Friday, 22 November 2013
Friday's Round Up
Overkill Overview
A good article from Pharmaceutical Technology covering the concept of overkill sterilisation cycles for steam sterilising cycles.
J&J fined for off-label marketing
Yet more woes for J&J and its subsidiaries after the company was fined $2.2 billion for promoting off-label use. A good reminder of the updated PV requirements of 2010/84/EU stipulating that all off-label & unlicensed use must be incorporated into the PV system.
USP update for particulate inspection
A new draft USP monograph has finally provided a definition for 'essentially free from particles'. The definition involves a 100% inspection meeting an AQL of 0.65% or tighter for visible particles. Subvisible particles remain unchanged.
EMA's Risk Aversion
A very interesting article giving an insight into the EMA's thoughts on risk versus benefit during drug assessments and the potential shift to accept more uncertainty in their assessment. It is an example of how competent authorities are incorporating ICH Q9 principles into their quality systems. Some of these concepts may be of use in your decision making process for recall scenarios.
Responses to GMP updates
The EC has published comments from industry following draft updates to the GMP guide, GDP and excipient GMP.
Online QP training
Inspired Pharma have recently launched online medicinal chemistry QP training module with more modules scheduled for release over the coming months.
Ian Hudson Interview
The Pharmaceutical Journal have published an interview with Ian Hudson, the newly appointed chief executive of the MHRA. The interview highlights the increase in more specialist medicines such as biologicals and the increase in conditional authorisations.
Compounding for death
US compounders are rarely out of the news and this article raises yet more questions.
Sunday, 3 November 2013
MS Vs MIA GMP
The MHRA have issued an interesting guidance document regarding GMP inspections of MS or 'Specials' licensed facilities. 'Specials' manufacturing is a predominately a UK based activity which allows MS license holders to manufacture large quantities of medications without the requirement for a marketing authorisation. This general concept comes under the special clinical need umbrella as described in Article 5 of Directive 2001/83/EC.The guidance document makes for some interesting comparisons and regulatory expectations compared to the EU GMP guide. I've highlighted some below:
1. Continuous Particle Monitoring
Clearly defined in Annex 1 to the EU GMP guide, continuous particle monitoring is required to be performed during the aseptic filling process. The 'Specials' guideline (3.5.22 & 23) states that where closed systems are utilised (eg isolator technology) or where residual particle generation is unavoidable (eg IMS spray, opening needles) then the requirement for continous particle monitoring may be waved.
This is a common sense approach by the MHRA. Fill times for 'specials' can be short (eg minutes) compared to the commerical scale filling lines where fill times may fun for days. Also the majority of starting materials used within 'specials' manufacture will be sterile, licensed medicinal products (eg vials of antitbiotics, cytotoxics etc). Together with the closed system processing (ie the product does not contact the external environment) then the risk of particulate contamination is low.
2. API controls
The FMD has introduced tight controls around the importation & distribution of APIs for human commercial products. The 'Specials' guideline (3.5.3) states that the FMD and its transposition into UK law (SI 2013/1855) does not cover APIs used in 'Specials' manufacturing. The guidance document goes onto explain that full supplier approval procedures are expected including supplier audits, desk audits etc.
3. Dedicated Facilities
Updates to both Chapter 3 and 5 reiterate the requirement for dedicated facilities for products deemed necessary by the MIA holder. Section 3.3.4 of the 'Specials' guideline states that dedicated facilities are not required where closed systems are used. Most 'Specials' manufacturers will have dedicated isolators for penicillins but would often have single isolators for cytotoxics, monocloncals and non-penicillin antibiotics.
These 3 highlights only provide a very brief overview of the MHRA's guideline. It is well worth a read especially for commerical trainee QPs as a number of your products will be manufactured in 'specials' licensed units across the UK.
Friday's Round Up
A little late this week....
Counterfeit Xanax uncovered
More counterfeit drugs have been seized in Zurich. It appears to have come from China and analysis of the products showed no active ingredient in them at all.
Thalidomide Overview
A great article describing the history of this well known drug and how it has been developed into treatments for cancer and leprosy.
