Study Toolbox Part 7: Mock Vivas

QP eligibility is largely determined by your performance during an oral assessment by members of the joint professional bodies.  You may have ticked all the boxes for the application process; submitted a fantastic application form; gained years of experience as a quality professional and been highly praised within your sponsor's form but without performing on the day of the assessment all this may go to waste.  With so much riding on the outcome of the assessment it is worth spending time to understand the assessment process and have a few practice sessions beforehand.  You wouldn't sit your driving test without first practicing out on the roads would you?

The Viva Process

QP viva assessments typically last between 60 and 90 minutes.  Within that time the assessors will need to assess your ability to meet the aspects of the study guide and to test your application of knowledge into real life scenarios.  Questions often consist of knowledge based, factual questions and scenarios where you play the part of a QP. 

The vivas are held at one of the headquarters of the 3 professional bodies in London and your friendly QP officer will be there to great you before you go in.  The panel consists of 3 assessors, one from each professional body with your own professional representative acting as the chair.  Your QP officer will be present to take notes during the assessment.  Occasionally trainee assessors and observers from the MHRA may be present but these personnel have no bearing on the outcome of your assessment.  Once the assessment has finished you are invited to step outside of the room whilst the assessors discuss your performance.  Usually within 5 to 10 minutes you are called back in to be told if you have been successful. 

Therefore the viva will subject you to a grilling by strangers in an unfamiliar environment, far removed from the comfort of your office.  In order to fully prepare for the viva it is important to try and replicate this as much as you can.

When should you begin mock vivas?

The short answer is; when you are ready.  There is little to gain jumping straight into mock vivas early on in your QP journey as you run the risk of becoming despondent and your confidence may take a hit.  I believe it is better to have gained the majority of your knowledge & experience; completed your visits and completed your training courses before attempting formal mock vivas. 

Informal Mock Vivas

The knowledge based questions are the easiest to practice as these require very little preparation by the 'assessor'.  As a result it is probably easiest to start off with these questions in order for you to practice saying answers out loud - something we are not always comfortable with.  Informal vivas can be performed with either your sponsor, colleagues or study partners especially if they are at a similar stage in their training.  These informal vivas can be performed at any convenient time during the day and will provide a good test of your knowledge base. 

Once you have performed a few of these informal vivas you should begin to develop your own strategy in your structured answers to common questions on legal/routine duties, legislative updates & QMS components.  Although informal you should always try and get some feedback from your performance.  It is important to know your strengths and areas for improvement so you need your sponsor/colleague etc to be honest and constructive in their criticism.

Formal Mock Vivas

Once you have experienced a few informal vivas you should begin arranging more formal mock vivas.  The aim of these is to try and recreate the real thing as far as possible.  This will often require a significant amount of preparation, usually by your sponsor.  Ideally you should clear at least 2 hours from your hectic schedules and book a room away from your office where you will not be disturbed, preferably in a room unfamiliar to you.  Your sponsor will also need to find time to prepare the questions and scenarios well in advance of the mock and invite at least one other person along to recreate a panel of assessors.

You should try and treat these formal mock vivas as if you were doing the real thing.  Your answers should be well structured and you should be acting as if you are already QP and to test run your strategy for answering scenario questions (eg using the PIPER mnemonic).  This is also a good opportunity to see how you react to potential mistakes you make in your answers to see if you can move on and focus on the next question.  Again, getting feedback from your 'assessors' is vital, even if what they say is not what you want to hear.  Hopefully you can take away those areas where you need more work and prepare better for the next one. 

Having your sponsor present during these mock vivas is important as they will be the only person who will be able to track your performance from your first few informal vivas all the way to formalised vivas.  It is good to ask your sponsor to play the part of an observer as you'll be fairly used to their line of questioning by this point.  Personally I liked having my sponsor present in all my mock vivas as I trusted his review of my performance without question and I wanted to impress him to show that I have been putting the work in!

