A national task force headed by CSIR chief Dr RA Mashelkar was set up in April 2004 to streamline the regulatory process involved in the approval of all recombinant DNA products. The Ministry of Environment and Forest (MoEF), which oversees the regulatory agency, Genetic Engineering Approval Committee (GEAC), had issued the notification for setting up the task force on April 20. The task force, which was asked to submit its report by May 2004, had the 12 members as part of the panel. The first meeting of the Task Force was held on May 12, 2004 and subsequently the task force met the industry and other stakeholders at several levels. The draft report of the Task Force on recombinant pharma is now ready.

Dr Dhananjay Patankar, head, biotechnology, Intas

On setting up the panel, industry leaders welcomed it and quickly evinced their suggestions to help the task force with the tasks ahead. Now that the draft will be circulated, industry has few quick comments to offer on the same.

Four great developments emanate from this report said the South Asia Office of The International Service for the Acquisition of Agri-biotech Applications (ISAAA).

• GEAC will not have a say if the final product doesn't involve LMOs. Most of the recombinant pharmaceuticals don't have living organism in their final products (only protein derived from LMOs/GMOs). It will be a savior for biotechnology industry. GEAC's role would be limited to inspection (if fermentation capacity is over 20l) only. Reversely, anything that involves LMOs/GMOs would come under the purview of GEAC irrespective of its risk categories. The report will have, if any, adverse impact on the growth of agricultural biotechnology.

• Constitution of Inter-ministerial Standing Committee on biotechnology regulation to address issues and anomalies concerning recombinant pharma that have never appeared before. It would strengthen coordination among different ministries and smoothen the process for approval of innovative products to be come in the market.

• Task force vehemently recognizes the importance of an independent institutional mechanism called National Biotechnology Regulatory Authority. Since both Prof. Swaminathan and Dr Mashelkar recognize the need to develop strong institutional structure and scientific body i.e., NBRA, the government must evolve this process rapidly to give fillip to investments and trade in biotechnology products.

• Protocol V would be detrimental to Indian biotechnology industry and dumping of biotech products in India. Eventually, it would promote "trading" than "innovation" in our country.

Since the final recommendations have not been made public yet, the comments to each of the individual points in the recommendations is difficult to make said Dr Dhananjay Patankar, head, biotechnology, Intas Pharmaceuticals Ltd. However, he made some general comments.

• We are overall quite satisfied with the draft recommendations of the Mashelkar Task Force. The main concerns of the industry in the existing framework was that various committees were looking at the same data, often outside their area of expertise, thus causing duplication and redundancy and delays. Further, there was a problem of infrequent meetings of the committees. The draft recommendations have streamlined the procedure such that different committees examine the data that fall under their field of expertise and there is no unnecessary duplication. The different committees like RCGM, GEAC have also on their own already increased the frequency of their meetings and increased their communication with the companies.

• We are very happy about the way the government has really responded to the industry's concerns and brought about simplification of procedures without diluting the stringency of the regulatory scrutiny of the data before according approval to products.

• For registration of imported biotech products, however, we have one further suggestion to the DCGI (although this was not under the scope of the Mashelkar Task Force). We believe that the DCGI should insist on inspection of the manufacturing facilities and GMP aspects of the manufacturer whose product is to be imported. As of now there is no such provision, and thus we cannot be sure of the quality of the production system of the manufacturer. The expenses for carrying out inspections can be recovered through application fees charged to the importer. The domestic manufacturers adhere to strict GMP regulations as per Schedule M but there is no method for ensuring that the foreign manufacturers are adhering to such quality systems.

Dr Dhananjay Patankar, head, biotechnology, Intas

Dr Prasanta Kumar Ghosh, senior vice president, Cadila Pharmaceuticals Ltd, Ahmedabad, who had served in various key positions in the government and retired as advisor from the DBT in May 2002, in his personal capacity, observed that the Indian rules on GMOs were framed when the knowledge base on nucleotide sequences including the promoters, the enhancers, terminator sequences etc. were inadequate. Information on safety of complete coding construct and transformed host were also inadequate. With the advent of knowledge, review of the Rules has become imminent. In that context the work of the Task Force (TF) is very relevant.

He added: "The TF is mandated essentially to recommend a transparent and streamlined regulatory mechanism and a regulatory process including mechanism for the use of LMOs in the pharmaceuticals industries as also for import of LMOs by the pharma sector. The analysis of the regulatory framework by the TF seems to somewhat myopic and the essence of the strength of the current framework of the regulation has largely been missed out. Few problems identified in the analysis seem to be supposition and some of the conclusion appears to be inexact."

Ghosh pointed out:

• As regards the recommendations appearing on Para 5 of the draft report the existing system has been found to be workable and largely status quo has been maintained for the roles of IBSC and RCGM (Para 5.1a and 5.1b).

• For recommendation at Para 5.1c, it has been stated that for the review of LMOs, GEAC will take note off or approve only the containment facilities for the use of LMOs including more than 20 liter fermentation capacity where the end product is a purified material intended for commercialization. This recommendation does not seem to be scientifically consistent with LMO substances containing nucleotide sequences consisting of coding sequences with or without promoters and terminator sequences. Presence of such sequences in adequate quantities in the purified finished product could be potentially harmful. For this recommendation, I think it should be modified for LMO substances for which there is no pharmacoepial specification and yet the nucleotide sequences are present in quantities less than 100 picogram per dose.

