Docket Management
Docket: 02D-0324 - Draft Guid.: Drugs, Biologics & Medical Devices Derived from Bioengineered Plants
Comment Number: EC -42

Accepted - Volume 9

Comment Record
Commentor Mr. Robert Gustines Date/Time 2003-01-10 10:37:00
Organization CropTech Corporation
Category Company

Comments for FDA General
1. General Comments CROPTECH CORPORATION RESPONSE TO DOCKET NO. 02D-0324 CROPTECH CONTACT: David Williams, 540-951-2888 January 10, 2003 Dockets Management Branch (HFA-305) Food and Drug Administration 5630 Fishers Lane Rm. 1061 Rockville, MD 20852 Docket No. 02D-0324 CropTech Corporation would like the opportunity to submit the following comments in response to the draft “Guidance for Industry: Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals” (September 12, 2002, Federal Register 67 Fed. Reg. 57828). CropTech Corporation is a company that has developed an innovative plant-based gene expression technology for the large-scale manufacture of bio-therapeutic proteins. CropTech employs this enabling technology in the development and production of its own proprietary products and those targeted by its commercial clients CropTech Corporation has been fully committed to the development of guidance and regulation that will help to ensure the highest degree of safety, health and environmental control based on sound scientific principles. CropTech Corporation has been in the forefront of organizing and developing a plant-made pharmaceutical industry group, and has worked closely with the FDA to help facilitate the development of this draft guidelines document. CropTech Corporation also supports the efforts of the USDA to develop guidelines which merge with FDA guidance to ensure a relatively seamless transition between USDA concerns and those of the FDA. Recommendations For The USDA And FDA Relative To The Guidance Document I. The Draft Guidance addresses those domains generally controlled by the USDA through specific regulation rather than through a guidance format. Those domains which are concerned with environmental safety and confinement measures related to the production of regulated products in plants should be addressed through regulation in 7 CFR 340 rather than a guidance document. The basic goal of the FDA is to protect the drug product to ensure safety and efficacy, whereas, the USDA has the responsibility for protecting the environment by ensuring that any plant host utilized is not harmful. Trying to manage such coupled, but diametrically different programs is difficult at best and should be addressed separately. CropTech’s recommendation is to regulate field activities through specific, mandatory regulation and not through a guidance document. These measures relate primarily to potential environmental and human health effects. II. CropTech Corporation wants to ensure that any guidance or regulation specifically delineates between those plant hosts that are traditionally viewed as food and feed crops and those, such as tobacco, which are not. A significant portion of the USDA recommendations focuses on the confinement and containment of traditional food and feed crops. CropTech wants to ensure that any regulation or guidance specifically impacting food and feed crops do not inappropriately affect any company utilizing a non-food or non-feed plant host, such as tobacco. III. CropTech recommends that all crops that are developed for industrial use not intended for food or feed be regulated as pharmaceuticals, under permit for both field-testing and upon commercialization. IV. The USDA should ensure that all academic institutions producing plant-made pharmaceuticals or industrial products not intended for food or feed be regulated under permit for all field activities. V. IB. CropTech would like to see plant residue waste material issues specifically addressed in this section with continued management by APHIS. VI. IB. CropTech would like to raise the issue of non- field grown plants (greenhouse produced) and the general categorical exclusion for APHIS permitting for greenhouse planting. CropTech recommends a continuation of the current policy for contained environment propagation and permitting for interstate movement. VII. IIA. CropTech recommends that line 224/225 is changed from non-food (or non-feed) to: “non-food/feed”. VIII. IIC1. CropTech recommends that there be expanded emphasis on testing and validated testing programs for both DNA and protein produced in the raw agricultural commodity. A testing program should include a designated third party (such as the USDA) to act as a depository for validated assays and standards. IX. IIC1. CropTech recommends that in line 272, “strongly recommends” be changed to “require”, and that both DNA and protein identity tests are emphasized. X. IIC2. CropTech would like to see specific references on characterization of DNA such as International Conference on Harmonization (ICH), FDA guidance and points-to-consider, and comments regarding harmonization with EU guidance documents. XI. IIC3. CropTech recommends changing “recommend” to “require” in line 306. XII. IIC3. This section does not fully address those issues impacting the use of clonal propagation as a stable transformation system. CropTech would like to see this section expanded to include comments on clonal