Cover Story

Regulating biologics

The absence of regulatory guidance or clarity is often followed by chaos and misunderstanding. World over, the biopharmaceutical industry, in all its perplexity, is waiting for concrete rules to take over the mildly regulated biologics. Aashruti Kak does a status check

In 2005, when a legislation was passed in the US that allowed the launch of biosimilars or generics of off-patent biopharmaceuticals (biogenerics), a magnanimous opportunity was unleashed upon the world. With scores of products going off patent in the next decade and beyond, the options seemed really bright for those interested in manufacturing biogenerics, especially in India, where even the pharma industry is largely generic. However, behind every opportunity lies a great fight. Since then, it has been a constant struggle to craft suitable guidelines for biopharmaceuticals.

Existing regulations

Currently, in India, the regulations that are in force are the Drugs and Cosmetics Act, 1940 and rules therein (Schedule-M), WHO current Good Manufacturing Practices (cGMP) requirements, Indian Council of Medical Research's (ICMR) Good Clinical Practices (GCP) guidelines, and the Indian Pharmacopoeia. "All regulations fall under the Schedule M of the Drugs and Cosmetics act and the relevant ICH guidelines on manufacturing of drug substances. Currently, there are no separate guidelines in India for biotechnology products. Though, there are certain relevant US Food and Drug Administration (US FDA) and European Medicines Agency (EMEA) guidelines that cover these products," informs Dr K I Varaprasad Reddy, Managing Director, Shantha Biotechnics.

Dr S S Jadhav, Executive Director, Serum Institute of India, says, "Presently, the regulation of biologicals in India with respect to the licensing and GMPs is mostly controlled by the Drug Controller General of India (DCGI) and Central and State Drugs Control departments like Central Drugs Standard Control Organisation (CDSCO) and Drug Regulatory Authorities (DRAs)." He adds, "However, in certain cases for example, where the product is developed or manufactured using recombinant-DNA (r-DNA) technology, the approval of various other agencies/committees is essential. These include Genetic Engineering Approval Council (GEAC), recombinant DNA advisory Committee (RDAC), Review Committee on Genetic Manipulation (RCGM), Institutional Biosafety Committee (IBSC) and many more such committees, at the state and district levels. This needs to be regulated through a single window clearance channel."

Dr S Anand Kumar, Honorary Scientist Advisor, Association of Biotechnology Led Enterprises (ABLE), explains, "It is the DGCI who is legally authorised to permit any biological product to be marketed in India. The official standards and specifications setting body is the Indian Pharmacopoeia Commission (IPC). For biologicals including recombinant DNA products the IPC works in collaboration with National Institute of Biologicals (NIB). IPC publishes periodically the Official Pharmacopeia, the latest being in 2007 and also publishes its supplements (latest in 2008) which contain specifications (monographs) of biologicals approved by the DCGI regarding recombinant human insulin, recombinant human erythropoietin (EPO), interferon (IFN), granulocyte colony stimulating factor (GCSF) and others." He also says that over the past three years, IPC has signed Memorandum of Understanding (MoU) with international standard setting bodies such as United States Pharmacopoeia (USP), EMEA, British Pharmacopeia and others, and is working on providing reference standards for the industry through these collaborations.

Internationally, the written standards are published in the US by the USP, in European Union (EU) by the European Pharmacopoeia and in China by the Chinese Pharmacopoeia. "Besides these, other regulatory guidelines also publish standards for biologicals for example, the USFDA's Center for Biological Evaluation and Research (CBER) publishes and supplies both written and material standards. Similarly, in European Union various agencies have been given the statutory mandate to regulate and control the biological medicinal products," says Jadhav. In Europe, various guidelines like EMEA Directives, Committee for Proprietary Medicinal Products (CPMP) and European and British Pharmacopoeia are currently in force, he says. "The material standards in US are supplied by CBER, and the World Health Organization (WHO) supplies international standards for most of the biologicals through the National Institute of Biological Standards and Control (NIBSC), London." Similarly, as per Jadhav, in most of the countries including India, China and Japan, where lot release system is approved and operational, the National Standards are produced and supplied to the manufacturers by their respective National Control Laboratories. WHO has been working on Regional Working Reference Standards (RWRS) network across South East Asia Region (SEAR), for certain selected vaccines for example, pertussis and Japanese Encephalitis.

