Friday, November 30, 2018

Chinese heparin maker banned by EMA over contamination risks

Chinese heparin maker banned by EMA over contamination risks

by Eric Palmer | Nov 29, 2018 10:44am

China has been a source of tainted crude heparin. (Pixabay)

World regulators are cautious about crude heparin after China-made APIs were responsible for dozens of deaths in the U.S. more than a decade ago. Now, European regulators are banning heparin from a Chinese facility after finding contamination risks. 

Italian inspectors recommended the European Medicines Agency pull the manufacturing approval for and ban the heparin from Yibin Lihao Bio-technology after they found significant issues at its facility in Yibin, Sichuan, China, during an October inspection. 

There are few details in the report the EMA posted to its EudraGMDP site, but it said investigators found two dozen violations, seven of them major, at the maker of crude heparin, an anticoagulant. Those included risk of contamination, unsatisfactory traceability of starting material, poor materials management and recovery of solvents as well as issues with buildings, facilities, equipment and storage. 

RELATED: Congressional investigation says tainted Chinese heparin may still be in U.S.

***> Two years ago, French regulators recalled heparin after finding Chinese company Dongying Tiandong Pharmaceutical in Shandong province had manipulated tests of crude heparin supplies that had showed the presence of ruminant DNA. It said there was no evidence that the samples used to perform retesting came from the same batches that showed the ruminant.

**** GMP rules require heparin be manufactured only from pig intestines, because when "ruminant" animals like cattle are used there is a chance the raw material could be contaminated with bovine spongiform encephalopathy or oversulfated chondroitin sulfate (OSCS), a cheap filler product that saves money but can be deadly to patients. In 2008, heparin contaminated with OSCS was tied to the deaths of 80 dialysis patients in the U.S.


***> Two years ago, French regulators recalled heparin after finding Chinese company Dongying Tiandong Pharmaceutical in Shandong province had manipulated tests of crude heparin supplies that had showed the presence of ruminant DNA. It said there was no evidence that the samples used to perform retesting came from the same batches that showed the ruminant.

***> GMP rules require heparin be manufactured only from pig intestines, because when "ruminant" animals like cattle are used there is a chance the raw material could be contaminated with bovine spongiform encephalopathy or oversulfated chondroitin sulfate (OSCS), a cheap filler product that saves money but can be deadly to patients. In 2008, heparin contaminated with OSCS was tied to the deaths of 80 dialysis patients in the U.S.

WEDNESDAY, JANUARY 28, 2015 

BOVINE HEPARIN POSITION STATEMENT ON THE REINTRODUCTION and POTENTIAL BSE TSE PRION RISK FACTORS THEREFROM


Monday, October 31, 2011 

Getting the Farm Out of Pharma for Heparin Production 


TUESDAY, AUGUST 1, 2017 

BSE INQUIRY DFA 17 Medicines and medical devices


TUESDAY, AUGUST 1, 2017 

Could diabetes spread like mad cow disease?


TUESDAY, AUGUST 1, 2017 

Could Insulin be contaminated with and potentially spread, Transmissible Spongiform Encephalopathy TSE Prion, what if?


FRIDAY, JUNE 29, 2018

Vaccines, TSE, Prion, risk factors? European Medicines Agency 

Science Medicines Health

25 January 2018


WEDNESDAY, JULY 11, 2018 

CONFIDENTIAL IN CONFIDENCE SPONGIFORM ENCEPHALOPATHY OF PIGS FDA EMERGENCY REQUEST FOR RULE CHANGE USA Section 21 C.F.R. 589.2000


TUESDAY, JULY 10, 2018 CONFIDENTIAL IN CONFIDENCE SPONGIFORM ENCEPHALOPATHY OF PIGS *** 

''but feeding of other ruminant protein, including scrapie-infected sheep, can continue to pigs.'' 