By this point both you & your sponsor should be in a good position to assess your readiness for submission.  For me my final test was to arrange a formal mock viva with one of the dragon's themselves.  It is worth remembering that usually your sponsor and any other QPs giving mock vivas only have experience of 1 real viva (unless your sponsor is an assessor, or they took more than 1 attempt...) whereas an assessor has had the 'pleasure' of sitting through numerous vivas and will provide a definitive review of your performance.  My formal mock was with Alex (@QPQuandary) who provided me with a recreation of an actual viva, including all the preamble regarding the purpose of the assessment and potential confidentiality issues.  My sponsor and I had decided that if this mock viva went well then I would submit my application form so it gave me something to work for.

Learning Points:

• You are allowed to say 'I don't know' as long as you can tell the assessor where you would look to find the answer
• You can move the line of questioning to cover products you are more familiar with
• Listen to and answer the question, not the question you thought (or wished) you had heard
• If you remember an answer to an earlier question that previously alluded you mention at a later stage in the viva
• Mock vivas are tiring, especially if they are examining all areas of the study guide.  Short breaks will be needed if the mocks last more than 2 hrs.
• Learn from your mistakes and take constructive criticism positively!
• vary your 'assessors', don't rely solely on your sponsor so dig out those business cards from your networking sessions
• Play the part of the assessor for a few informal vivas as this will give you a different perspective to the viva process.

Summary

Mock vivas are a great tool to help with your preparation for the real thing.  They can provide a good insight into your readiness for submitting as long as you are ready to go through the process.  Having a mixture of formal and informal mock vivas should ensure a thorough test of your knowledge, provide you with ample opportunities to polish your answers to common viva questions and take your scenario strategy for numerous test runs.  Good Luck!

Think interview not firing squad!

Study Toolbox Part 1:  The Onion
Study Toolbox Part 2:  Introduction to Mindmaps 
Study Toolbox Part 3:  Keeping up to date 
Study Toolbox Part 4:  Training Courses
Study Toolbox Part 5:  Visits
Study Toolbox Part 6:  Teleconferences

Friday's Round Up

Class 4 Drug Alert - Fentanyl Patches

Takeda have issued a class 4 drug alert for one of their fentanyl transdermal patch preparations due to incorrect packaging details.  The details of the drug alert would suggest that this may be escalated to a recall once corrected stock is available.

Class 2 Drug Alert - Tixylix Oral Liquids

Novartis are recalling a number of batches of their Tixylix cough preparations due to a manufacturing fault with the primary container.  This echoes the Boots manufacturer's led recall from last week.   Why one was deemed a class 2 recall and the other a manufacturer's led recall  is unclear to me....

More UK Investment from GSK

More good news for the UK's pharmaceutical manufacturing industry as GSK has announced further investment into their Ware and Worthing sites.  Will they need more QPs??

New Local Laws in UK

Following the introduction of new drug driving laws to be implemented shortly, the MHRA has issued a statement requiring MA holders of specific drugs to update their packaging components with new warnings for drug driving.  A good example of how QPs need to be aware of updates to local laws - not just GMP updates.....

Deficiencies at API manufacturers

An article detailing the inspector training and common deficiencies identified by PIC/s during inspections of API manufacturers.

QbD for Sterile Manufacturing

QbD has been well described in the non sterile solid dosage form arena over the past few years.  This article describes the challenges of implementing QbD in sterile manufacturing processes.

Horizon 2020 Launched

The EC's funding stream was launched this week and follows on from the framework funding programmes (FP7).  The EC has made 71 billion Euros available for grants over a 7 year period for a range of scientific disciplines including healthcare. 


Happy Reading!

Friday's Round Up

Locals Laws & the QP

Industry responses to the draft annex 16 suggest that the requirement for QPs to know all the local laws in all markets is unrealistic.  That maybe so but the QP legal duties defined in 2001/83/EC are pretty clear....

