GOING Into the Clinic

Do You Know What You Need to Know?

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By Dr. David G. Barnes and Jerry Calver, PhD

Product innovators in Canada are an increasingly savvy lot. Today’s scientists attend bio-medical conferences where basic science and clinical research are presented side-by-side with patent law and venture capital. Technology transfer offices and incubators are helping innovators identify commercialization opportunities and protect intellectual property. Appropriately, the focus has been on transferring the technology out of academic institutions and into the real (business) world. Transferring the technology into the clinic is another story.

As companies nurture their products toward clinical trials, often at breakneck speed to reach business milestones and keep investment dollars coming in, they can find themselves in the position of having a product well into development without comprehensive knowledge of what federal regulators expect and require. This ranges from what specifications and production process QA documentation regulatory authorities require (and at what stage of R&D) through to what amount of patient exposure will be required for successful product licensing.

Companies (sponsors) doing drug or nutraceutical development work in Canada must contend with multiple levels of domestic policy, regulations, laws, and international guidelines and conventions (such as ICH and Helsinki). Chemistry and manufacturing (quality) requirements are complex and strict. A substantial amount of quality data are required before a clinical trial can start, both for submission of a clinical trial application (CTA) and for possible inspection by the inspectorate.

Virtually anything is fair game for the Health Canada Inspectorate, from manufacturing sites, facilities and equipment, to facility floor plans and process diagrams, to validated bio-burden data. The same goes for the U.S. Food and Drug Administration. A comprehensive ICH-compliant quality dossier (in CTD format) must be submitted as part of the New Drug Submission. ICH Good Clinical Practice guidelines must be followed before, during and after clinical trials, including the assessment and reporting of adverse events to Health Canada (pharmacovigilance). Importantly, the clinical data accruing from the trial should satisfy the product development strategy, and ultimately, the clinical reviewers.

The complexity of the regulatory environment means that innovators are often left out to sea when it comes to understanding what information and data regulators want to see on site or in submissions, or when they want to see it during the R&D cycle. The following focuses on important chemistry and manufacturing considerations for sponsors planning clinical trials of their products.

As a standard approach, the “lots” of investigational product used in preclinical studies should be representative of the formulation intended for the clinical investigation program (clinical trials). Ideally, although not a regulatory requirement, preclinical testing should be done on the same lot as proposed for clinical trials.

Material to be used in preclinical studies (including toxicology) to support a CTA must be tested under Good Laboratory Practice (GLP) guidelines. GLP is an auditing system and the claim of compliance is made for each individual study, not for all the operations of the facility, as with Good Manufacturing Practice (GMP). GLP is a detailed set of regulations on laboratory management to be adhered to by any laboratory providing data from non-clinical studies. The preclinical study must take place according to Standard Operating Procedures (SOPs) in a laboratory having proper organization. SOPs should be developed for all aspects of production. They should be constantly revised and updated and should be available for inspection by Health Canada. A QA program is required to ascertain that the study is in compliance.

C.05.010 (j) requires that the product to be used in clinical trials in humans must be produced and tested according to GMP referred to in Divisions 2 and 4 of Part C of the Food and Drug Regulations. This ensures that trial subjects are not placed at risk and that the results of clinical trials are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture. Consistency between batches of the same clinical trial product used in the same or different trials is assured.

Bio-burden is a major concern of regulators. Microbial contamination must be considered at every step during the manufacture of a biologic. The level of isolation required for the micro-organism derived by recombinant techniques depends on the properties of the components used in the recombinant process. In any research with genes coding for hazardous products, host vector systems with limited ability to survive outside the laboratory (that is, offering biological containment) should be used. Biosafety guidelines must be adhered to during all phases of product development, including research. Raw or starting biological material is to be certified by the supplier to be free of adventitious agents. Appropriate in-house testing for viruses, bacteria, mycoplasma and fungi is conducted to confirm adequacy for use. Bovine material is sourced only from herds from bovine spongiform encephalopathy-free countries.

