discussion on solutions for the problem that clarity of part cefradine preparations is out of limits and enhance control of quality risks in production of rubber stoppers
meeting minutes on symposium of part rubber stopper manufacturers held by cnppa
date: sep 29, 2008
place: guo er zhao hotel, beijing
assessment on impacts to drug quality caused by change of formula of rubber stopper.
invite some experts and leaders on drug safety & quality to discuss solutions for clarity (turbidity) of ceclor preparations out of limit in validity.
strengthen consciousness of manufacturers of rubber stopper against of quality risks
lanling, hubei huaqiang, jiangsu shengzhou, jiangsu bosheng, aoxing, shijiazhuang xiangyi, anhui huafeng, hebei songshan and zhejiang jintai.
director hu changqin and director yang from national institute for the control of pharmaceutical and biological products
mr. jia and mr. feng guoping from registration authorities of sfda
mr. ji wei from shanghai food and drug packaging material control center
dong xiaofei, journalist from economic news section of china pharmaceutical news
this symposium was presided by secretary of cnppa.
hu changqin, the director of national institute for the control of pharmaceutical and biological products circulated a notice on test of ceclor preparation in recent phase:
early in 2005, national institute for the control of pharmaceutical and biological products found turbidity was out of limits at a large proportion during sampling test of cephazolin sodium. at that moment, pharmaceutical butyl rubber stopper just took off (use butyl rubber stopper to substitute natural rubber stopper), it was unable to change rubber stopper, so pharmaceutical enterprise accelerated circulation and hospital used such cephazolin sodium out in 6 months. in this case, national institute for the control of pharmaceutical and biological products can't list ceclor preparations as objects for sampling inspection. so contradict and drug safety problem didn't emerge.
in recent years, defective rate of clarity of cephazolin sodium is 17－20％. since 2005, over 100 tests were conducted to ceclor preparations, which proved incompatibility between butyl rubber stopper and cephazolin sodium was mainly caused by bht.
it is reported by the adverse drug reaction monitoring center that death cases caused by cephazolin sodium used in clinic are over 170 (period not specified), which was 5 times more than cefoperazone and cefotaxime sodium.
deaths were caused by anaphylactic reaction, then does butyl rubber stopper has any relation to this?
in this case, animal test was carried out. make cephazolin sodium with turbidity of up to 3# high speed centrifugation, at this moment, drug of top half in test tube was clear, while the lower half was turbid, then inject them into animals respectively. the test results showed turbid drug had strong feature to cause anaphylactic reaction. so, butyl rubber stopper might have some relations with the adverse reaction.
pharmaceutical enterprises were full of complaints about this matter: on one hand, butyl rubber stoppers were less for their selection; on the other hand, even if test was completed at that moment, but manufacturer of rubber stoppers changed their formula once way, "they were always changing", this was a problem that many domestic pharmaceutical enterprises reflected. hu changqin hoped manufacturers of rubber stoppers could give some quantitative indexes to prove uniformity of their products.
director yang of national institute for the control of pharmaceutical and biological products:
results of sampling inspection of ceclor preparations in 2008 was severe, over 50% manufacturers appeared defects. we think some factor with larger influence surface played a key role. it is undesirable for manufacturers of rubber stoppers to produce at low cost and low price. any formula change shall supplement proper procedures otherwise it may be dangerous.
representative of manufacturers of rubber stoppers said:
now, manufacturers of halogenated butyl rubber don't use bht any more. due to high saturation level of halogenated butyl rubber stopper, there is no need for all manufacturers of rubber stoppers to add aging resister or antioxidant, so bht will never appear in butyl rubber stopper.
silicon oil will affect water-solubility of antibiotics, as low polymer, will it affect stability of ceclor preparations? in addition to manufacturers of rubber stoppers, pharmaceutical enterprises often add silicon oil to make rubber stopper suitable for filling machine production and nonuniformity of the silicon oil exists universally.
all enterprises on this symposium condemned vicious competition at low cost and low price, "for rubber rated at rmb100000/ton, how can φ13 rubber stopper be sold at rmb0.05~0.06 (φ20 rubber stopper at rmb0.08)?" in deed, some enterprises lack of sense of responsibilities added epdm, br in pharmaceutical rubber stopper for distribution at a lower price as epdm and br are sold at rmb24000/ton at most.
hu changqin, the director of national institute for the control of pharmaceutical and biological products continued: everyone thinks your own rubber stopper is suitable for ceclor preparations, then now, are all problems caused by cheap rubber stopper?
representative of lanling company introduced:
since 2001, for solutions for turbidity problem of ceclor preparations, lanling company doesn't take ordinary measures to adjust formula but implements shielding extractions: one is pet film and the other is teflon film, both of which are the origin of technology of compound film.