Drug Alert - Sodium Bicarbonate

BBraun has issued a class 4 drug alert for a number of batches of sodium bicarbonate due to the presence of precipitation within retained samples.  This appears to be caused by defect in the rubber stoppers.  A great example of how changes to primary containers/closures can have a significant effect on product quality that may not manifest itself for a number of years (batch was distributed March 2012).  Another interesting point is the statement explaining that a recall is not an option at this time due to the potential of product shortage within the market.  It will be interesting to see if these batches will be recalled at a later date once additional supply has been introduced into the market.

Rapid Drug Quality testing

An article describing an innovative technology that can be used to test for active ingredient concentrations within finished products.  This technology is being targeted for use by clinicians to help in the fight against counterfeit medicines.

ICH steering committee

Details from November's ICH steering committee. 

EMA offers greater orphan incentives

Orphan drugs are rarely out of the news but despite the huge increase in orphan development and huge returns for those companies developing them, the EMA is applying even more incentives for orphan drugs.

Drug shortages causing patient harm

An interesting article describing how drug shortages within the UK is having a direct effect on patient health.  Something to ponder during your viva scenarios when deciding whether to recall or not.


Micro OOS webinar

A free on-demand webinar (once your details are submitted) on managing out of specification investigations originating from the micro lab. 



Happy Reading!

Friday's Round Up

GSK continues with UK manufacturing investment

News that GSK is ploughing further investment into its UK manufacturing arms.  After recent investments into their Ulverston site there is a further £23million for expansion of their Montrose facility in Scotland.  Great to see GSK bucking the trend of outsourcing UK manufacturing.

Boot's Pharmaceuticals recall - Oral liquids

A company led recall issued by Boot's via the MHRA website.  Remember these recalls are considered low risk and hence are not disseminated via the Drug Alert system.  The recall is due to potential faulty tamper seals on a range of their liquid formulations.

New Drug Target for Malaria

Novartis has published data on a novel drug target and new class of antimalarial compounds in the journal Nature.  

Baxter recalls Nitroglycerin Injection

Another recall due to potential particulate contamination within a sterile product.  A good reminder to revise the tests used for both visible and subvisible particles in finished products. 

US Congress gives more power to FDA over compounders

Following the fallout from the NECC compounding disaster from 2012, Congress has finally reached an agreement to update the legislative framework overseeing this high risk activity.  The revised bill gives the FDA more power and establishes a voluntary program for compounders to register with the FDA and agree to meet relevant quality standards.

API catalysis

An interesting article describing the advances in the use of catalysts in both chemical and biological API production.  A good prompt to revise the recently published draft ICH guidelines on elemental impurities.

FDA/EMA QbD Q&As

The FDA and EMA have published an update to their joint guidance document on quality by design.

Comments on Annex 16 published

The EC yesterday published comments on the proposed update to Annex 16.

Update to GDP Guidelines

A new version of the GDP guidelines has been published to correct some factual errors and give a formal date of coming into operation (24th November 2013)



 Happy Reading!

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. 

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!

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:

• 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.

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!

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!

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!

Friday's Round Up

Putting QbD into practice

Lilly have provided an good insight into their implementation of QbD within their manufacturing processes.  continuous manufacturing has been well established for years in food and medical device industries so it is about time the Pharma industry caught up.

Eye Drop recall (FDA)

A recall following mould being discovered within sterile eye drops.  There are concerns that the preservative fails to protect the product during its in-use shelf life.  This should prompt you to check the preservative efficacy testing methods and limits for different dosage forms.  It is also worth thinking about possible causes for the lack of efficacy of the preservative such as; increased bioburden of raw materials; change in primary container plastic causing preservative adsorption; pH change of formulation; container integrity fail etc

Motrin Recall (FDA)

A recall of an infant oral formulation due to a risk of particulate contamination in the API.

Micro website

 A useful website for your microbiology revision.  There is a popular forum for which to post your questions. 

