recommends manufacturers include intra-batch as well as inter-batch variation as part of their continued verification program. PQ sampling levels should continue until variability is assessed.

The draft guidance suggests that a statistician be involved in the development of the company's data collection plan and in the selection of statistical methods to evaluate process stability and capability. Included in this review should be quantitative statistical methods where feasible. Process flow diagrams for commercial manufacturing, for example, should be completed as follows:

  • Describe each unit operation and placement in the process

  • Describe process monitoring and control points

  • Describe components and other processing material inputs

  • Describe expected outputs (e.g., in-process and finished products).

In addition, the flow diagrams should preserve a life-cycle approach to facilitate comparison and decision-making regarding their comparability.

Technology transfer

Assuming that the manufacturing process design space has been properly developed and CQAs and DOEs have been verified, technology transfer, as well as scale-up, should go smoothly. As with most typical API-manufacturing operations, process design and controls ensure a state of control. When these approaches and technologies are applied to a batch-based system, they may, in the future, lead to more continuous sterile processing due to the increased level of control.

The following sterile-process technologies are well defined in the literature: sterile filtration (F), autoclaves (A), steam cycles, dry-heat (DH) ovens and tunnels, gas sterilization (ETO), chlorine dioxide (ClO2), ionization radiation (ebeam, gamma), and terminal sterilization (steam, gamma radiation). These technologies must be validated with the specific component, drug product, or commodity.

Sterilization technology review. Sterile filtration. Filter validation is normally done by filter manufacturers or outside laboratories but the responsibility remains with the drug manufacturer (5).

Steam sterilization. Steam sterilization (i.e., autoclaves, sterilize-in-place [SIP]), is the method of choice whenever possible due to data available and capability to assure sterility. This method is used for transfers into the aseptic area, process sterilization, SIP of the product delivery system, and product contact-component sterilization. Steam sterilization is limited by its temperature and pressure impact. Many plastic items, therefore, require other methods of sterilization. Control is typically ≥121.1 °C. Product contact components must have had prior pyrogen removal steps to ensure expectation of a minimum 3-log reduction.

Dry-heat sterilization. The DH approach is mainly used for glass components because of the temperature during processing (a dry-heat oven is typically controlled ≥200–250 °F and dry-heat tunnels are typically controlled at 275–350 °F). Dry-heat sterilization can also be validated for a 3-log or greater pyrogen reduction.

ETO. Gas sterilization or ETO, is used for product contact plastics and commodity transfers. The method is not used in processes and operations due to safety issues. Product contact components require ETO degassing after the cycle is completed. ETO is a toxic and hazardous chemical. Cycle control includes ETO concentration, humidity, and pressure and similar to steam sterilization, requires prior pyrogen removal steps.

Ebeam. Ebeam is easy to define and makes it easy to control sterilization of the surface and, to some extent, the depth of exposure and microbial kill. Recently, the ebeam method has been used to sterilize the lids of syringe bulk containers before filling. Because ebeam is not currently used for product contact components, pyrogens are not an issue. The sterilization dose for radiation processes (i.e., ebeam and gamma) are 25 kGy (2.5 Mrad).

Vaporized hydrogen peroxide (VHP). VHP is currently the method of choice for isolator decontamination. Sterility is sometimes claimed. Because VHP is not a true gas, it can be affected by cold spots. VHP also can be used to sanitize transfer items into aseptic-filling operations, but cannot be used to sterilize or depyrogenate components. Cycle requires control of concentration of H2O2, relative humidity, and temperature. Circulation fans within an isolator are often used to help provide constant conditions within the isolator (5).

Chlorine Dioxide (CD). CD is currently the least used method throughout industry for sterilization, but provides significant opportunities because it is a true gas and can be validated for sterility. Areas of opportunity include isolators, transfers to the aseptic area, and processing equipment. CD is widely used in the food industry for sanitization and disinfection. Concentration can be monitored and controlled. Aeration is repeatable. Passivation of stainless steel may be required. Controls consists of concentration, humidity, temperature, and pressure.