Hunt for a protocol

"We do not see any major hurdles in forming a biopharmacopoeia. However, it is up to the policy makers to consider the recommendations, finalise and go ahead with these products" - Dr S S Jadhav Executive Director Serum Institute of India

According to Jadhav, standards for biologicals fall basically into two categories: firstly, written standards and secondly, material standards. The written standards for biologicals are set up by various pharmacopeia as monographs and WHO, through their guidance documents/requirements called Technical Report Series (TRS). Besides the individual product specific monographs of Indian Pharmacopoeia, we follow the WHO requirements, as these are widely and universally accepted. As far as material standards are concerned, the government produces and supplies these standards only for a few vaccines and sera, through the Central Drugs Laboratory (CDL), Kasauli, which is the National Control Laboratory for Biologicals.

Dr K K Tripathi, Advisor, Department of Biotechnology (DBT), says, "The issue of biologics is being addressed by all countries/authorities. Biologics, as a terminology itself does not have a definition. Our regulatory system has been taking the help of the US FDA and EMEA guidelines."

Dr M K Bhan, Secretary, Government of India, DBT, says, "The first question is do we have written guidelines available to people? Currently, we have a large committee of about 30 people in the Review Committee on Genetic Manipulation (RCGM) which frequently discusses the current FDA and EMEA guidelines and makes sure that it is updated as per the guidelines in case by case approvals. The essential discussion that I have heard, which seem relevant to me, is about two extreme cases. We have recombinant products and antibodies and for the recombinant products, by and large the existing guidelines serve the purpose. But for antibodies, the manufacturing process variability is a bigger issue." So, there is a recognition that manufacturing of biologicals is subject to variability and is process driven.

To make sure that the product is identical or original is harder for biologicals than for chemical entities. "So the next question is, what is the degree of difficulty you create to be sure that some of the products in the in vitro laboratories and the strength of the biomolecule, are to be characterised in details, and the other side is how expensive should the chemical evaluation be? At this moment, RCGM is seeing the issues and is in touch with both the FDA and the EMEA, and they are taking case by case decisions while trying to standardise the minimum information that is required to show how companies have characterised their products." The DBT has been in an intense phase of discussion on this and it took them quite a lot of time to reach this position, because a lot of advice that they got varied on the interests of the industry, regulators, academicians, scientists etc. "If we ask a big established company on this issue they will tell us to be strict, whereas a smaller company will suggest otherwise. What we are trying to do is be very scientific and come to a conclusion," says Bhan.

"The main issue the industry faces currently is the availability of appropriate reference standard. They are either not available or available in limited amounts. The limits given in monographs are much wider than the actual quality of the pharmacopoeial standard" - Samir Sangitrao RAC, Head-Regulatory Affairs, IBPL

According to Bhan, last year, DBT had a decision on this and was contemplating announcing it but thought better of it and decided that it should debate this some more while consulting the FDA and the European authorities. Doing so, it has studied their documents and their cases. "The Indian committee system, because of the duality of RCGM and the DCGI (the two tier system), the degree of stringency is very high as a lot of technical expertise has gone into it, even though the characterisation of detail of these products is not clear.

But, I think now we are in a better position to actually come forward and publish a statement on the matter. It is not good to change the regulation every six months because it would not work in this case. Even the FDA advised us not to close the issue so fast. So, when we re-composed the RCGM committee this time, we made sure that the expertise is strong," says Bhan. "Apart from our members, we tried to avail the experience of companies as well, as they have very good scientists who are in constant interaction with various regulatory bodies; to get their stand as well, which was earlier missing," informs Tripathi.

The DBT has also funded the National Centre for Biological Sciences for a new 'Centre for Characterisation of Biomolecules' which will become another support system for the regulatory system where they will have a pool of their own scientists. Samir Sangitrao, RAC, Head-Regulatory Affairs, Intas Biopharmaceuticals (IBPL) informs that the Indian Pharmacopoeia has already started the initiative for introducing the biotech molecule monographs on the same lines as European Pharmacopoeia. "What the system requires is the comparability of a biosimilar product to an innovator product in terms of quality comparability, non clinical comparability and clinical comparability (phase I to III)," he adds.

Global scenario

"So many products are in the pipeline, and a new problem arises every time there is a new product coming. So, I must say that the process of regulation is not static, but dynamic" - Dr K K Tripathi Advisor Department of Biotechnology

According to Tripathi, US is in the process of enacting their legislation, which is almost ready. EMEA already has a legislation for which they have five guidelines in place, especially for biosimilars. Regarding this, the FDA is still in a dilemma about what terminology has to be used-whether the products are to be called biosimilars, follow-on proteins, or biopharmaceuticals. Reddy adds, "US and Europe have regular committees that meet at least twice a year to finalise and update the parameters for the evaluation of biological products. Recently, there has been harmonisation between the European and British Pharmacopoeia where in the products can be licensed on the basis of either one of them."