Monoclonal Antibody Stability

This website is a good resource for the stability of monoclonals when compounded into ready to administer formulations.  It is useful to know how your MAbs are being used within 'specials' compounders and their take on stability studies.   It is also a good opportunity to compare the ICH stability requirements versus the information within this website. 

PQG QP seminar

A reminder of the PQG QP seminar on 16th October.   These seminars are an excellent introduction to QP training, scenarios and the all important networking.  I'll be attending so hopefully I'll see you there!


Happy Reading!

Off label Use

I came across an interesting example of off-label use this week.  'Off label' use is where a product with a marketing authorisation is being used outside of it's licensed indication, administration route or dosage requirements.  Off label use is frequently used within both human and veterinary medicine where there is a need to meet specific requirements of  a patient where existing treatment is unsuitable or ineffective. 

There are numerous examples of off-label use within the UK.  A recent, well publicised example is the use of Avastin in the treatment of wet macular degeneration in place of the more expensive Leucentis that is actually licensed for this indication.  Another common example is the use of Viagra in the treatment of pulmonary hypotension in young children.  Rare examples include the use of Pridel (lithium) in the treatment of thyrotoxicosis.

The example uncovered this week was the use of a drug licensed for IV use but actually administered via the intrathecal route (IT).  The vial was reconstituted within an aseptic facility to produce the final IT syringe ready for administration.  One of the first things that came to my mind was the risk of endotoxin.  From your microbiology revision you should be aware that the BP endotoxin limits for IV and IT administration is different.  Products licensed for IV administration have a limit of 5 EU/kg/hr whereas IT products have a limit of 0.2 EU/kg/hr. 

Therefore using a product licensed for IV administration for IT administration may mean that the patient is at a potential risk of receiving upto 25 times the amount of endotoxin normally expected via this route.  The risks are mitigated some degree by the fact that the volumes administered via the IT route are very small, typically in the region of 1-3ml and patients are often closely supervised following administration. 

The other question is who is responsible for this off label use?  Within the GPC prescribing guidelines it states that doctors are responsible for the prescribing and to ensure the efficacy & safety of the unlicensed use.  Presribers are require to understand the risks associated with off label use.  Would the prescribers actually be aware of the different endotoxin limits for IT vs IV administration?  Would the pharmacist taking responsibility of the quality of the product know about this?  In my experience I would hazard a guess that in most instances neither professional would take this into account. 

A QP's perspective

As a QP are you aware of how & why your products are used off label within your markets?  Having this knowledge should help you respond to any potential PV complaints surrounding off label use.  Another point worth considering is the update to the PV requirements following 2010/84/EU which came into force in the UK last year via SI 2012/1916.  These requirements now stipulate that any unlicensed, off label, abuse or overdose of your product needs to be captured within your PV system. 

Friday's Round Up

Teva Ranitidine Recall

The FDA has issued a recall for 5 batches of ranitidine tablets due to raw material contamination with a Pseudomonas species.  This shows that recalls can still be required for microbial contamination of non-sterile dosage forms.  A good chance to review the likely sources of Pseudomonas within a solid dosage form.  Purified water? Tablet coating? Is Pseudomonas an objectionable organism for oral preparations according to the BP?

Process Validation Guidelines from Asia

Draft PV guidelines have been published within the Asian area which are largely based on the FDA and EMA guidance already in circulation. 

Inhaled Insulin

Phase 3 studies have shown some promising results for insulin delivery via the inhaled route.  A good time to review the pros and cons of s/c protein suspensions vs powder protein for inhalation with regards stability, manufacturing, patient concordance etc

Risk of CJD found in medical devices

A report from the USA that describes patients put at risk from contaminated medical devices infecting patients with CJD.  It is interesting to note that the sterilisation process utilised within the hospitals were incapable of killing the prions responsible and that there is no diagnostic test for CJD. 

GSK's long term plan for China

 Following on from GSK's bribery case in China the pharmaceutical giant is said to be contemplating its future presence within China.  There is also rumours that GSK is poised to sell off some of its iconic consumer brands Lucozade and Ribena to focus on its core pharmaceutical business.

