Focus on Standardization, Quality by Design, and Regulatory GMP

IBC: FOCUS ON STANDARDIZATION

At the IBC Single-Use Applications meeting, held in Boston on Jun. 6–9, 2011, I gave a talk entitled "Standardization of Single-Use...Pros, Cons and Possibilities." The topic of standardization has appeared in many surveys as one of the top 10 needs for expanding single-use implementation. However, there is little definition of what is meant by "standardization," which could be applied to many areas.

Jerold Martin

One particular area of discussion is the interchangeability of sterile connectors to enable single-use unit systems with sterile connectors from different suppliers to be linked. In preparing my talk, I also discovered that there is already an interchangeable "standard sterile connector" recognized by industry. If you search for this phrase in Google Images, you'll find a photo of a traditional two-way hosebarb fitting.

In my talk, I discussed how standardization of advanced sterile connectors must begin with the end-user's company. Different systems' assemblers and integrators can generally source whatever advanced sterile connector is specified, so the first effort must be for the end-user's company to decide what its preferred sterile connector will be. Since the introduction of the first advanced sterile connector (Pall's Kleenpak), there are now five additional designs on the market from other suppliers, but there is still no industry consensus on which design might become the "standard" of the future. Unlike the easily copied tri-clamp style hygienic flange connector, which is commonly used in stainless-steel and some single-use systems, or the aforementioned hosebarb fitting, many advanced single-use sterile connectors incorporate patented technology and designs. Users calling for the standardization of sterile connectors have yet to address which design should dominate or why the patent-holder should license their design to competitive suppliers. Once bioprocessers agree on a preferred design within their own facilities or companies, once there is consensus on an industry-preferred design (such as happened with tri-clamp style connectors), and once patents expire, options will appear to either "standardize" one of the original sterile connector designs. The alternative is that users will prefer an innovative proprietary design that is superior to current designs, but has yet to be seen. Until then, care has to be taken to avoid inhibiting innovation and it may not be realistic to expect meaningful voluntary standardization from the bioprocessing supply industry.

One area where there is an industry initiative underway to standardize connectors, however, is for polymeric tri-clamp style hygienic flange seal connectors. In response to stimulus letter from the Bio-Process Systems Alliance (BPSA), the American Society of Mechanical Engineers bioprocessing equipment standards group (ASME–BPE) has formed a task force to review the requirements for single-use polymeric tri-clamp style connectors and how the ASME–BPE Standard for stainless steel hygienic flange seal connectors can be modified in response to accomodate their use. Unlike their stainless steel counterparts, single-use polymeric tri-clamp connectors do not require cleanable finishes, crevice-free cleanable seals, or thermal resistance and mechanical strength suitable for steaming in place. They also do not require tolerances that are readily achieved with stainless steel on a lathe, but are difficult to achieve with plastic molding, thus incurring unnecessary mold costs. Expansion and relaxation of the ASME–BPE standard to cover the specific requirements for single-use polymeric tri-clamp style connectors will be a benefit to both suppliers and users.

PDA: FOCUS ON QBD

The PDA held its first Single-Use Workshop in Bethesda on June 22–23, 2011. The main focus was to preview the draft PDA Technical Report on Single-use Manufacturing, which is currently in development, and to solicit attendee feedback. As a member of the PDA Single-use Task Force, I served on the planning committee and as a moderator and presenter on the report for this workshop.

The purpose of the new report is to provide the reader with critical concepts and topics to consider when implementing a single-use manufacturing strategy for drug or vaccine production. The draft report discusses single-use systems that may be in direct or indirect contact with raw materials, intermediates, intermediate products, pharmaceutical drug substances or the drug product. The primary goals for developing a single-use manufacturing strategy are customer-based and focus on patient safety and product availability, as well as product and process understanding and control.

The workshop program focused on QbD principles and other high-level topics to guide users on their initial decision, selection, validation, and implementation of single-use processes. The workshop included several opportunities for Q&A and open discussion, which gave the task force valuable feedback from attendees on the draft report. Key take away points included:

• The report should aim to help end-users move away from 'gut-feeling' to fact-based decisions.

• Control of suppliers will also come under more scrutiny and supplier audits can be expected to increase.

• More detail on materials and manufacturing methods (e.g., films) may be required.

• Partnership between the supplier and end user was stressed; those companies that truly embrace partnership will be the ones most likely to achieve success.

• The industry will expect suppliers to have pharmaceutical standard quality systems in place, particularly with regard to having an appropriate materials change control and change notification program.