Imigran Recall (UK)
A class 2 recall in the UK for the migraine treatment Imigran due to protruding needles. A good example of how medicinal products are often combined with medical devices (eg needles/syringes) for drug delivery purposes. Defects in these devices can be as significant as those to the drug itself so you need to be aware of the relevant functional testing of the finished product and delivery systems.
Paracetamol Suspension Recall (USA)
Another example of how a defect in a co-packaged medical device leads to a product recall. The risk of overdose in paracetamol without graduated syringe markers is severe, hence the recall. What would be your actions if this product was life critical with no alternatives?
Novomix Insulin Recall (UK)
A class 2 recall issued due to potential for variance in fill levels of insulin cartridges. The drug alert is very comprehensive and provides detailed information for both patients and clinicians with regards to this recall.
Happy Reading!
Counterfeit Xanax uncovered
More counterfeit drugs have been seized in Zurich. It appears to have come from China and analysis of the products showed no active ingredient in them at all.
Thalidomide Overview
A great article describing the history of this well known drug and how it has been developed into treatments for cancer and leprosy.
Imigran Recall (UK)
A class 2 recall in the UK for the migraine treatment Imigran due to protruding needles. A good example of how medicinal products are often combined with medical devices (eg needles/syringes) for drug delivery purposes. Defects in these devices can be as significant as those to the drug itself so you need to be aware of the relevant functional testing of the finished product and delivery systems.
Paracetamol Suspension Recall (USA)
Another example of how a defect in a co-packaged medical device leads to a product recall. The risk of overdose in paracetamol without graduated syringe markers is severe, hence the recall. What would be your actions if this product was life critical with no alternatives?
Novomix Insulin Recall (UK)
A class 2 recall issued due to potential for variance in fill levels of insulin cartridges. The drug alert is very comprehensive and provides detailed information for both patients and clinicians with regards to this recall.
Happy Reading!
Friday, 18 October 2013
Friday's Round Up
Ben Venue Closure
Boehringer Ingelheim have finally decided to close their Ben Venue site in the USA following a number of quality problems. Closure of facilities has been asked in QP vivas in the past and it is a good opportunity to consider your plan to manage this change.
Wockhardt Troubles continue
The MHRA have revoked their GMP certificate for another one of Wockhardt's manufacturing sites in India. As a result the the facility will no longer be able to supply products to the UK.
Wockhardt Recall
Following the MHRA's action to revoke their GMP certificate a multi product recall was always on the cards.
Recall following media fill fail
A recall of a sterile inhalation solution due to a media fill failure. A good reminder to review your microbiology module and annex 1 for the requirements of media fills in sterile manufacturing and how you would handle a potential failure.
Actavis Bioequivalence problem
An interesting read regarding a failure of bioequivalence data for an existing product.
USP draft for non-sterile product bioburden
Bioburden is generally considered for sterile manufacturing. Of note is the list of non sterile products in order of their potential risk of microbiological contamination:
Irish Rx charge increase
The Irish government has announced a 66% increase in prescription charges. Will this increase the demand of patients seeking to find cheaper alternatives and hence lead to an increase in counterfeit risk in Ireland?
MHRA Q&A for MS holders
An interesting article for those who have little experience or appreciation of how aspects of the EU GMP guide is applied to MS (specials) manufacturers.
Boehringer Ingelheim have finally decided to close their Ben Venue site in the USA following a number of quality problems. Closure of facilities has been asked in QP vivas in the past and it is a good opportunity to consider your plan to manage this change.
Wockhardt Troubles continue
The MHRA have revoked their GMP certificate for another one of Wockhardt's manufacturing sites in India. As a result the the facility will no longer be able to supply products to the UK.
Wockhardt Recall
Following the MHRA's action to revoke their GMP certificate a multi product recall was always on the cards.
Recall following media fill fail
A recall of a sterile inhalation solution due to a media fill failure. A good reminder to review your microbiology module and annex 1 for the requirements of media fills in sterile manufacturing and how you would handle a potential failure.
Actavis Bioequivalence problem
An interesting read regarding a failure of bioequivalence data for an existing product.