Sterile compounder recall

Yet another recall issued from a US steriles compounder due to questions over contract sterility testing methods.

Free Webcast - containment strategies in high-potency manufacture

The cost of Drug Development

An interesting article where NICE is questioning Pfizer's estimate of the cost of bringing a drug to the market.  The quote from the NICE chief exec sums it up nicely:

     “if it really does cost £1.2 billion to develop a new drug, the question the pharmaceutical industry must be able to answer is this: are you absolutely confident that it needs to?”

will QbD bring about a reduction in these costs?

Spanish Pharmacy Debt

Bail outs are often associated with the financial sector so this article came as a surprise to me.  As a potential QP releasing product to Spain you should be aware of these policies as it may affect your market.  If pharmacies do close down will there be an increase in demand?  Will this increase lead to counterfeit risk? Will patients turn to the internet?  Will this manifest as a change in your PV complaints from this market?

Hospira Recall

Hospira has issued a recall of Aminosyn II sterile infusion due to the presence of a human hair within the product.  This should make you question the gowning requirements for aseptic filling.  How would you tackle this as a potential scenario? 

New Herceptin Formulation

Roche has received approval for a sub-cutaneous version of Herceptin.  This will help offset the risk of patent expiry of the IV formulation for a few more years.  A good time to review the administration risks of SC vs IV.  It is also worth considering how the IV version is actually administered to patients.  Read section 6.6 of the SPC and see for yourself!  Hopefully the SC formulation will be easier to administer.

QP as leaders

A great article examining the role of leaders within the ever changing world of biotechnology.  QPs should be leaders and 'change agents' not only within the quality department but throughout the entire organisation.  These soft skills are an essential element to your QP training.


Happy Reading!

Friday's Round Up

Rapid Micro ID

BioMerieux has received FDA approval for their Vitek Mass spec system for rapid identification of organisms.  The main advantage of this over the traditional Vitek system is that no culturing or gram staining is required before identification.  Organisms can be taken straight from the agar plate, mixed with a solvent and injected into the mass spec.  Results are compared against a database and usually given within 30mins. 

More US compounding woes

This time the focus is on inadequate sterility testing performed by a contract laboratory.

CEP database

Although this database has been available for some time now, I only discovered this recently so I thought I'd share in case some of you haven't seen it before.  A useful link for checking the CEP status of your relevant APIs.

FDA Inspection Reports

A good overview of the 3 main inspection reports issued during FDA inspections.  Useful information if, like me, you dont have the pleasure of hosting FDA inspections.

Pharmacogenomics Webinar

A free webinar on the use of pharmacogenomic profiling during drug development.  Pharmacogenomics involves the profiling of patients' genetic or proteomic profiles in order to tailor their treatments to those drugs with highest probability of being clinically effective.  This is often associated with the term personalised therapy.

FDA Recall - Glass particles

A recall for daptomycin due to the presence of glass particles in a number of batches.  A useful reminder to review the methods for visible & sub visible particle inspection in final product testing. 

New caps for tylenol

This news article shows how J&J are trying to reduce the risks of overdose with tylenol (aka paracetamol).  I've posted this just to get you thinking about how you would manage this change control as a QP.  Apart from the obvious regulatory variations etc, think about the practical issues such as how to reconcile the old caps from warehousing before bringing in the new caps; how will the cap changeover occur - run down old stock before introducing new caps or full changeover on a single date?

21 CFR 11 overview

A useful overview of the impact of 21 CFR 11 compliance.

Friday's Round Up

Webinar: QC testing of culture media 

An on-demand webinar covering the use of control strains for QC testing of culture media.

Soliris Recall

A recall of Alexion's orphan drug soliris due to particulate contamination identified in vials.   Interesting that the particles were identified following routine testing of retained samples.  Did the CMO have a validated method for particulate testing?  If not, then where was the QP oversight?