CONFIDENTIAL 

SPONGIFORM ENCEPHALOPATHY OF PIGS 


MONDAY, NOVEMBER 26, 2018 

***> The agent of chronic wasting disease from pigs is infectious in transgenic mice expressing human PRNP


***> Cervid to human prion transmission 5R01NS088604-04 Update

National Institute of Health (NIH)



MONDAY, NOVEMBER 26, 2018 

***> The agent of chronic wasting disease from pigs is infectious in transgenic mice expressing human PRNP


cwd scrapie pigs oral routes

***> However, at 51 months of incubation or greater, 5 animals were positive by one or more diagnostic methods. Furthermore, positive bioassay results were obtained from all inoculated groups (oral and intracranial; market weight and end of study) suggesting that swine are potential hosts for the agent of scrapie. <*** 

 >*** Although the current U.S. feed ban is based on keeping tissues from TSE infected cattle from contaminating animal feed, swine rations in the U.S. could contain animal derived components including materials from scrapie infected sheep and goats. These results indicating the susceptibility of pigs to sheep scrapie, coupled with the limitations of the current feed ban, indicates that a revision of the feed ban may be necessary to protect swine production and potentially human health. <*** 


***> Results: PrPSc was not detected by EIA and IHC in any RPLNs. All tonsils and MLNs were negative by IHC, though the MLN from one pig in the oral <6 5="" 6="" at="" by="" detected="" eia.="" examined="" group="" in="" intracranial="" least="" lymphoid="" month="" months="" of="" one="" pigs="" positive="" prpsc="" quic="" the="" tissues="" was="">6 months group, 5/6 pigs in the oral <6 4="" and="" group="" months="" oral="">6 months group. Overall, the MLN was positive in 14/19 (74%) of samples examined, the RPLN in 8/18 (44%), and the tonsil in 10/25 (40%). 

***> Conclusions: This study demonstrates that PrPSc accumulates in lymphoid tissues from pigs challenged intracranially or orally with the CWD agent, and can be detected as early as 4 months after challenge. CWD-infected pigs rarely develop clinical disease and if they do, they do so after a long incubation period. 

This raises the possibility that CWD-infected pigs could shed prions into their environment long before they develop clinical disease. 

Furthermore, lymphoid tissues from CWD-infected pigs could present a potential source of CWD infectivity in the animal and human food chains. 





***>This raises the possibility that CWD-infected pigs could shed prions into their environment long before they develop clinical disease. Furthermore, lymphoid tissues from CWD-infected pigs could present a potential source of CWD infectivity in the animal and human food chains.<*** 

CONFIDENTIAL EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY 

While this clearly is a cause for concern we should not jump to the conclusion that this means that pigs will necessarily be infected by bone and meat meal fed by the oral route as is the case with cattle. ... 


we cannot rule out the possibility that unrecognised subclinical spongiform encephalopathy could be present in British pigs though there is no evidence for this: only with parenteral/implantable pharmaceuticals/devices is the theoretical risk to humans of sufficient concern to consider any action. 


***> CONFIDENTIAL SPONGIFORM ENCEPHALOPATH IN PIGS

May I, at the outset, reiterate that we should avoid dissemination of papers relating to this experimental finding to prevent premature release of the information. ... http://web.archive.org/web/20030822052332/www.bseinquiry.gov.uk/files/yb/1990/09/11005001.pdf

3. It is particularly important that this information is not passed outside the Department, until Ministers have decided how they wish it to be handled. ... 


***> CONFIDENTIAL SPONGIFORM ENCEPHALOPATHY IN PIGS

But it would be easier for us if pharmaceuticals/devices are not directly mentioned at all. ... 


Our records show that while some use is made of porcine materials in medicinal products, the only products which would appear to be in a hypothetically ''higher risk'' area are the adrenocorticotrophic hormone for which the source material comes from outside the United Kingdom, namely America China Sweden France and Germany. The products are manufactured by Ferring and Armour. A further product, ''Zenoderm Corium implant'' manufactured by Ethicon, makes use of porcine skin - which is not considered to be a ''high risk'' tissue, but one of its uses is described in the data sheet as ''in dural replacement''. This product is sourced from the United Kingdom..... 


snip... 

It was not until . . . August 1990, that the result from the pig persuaded both SEAC and us to change our view and to take out of pig rations any residual infectivity that might have arisen from the SBOs. 


