Analytical biochemistry is the key enabling technology supporting the biotech revolution. Written and validated methods are used to monitor and control the production of biotherapeutics throughout the product life cycle—from matching a disease to a drug candidate, to development, to postmarket support (see Figure 1). Method transfer takes place between originating labs and receiving labs, and can be difficult and time-consuming. For example, the FDA licenses a drug product for marketing. After a period of time, things may change—how does one prove that the therapeutic sold today is the same as that originally approved by the FDA?
Figure 1 – Life cycle of a biotherapeutic. Key events: decision to proceed with development of candidate from R&D. Information for application of IND (investigational new drug) developed; approval of IND application. Phases I and II investigate drug safety in humans. EOP2 is end of Phase II. Phase III investigates efficacy. BLA (Biologics License Application) demonstrates efficacy of the drug in humans and documents the intended production process; formulation is developed and validated. After the BLA is approved, the enterprise can place the drug on the market (Phase IV) but must complete the postmarket commitments and comply with other reporting requirements.“Successful Strategies for Tech Transfers,” held October 13, 2016, in South San Francisco, California, covered best practices in method transfer. The report is given below.
Regulatory guidance
To assure the safety and efficacy of therapeutics, the FDA includes analytical methods as an essential part of the technology package in a Biological License Application (BLA). When the BLA is approved, the FDA issues a notice of licensure, which allows the applicant to place the therapeutic on the market in the U.S.A. (Figure 1).
Rapidly improving analytics such as HPLC and capillary electrophoresis allowed scientists and regulators to recognize that it would be possible to regulate biotherapeutics in the same manner as had evolved for small-molecule drugs. Defined active pharmaceutical ingredients (APIs) were mixed with excipients and regulatory verbiage and packaged for sale. This new regulatory paradigm focused on risk analysis and science-based methods as the basis for ensuring quality, safety and efficacy, and showed that biotherapeutics could be measured and understood. The FDA-led initiative called Process Analytical Technology (PAT) was designed to enable the biotech industry to catch up technically with the world’s bioprocessing leaders. In particular, when manufacturing changes occur during product development, comparabilty of pre- and post-change products should be assessed. According to ICH Q5E, one should not expect that the pre- and post-change products are identical; however, they are comparable if the evidence shows they are sufficiently similar such that any differences have no adverse effect on product safety or efficacy.
A draft guidance issued in April 20161 updates a document issued in 2003. This comparability protocol focuses on analytical test methods used to develop and produce therapeutics. The sponsor is responsible for identifying and validating analytical methods that support the critical quality attributes of the product.
The FDA acknowledges that the amount of information about a potential product grows as the candidate product moves from investigational new drug (IND) through each phase of the process. Joslyn Brunelle, Ph.D., with CDER and FDA in Silver Spring, Maryland, explained that in the early stages of product development there is not sufficient data from multiple lots to support a rigorous comparability protocol. She advises talking with the agency prior to making major manufacturing changes, and that it will be necessary to show data. She also discussed the updated guidance document.2 If an expedited program is the goal, the Agency will work with the developers to meet the needs of the afflicted patients. Assuming efficacy is established, any missing information will be added later.
An industry view
Symposium attendees were from very small startups and large firms. The smallest are virtual biotechs that contract out nearly everything—including research, development and manufacturing.
Representing a large-scale organization, Dr. Camille Dycke of Genentech (South San Francisco, Calif.) lectured on “Biopharmaceutical Method Transfer: How to Marry Quality & Compliance with Productivity and Speed.” Genentech expects that methods used in support of development will often involve one lab and 2–5 analysts. The first method transfer occurs at the development stage when the methods enter the method life-cycle management paradigms. This involves 2–5 labs and 4–15 analysts at a few sites, including contract manufacturing organizations (CMOs) and potential partners. Some countries require in-country testing.
Method transfer appears to be an enterprise-wide infrastructure that encompasses most technical operations and the product life cycle from prediscovery to product termination. At one level, the focus is on qualifying a receiving laboratory’s procedural knowledge and that necessary resources are available to perform the assay (USP 1224), the goal being that the receiving lab obtains results comparable to other labs without introducing undesirable variability. Continuous introspective gap assessments seek to find and mitigate sources of variance including 41training, software and reagents. Inter-laboratory results comparison is ongoing.
Genentech starts the transfer process with planning, which includes a gap assessment. Next, a Method Transfer Master Plan (MTMP) is prepared. Scientists then implement supporting method transfer protocols, which define transfer experiments and acceptance criteria. The receiving lab attains resources such as training and new equipment. After the execution phase of the MTMP, the results are critically evaluated and recorded in a Method Transfer Report (MTR).
The plan is executed by a cross-functional Analytical Tech Transfer Team (ATTT). Each project starts with a face-to-face kick-off meeting. Single point of contacts (SPOCs) for originating and receiving labs are introduced to facilitate communication between supporting subject-matter experts (SMEs). SPOCs are responsible for site visits, protocols, co-validation, and troubleshooting.
Over time, MTMPs and MTPs have led to creation of document templates that include best practices covering the entire transfer process. Document templates expedite the preparation of project-specific documents.
Dycke pointed out that communication is key to avoiding problems before they escalate. For example, when a new method is introduced to a second lab, staff members from the receiving group are trained in the originating laboratory. A senior SME then goes to the receiving lab to assist in start-up and debugging. Genentech has implemented a program to continuously monitor method performance globally in an effort to detect method failures.
Best practices
Nine workgroups were assembled to discuss a focused issue under the general topic of method transfer:
- Roundtables 1 and 8: Transferring Processes and Analytical Methods to CMOs and CROs (contract research organizations)
- Roundtables 2 and 9: Phase-Appropriate Comparability Assessments
- Roundtable 3: Powering Bioassays for Transfer Comparability
- Roundtable 4: Bridging Analytical Methods
- Roundtable 5: Statistical-Based Approach for Analytical Method Transfer
- Roundtable 6: Tech Transfer Considerations of “Breakthrough Therapy” Designation
- Roundtable 7: Transfer Consideration for Inspections (postapproval commitments [PCAs])
Perspective
I’m impressed with the advances in regulatory science and philosophy made by the FDA. In the 1990s, the product was defined by the process and facility that produced it. In the absence of relevant science, the process was locked down. All changes were suspect and no major changes were permitted. The Center for Biologics Evaluation and Research (CBER) was playing catch-up with the sponsors in technology. However, over the years, FDA staffers have taken advantage of their industry-wide perspective to advance regulatory science. They can help sponsors consider what they have learned from numerous meetings and filings. Vendors have developed exquisite analytical tools to enable methods. I have confidence and respect in the biotherapeutic industry, including the regulators.
The program committee, led by Judy Chou (Medivation, Inc., San Francisco, Calif.) and Lance Wong (Strand Bio, San Mateo, Calif.), deserve special thanks for organizing the technical program. Thank you also to Linda Mansouria and the CASSS staff for organizing the meeting.
References
- www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM496611.pdf
- www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm
Robert L. Stevenson, Ph.D., is Editor Emeritus, American Laboratory Labcompare; e-mail: [email protected]