QP review of BMRs

An interesting overview by the ECA on the expectation of the QP on reviewing BMRs prior to certification

APIC guideline for contracted QC

This guideline covers the management & qualification of contract QC labs

Monoject Recall - FDA

A recall of flush syringes used to maintain paucity of patient infusion lines.  Major failures in segregation and sterilisation control are obvious.

FMD finally transposed

I'm sure you have heard about this already but worth looking at an alternative view regarding changes to professions who can now legally prescribe and supply your products.

Webinar:  RA for global registrations

Webinar: GMP for EM systems

FDA's lack of power over compounders

An interesting article highlighting the limits of the FDA's authority over compounders in the USA.  Looks like the FDA is stuck between a rock and a hard place.....

BFS overview

A short youtube clip showing the process of blow-fill-seal technology.  Youtube is an excellent source for getting overviews of processes not familiar to you and for preparing for your visits.

How the FDA assesses defect reports

A great insight into how the FDA assesses defect reports. I'm sure the DMRC will have a similar process.

The role of Microbial Testing in Biotech

A comprehensive article exploring the microbial testing requirements for biotech products. 


Happy Reading!

Transposition of FMD into UK Law

Today saw the amendment to the Human Medicines Regulations come into force following the falsified medicines directive (2011/62/EU).  This was the first time that the UK missed a deadline for transposition of EU directives and I covered this in detail in a previous post.
As of today written confirmations for API importation from 3rd countries is now a legal requirement in the UK.  The only aspect remaining of the FMD that requires transposition is the introduction of safety features & associated serialisation.

Aside from the obvious inclusion of brokers, GDP, wholesaling, API importation, QP declaration etc there are a couple of additional points to consider that may have flown under the radar:

• MHRA Guidance on FMD

The MHRA have a comprehensive section of their website dedicated to the implementation of the FMD.   This section covers all you need to know about the 4 main pillars of the FMD and provides an excellent training resource for your law & admin revision.

• New Prescribers

The updated legislation has extended the scope of independent prescribing.  independent prescribers are allowed to prescribe specific medications without the supervision of a doctor or dentist and previously this privilege was limited to specialist nurses, optometrists & pharmacists.  As of today physiotherapists and podiatrists will be able to become independent prescribers.  These independent prescribers can also mix, sell or supply certain medicines.

Why is this important to QPs?  Well, prescribers directly influence how your products are used.  Do podiatrists have the knowledge and skills to understand the stability implications for mixing certain medicines?  Do physiotherapists fully understand the potential for complex pharmacological interactions with other medicines?  Pharmacists & doctors are no longer the primary gatekeepers of your prescription only medications.  These new pathways will need to be covered in communication of future recalls.  Also, could these changes lead to a change in the baseline level of complaints received by your PV department?

Summary

New legislation on FMD transposition is finally with us.  It is important to consider the wider implications of new legislation and look beyond the obvious headlines of GDP & written confirmations.  Having this wider appreciation of updates and how they may impact your area of practice is a key skill for the QP.

Friday's Round Up

The Buccal Route

I came across this paper this week and, although fairly old, it still provides a good overview of the buccal route for systemic drug absorption.  All relevant stuff for your formulation & medicinal chemistry modules.

Yet another FDA 483 for compounders

Following on from previous 483s for drug compounders, Speciality Compounding were inspected in March this year and this only came to my attention following their product recall last week.   The FDA are now taking some flak for the delay between the 483 and issuing the recall.  This 483 should be useful for solid dose trainees as an introduction to poor sterile manufacturing practice.

Patch in a Can

An interesting new development in transdermal drug delivery.

Biobetters Vs Biosimilars

Teva has announced new EU drug approvals for 'biobetters' which apparently improves on the original innovator product on which this new product is based.

South Africa MRA on the Horizon?

Legislative changes in South Africa may provide the potential for future MRAs with EU and FDA

Counterfeit seizure in Ukraine

A large counterfeiting operation has been uncovered in Ukraine.

