| Comment Record|
Dr. Donna Delaney ||
2003-01-10 16:33:40 |
| Comments for FDA General |
1. General Comments
101 Gateway Boulevard, Suite 100
College Station, TX 77845
Tel. (979) 690-8537
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10th January 2003
Dockets Management Branch (HFA-305)
Food and Drug Administration
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Rockville, MD 20852
Re: Docket No. 02D-0324
To whom it may concern,
The following constitute comments by ProdiGene on the Draft Guidance for Industry: ‘Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals’. ProdiGene is a privately held biotechnology company active in using plants to produce proteins, including drugs and biologics.
ProdiGene is whole-heartedly committed to ensuring a high level of safety in taking these products through the entire process of their production. We believe that these products and the processes used to manufacture them should be held to the same high standards as other regulated products. The company strongly supports the establishment of guidelines to aid the industry in achieving safe production processes for drugs and biologics produced in bioengineered plants. ProdiGene wishes to work closely with the relevant government agencies in ensuring that the guidelines will ensure the desired high levels of safety. ProdiGene does have some feedback on the draft guidance document and the company’s comments are given below along with the line numbers in the original guidance document to which the comments refer.
ProdiGene personnel are available and are very willing to further discuss these draft guidelines, our responses to these guidelines (listed below) and any other matters associated with regulatory compliance and ensuring product and production process safety.
Donna E. Delaney, Ph.D.
Regulatory Affairs Specialist
Comments from ProdiGene on the draft guidance for industry
1. (Lines 272-274, and also applies to lines 497-499) We concur that tests should be available to detect the presence of the target gene and the protein product in the raw agricultural commodity. We wish to point out that such tests are subject to limits of detection and we believe that it should be understood that any relevant test could only detect the presence of a target gene or protein product at or above that detection limit. Furthermore, we think that it should be noted that the relevant tests for proteins are likely to be fairly sophisticated, requiring specialized reagents and skilled users. These tests are unlikely to be widely available or easily set up outside the organizations generating the material or the regulatory agencies themselves. We suggest the guidelines acknowledge that there are practical detection limits on any assays and that the guidelines also clarify whether sophisticated protein assays requiring skilled users are acceptable as a means of detection.
2. (Lines 305-307, and also applies to lines 373-379) To our understanding there is no current widely understood and accepted definition of ‘Master Seeds’, ‘Master Seed Banks’, ‘Working Seeds’ or ‘Working Seed Banks’. ProdiGene would like to be involved in assisting the relevant agencies to establish these definitions.
3. (Lines 385-396) We wish to point out that expression levels can vary considerably from generation to generation and also within one generation among different field harvests and even among individual plants in a single field. This may partly reflect environmental conditions. Thus, for each product we recommended establishing a range of suitable expression that can be reliably achieved in the chosen crop and that is suitable for subsequent product processing.
4. (Lines 400-407) We accept that the bioengineered plants should be assessed for the relevant proteins to determine whether the expression pattern predicted from the regulatory sequences is upheld. However, as outlined in point 1 above, we wish to point out that such tests are subject to limits of detection. In addition, the detection limits may vary in different tissue types. The approximate accuracy of the assay needs to be stated along with any number value. Also, in the guidelines this passage refers to all inserted coded regions, which could be interpreted to include the biological marker (such as herbicide resistance) used to select the plants in the field. We question the requirement to assay for this marker, since typically this is also present in non-regulated field crops.
5. (Lines 478-484) We believe that the use of clearly identifiable biological markers may be neither practical nor desirable. We have given some detailed consideration to such strategies, but the plant germplasm harboring the marker trait is generally not compatible with the economic production requirements of the crop. In the case of an auxotrophic marker, the presence of such a mutant gene would be likely to seriously compromise the healthy growth of plants in the field. In addition, clearly identifiable biological markers could attract the attention of saboteurs who may then intentionally or accidentally release bioengineered plant material into the surrounding environment.
6. (Lines 507-516) We agree that careful control should be kept over the inventory and disposition of seeds. We suggest that accuracy limits for weight and volume measurements of seed should be set.
7. (Lines 533-534) We feel that perimeter fencing for all bioengineered plants is neither economically practical, nor effectively excludes wildlife. Even if specific field locations were always used, plot size would vary considerably season to season, necessitating the repeated re-fencing of areas. Furthermore, fences provide little or no protection from most wildlife particularly small burrowing mammals, birds and insects.
8. (Lines 565-571) We concur that liquid wastes should be inactivated prior to disposal, but we feel that this is not technically practical for solid wastes and residual source plant material. Rather we recommend documented disposal, ensuring that the material is kept out of any food or feed stream (unless as stated in the guidelines the manufacturer has specifically consulted the FDA for the use of the material in food or feed products). In addition we feel that guidance should be provided stating at what scale of operations the inactivation of all liquid waste and the documented disposal of all solid waste is implemented. Recommendations for production scale may not be necessary for pilot, or especially bench top scale. Also, lines 569-571 appear to contradict lines 543-547. We feel that lines 569-571 are the more appropriate of the two.
9. (Lines 676-680) We agree that analytical tests should be applied to the final product, both to assess this product and identify any impurities, a list of which will need to be developed. However, we question the requirement for these tests at every stage in the purification process. Also, the process that defines the starting point of product purification should be defined.
10. (Lines 724-726) It is not clear to us what is meant by ‘process-derived contaminants’ in the context of the harvest. We feel this is more appropriate within the section of the guidelines entitled ‘Initial processing of source material’.
11. (Lines 977-984, and also applies to lines 928-930) We believe that plant specific modifications of protein products, such as alternative glycosylation, should be treated in the same way as modifications specific to other production systems. We feel that it is inappropriate to focus specifically on glycosylation because it has been shown that plant-specific glycans are not in themselves allergenic. For this reason we prefer the emphasis to be placed on allergenicity testing.