ICH Draft Guidance on Q8 Pharmaceutical Development

S8 Immunotoxicity Studies for Human Pharmaceuticals – Step 2 Released for consultation

The FDA announced in a Federal Register notice of October 4, 2004, the availability of a guidance for industry entitled “Sterile Drug Products Produced by Aseptic Processing -Current Good Manufacturing Practice.'' This guidance explains FDA's current thinking on manufacturing of sterile drug products produced by aseptic processing in the context of complying with certain sections of the current good manufacturing practice (CGMP) regulations for drug and biological products. This guidance is issued with the goal of providing clear and consistent communication of regulatory expectations to promote voluntary compliance with current FDA requirements.

The FDA announced in a Federal Register notice of October 4, 2004, the availability of a draft guidance for industry entitled “Current Good Manufacturing Practices for Combination Products.” Once finalized, this guidance will provide guidance to industry and FDA staff on the applicability of current good manufacturing practices (CGMP) for combination products.

Rule Aims to Prevent Disease Transmission Through Tissue Transplants
FDA has finalized a rule to establish eligibility criteria for donors of human cells, tissues, and cellular and tissue-based products to help prevent transmission of communicable disease through transplants of these products. The new rule expands on an existing regulation that previously applied only to certain tissues and diseases.
The final rule becomes effective on May 25, 2005. It is accompanied by draft guidance that provides recommendations for complying with the requirements in the donor eligibility rule. Comments on the draft guidance should be received by August 23, 2004 (90 days from the publication date) to assure consideration in the final guidance.
The rule is available on FDA's website at http://www.fda.gov/cber/rules/suitdonor.pdf and the guidance is available at http://www.fda.gov/cber/gdlns/tissdonor.pdf.
Questions and Answers are available on http://www.fda.gov/cber/rules/suitdonorq&a.htm

FDA has prepared draft guidance for reviewers entitled "Instructions and Template for Chemistry, Manufacturing, and Control (CMC) Reviewers of Human Somatic Cell Therapy Investigational New Drug Applications (INDs)." Notice of the guidance is to be published 18 August in the Federal Register. The notice can be viewed on http://www.fda.gov/OHRMS/DOCKETS/98fr/03D-0349-NAD000.pdf. The draft document states that human somatic cell therapies present a multitude of manufacturing challenges that must be overcome in order to deliver a safe, consistent and potent product. The guidance is intended to provide instructions to CMC reviewers about what information to record and assess as part of reviews of original investigational new drug applications. It is clear that there was a need for guidance on cell therapies as the current guidelines for other types of biologics were not applicable. The guideline deals only with human cell products (allogeneic and autologous). Screening of the donated cell materials is clearly defined as well as the cell culture requirements. There is an acknowledgement that not all of the required microbiological safety testing will be completed before the use of materials with patients, however the testing should be completed even if this is after the patients are treated. For the testing for mycoplasma it is acknowledged that polymerase chain reaction can be applied to aid in ensuring that the products are mycoplasma free. Adventitious agent testing follows a similar pattern to the screening of cell lines in other biologics. However it is important to note the requirement for identity of the final product. A method has to be used to identify the specific cell types in the product. This may prove difficult for some products. Endotoxin specifications also may be difficult to fulfil given the small volumes that are used in each product.

Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products
in Humans

FDA issued on 3 April 2003 the final guidance, "Source Animal, Product, Preclinical and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans", describing the issues it expects to be addressed in INDs and BLAs involved in the transplantation of live cells, tissues or organs from animals into humans. The guidance, issued by the Center for Biologics Evaluation and Research (CBER) covers the production, testing and evaluation of products intended for use in xenotransplantation and gives a thorough overview of the reviewers concerns regarding the use of animal derived cells in the treatment of humans. The safety issues in the use of these cell types are pre-eminent and highlights a potential threat to humans of zoonotic or other infectious agents being transferred to humans through xenotransplantation products. The document includes recommendations of "specific practices intended to prevent the introduction and spread of infectious agents of animal origin into the human population." The guidance states that FDA expects "scientifically rigorous" efforts to be made by sponsors of new methods to address specific issues and that "sufficient data will be presented to justify their use." The safety of the source animals is covered detailing the animal husbandry and health screening of the animals prior to harvesting the cells. The qualification of the source animal prior to harvesting may involve extensive microbiological safety testing and differs depending on species chosen. The safety testing of the harvested cells is also clearly outlined and is significantly more extensive than is performed with equivalent cell lines. Monitoring of the patients treated with the xenotransplant is also detailed with the timelines and types of testing required. In conclusion this document is a well thought out protocol which clearly details what would be required should a sponsor wish to investigate a novel cell therapy product sourced from animals.

The Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER), USA posted (6 September 2002) notice of Draft Guidance for Industry: Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals. This draft guidance document has been released for comment from interested parties.

Issued (14 June 2002) The draft guidance document provides information that would assist manufacturers of human cellular and tissue-based products in minimizing the possible risk of transmission of CJD/vCJD by HCT/Ps through deferral of donors with possible exposure to the agents of CJD and vCJD. Because there is no readily available demographic information about the HCT/P donor population, FDA encourages establishments to submit with their comments study data concerning the effect that implementation of these recommendations could have on the HCT/P supply.

CBER posted (11 July 2002) the Gene Therapy Patient Tracking System (GTPTS).
The GTPTS is intended to supplement or replace current systems for assessing and promoting the safety of gene therapy so that the oversight system will be optimized for dealing with relatively specific gene therapy issues. CBER has identified five areas in which the GTPTS can improve upon pre-existing FDA (Food and Drug Administration) systems for assessing and promoting product safety.

Posted: 2/1/2002 Issued: 2/1/2002 The Food and Drug Administration (FDA) is announcing the availability of a draft document entitled "Guidance for Industry: Precautionary Measures to Reduce the Possible Risk of Transmission of Zoonoses by Blood and Blood Products From Xenotransplantation Product Recipients and Their Intimate Contacts" dated February 2002. The draft guidance document provides recommendations to all registered blood and plasma establishments, and establishments engaged in manufacturing plasma derivatives. The draft guidance document, when finalized, is intended to provide recommendations regarding the disposition of blood products manufactured from a donor who is retrospectively discovered to have received a xenotransplantation product or to have been an intimate contact of a xenotransplantation product recipient. This is the second draft guidance document and it incorporates revisions based on public comments received on the first draft guidance document by the same name announced in the Federal Register of December 30, 1999 (64 FR 73562).

Posted on CBER website on January 9th 2002, dated January 2002. This guidance document contains comprehensive revised recommendations, to all registered blood and plasma establishments for deferral of donors with possible exposure to the agent of vCJD, based upon advisory committee discussions, internal Public Health Service and FDA deliberations, and public comments. FDA has developed recommendations for donor deferral, and product retrieval, quarantine, and disposition based upon consideration of risk in the donor and product, and the effect that withdrawals and deferrals might have on the supply of life- and health-sustaining blood components and plasma derivatives. The new recommendations are intended to minimize the possible risk of CJD and vCJD transmission from blood and blood products while maintaining their availability.
The guidance document finalizes the draft guidance of the same title, dated August 2001, and supersedes the guidance document entitled "Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and New Variant Creutzfeldt-Jakob Disease (nvCJD) by Blood and Blood Products" dated November 1999.

The FDA has announced the availability of guidance entitled "M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use" (M4 CTD). The guidance was developed under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The guidance, which is being made available simultaneously in four parts (general organization, quality, safety, and efficacy), describes a harmonized format for new product applications (including applications for biotechnology-derived products) for submission to the regulatory authorities in the three ICH regions. The M4 CTD is intended to reduce the time and resources used to compile applications, ease the preparation of electronic submissions, facilitate regulatory reviews and communication with the applicant, and simplify the exchange of regulatory information among regulatory authorities.