EMA Paper on Nanotechnology coating

Novel Endotoxin testing

Something new to me this week following some revision of the standard endotoxin tests.  This test method is based on bacteriophage binding to LPS and removes the requirement for LAL. 

Revised PDA technical report

An updated revision of the PDA's technical report into dry heat sterilisation & depyrogenation methods.

P&G recall

Although for dog food these recalls can still provide useful scenario questions.  In this case, what is the potential sources of salmonella, clinical impact of salmonella, microbiology of salmonella etc



Happy reading!

Friday's Round Up

Teva UK Temazepam Recall

An example of a company-led recall as opposed to the recalls issued via the Drug Alert mechanism.  Company led recalls do not have a classification to portray the patient risk (eg class 1, 2 etc) and are therefore considered to be generally low risk to patient safety.  There appears to be 2 issues with the batches in question.  Firstly 2 batches have been released into the UK market incorrectly and secondly the final release testing for dissolution is at the lower end of specification.

Overview of worldwide serialisation deadlines & methods

A nice pdf overview of the different serialisation methods in the pipeline across the world & their proposed implementation deadlines.  Worldwide harmonisation on serialisation looks extremely remote!

Annex 16 update webinar

NSF-DBA are hosting a webinar on the changes to the draft annex 16 update on 9th September 2013 @ 16:00 GMT

US supplements with undeclared API

The FDA has issued a recall for sleep supplements containing undeclared doxepin & chlorpromazine.  The FDA have issued a number of similar recalls but I cannot remember anything similar arising from the UK via the MHRA.  Perhaps this highlights the scope of the FDA's testing programme within the USA.

Self Expiring Packaging

An interesting design to highlight when blister packs expire.  I cant see this being particularly important for patients with chronic conditions as blister packs are typically used within a month.  This will more likely highlight those old packs of paracetamol at the back of the cupboard for that occasional headache!  Once the packaging has expired will it still be in compliance with both the MA and legal requirement for labelling?

Trends in USA Drug Approvals

An interesting overview of the numbers of new drug approvals in the USA between 1987 and 2011.  Hopefully the upward trend since 2005 continues and is replicated within the EU?

Counterfeit Drugs in Clinical Trials

A slightly naive post regarding the risk of counterfeit drugs entering clinical trials.  Given that comparators are sourced on the open market and pressures to source the cheapest product then this risk is fairly obvious. Although the FMD does not apply directly to IMPs it will apply to comparator products which may reduce this risk if sourced from the EU wholesale distribution network.

Not one to read over dinner

everyday is a school day after all, this was certainly something I'd never heard of before!

Finally.....

An interesting time lapse video of fungi growing on culture media.  At around 0.50 you can clearly see  sporulation during the growth phase.   Certainly not something you want in your product or clean room.

Happy Reading!

Friday's Round Up

Teva UK Warfarin Recall

A class 3 recall was issued this week following ongoing stability issues surrounding degradation products for Teva UK's warfarin tablets.  Interestingly only the 3mg tablets are affected and not the 0.5mg, 1mg or 5mg tablets.  For all you non-pharmacists it is worth learning about warfarin as it is a somewhat unique drug in terms of its ongoing patient monitoring, side effects and drug-drug & food-drug interactions.

Now that's what I call a recall (FDA)

Probably the largest multi product recall I have ever come across.  This recall is from a USA Pharmacy drug compounder and the FDA has obviously uncovered some serious failures in their sterility assurance.  This echoes the previous case of the NECC from earlier this year. 

Benztropine Recall (FDA)

Visible particulate matter within the vial is the reason behind this recall.  The FDA provides a useful overview of the risks of injecting particulate matter into the body.

Cold Chain Presentation by Ian Holloway 

This presentation covers the cold chain distribution, deviation management, use of MKT, calibration certificates & investigation practice.  A very useful 30 minutes and will provide a great deal of information surrounding potential scenario questions on temperature deviations within the supply chain.
NB: This link will require registration with the website to watch the full length video.  There is no confirmation email so any email can be stated on the registration form.

