Summer 1996

Regulatory Notes
Ed Oliver, MSc. - President of CPCS, Inc.

Documentation Compliance

Compliance in R&D was a featured topic at a recent PDA meeting in Chicago. With the merging of clinical and commercial supplies regulatory requirements, it is critical to make sure that quality and compliance are woven into the development process, instead of attempting to later mould development to meet compliance requirements. At the heart of this is the laboratory notebook. It not only forms the secure basis for patent protection, but it is also the foundation of good compliance habits. Critical notebook elements to observe are:

All entries in permanent ink
Signatures on each page to verify work as actually performed
No use of white-out or erasures
Initials and dates for errors and corrections
Full identification of task and support elements
Witness signatures on pre-determined cycle
Start and end dates
Descriptions and references to methods and parameters used
Identification of equipment, reagents and standards
Recording of all data in the notebook

The development of departmental guidelines for notebook usage and standardized reporting formats encourages good compliance habits, which enable compliance to be a feature in all studies used on the road to creating drug products.

Regulatory News Canada

The HPB seems to be paralleling the FDA stance on a GMP compliance programme for drugs used in clinical trails. The Canadian Drug Programme Task Force on Inspection Strategy has recommended that such a programme be designed to meet both Canadian needs and international standards. Among other recommendations the Task Force provided were:

A potential switch to a two year inspectional cycle,
Requiring a manufacturer to provide an on-site master file
Development of the Biologics GMP guidelines as an annex to the existing pharmaceutical product guidelines.

The new edition of the HPB's GMP Guidelines (4th Edition) contains significant amendments, which will be part of the 1997 inspection evaluations, namely;

Process and cleaning validation of equipment have been introduced for the first time.
Use of electronic signatures and records storage.
Stability requirements to harmonized with ICH
New sub-section on the production of sterile products water.
Enhancement of concepts of reprocessing, investigations and change control procedures.

For the 12 months following publication, no non-compliance ratings will be assigned based on deviations from the revised guidelines unless a health hazard is established. It is expected that manufacturers will develop validation master plans in the interim. It has been decided to phase out the use of Plant Master Files for compliance demonstration for foreign plants as of January 1, 1996. Manufacturers and importers are encouraged to obtain viable plant inspection reports from the relevant national authorities, if available.

Regulatory News United States

Internal FDA reform measures reportedly being discussed would, if enacted, provide for increased regulatory flexibility for biotech manufacturing and enable closer integration of CBER and CDER regulations. However, despite broad Congressional support for Food and Drug Administration reform, the odds for FDA reform measures passing in this election year appear to be only 50/50. Critics of the FDA continue to say that approval takes too long; citing that it now takes 15 years to get a new drug to market in the United States, compared to six years in the mid 1960s, with the result that other countries benefit first from medical innovations developed by U.S. companies. Between 1987 and 1993, close to 75% of the drugs approved by the FDA first received regulatory approval in other countries.

The bill before the House has a provision which allows medical devices and products to be reviewed by a certified third party (as is widely used in Europe), rather than the FDA. An idea yet to be endorsed by FDA management. Companies could save money under the plan because it would take less time to test products for marketability. Two other legislative issues important to biotechnology - tax credit for research and development and capital gains tax reduction - have suffered in the battle over a balanced federal budget.

International Conference on Harmonization (ICH)

Analysis of the Expression Construct in cells used for the Production of r-DNA Derived Protein Products (Q5B); Step 4:

Viral Safety Evaluation (Q5A); Step 2

Cell Substrates (Q5D); Step 2

Characterization of cell banks

Specifications for biotechnological Products (New); Step 1;

Specifications and test methods for biotechnology products