4.303 The minutes of the meeting record that: It was very difficult to draw conclusions from one experimental result for what may happen in the field. However it would be prudent to exclude specified bovine offals from the pig diet. Although any relationship between BSE and the finding of a spongiform encephalopathy in cats had yet to be demonstrated, the fact that this had occurred suggested that a cautious view should be taken of those species which might be susceptible. The 'specified offals' of bovines should therefore be excluded from the feed of all species. 17 


IN CONFIENCE EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY 

1. CMO should be aware that a pig inoculated experimentally (ic, iv, and ip) with BSE brain suspension has after 15 months developed an illness, now confirmed as a spongiform encephalopathy. This is the first ever description of such a disease in a pig, although it seems there ar no previous attempts at experimental inoculation with animal material. The Southwood group had thought igs would not be susceptible. Most pigs are slaughtered when a few weeks old but there have been no reports of relevant neurological illness in breeding sows or other elderly pigs. .

...see full text ; 


IN CONFIDENCE 

So it is plausible pigs could be preclinically affected with BSE but since so few are allowed to reach adulthood this has not been recognised through clinical disease. ... 


CONFIDENTIAL 

EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY 

While this clearly is a cause for concern we should not jump to the conclusion that this means that pigs will necessarily be infected by bone and meat meal fed by the oral route as is the case with cattle. ... 


we cannot rule out the possibility that unrecognised subclinical spongiform encephalopathy could be present in British pigs though there is no evidence for this: only with parenteral/implantable pharmaceuticals/devices is the theoretical risk to humans of sufficient concern to consider any action. 


May I, at the outset, reiterate that we should avoid dissemination of papers relating to this experimental finding to prevent premature release of the information. ... 


3. It is particularly important that this information is not passed outside the Department, until Ministers have decided how they wish it to be handled. ... 


But it would be easier for us if pharmaceuticals/devices are not directly mentioned at all. ... 


Our records show that while some use is made of porcine materials in medicinal products, the only products which would appear to be in a hypothetically ''higher risk'' area are the adrenocorticotrophic hormone for which the source material comes from outside the United Kingdom, namely America China Sweden France and Germany. 

The products are manufactured by Ferring and Armour. 

A further product, ''Zenoderm Corium implant'' manufactured by Ethicon, makes use of porcine skin - which is not considered to be a ''high risk'' tissue, but one of its uses is described in the data sheet as ''in dural replacement''. This product is sourced from the United Kingdom..... 


BSE TO PIGS 

NEWS RELEASE 


CONFIDENTIAL 

BSE: PRESS PRESENTATION 






INDUSTRY RESPONSE TYPICAL 


DEFENSIVE BRIEFING 


CONFIDENTIAL pigs & pharmaceuticals 





COMMERCIAL IN CONFIDENCE 

COMMITTEE ON SAFETY OF MEDICINE NOT FOR PUBLICATION BOVINE SPONGIFORM ENCEPHALOPATHY WORKING GROUP 

There are only two products using porcine brain and these use corticotrophin BP, made from porcine pituitary, source from outside the UK............. 


snip... 

7 OF 10 LITTLE PIGGIES WENT ON TO DEVELOP BSE; 

1: J Comp Pathol. 2000 Feb-Apr; 122(2-3): 131-43. Related Articles, The neuropathology of experimental bovine spongiform encephalopathy in the pig. Ryder SJ, Hawkins SA, Dawson M, Wells GA. Veterinary Laboratories Agency Weybridge, Woodham Lane, New Haw, Addlestone, Surrey, KT15 3NB, UK. 

In an experimental study of the transmissibility of BSE to the pig, seven of 10 pigs, infected at 1-2 weeks of age by multiple-route parenteral inoculation with a homogenate of bovine brain from natural BSE cases developed lesions typical of spongiform encephalopathy. 

The lesions consisted principally of severe neuropil vacuolation affecting most areas of the brain, but mainly the forebrain. 

In addition, some vacuolar change was identified in the rostral colliculi and hypothalamic areas of normal control pigs. 

PrP accumulations were detected immunocytochemically in the brains of BSE-infected animals. 

PrP accumulation was sparse in many areas and its density was not obviously related to the degree of vacuolation. 

The patterns of PrP immunolabelling in control pigs differed strikingly from those in the infected animals. 

PMID: 10684682 [PubMed - indexed for MEDLINE] 


snip... 