USP draft for non-sterile product bioburden
Bioburden is generally considered for sterile manufacturing. Of note is the list of non sterile products in order of their potential risk of microbiological contamination:
- metered-dose and dry powder inhalants
- nasal sprays
- otics
- vaginal suppositories
- topicals
- rectal suppositories
- oral liquids (aqueous)
- liquid-filled capsules
- oral tablets and powder-filled capsules
Irish Rx charge increase
The Irish government has announced a 66% increase in prescription charges. Will this increase the demand of patients seeking to find cheaper alternatives and hence lead to an increase in counterfeit risk in Ireland?
MHRA Q&A for MS holders
An interesting article for those who have little experience or appreciation of how aspects of the EU GMP guide is applied to MS (specials) manufacturers.
Saturday, 12 October 2013
Friday's Round Up
Recall - glass particles
Hospira have recalled two injection products due to a defect in the primary container leading to a risk of glass particles within the solution. There are a number of issues to think about here with regards to QP study. Firstly was the AQL sampling of the primary containers at a suitable level? What type of glass is used (type 1/2?) A new component supplier? Automated inspections for particles & ampoule integrity will not detect these types of defects. This is also a good example of considering the extent of the defect as clearly the same primary containers are used for more than 1 product. What would you response be to this - increased AQL sampling? For cause audit? Additional QC testing on container receipt?
Safety Reporting requirements of new CT Regulation
A good article highlight the proposed changes to the safety reporting requirements for investigators & sponsors.
Medical Device EU Safety Update
The EC has introduced two new safety measures for medical devices. The new rules are focused on the notified bodies with regards to their auditing & assessment of manufacturers and clarifying the criteria these NBs need to meet.
FDA 483 for Indian API site
An interesting 483 report highlighting the deficiencies of an Indian API site. For each audit observation it is good practice to talk through how you would take these findings forward if you were auditing this site as an API supplier of your finished product.
PV Black Triangle video
The EMA have published a patient-focused video describing the introduction of the black triangle system for medicines subjected to intensive PV monitoring.
Update to EU-Japan MRA
The EMA has updated the MRA with Japan to permit the sharing of GMP data between manufacturers. This means that the Japanese regulatory authority can accept reference to the EudraGMDP certificates.
Sterilisation & Disinfection Standards
A comprehensive list of all standards relating to sterilisation & disinfection. A useful reference.
Doxil Drug Shortages
Yet more fall out from the ongoing issues surrounding J&J's Ben Venue facility in the USA. A good reminder of the requirement for MAHs to inform the competent authority in all markets when drug shortages are expected. Something to consider during your recall scenarios.
Hospira Recall - Particle contamination
A recall of a sterile injection due to a report of a dark particulate contaminant. This has been identified as oxidized stainless steel. What would be the likely source? 100% inspection performed manually or via automatic camera detector - one of the methods failed in this case.
Changing manufacturing facilities
Following the ongoing issues Ranbaxy is having with their existing sites in India the company is looking at purchasing a new site and transferring production. This is a good example of a common scenario question of a change in supplier or site. As a QP what would you need to see before manufacturing at the new site is started? A change control would be a good starting point.....
EMA PV signals
The EMA have begun publishing PV signals reviewed by the PRAC.
Malaria Vaccine
GSK look set to apply to the EMA for approval of their malarial vaccine during 2014. It is not clear if this product is to be manufactured within GSK's new Ulverston site.
Happy Reading!
Hospira have recalled two injection products due to a defect in the primary container leading to a risk of glass particles within the solution. There are a number of issues to think about here with regards to QP study. Firstly was the AQL sampling of the primary containers at a suitable level? What type of glass is used (type 1/2?) A new component supplier? Automated inspections for particles & ampoule integrity will not detect these types of defects. This is also a good example of considering the extent of the defect as clearly the same primary containers are used for more than 1 product. What would you response be to this - increased AQL sampling? For cause audit? Additional QC testing on container receipt?
Safety Reporting requirements of new CT Regulation
A good article highlight the proposed changes to the safety reporting requirements for investigators & sponsors.
Medical Device EU Safety Update
The EC has introduced two new safety measures for medical devices. The new rules are focused on the notified bodies with regards to their auditing & assessment of manufacturers and clarifying the criteria these NBs need to meet.
FDA 483 for Indian API site
An interesting 483 report highlighting the deficiencies of an Indian API site. For each audit observation it is good practice to talk through how you would take these findings forward if you were auditing this site as an API supplier of your finished product.