propagation. XIII. IIC4. CropTech recommends that some statement or position should address transient system stability, a sampling system to detect genetic drift after transfection, and a requirement to establish limits of genetic drift. XIV. IIC5. CropTech would like to see an expanded definition of what constitutes a Master Seed Bank (MSB) and Working Seed Bank (WSB) relative to standard agronomic practices. XV. IIC5. CropTech would like to see an expanded definition of what constitutes a MSB and WSB relative to clonal propagation practices of plants. XVI. IIC5. CropTech would like the guidance document to define and detail the validation of a MSB and WSB plant host. XVII. IIC5 CropTech would like to see lines 373 – 375 changed to “Regardless of whether a transient-transfection system or stable transfection system is used, you should prepare a banking system that will ensure consistent lot-to-lot growth of the plant and expression of the regulated product. XVIII. IIC6. CropTech would like to see clarification regarding tissue distribution. What is the intent of this proposal? Is this an APHIS or FDA issue? XIX. IIIB. CropTech believes that categorical exclusion under 21 CFR is valid for manufacturing facilities designed for standard containment practices. XX. IIIB. CropTech recommends that there be no categorical exclusion for an Environmental Assessment (EA) or an Environmental Impact Statement (EIS) regarding field activities under 7 CFR. Requirements should be product specific. XXI. IIIB. CropTech would like to see general language written into this section that describes those issues that would trigger an EA. XXII. IIIC. CropTech recommends that there be expanded recommendations on testing and validated testing programs for both DNA and protein produced in the raw agricultural commodity. A certified testing program should include a designated third party (such as the USDA) to act as a depository for validated assays and standards. XXIII. IIIC1. CropTech sees a conflict between providing security of a field and the recommendation for some type of phenotypic characteristic to distinguish between transgenic and non-transgenic plant. CropTech recommends that field site security take priority over phenotypic differentiation. XXIV. IIIC1. CropTech recommends that the language “… strongly recommend that you have tests available…” should be changed to “… require that you have tests available…” XXV. IIIC1. CropTech recommends that a statement be included that requires a test certification and standardization program which resides within the USDA. XXVI. IIIC1. CropTech recommends inserting language specifically noting the use of SOP’s, batch records, and good agricultural practices as control measures to restrict unintended exposure of a regulated product. XXVII. IIIC3. CropTech recommends clarification of the statement regarding the use of perimeter fencing. The use of fencing may be in conflict with security measures based on concealment. The use of fencing would also be problematic with regard to birds, insects, and small mammals. Any issue regarding fencing should be based on specific product review regarding toxicity, environmental impact, etc. and specific issues should dictate the level of fencing (containment). XXVIII. IVB. CropTech recommends that this section should include some reference to a validated testing system that addresses consistent levels of target product in the plant host. XXIX. IVD3. The term “recommends” with regard to dedicated equipment should be changed to “require”, and the last sentence, line 746, “If the equipment is not dedicated to harvesting only the source material, other uses should be documented”, should be deleted. XXX. IVD3. CropTech recommends that “dedicated equipment” be defined as equipment used only in the production of plants used for producing transgenic proteins. Equipment can be used for different protein entities if there is a validated cleaning protocol and changeover protocol utilized prior to use. Equipment utilized for the production of transgenic proteins should never be used concurrently in a general food/feed agricultural environment. XXXI. IVD4. CropTech recommends that a statement such as: “dedicated equipment should be used for the transport and storage of food/feed related source material” be added to this section, and that a definition for dedicated equipment as in the previous section be used. XXXII. IVD5. This section should be expanded to address container requirements for handling and processing transgenic plants in an effort to ensure that dedicated containers are utilized and not used interchangeably with standard food/feed operations. XXXIII. IVD6. This section includes references for Extraction (6) and Aseptic Processing (7). Although purification processes will be similar to those already employed for biotechnologically derived proteins, transgenic plants will have unique purification requirements. We recommend that a section addressing purification be added after section IV.D.6. This section should include requirements for validated procedures for the removal normal process derived impurities such as host plant proteins and host plant DNA as well as pesticides, herbicide, fungicide and fertilizer residues. XXXIV. VB1. Change “may be appropriate”, line 940, to “shall be performed”

EC -42