An expert of the Chinese Pharmacopoeia Commission (hereinafter referred to as "ChPC") once vividly said that a reference listed drug may need glass to be used as an excipient, but we don't have glass, and can only manage to use a material similar to glass as the excipient. "A product fabricated through imitation will be quite different from the reference listed drug in terms of clinical effect," the expert said.

    The Circular on Study on the Quality Consistency Appraisal Proposal of Generic Drugs in 2013 issued by the China Food and Drug Administration (hereinafter referred to as the "CFDA") in 2013 specifies that a quality comparison shall be made between the first batch of 75 generic drugs and the reference listed drugs of multinational pharmaceutical enterprises, and the results shall all be reported by September 30. The Circular probably will eventually solve the quality consistency problem between generic drugs of our country and reference listed drugs.

    Before, the quality difference between foreign reference listed drugs and local generic drugs has long been criticized, and such difference, to a great extent, is caused by the quality difference between excipients used in foreign and local drugs.

    Nevertheless, no sufficient importance has been attached to excipients in the research and manufacturing of drugs in our country.

    An expert of the ChPC who did not want to be named said: "Peasant workers have done the most important work of cities, but are not recognized and even discriminated. Excipients are like the 'peasant workers' in drugs." The negligence on the "peasant workers" in drugs largely caused the event of "excessive chromium capsules", the fake Armillarisni A injection event of Qiqihar No.2 Pharmaceutical Co., Ltd. and other events.

    Why has insufficient importance been attached to pharmaceutical excipients in our country for so many years? Has the "peasant worker" treatment of excipients been improved?

    At least for now, the answers to these questions are hardly optimistic.

Difference in quality

    Clinic feedbacks have indicated that the therapeutic effect of taking foreign original Lansoprazole enteric-coated tablets was different from that of taking the relevant local generic drug.

    The difference has come to the attention of Jin Shaohong, a researcher of the National Institutes for Food and Drug Control.

    Lansoprazole is a poorly water soluble drug, and the key of its oral preparation is bioavailability, so improving the dissolution rate of the preparation is the key of manufacturing process. Jin Shaohong has conducted tests on and analysis of the reference listed drugs and the generic drugs.

    The results indicated that the dissolution rate of the product of the foreign reference listed drug manufacturer and some good local generic drugs averagely reached 80% or above in 20 minutes in pH6.8 buffer solution.

    However, although the dissolution rate of some other generic drugs reached 75% of the labeled amount in 45 minutes, the dissolution was almost zero in the first 15 minutes, which could have caused the clinic therapeutic difference.

    Actually, the Lansoprazole enteric-coated tablet is not a single case, and the therapeutic effect of many local generic drugs is not as good as reference listed drugs.

    The difference between generic drugs and reference listed drugs is due to many reasons, and one of the major impact factors is different excipients used by generic drugs and reference listed drugs.

    An expert of the ChPC once vividly said that a reference listed drug may need glass to be used as an excipient, but we don't have glass, and can only manage to use a material similar to glass as the excipient.

    "A product fabricated through imitation will be quite different from the reference listed drug in terms of clinical effect," the expert said.

Insufficient importance attached to research

    In 2006, due to serious adverse reactions such as anaphylactic shock, systemic anaphylactic reaction, dyspnea as well as death cases, the use and approval of cordate houttuynia injections were required to stop. This is another iconic event happening in the pharmaceutical industry. The case reflects the reality that we shall take the research on excipients seriously.

    Actually, cordate houttuynia per se does not cause any anaphylactic reaction, but will have a positive reaction as soon as being added with 1% cosolvent polysorbate 80. It will not react with other cosolvents.

    Experiments have proved that the main cause of adverse clinic reactions of cordate houttuynia is the random use of polysorbate 80.

    The analysis of 19 lots of cordate houttuynia injections from nine manufacturers indicated that the contents of excipient, polysorbate 80, used by them were 0.07% and 0.59% respectively, as many as eight times different. "It's an indication that some manufacturers are random in adding polysorbate 80," Jin Shaohong said.

    It is learnt that the composition of the excipients of some drugs is more complicated than the raw materials, while medicine enterprises carry out only simple and rough tests over excipients.

    Gan Yong, a researcher of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, thought that excipients are generally high polymer materials, have certain molecular weight distribution, and are not of singular ingredient. Therefore, it is difficult to make tests with a simple content index, and excipients under the same name may be quite different in the products of different manufacturers.

    "At present, the current domestic test standards for excipients are generally simple. For example, starch, a common excipient, is tested per the current pharmacopeia standard, but testing organizations can only determine the substance is starch, and cannot test the fine property parameters of starch, including molecular weight distribution, which may actually remarkably influence the quality of drugs," Gan Yong said.

    According to the introduction by Gan Yong, when choosing a plant of an excipient, foreign drug manufacturers will generally propose the specific internal control requirements on molecular weight, particle size, and other particulars, and these internal control standards are generally the key to the stable quality of drugs.