Other sterilization technologies include gamma radiation, which is used for product terminal sterilization and component sterilization by contract manufacturing organizations (CMOs). Gamma-radiated presterilized syringes are a common usage of this technology in the industry. Transfer of these types of presterilized components to aseptic-filling areas can be troublesome, however, without a defined transfer sterilization method. Recently, some equipment suppliers have included ebeam sterilization to improve this transfer. Ozone (O3) technology has potential as a sterilization method as well, but is not currently commercially available. Peracetic acid as a sterilization technology may still be used by a few companies, but most have switched to VHP. Other forms of sterilization or environmental control have limited support data and therefore represent an increased risk requiring in-house technical knowledge (e.g., high-intensity light, ultraviolet light).

Environmental testing and validation

Environmental testing is designed to check facility, process, personnel and environmental cleaning methods to determine: (A) that after being in a state of shutdown that includes relaxed gowning, the facility and equipment can be cleaned, sanitized, and in a state of microbial control appropriate for pharmaceutical operations; and (B) that the facility can maintain a level of environmental control during normal processing operations.

Critical testing required before startup include: high-efficiency particulate air (HEPA) filter testing, room differential verifications (e.g., air flows, alarms), cleanroom smoke studies, and environmental mapping during static and dynamic conditions (i.e., nonoperational and operational conditions). Note that any physical change(s) made in aseptic processing (e.g., facilities, equipment, layout) when adding a new process requires revalidation.

Aseptic processing

Aseptic processing includes sterile manufacturing, aseptic filling, lyophilization, stoppering, sealing, and spray-drying. Examples of facility and processing-type CQAs that enhance overall process control from outside influence are outlined below.

  • Aseptic operations should be protected from potential leaks (e.g., roof leaks and process leaks, including condensation from heat, ventilation, and air conditioning [HVAC] systems). Some processing equipment (e.g., restricted access barrier systems [RABS]) may also contain HVAC or refrigeration that create moisture issues.

  • Critical operations should be visible without environmental impact. The objective is to keep personnel out of the critical processing areas while still being able to view operations for documentation and training.

  • Gowning areas, including barriers such as the step-over for applying booties, are typically dirty due to employee activity. Consider airflow turns higher than normally recommended (at least 80 air turns is preferred).

  • Cleanroom airlocks should be designed at the same classification as the area they support. Consider having sweeping airflow from the clean side to the dirty side with the return close to the dirty side's entry door.

  • Cleanrooms should be designed to take up just one classification level, thereby eliminating confusion (e.g., no Class A (ISO 5] and Class B [ISO 6] in the same room).

  • Filling lines and critical processes should be physically separated from operators. Equipment within isolators or RABS can help to significantly control contamination.

  • When using isolators with VHP (H2O2), consider the location of HVAC room inlets and returns to avoid potential cooling impact on the sterilization process.

  • Cleanroom access should be limited to those personnel essential to the operation, including quality assurance personnel. It is amazing to see how the industry has added nonessential personnel to critical areas in the guise of quality when people are the number one environment problem.

  • Each processing area should have its own separate gowning area and exit, without overlapping pathways.

  • Environmental-monitoring (EM) data control should be automated. Software systems are available that effectively track and manage all environmental data based on the latest regulatory guidelines.

  • Design equipment to limit product exposure to personnel and the environment, including any environmental monitoring.

  • Include capability to clean-in-place and sterilize-in-place (CIP/SIP).

  • Consider 100% check weighing.

  • Check preventative maintenance operations capability from outside the aseptic area. Determine whether there is a need for process-piping temperature control from the manufacturing process through filling. Does the piping travel through noncontrolled environments?

  • Determine whether there is a maximum time for filled product to be removed from cold storage. These operations should be considered as automation of process.

  • Use of disposables and presterilized items can be positive, but transfers into Class-A areas without a verifiable method of sterilizing the bagged sterile items can be troublesome. Use VHP or CLO2 to mitigate this concern.