• In Para 5.1d, it has been stated that the DCGI would examine animal toxicity, allergenicity and QC data. Here too the recommendation need to be modified to include only those LMO drug substances that have been incorporated in Indian Pharmacoepia or in any other Pharmacoepia accepted by the Indian authorities.

• In recommendation Para 5.2a, it has been stated that "It was agreed that... for conducting Phase III human trials". The conclusion seem to be inconsistent with the existing law the reason for the GEAC to state that it has no objection to the conduct of trails on human including Phase I or Phase II or Phase III or Phase IV when GEAC is satisfied that the animal safety data generated by the applicant indicates that the product is reasonably safe. GEAC works under EPA and it has been the responsibility GEAC to examine whether a pharmaceutical product derived from LMO is safe to human and animal. Safety information emanating from the presence of Host DNA and Host nucleotide sequences as well as trans nucleotide sequences are within the purview of GEAC under Indian EPA.

• The recommendations at Para 5.2 a 2,3,4 seems to be okay and they are consistent with sound logic and good argument. These are also being generally followed presently.

• Recommendation at Para 5.2a 5 do not seem to be okay for new drugs derived from rDNA technology. These can be okay for Pharmacoepial drugs only.

• The recommendations at Para 5.2b2 does not seem to be correct as the presence of large quantities of the coding sequences can be potentially dangerous to human health.

• The recommendation at Para 5.2b3 is consistent if it is a Pharmacoepial drug. This recommendation is therefore not required for situations where LMO's are Pharmacoepial drugs.

• Recommendations 5.2b4 is also inconsistent with LMO drug that are Pharmacoepial

• The recommendation at Para 5.2c on import and marketing of recombinant Pharma products also needs to be revised and perhaps for recommendation on 5.2c1 it can be stated that for import of recombinant pharma products where the presence of Host DNA or the transgenic DNA is less than 100 picogram each per dose, GEAC approval is not required. Otherwise all such substances should require GEAC approval. Obviously, Pharmacoepial LMO products will not require approval of GEAC.

• Para 5.2c2 can be modified to incorporate that LMOs approved in any acceptable Pharmacoepial will not require GEAC approval.

• He suggested the report could have been made much more simplified by excluding:

• All substances produced by LMOs where the substances are so pure that the presence of transnucleotide sequences as well as Host related proteins and DNA are not detectable by standard scientific practices

• All Pharmacoepial drugs including LMOs and products thereof would not require the approval of GEAC.

Dr Dhananjay Patankar, head, biotechnology, Intas

GEAC could also publish a list of nucleotide sequences, pharmacoepial drugs produced by rDNA technology, as well as other GRAS organisms on which there is no known environmental risk as exempt from the GEAC provisions. These would simplify the situation substantially he noted.

Rajesh Jain, joint managing director, Panacea Biotec Ltd, has his share of suggestions for the draft report on specific issues.

Containment facilities

• Inspection and approval of containment facilities (less than 20 ltr) may be provided by IBSC.

• RCGM may be involved in inspection and approval of containment facilities with capacity of more than 20 liters.

• GEAC may not get involved in approval of containment facilities.

• Clearance of proposal using various risk category organism

• All proposals using a category risk II microorganism be examined and approved by IBSC. The organisms under category I risk are non-pathogen and are exempt for any clearance.

• The proposals using organisms belonging to category risk III, IV or higher risk be first examined by IBSC and recommendations may be made to RCGM for approval.

Pre-clinical toxicology protocol/data

• RCGM should restrict its role in examining the proposal relating to the specifications, characterizations and information on rDNA biologicals materials. The RCGM should consider providing permission for generation of preclinical toxicology data.

• The preclinical toxicology protocol to be used would vary depending upon the requirements and products and such protocols are usually designed after discussion with appropriate laboratory or center involved in conduction of clinical trials. Therefore the precise protocol to be used would ideal be left to the investigators.

• The preclinical toxicology data so generated be examined by "rDNA expert committee" located in the DCGI office.

• Strengthening of IBSC and rDNA expert committee

• In both of these committees, the nominee of GEAC may also be included as member, so that all aspects relating to environment could be addressed at the initiation of the proposal and during examination of the data so generated.

Nonetheless no one is disputing the fact that the Mashelkar report is a sincere attempt to examine various issues and find reasonably sound solutions given the mandates of different authorities involved. "It is good that importers of biotech products (rDNA not containing LMOs) need not seek GEAC approval. Indigenous manufacturers now have a structured process and will benefit from IBSC, RCGM, RDAC and DCGI as long as timelines for approval are met. There is need for a stricter mandate on meeting timelines. The intention to provide impetus to the Indian industry is seen in the report but actions have to match it specially the pace with which each independent authority operates. The inter-ministerial committee on BT regulation is forward looking and if the single window approach could become a reality through National Biotechnology Regulatory Authority (NBRA) similar to US FDA it would be a boon and indeed pave the way for a brighter future for the Indian industry," informed Rajiv Gulati, MD and Chairman, Eli Lilly India.

Srinivas Rao