Control of viable and non-viable airborne particulates in the production and purification areas is required. Any manipulations that might expose the product to the open environment must be conducted under Class 100 laminar airflow conditions. Non-terminally sterilized products, such as those prepared under aseptic conditions from previously sterilized materials, can be processed in clean areas until they have been sterilized, but must be subsequently filled into the final sterile containers in aseptic areas. During development, various analytical methods are applied and adapted as required. Development focuses first on providing a validated manufacturing process. As a product moves through its development cycle it becomes increasingly difficult to change the process.

For a product entering human clinical trials, sufficient data should be generated to support the stability of the product for the duration of the preclinical and clinical trial. In certain cases, stability data acquired at an accelerated temperature may be used to support preliminary data generated at the normal storage temperature.

Consistency and QA are also regulatory hot buttons. A need exists to identify and set critical parameters at different stages during the production process in order to make a safe and viable product. In-process controls are performed at critical steps where data serve to confirm consistency of the process. In-process controls must not only ensure product quality, but must also meet validation and testing standards. The product is partially characterized by this in-process testing system. These tests are performed during manufacture of either the drug substance or the drug product and are in addition to the formal battery of release tests.

Process controls during fabrication are needed to ensure consistency in quality of the end product. A major challenge exists in determining where the critical process steps occur. Then, in-process tests are applied and specifications and acceptance criteria are established. It is important to understand when to increase the number and scope of controls on the process and when to change in-process product characterization. Specifications are chosen to confirm the quality of the product, rather than establish full characterization of the product, and should focus on molecular and biological characterization associated with ensuring safety and efficacy of the drug substance and drug product. Conformance to specifications means that the drug substance and/or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria and is hence considered acceptable for its intended use.

Specifications are linked to the manufacturing process and associated analytical procedures. Specifications are adopted at various rationally pre-selected points of manufacture (in-process, purified drug substance, drug product) on assurance that product consistency and quality are upheld. A reasonable range of expected analytical and manufacturing variability should be considered. Specification setting starts with the development and adoption of realistic operational quality limits. The data obtained during development and validation runs provide the basis for provisional action limits to be set for the manufacturing process. The process progresses to establishment and adoption of more stringent specifications.

The burden falls on the sponsor to provide assurance to the regulators that its product meets the final specifications, that it is always made by the same procedures under the same conditions, and that it has been adequately tested for toxicity.

Dr. David G. Barnes is managing partner of BioTheraGene Consultants Inc. (Ottawa, ON), CEO of Boreal Primum Inc. (Montreal, QC), and regulatory advisor to and member of the board of directors of TrialStat Corp. (Ottawa, ON). Barnes is a former clinical evaluator, Biologics and Genetic Therapies Directorate and former head, Biotechnology Products Surveillance Unit, Marketed Health Products Directorate, Health Canada. A physician and molecular biologist, Barnes also guest lectures on product development at Canadian universities. He has been consulting to industry and government in the clinical development, regulation and safety of biologics since 2001. E-mail dbarnes@cheo.on.ca or d.barnes@borealprimum.com. www.biotheragene.com.

Jerry Calver, PhD is president of Calver Biologics Consulting Inc. (Ottawa, ON). Calver has 32 years of federal experience in vaccines and other biologics. He is former acting chief of Vaccines, former head of Bacterial and Parasitological Vaccines and former head of Pertussis and Neisseria Section, Biologics and Genetic Therapies Directorate, Health Canada. Calver has conducted inspections of biological/vaccine manufacturing facilities nationally and internationally and reviewed chemistry and manufacturing sections of drug submissions for vaccines and biotherapeutics. He has designed and managed the lot-by-lot release, laboratory testing program for bacterial vaccines for Canada and the World Health Organization. Calver provides advice to manufacturers, government and universities on the regulatory process for vaccines and other biologics and provides training sessions on regulation of biologics. www.calverbiologics.com.