PV Black Triangle video
The EMA have published a patient-focused video describing the introduction of the black triangle system for medicines subjected to intensive PV monitoring.
Update to EU-Japan MRA
The EMA has updated the MRA with Japan to permit the sharing of GMP data between manufacturers. This means that the Japanese regulatory authority can accept reference to the EudraGMDP certificates.
Sterilisation & Disinfection Standards
A comprehensive list of all standards relating to sterilisation & disinfection. A useful reference.
Doxil Drug Shortages
Yet more fall out from the ongoing issues surrounding J&J's Ben Venue facility in the USA. A good reminder of the requirement for MAHs to inform the competent authority in all markets when drug shortages are expected. Something to consider during your recall scenarios.
Hospira Recall - Particle contamination
A recall of a sterile injection due to a report of a dark particulate contaminant. This has been identified as oxidized stainless steel. What would be the likely source? 100% inspection performed manually or via automatic camera detector - one of the methods failed in this case.
Changing manufacturing facilities
Following the ongoing issues Ranbaxy is having with their existing sites in India the company is looking at purchasing a new site and transferring production. This is a good example of a common scenario question of a change in supplier or site. As a QP what would you need to see before manufacturing at the new site is started? A change control would be a good starting point.....
EMA PV signals
The EMA have begun publishing PV signals reviewed by the PRAC.
Malaria Vaccine
GSK look set to apply to the EMA for approval of their malarial vaccine during 2014. It is not clear if this product is to be manufactured within GSK's new Ulverston site.
Happy Reading!
Friday, 27 September 2013
Friday's Round Up
Counterfeit Viagra & Cialis seizure
A large seizure of these popular lifestyle drugs has been reported in the Czech Republic. It is not clear how the counterfeit products were identified. It makes you wonder if any have actually gone through the system and ended up in the legitimate supply chain.
FDA Flu Vaccines
A good brief overview of the process of influenza vaccine production by the FDA. Interestingly the article states that the FDA actually release the vaccines into the US market. This mirrors some of the UK animal vaccine products that are released to market by the VMD and not the QP (although each batch does require QP certification prior to VMD release).
UK Class 2 recall
A recall of buprenorphine tablets due to a potential printing error with the carton supplier. This is a good example of when carton suppliers print the batch number as opposed to printing on-line in the high speed packaging lines. It is also a good opportunity to review the on line packaging controls that may have prevented this error. I'm guess that a blob detector was used to detect the presence of ink within the space for the batch number. A more complex optical character verification system may have prevented this error.
Poland's human tissue legislation not good enough
The EC has taken Poland to court as their transposition of EU directives surrounding the quality & safety of human tissues. I wonder where this leaves the QP's responsibility? If for example a UK IMP QP was certifying ATMPs manufactured in Poland.....
ATMPs on the radar
Only the 3rd ATMP application to the CAT and the 1st to include non-clinical data and eludes to more ATMP applications on the horizon. It is worth mentioning that a new MIA has established as part of ATMP manufacturing in a hospital setting. The MIA is termed 'MeAT'
FDA recall (Budesonide)
More sterility assurance issues with compounders in the States. This time a bottle of budesonide has been contaminated with fungal spores.
Medical Device Safety
The EC has introduced more measures to improve the safety of medical devices. This appears to focus the attention on the oversight of the Notifying Bodies. Yet more work for the MHRA.......
Happy Reading!
A large seizure of these popular lifestyle drugs has been reported in the Czech Republic. It is not clear how the counterfeit products were identified. It makes you wonder if any have actually gone through the system and ended up in the legitimate supply chain.
FDA Flu Vaccines
A good brief overview of the process of influenza vaccine production by the FDA. Interestingly the article states that the FDA actually release the vaccines into the US market. This mirrors some of the UK animal vaccine products that are released to market by the VMD and not the QP (although each batch does require QP certification prior to VMD release).
UK Class 2 recall
A recall of buprenorphine tablets due to a potential printing error with the carton supplier. This is a good example of when carton suppliers print the batch number as opposed to printing on-line in the high speed packaging lines. It is also a good opportunity to review the on line packaging controls that may have prevented this error. I'm guess that a blob detector was used to detect the presence of ink within the space for the batch number. A more complex optical character verification system may have prevented this error.