In the United States, feeding of ruminant by-products to ruminants is prohibited, but feeding of ruminant materials to swine and poultry still occurs. The potential for swine to have access to scrapie-contaminated feedstuffs exists, but the potential for swine to serve as a host for replication/accumulation of the agent of scrapie is unknown. The purpose of this study was to perform oral and intracerebral inoculation of the U.S. scrapie agent to determine the potential of swine as a host for the scrapie agent and their clinical susceptibility. see full text and more transmission studies here ; http://chronic-wasting-disease.blogspot.com/2011/07/swine-are-susceptible-to-chronic.html Transgenic mice expressing porcine prion protein resistant to classical scrapie but susceptible to sheep bovine spongiform encephalopathy and atypical scrapie. 

Emerg Infect Dis. 2009 Aug; [Epub ahead of print] 



PRION CONFERENCE 2018

O3 Experimental studies on prion transmission barrier and TSE pathogenesis in large animals 

Rosa Bolea(1), Acín C(1)Marín B(1), Hedman C(1), Raksa H(1), Barrio T(1), Otero A(1), LópezPérez O(1), Monleón E(1),Martín-Burriel(1), Monzón M(1), Garza MC(1), Filali H(1),Pitarch JL(1), Garcés M(1), Betancor M(1), GuijarroIM(1), GarcíaM(1), Moreno B(1),Vargas A(1), Vidal E(2), Pumarola M(2), Castilla J(3), Andréoletti O(4), Espinosa JC(5), Torres JM(5), Badiola JJ(1). 

1Centro de Investigación en Encefalopatías y Enfermedades Transmisibles Emergentes, VeterinaryFaculty, Universidad de Zaragoza; Zaragoza,Spain.2 RTA, Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB) 3 4 INRA, ÉcoleVétérinaire, Toulouse, France.5CIC bioGUNE, Prion researchlab, Derio, Spain CISA- INIA, Valdeolmos, Madrid 28130, Spain. 

Experimental transmission of Transmissible Spongiform Encephalopathies (TSE) has been understood and related with several factors that could modify the natural development of these diseases. In fact, the behaviour of the natural disease does not match exactly in each animal, being modified by parameters such as the age at infection, the genotype, the breed or the causative strain. Moreover, different TSE strains can target different animal species or tissues, what complicate the prediction of its transmissibility when is tested in a different species of the origin source. The aim of the experimental studies in large animals is to homogenize all those factors, trying to minimize as much as possible variations between individuals. These effects can be flattened by experimental transmission in mice, in which a specific strain can be selected after several passages. With this objective, several experimental studies in large animals have been developed by the presenter research team. 

Classical scrapie agent has been inoculated in cow, with the aim of demonstrate the resistance or susceptibility of this species to the first well known TSE; Atypical scrapie has been inoculated in sheep (using several routes of infection), cow and pig, with the objective of evaluating the potential pathogenicity of this strain; Classical Bovine Spongiform Encephalopathy (BSE) has been inoculated in goats aiming to demonstrate if the genetic background of this species could protect against this strain; goat BSE and sheep BSE have been inoculated in goats and pigs respectively to evaluate the effect of species barrier; and finally atypical BSE has been inoculated in cattle to assess the transmissibility properties of this newly introduced strain. 

Once the experiments have been carried out on large animal species, a collection of samples from animals studied were inoculated in different types of tg mice overexpressing PrPcin order to study the infectivity of the tissues, and also were studied using PMCA. 

In summary, the parameters that have been controlled are the species, the strain, the route of inoculation, the time at infection, the genotype, the age, and the environmental conditions. 

To date, 

***> eleven of the atypical scrapie intracerebrally inoculated sheep have succumbed to atypical scrapie disease; 

***> six pigs to sheep BSE; 

***> one cow to classical scrapie; 

***> nine goats to goat BSE and 

***> five goats to classical BSE. 

***> PrPSC has been demonstrated in all cases by immunohistochemistry and western blot. 

=====> PRION CONFERENCE 2018 


***> GLOBAL REPORT ON TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY TSE PRION DISEASE November 30, 2018 

FRIDAY, NOVEMBER 30, 2018 

The European Union summary report on surveillance for the presence of transmissible spongiform encephalopathies (TSEs) in 2017



Terry S. Singeltary Sr. 

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