Regarding the regulatory scene in China, Tripathi reveals, "The Chinese are silent, because our system has seen that many of the products being imported from China are not up to the quality mark. Chinese regulators say they are also working on it, without disclosing anything. China is the only country where a gene therapy product has been approved." He continues, "Now the Chinese products are getting more access because they need not come to RCGM, because they are purified products, and because we are working under the Environment Protection Agency, under which these products are not covered. So this as a protocol has become a boon for traders." For instance, Tripathi recalls an instance where a rabies liquid vaccine from China was tested and compared with a similar vaccine from an Indian manufacturer; it had stability issues. "So when Chinese exporters come into India, they just have to register with the DCGI, after which it is up to the DCGI whether he wants to ask for a quality control dossier or get the products tested," says Tripathi.

Speaking about the regulatory system in Canada, Australia, Japan, etc Sangitrao says that these countries are actively considering a pathway for biosimilar molecules. According to him, WHO's guidance to harmonise authorisation requirement is ongoing as WHO is also coming up with biosimilar guidelines.

As far as the pharmacopoeial monograph is concerned, Sangitrao says that the USP has already started working on biotech monographs with special emphasis on bioassays, whereas Europe already has biosimilar molecule monographs for key off patent products (GCSF, EPO, IFN-alpha, etc.) So far, the IPC has published four biotech monographs in the Indian Pharmacopoeia in 2007 after consultations from industry as well as academics. "Companies working on biosimilars are confused as to whether they should use the innovator products as the reference standard or the European Pharmacopoeia or NIBSC reference standards. This needs to be clearly addressed," he adds.

Whatever said and done so far, Reddy feels that there have been no concrete efforts on the issue of biological standards. Though there have been revisions in the Indian Pharmacopeia for certain biotech products and vaccines, a lot is yet needed in this field.

Do we need a 'biopharmacopoeia'?

"Success is not important here, what is important is experience. The more we do, more will the regulators learn, so will managers and investors and so on" - Dr M K Bhan Secretary, Government of India, Department of Biotechnology

Most of the industry, and to an extent, the regulators, seem to have a unanimous agreement on having a separate rulebook for biologics. Jadhav concurs, "There must be separate regulation/GMP requirements for biologics, as by nature these are different products when compared to pharmaceuticals."

However, some may differ. "IPC, along with NIB will be able to review monographs submitted for inclusion in the Indian Pharmacopeia and advise on matters related to analytical procedures. A biopharmacopoeia is unnecessary since all biologicals are treated as drugs and approved by the DCGI; they must be included in the Indian Pharmacopeia," opines Kumar.

Sangitrao and Reddy both feel that although the pharmacopoeia contains everything and there is no precedence across the globe in this regard, considering that the US, British and European Pharmacopoeia, all have both pharma and biotech products together, it would be ideal to have a biopharmacopoeia for biological products and vaccines separately to address the biologics industry where the emphasis will be on the requirements of a biologics molecule and more details on the required topic will be covered.

As per Jadhav, the Indian Pharmacopoeia publishes standards for most biologicals through its general and product specific monographs. In 2007, the Indian Pharmacopoeia segregated all biological products monographs and published them as a separate section. Although it would be appropriate and logical to publish a biopharmacopoeia separately, this effort would need a separate infrastructure and approval from Government of India. "As of now, the IPC is entrusted with the job of publishing the Indian Pharmacopoeia, which is revised almost every 10 years. A separate biopharmacopoeia may be revised on an annual basis and thus might be able to incorporate the latest developments occurring in the field of biologicals. For doing so, the government needs to establish a separate commission led by eminent people," avers Jadhav.

But till the time that happens, companies are dependent on the product specific monographs published by the Indian Pharmacopoeia. "Since almost 45 percent of the submission data is based on analytics, the monograph will be helpful throughout the development of the biosimilar product," says Sangitrao. But, he also says that the monograph will be beneficial to the industry if it addresses the methods and specifications geared towards regulatory expectations, the monograph specifications should be based on the approved products, there should be one reference standard for both purity tests and bioassays (quality same as the approved product), reference standards should be made available before the monograph is published, methods based on inherent issues and structural issues of molecules should be included, and extensive collaborative analysis should be done prior to the finalisation of the monograph and reference standards. Based on the estimated duration of patents of the innovator product, it would be favourable to publish monograph seven years prior to patent expiry so that the biosimilar companies can start their work at that time, he adds.