Poland's human tissue legislation not good enough
The EC has taken Poland to court as their transposition of EU directives surrounding the quality & safety of human tissues. I wonder where this leaves the QP's responsibility? If for example a UK IMP QP was certifying ATMPs manufactured in Poland.....
ATMPs on the radar
Only the 3rd ATMP application to the CAT and the 1st to include non-clinical data and eludes to more ATMP applications on the horizon. It is worth mentioning that a new MIA has established as part of ATMP manufacturing in a hospital setting. The MIA is termed 'MeAT'
FDA recall (Budesonide)
More sterility assurance issues with compounders in the States. This time a bottle of budesonide has been contaminated with fungal spores.
Medical Device Safety
The EC has introduced more measures to improve the safety of medical devices. This appears to focus the attention on the oversight of the Notifying Bodies. Yet more work for the MHRA.......
Happy Reading!
Friday, 20 September 2013
Friday's Round Up
More Indian woes for Ranbaxy
The FDA have issued an import alert on another Ranbaxy site within India.
Modified Release Technologies
A good overview of the methods for modifying the release characteristics of APIs and how PAT can be used to control the manufacture of these complex formulations.
Generic Xeloda
Teva has received FDA approval for generic capecitabine. This drug is a good example of a pro-drug whereby the drug is converted into 5-FU only in the presence of specific enzymes overexpressed in specific tumours. Oral oncology treatments are enabling more patients to be treated at home and enables cancer to be viewed more as a chronic disease state.
Risperdal Consta Recall
J&J have issued a recall of one batch due to the presence of a mould within vials during QC testing. This suspension of microspheres is administered IM to provide sustained release of active over 14 days for schizophrenic treatment.
Clinical trial data
An interesting report from the Guardian that discuses the publication of all clinical trial data following a parliamentary report.
More UK manufacturing investment
More good news for UK Pharma.
US compounding legislation
US Congress have release draft legislation for the control over pharmaceutical compounding following the NECC disaster in 2012. The proposed text makes for some interesting reading. It makes me wonder if this may eventually impact the compounding activities in the UK.
10 Rules of GMP
Tim Sandle's 10 rules of GMP for use as a training aid.
Bydureon Recall
A recall of one batch of Bydureon due to underfilled vials. This highlighted the fact that my
knowledge of final volume checking within high speed filling lines is lacking. I would guess this can be performed on 100% of vials via checkweighers, automatic particulate camera detectors and/or visible inspection.....I'd better look this up
New Arrival
Baby Sean arrived this week and has added a new challenge to QP studying!
The FDA have issued an import alert on another Ranbaxy site within India.
Modified Release Technologies
A good overview of the methods for modifying the release characteristics of APIs and how PAT can be used to control the manufacture of these complex formulations.
Generic Xeloda
Teva has received FDA approval for generic capecitabine. This drug is a good example of a pro-drug whereby the drug is converted into 5-FU only in the presence of specific enzymes overexpressed in specific tumours. Oral oncology treatments are enabling more patients to be treated at home and enables cancer to be viewed more as a chronic disease state.
Risperdal Consta Recall
J&J have issued a recall of one batch due to the presence of a mould within vials during QC testing. This suspension of microspheres is administered IM to provide sustained release of active over 14 days for schizophrenic treatment.
Clinical trial data
An interesting report from the Guardian that discuses the publication of all clinical trial data following a parliamentary report.
More UK manufacturing investment
More good news for UK Pharma.
US compounding legislation
US Congress have release draft legislation for the control over pharmaceutical compounding following the NECC disaster in 2012. The proposed text makes for some interesting reading. It makes me wonder if this may eventually impact the compounding activities in the UK.
10 Rules of GMP
Tim Sandle's 10 rules of GMP for use as a training aid.
Bydureon Recall
A recall of one batch of Bydureon due to underfilled vials. This highlighted the fact that my
knowledge of final volume checking within high speed filling lines is lacking. I would guess this can be performed on 100% of vials via checkweighers, automatic particulate camera detectors and/or visible inspection.....I'd better look this up
New Arrival
Baby Sean arrived this week and has added a new challenge to QP studying!
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