Domestic drug manufacturers lack the corresponding excipient research and internal control standards.

    The reason why foreign drug manufactures attach so much importance to the research of excipients is because there may be one or several kinds of certain impurities in some excipients. Impurities per se may produce uncertain pharmacological effect under the application environment, and hence bring potential hazards to the safety of products. Meanwhile, chemical reactions may happen among impurities to produce new uncertain impurities, which will further react with the drugs or impurities, intensifying the potential hazards to the safety of products.

    Therefore, Jin Shaohong emphasized that though pharmaceutical excipients play a supporting role in drugs, they are as important as raw materials. The same importance shall be attached to the research of excipients as the research of raw materials and the interaction between raw materials and excipients shall be studied as well, which have proposed new requirements on the drug testing and research and development capabilities of manufacturers.

    "Chinese drug manufacturers have always been imitating drugs for the sake of imitation, making things too simple. Taking shortcuts in preparation research and merely pursuing similarity in form have resulted in great difference in therapeutic effect," Jin Shaohong said. Manufacturers have not exerted their efforts on the selection of excipients and preparation processes, and this condition must be changed.

    Fortunately, the CFDA has gradually issued since 2011 relevant policies on various kinds of pharmaceutical excipients, which are more stringent year by year.

    The Provisions on Enhancing the Supervision and Administration of Pharmaceutical Excipients formally implemented on February 1, 2013 emphasize that the manufacturers of pharmaceutical excipients must implement the GMP standard for pharmaceutical excipients. The 12th Five-year Plan for Pharmaceutical Industry includes pharmaceutical excipients in the five major development fields for the first time.

Difficulty in policy promotion

    Since the beginning of this year, Li Jianxin has felt a lot of pressure.

    As a research and development staff member of Shandong Lukang Pharmaceutical Co., Ltd, he has been devoting himself to the research and development of drugs since 1982, and hasn't lost interests in the work ever since.

    However in this year, his pressure - and also the common pressure of drug manufacturers - comes from the great impact that may be brought by a new policy.

    At the end of last year, the Proposal on the Quality Consistency Appraisal of Generic Drugs (Draft for Comment) was issued. It is mentioned in the Proposal that, as a result of relatively weak fundamental pharmacy research on generic drugs, some generic drugs are considerably inferior to their reference listed drugs in quality, and cannot achieve the same clinic therapeutic effect as the reference listed drugs. The 12th Five-year Plan for National Drug Safety clearly requires that a comprehensive comparative study of generic drugs which have been approved for marketing before the implementation of the Administrative Measures for Drug Registration revised in 2007 and the reference listed drugs shall be conducted in five to ten years by phase and by batch, to have them be consistent with each other.

    Professor Zhou Jianping, Chief of the Specialized Preparation Committee of the ChPC said that eliminating drugs of poor quality from the market to improve the overall quality level of drugs in China is the starting point of consistency appraisal. For enterprises, the consistency appraisal is a "sweet burden".

    In theory, generic drugs will, if being close or identical to reference listed drugs in therapeutic effect, be better recognized by the market. However, appraisal per se is like re-research and -development to manufacturers, requiring large amounts of resources. "The difference in excipients has certain impact on the therapeutic effect. If a drug is to be compared with the reference listed drug, a good excipient must be chosen during product research and development, and the quality consistency can only be ensured if the generic drug is identical to the foreign reference listed drug," Li Jianxin said.

    Therefore, though Yin Liming, Minister of the CFDA, clearly put forward the work target of consistency appraisal of generic drugs at the working conference of national food and drug supervision held at the year beginning, no drug has passed the consistency appraisal by now, the second half of the year.

Hidden risk of low price

    There are other reasons why manufacturers take a wait-and-see attitude on the consistency appraisal.

    On May 17, the Guangdong Provincial Leading Group Office for Centralized Drug Procurement issued the Circular on Seeking Comments on the Revision of Rules of Guangdong Province for Drug Transactions (Draft for Comment). The provision of "Proposals with the lowest bid price shall win the bidding, where the quality proposal and the commercial proposal shall respectively account for 10 points and 90 points" has stirred intense objection.

    Some insiders believed valuing more on price than quality in the new Rules will cause drug manufacturers to drain the pond to get all the fish - they would, after winning the bidding, refuse to supply the products because the price is too low and they cannot afford the loss, or cheat on workmanship and materials, in which case excipients that have not been attached with sufficient importance at first could be subject to more potential risks.

    "At present, pricing and tendering of drugs take production cost into consideration only, and this is not scientific," Jin Shaohong thought. In pricing a drug at a foreign country, the real production cost may not be high, and the sales price is hundreds of times higher than the cost due to the research and development cost and the possession of patent.

    Furthermore, the consistency appraisal on new generic drugs and those available on the market both requires drug manufacturers to collect raw materials and excipients of local famous plants for preliminary study. "With the permutation and combination of different raw materials and excipients, the development period would be lengthened from three years to five years, so the cost becomes higher naturally," Li Jianxin said.