Quality risk-management review

Sterile-filling equipment and product delivery systems support processes (e.g., CIP/SIP, sterile filtration) and are well defined in industry. Use risk-assessment tools to review automation software, controls, alarms, and to define PAT needs using a QbD approach. Table I includes instructions and a key for severity, occurrence, and detection for use in Table II. Table II includes three examples to demonstrate the use of risk assessment as described below. (This methodology provides a number [e.g., ≥50 fails], which makes a result a clear decision, requiring modifications either to the process or finding a PAT alternative.)

Table I: Sample risk-analysis evaluation.

Isolators on a filling line. Risk assessment in this case can highlight and quantify benefits. Assessment involves product and personnel safety and requires process modifications to be successful.

Table II: Sample risk-analysis worksheet.

Manual loading of filled vials into a freeze dryer as compared with automatic loading. It is possible to eliminate the need for using trays if the design includes the capability to transfer the freeze-dried vial after processing in the freeze drier directly to a capper.

Automation software used in conjunction with unit operations and equipment. This risk assessment example involves a sterile filler designed for 10% check weighing and compares it with 100% check-weighing capability (6). Risk assessment can help demonstrate the importance of good CQA choices to support management approvals.

Draft guidance questions and concerns

There are some remaining questions despite the thoroughness of the draft guidance. Below are a few key issues.

  • What is required for final PQ approval? The final guidance should include clarification on what constitutes validation. This clarification is critical because the common practice of using three batches to verify validation no longer applies (3).

  • In the case of a PAT strategy, will the approach to process qualification be different from other process designs? The final guidance needs to include more specifics with regard to what degree of PAT is required to positively impact validation and approvals (3). This clarification is especially important because often, the more PAT involved, the more investment and validation required.

  • Industry needs to have a sense of which statistical methods and levels of sampling FDA recommends. Reference to specific documents and testing level(s) may suffice (3).

  • The final guidance should discuss the impact of the new guidance on existing products and processes and how to integrate them into the new approach (3).

  • The final guidance should discuss potential impact on current and future new drug and abbreviated new drug applications (NDAs and ANDAs) and their site of manufacture. For example, is there an expected date to have the new process validation requirements implemented in applications? For NDAs, additional time may be needed and patents may be affected. For ANDAs, shouldn't companies be required to demonstrate equivalency of control as the innovator process?

  • Finally, there is a concern that product development information could become available though freedom of information, thus revealing data that have significant confidential information about the process. How will this be handled?

In conclusion, the 2008 Draft Guidance for Industry on Process Validation: General Principles and Practices brings the product life-cycle approach to process development. The document provides insight into the "how" with regard to holding discussions on project management, documentation, verification, reviews, and methods (e.g., QbD, DOE, risk assessment) and reviews expectations from development to commercial processes for testing, validation, verification, and release. It is important that all pharmaceutical companies review the draft guidance and understand how it may affect their sterile manufacturing processes. The impact on confidentiality may be industry's biggest concern because process design and associated technical knowledge are what define a company's success.

Warren Charlton is a consultant at WHC Bio Pharma Technical Services, PO Box 20309, Greenville, NC 27858, tel. 252.327.4733, fax 252.756.4733,


1. ICH, Q8(R1) Pharmaceutical Development (Geneva, Switzerland, Nov. 10, 2005; Rev. 2008).

2. ICH, Q9 Quality Risk Management (Geneva, Switzerland, Nov. 9. 2005).

3. J. Agalloco et al., "FDA's Guidance for Industry: Process Validation: General Principles and Practices," presented at PDA, Jan. 14, 2009.

4. FDA, Draft Guidance for Industry—Process Validation: General Principles and Practices (Rockville, MD, Nov. 2008).

5. W. Charlton, T. Ingallinera, and D. Shive, "Validation of Clinical Manufacturing," and Validation Chapter, in Validation of Pharmaceutical Process, J. Agalloco and F. Carleton, eds. (Informa Healthcare, New York, 3rd ed., 2008), pp. 542–544.

6. Bausch & Stroebel Risk Analysis System.