Compiling the rule book

There are a few issues that need to be addressed while putting together a biopharmacopoeia. There needs to be an annual revision, which will involve the inclusion of new developments with time, incorporating new methods and specifications. It should also be a representation of the industry and it should harmonise with international/global regulatory requirements for example WHO, EU and USP etc, says Jadhav. Sangitrao agrees to say that each country should not have its individual biopharmacopoeia. If this concept is going to be implemented, it should be ideally under the banner of ICH or some international recognised body. "We do not see any major hurdles in forming a biopharmacopoeia. However, it is up to the policy makers to consider the recommendations, finalise and go ahead," he says.

Reddy believes that it is very important to emphasise certain issues which are critical in biologicals and vaccines, such as the physicochemical characterisation of the product, assays for biological activity and standardisation, and batch testing and release parameters.

Sangitrao lists his specific expectations from the biopharmacopoeia, "The main issues the industry faces currently is the availability of appropriate reference standards. They are either not available or available in limited amounts.” The limits given in monographs are much wider than the actual quality of the pharmacopoeial standard. The data are not published from the collaborative multi lab analysis in all cases before finalisation of the monograph." The biopharmacopoeia should have general chapters on methods for cell bank characterisation, product characterisation, structural characterisation for product/process comparability and extent of structural studies needed, glycan characterisation immunogenecity and stability indicating methods as well as specifications. The biopharmacopoeia also should consider reducing requirements of redevelopment, revalidation, reducing the repetition of method comparability and the development cost, ensuring same quality of drug to patients, the ease of regulatory agency review in quality section, and speed to market. It would be ideal to have a global monograph, global reference standards and establishment of an International Central Testing laboratory for biosimilar testing and characterisation.

All said and done, Bhan says that issues regarding biologics will be many, but from a regulator's point of view, the top priority would be the nomenclature of these products, and the minimum characterisation standards as provisions. "The point is, does a company today know, specifically, what information they need about biologicals in its dossier—the basic protocol. The difficulty with the situation is that when a company comes to the RCGM it has to 'imagine' what the regulator wants, based on what they hear. And then, it is quite possible the committee might reject them or tell them their documents are incomplete or invalid. The second issue is how much clinical evaluation should be done. In addition, we also have to know in what way the clinical evaluation of follow-on products is different from that of biogenerics," he says.

According to Tripathi the first rough draft of the RCGM and sub-committee decision regarding the protocols and standard procedures for biologics will be ready by the end of June or July this year. "We will go through it and study it in detail. We will try to disseminate the information as widely as possible by maybe holding regional workshops for the benefit of the industry," he says.

While the regulations are in the process of being drafted, the Indian Government needs to protect the interests of these companies. Past efforts include the Small Business Innovation Research Initiative (SBIRI) which supports the high-risk pre-proof-of-concept research and late stage development in small and medium companies lead by innovators. The Biotechnology Industry Partnership Programme (BIPP) was then launched in November 2008. SBIRI has a loan limit from Rs 50 lakh to Rs 10 crore, whereas BIPP aims at much larger projects of higher costs with a mission of IP generation in India.

And miles to go…

Before one starts to regulate biologics based on all the discussed issues, one has to first establish their meaning, come up with a uniform system. Nomenclature and other provisions come much later. And most importantly there needs to be a consensus on who is going to control and enforce these regulation. "So many products are in the pipeline, and a new problem arises every time there is a new product coming. As of now there are 20 products in the market recommended by the RCGM and the DCGI. Each product, except one or two that are either being imported or marketed, is produced here by at least six companies. So, I must say that the process of regulation is not static, but dynamic," says Tripathi. Reddy agrees, "Let us not hunt for loopholes at this moment because there is always scope for improvement. The present policy is not at its ultimate best right now, but will be later. More than that, it is not enough to just have a policy; it should be implemented in good spirit as well."

Bhan avers that everyone is concerned about this issue and is wondering where and how can it be fine tuned, which is why he is for the idea that there should be a separate rule book for biologicals. "Obviously, experience will teach you how correct that is. I would say that this is a period of learning. Success is not important here, what is important is experience. The more we do, more will the regulators learn, so will managers and investors and so on. Who is going to decide how to deal with biologicals unless you create the people who are engaged? Experience is built by doing, and doing teaches you how to regulate well in many ways," he concludes.

aashrutikak@expressindia.com