    The continuous lowering of drug price in the face of increasingly higher cost will certainly aggravate the phenomenon of cheating on workmanship and materials. Excipients will be the first to be affected. The occurrence of the fake Armillarisni A injection event of Qiqihar No.2 Pharmaceutical Co., Ltd. was because of the excessive profit compression to a certain degree.

Innovation impeded by strict supervision

    Compared with drug manufacturers, research institutions also have a lot of depressing matters.

    Recently, Gan Yong's research group has been studying on a new drug type, and has been forced to retrace their steps, resulting in redoing almost half of the research and development work that has been done.

    It is because the bioavailability of the new drug is very poor by oral admission, and the research group needs to use an excipient available in foreign markets to improve the bioavailability.

"Relevant supervision is very strict, especially for injections. If the import permit for the excipient used is not obtained, the product would not be approved for a launch in the market, even if it is an advanced high-end preparation," Gan Yong said.

    So, the problem emerges.

    The research has been completed, and the clinical research is going to take place, but the excipient permit has not been issued.

    "The preliminary effect of research and development was very good, but a new prescription has to be developed now," Gan Yong said. "Because the class 1 new drug compound patent has been applied for this drug, and the patent protection is valid for 20 years only, the loss would be high if we take time to wait for the excipient permit."

    In the meantime, if the excipient is to be changed, a minimum of another eight months will be required for the re-research.

    "The State applies excessively strict supervision on excipients, especially the imported excipients. The excipient filing system shall be implemented at the earliest time possible," Gan Yong said.

    It is learnt that in the United States, all "substances recognized as being safe" can be used as pharmaceutical excipients.

    Only 132 pharmaceutical excipients are specified in the pharmacopeia of our country, while the types of pharmaceutical excipients in the world are more than 1,200 in 2011.

In foreign countries, while new excipients are developed, close attention is also paid to the research of excipient recipe and its application, so not only the main excipient is promoted, other excipients in the recipe are also promoted and applied in the meantime, and the optimal compound excipients, such as avicel series (containing microcrystalline cellulose and carboxymethlcellulose of different proportions) and suppeiye series (compound suppository ground substance), are found in combination with the actual production.

    "New processes and excipients could be completely used in our present imitation, but excessive restrictions are imposed by the State," Zhou Jianping believed. This would strangle innovation.

(Source: Wechat public account of E Drug Manager)

【Comments】

Mary Y. Zhang: The Circular on Study on the Quality Consistency Appraisal Proposal of Generic Drugs in 2013 (hereinafter referred to as the "Circular") issued by the China Food and Drug Administration in 2013 specifies that the first batch of 75 generic drugs shall be compared with the reference listed drugs of multinational pharmaceutical enterprises in quality, to eventually solve the quality consistency problem between generic drugs of our country and reference listed drugs that has always been existing.

    As everyone knows, there is quality difference existing between foreign reference listed drugs and local generic drugs, and such difference, to a great extent, is caused by the quality difference between excipients used in foreign and local drugs.

    To accomplish the tasks specified in the Circular, local generic drug manufacturers may take different countermeasures due to their different understanding of the tasks. Specifically, two kinds of diametrically opposite countermeasures may be taken:

    (1) one kind of manufacturers will regard the tasks as compulsive tasks, and do it passively and for the sake of fulfillment only;
    (2) the other kind of manufacturers will regard the tasks as an opportunity and challenge, and try to fundamentally improve the pharmaceutical excipient quality of their generic drugs while fulfilling the tasks specified in the Circular, thus to eventually solve the existing problems of insufficient research and development effort for and poor quality of pharmaceutical excipients.

    I would like to take this opportunity to warn the generic drug manufacturers that only by adequately realizing their existing problems and investing reasonable research and development funds, human resources and materials can they improve their research and development ability. During this course, generic drug manufacturers can even propose new technical schemes for the newly researched and developed pharmaceutical excipients while fulfilling the tasks, and according to different circumstances, apply patent protection or know-how protection for the new technical schemes they propose.

    Moreover, generic drug manufacturers can even develop new dosage forms during the course, or research polymorphs with new active ingredients, thus to solve the problems in stability, bioavailability, or other aspects of active ingredients, for which, generic drug manufacturers can also apply for patent protection to form a patent pool, to contend against the patent siege of the reference listed drug manufacturers, or even form patent complementation with the reference listed drug manufacturers to provide conditions and chips for cross patent permit with the reference listed drug manufacturers.

    Meanwhile, generic drug manufacturers are suggested to establish a strict internal control standard during the course, especially for the control of fine property parameters of excipients, such as molecular weight and particle size, thus to realize the control over quality consistency of drugs.

    In short, the earlier generic drug manufacturers engage in the research and development and quality control of pharmaceutical excipients, the earlier they can promote their competitive strength to realize the improvement from a generic drug manufacturer to a reference listed drug manufacturer and build the confidence of the entire society and patients in local generic drug manufacturers.