opinion of mr. ji wei from shanghai food and drug packaging material control center:
he introduced test status of 6 months' ceclor preparation samples produced by main manufacturers of butyl rubber stoppers stored under ambient temperature for 10 months after compatibility test. bht was found in ceclor preparation samples with eligible clarity, including ceftriaxone sodium.
supplementary opinions of hu changqin, the director of national institute for the control of pharmaceutical and biological products:
we've held several special meetings, are there solutions for clarity problem of ceclor preparations? it is proved by the completed test that compound film rubber stopper can absolutely make it. in case price is a problem, then ndrc will consider. but, it is not this problem, as we all know market price of drugs has a great gap with approved price.
now, sfda has expressly given a two-month buffer period. in the two months, all manufacturers shall conduct self-check, including products called back due to turbidity out of limits. any manufacturer which actively call back defective product, sfda will not punish it. but after the two months, sfda will increase supervisory strength, turbidity must comply with standard.
next, sfda will require pharmaceutical enterprise to register in case it changes manufacturer of rubber stopper.
in order to make pharmaceutical enterprise have a diagnostic approach to the test, mr. hu changqin gave a fast test condition, which is suitable for ceftriaxone sodium, results were easily found: 60℃*5 days/inversion.
opinions of supervisor feng guoping:
seeing from sampling results, the problem is severe. among all adverse reactions of drugs, anaphylactic reaction is the fastest, and now intravenous administration are mostly done with basic transfusion, so chance of anaphylactic reaction will increase.
national institute for the control of pharmaceutical and biological products wants to test compatibility of imported ceclor preparations. can they well complete such test in case the drug validity is coming?
manufacturers of rubber stopper and drugs shall enhance communications and exchange, manufacturer of rubber stopper shall well do uniformity between batches, which is the pharmaceutical enterprise concerned most. manufacturer of rubber stopper shall submit some data and indexes to explain.
cnppa shall take the lead to make out standards for rubber materials.
compatibility of drugs is not a new problem. manufacturer of rubber stopper won't produce too many formulas, no less than 20. supervisory authorities shall propose strict requirements to pharmaceutical enterprise, never pursue the said rubber stopper at low price. now, the problem that drug price can't go on doesn't exists, don't make things confused.
in case origin of rubber changes, supplement application. for technical approval, registration authority can try to accelerate. auxiliary materials and additives can be listed in the application with a certain proportion range, which shall solve actual problem.
cnppa still have another things to do: first, ask rubber stopper manufacturer to fix a cost price, regular fix and publish in month or quarter for reference of pharmaceutical enterprises when procurement; second, supervisory authorities shall take proper measures; third, report to department of industry and commerce and commerce department to solve problem from repression of untair competition in order to build industry regulations, anyone who violates such regulations will be exposed.
we suggest stop approval of newly built enterprises as newly built projects of butyl rubber stopper has been listed as restricted by the state.
cnppa collected the content on this symposium and published in the form of meeting minutes.
lanling understood and suggested:
1. related authorities had specified that ceclor preparations must arrive at standards within the validity. but it was said that not all of products tested recently were near the time limit, so it was strict if actual situation of clarity out of limit was measured by time scale.
2. it was introduced by an international pharmaceutical enterprise which has significant influence worldwide, all of test items must achieve standards within the validity, that was to say, including the last day of the validity. emergency treatment included call-back and publishing to the society, which were moral responsibility of drug manufacturers.
3. sfda published a notice on "release general technical requirements for chemical drugs and multicomponent biological drugs for injections (sfda registration  no. 7)" in which validity of injection preparations were specified: validity of injection preparations should depend on results of long-term tests. the specified validity could not out of a final point-in-time within the limit as per quality standards.
prime minister emphasized again and again when visiting children involved in "then sanlu scandle" that in no case we should give up health and life of human beings to gain corporate benefits and economic development but insist on public drug safety and keep public health superior.
5. however, still a part of pharmaceuticals were not clear about time limit of safety and effectiveness of drugs in validity, they thought my products were ok in delivery inspection or in a short time, such consciousness to quality risk was so inactive. for the high-risk industry that we were engaged in, the consciousness of "it is always wise to play safe" must be built (as risk of our products was so high and results were different after taking responsibilities), it didn't matter in case no problem, but once any problem appeared, we couldn't imagine what consequence would be, which was approved by "qieryao event", "fuyang huayuan" and "the sanlu scandle".
6. strong consciousness of quality risk had direct relations with corporate legal representative as well as levels of importance, methods & pattens. in view of safety danger caused by turbidity (clarity) out of limits in the past 5 years, there was no deep study or complete, objective and masterful assessments or government and supervisory authorities didn't punish them. this symposium had proposed such problem. lanling was obliged to warn pharmaceutical enterprises to report known things or offer an basis at least.
member of hualan group -- jiangyin lanling bottle stopper co., ltd