• Training in single-use will also be a key requirement/capability from suppliers.

• Clear communication strategies encompassing quality, trust, track record, openness, and security will be in focus.

The target date for the report's publication is by the end of this calendar year. Current activities entail completion of the manuscript incorporating the feedback from the June workshop and final technical review of completed sections. Follow-on workshops are planned for Uppsala, Sweden, on Nov. 28, 2011 and Phoenix, AZ, on Apr. 18–19 2012 (see www.pda.org for details).

REGULATORY GMP FOCUS EXPLAINED AT BPSA CONFERENCE

The third important single-use conference of the summer was the BPSA International Single-use Summit, which was held in Washington, DC, on Jul. 27–29 2011. This inaugural conference for BPSA served as a forum for suppliers and users to highlight the business model for single-use. In addition to business leader speakers, the summit featured J. David Doleski, the consumer safety officer at FDA's Center for Drug Evaluation and Research. Doleski opened with a review of relevant FDA regulations that impact single-use manufacturing, including 21 CFR 211.65 on Equipment, 211.94 on Drug Containers, 600.3 on Biological Purity and 600.11 on Biological Control. Each of these has similar statements about assuring that process equipment and containers do not adversely affect the drug or biological product. Additional compendial standards noted were USP General Chapters <87> and <88> on Biological Reactivity, <661> on Plastics, and <381> on Elastomers, as well as relevant FDA guidances, including cGMP for Phase I Investigational Drugs (July 2008) and Container Closure Systems for Packaging Human Drugs and Biologics (May 1999).

Advantages of single-use manufacturing were recognized as:

• Reduced need for cleaning and sterilization systems and validation

• Reduced risk of cross-contamination

• Improved containment

• Potentially greater control over aseptic operations (as facilitated with sterile connectors/disconnectors and tube welders/sealers).

Doleski's talk continued with an excellent overview of topics that should be incorporated in process documentation and FDA filings. Initially highlighted were considerations for vendor partnerships and materials control, included establishment of manufacturing (quality) agreements, vendor audits, notifications of changes in product (materials or design), certificates of analyses, and flow path testing for endotoxin, particulates and bioburden (where necessary). With regard to sanitization (e.g., irradiation for microbial control) or sterilization, bioprocessers should note where sterilization is performed (i.e., contract irradiator) and provide documentation on the sterilization validation method, sterilization records, impact on materials (supplier validation data) and repeated sterilization where applied (note that single-use systems are generally not suitable for multiple irradiations at doses > 25 kGy).

Extractables and leachables studies are performed to assess the potential impact of leachables on product quality, efficacy, and safety. This can begin with compatibility and extractables data from the supplier, testing with additional model solvents under manufacturing process parameters (e.g., temperature, pH, pressure, and time) where needed, considering the cumulative effect of all manufacturing equipment and conducting further risk assessments to determine if a leachable study is necessary (e.g., for final product formulation).

Process-validation considerations should take into account the full range of the manufacturing process, and incorporate multiple unit operations and actual manufacturing parameters, such as mixing speed and duration of perfusion culture. Sterile-media simulations should be conducted for filling of sterile product (i.e., bulk or unit dosage). Where fluids are stored in single-use containers, validation should include the length of time and temperature range, with assessments of the impact of fluid on materials, and the impact of materials on product, buffers or media, and container integrity (i.e., leakage) after storage. Where bulk fluids are shipped, considerations should include the effect of pressure changes, such as altitude, effect of motion (i.e., acceleration or vibration) and the protection offered by external containers. Other environmental considerations can include light, chemicals, and other mechanical forces that may affect the contained fluid.

Despite commonly cited concerns, leak integrity issues with today's improved biocontainer designs are rare. However, possible issues should be qualified and noted, such as movement or shipping of storage containers, operator error (handling training), improper operation parameters (i.e., tube welding), and exposure to extreme temperature.

Doleski summarized his talk by saying that FDA recognizes the importance of the user's relationship with their single-use equipment suppliers and expects users to work with suppliers to develop knowledge of their single use equipment, understand their product and processes, consider potential issues, conduct a corresponding risk assessment, perform appropriate validation, and establish proper quality systems to maintain a state of control.

Jerold Martin is senior vice-president of global scientific affairs at Pall Life Sciences, Port Washington, NY, and chairman of the board and technology committee at Bio-Process Systems Alliance, jerold_martin@pall.com.