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.

Warren Charlton

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Draft Guidance for Industry on Process Validation: General Principles and Practices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 The draft guidance clarifies the quality-by-design (QbD) approach to processing human and veterinary drugs, including biologics, active pharmaceutical ingredients (APIs), and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 

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 This article provides an overview of FDA's draft guidance on process validation and QbD's impact on sterile manufacturing operations.  

The following sections discuss how the draft guidance may influence the manufacturing process and product development.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).  

Figure 1. (ALL FIGURES ARE COURTESY OF THE AUTHOR) 

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 (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).  

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. 

 "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. 

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 (ClO

), 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 (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. 

 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. 

  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 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). 

  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 H

, relative humidity, and temperature. Circulation fans within an isolator are often used to help provide constant conditions within the isolator (5). 

 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 (O

) 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 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 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.

), consider the location of HVAC room inlets and returns to avoid potential cooling impact on the sterilization process.

Articles

The author reviews the draft guidance on process validation, its QbD applications, and its potential impact on sterile manufacturing operations.