Cosmetic GMP Guidelines

The FDA has published draft guidelines for GMP for cosmetic products.

Update to CEP guidelines

This follows on from last week's update surrounding the changes to the format of the CEP to include all manufacturers.  The guidance document provides a good overview of the requirements for informing the EDQM of revisions/renewals to the CEP.

Hitting 2 birds with 1 stone

An interesting article highlighting Genentech's progress in their research division.

Webinar - QC testing of Culture Media

A webinar on the use of control strains in the QC testing of culture media.  14th August 2013 @ 4pm (BST)

Medical Device Application process

A nice diagrammatic representation of the process of the medical device approval process.  Medical devices are a relatively hot topic lately as the EU has issued proposals to tighten up the regulatory oversight of medical devices following the PIP scandal.  Further information on these changes can be found here

Danish Regulatory API confirmation Q&As

Another competent authority's take on the written confirmation requirements for API importation.

Death Row & the FDA

A very interesting article surround the FDA's earlier decision to import unlicensed thiopental into the USA to alleviate drug shortages.  This has been successfully challenged by a number of death row inmates. 

Acetaminophen & risk of skin disorders

The FDA has issued a warning regarding the potential for Steven's Johnson syndrome with acetaminophen use.  This drug is known as paracetamol within the UK and in my previous life as a pharmacist I have never encountered this effect.  I've added this alert to highlight the need to be aware of PV issues surrounding products that are well established on the market. 

Happy Reading!

Study Toolbox Part 6: Teleconferences

Throughout my QP training process teleconferences have been a regular and enjoyable way to assess my knowledge and progress towards submission.

1 to 1 teleconferences

The secret behind arranging teleconferences is your ability to network within your peers.  Networking via training courses, conferences, social media and within your company is key to identify potential candidates to arrange teleconferences with.  The ideal candidate will be one who is at a similar stage in their QP training and works in an area different from your own. Your sponsor should be able to provide you with potential contacts to get you started.

1 to 1 teleconferences give you the ability to dictate what topics are discussed and will provide less nervousness if giving incorrect answers.  My weekly chat is with a trainee QP from 'big pharma' who specialises in solid dose manufacture.  As my background is small scale sterile IMP manufacturing the contrasts are apparent and I certainly have gained great detailed knowledge into solid dose manufacturing just from these 30minute weekly sessions.  A common theme for the discussions is to talk through lists of previous viva questions & scenarios.  This provides a good insight into each other's thought processes and techniques in dealing with scenarios.  This arrangement came about after a chance meeting at a PQG seminar last year.  Therefore don't be afraid to approach people even if your introverted tendencies maybe telling you otherwise.
 

Multi person teleconferences

Multi person teleconferences are obviously harder to arrange.  If your network is large enough then this should not be too difficult to arrange yourself using popular teleconference software such as PowWowNow & free conference call.  With an increase in numbers comes an increase in opinions and diversity of relevant topics.  Occasionally you may have to listen to discussions surrounding topics that are not relevant to you.  Multi person teleconferences can be more intimidating especially if you are a new addition to the regulars and you don't want to come across as a complete fool!  Often you will find someone who 'chairs' the conference call to ensure all callers are included in the discussions and know when to move onto a different topic.  Knowing that there are multiple callers means you can take a backseat to absorb what is being discussed without having to do any preparation before hand.  This is useful for the initial few calls but to gain the most out of teleconferences you have to get involved and put your thoughts across.  You really do get out what you put in.

There are a few established teleconferences that occur regularly throughout the working week.  Alex at QPQuandary arranges 2 calls per week on Mondays and Fridays and often attracts wide range of callers most weeks.  This is coupled to an extensive email network that provides a good forum for requests and follow up discussion if particularly interesting points are raised during the call.  For me these have been an essential part to my QP training because the majority of callers are from commercial pharma so I can gain valuable information into the way commerical trainees handle scenarios and issues relevant to their practice.  Over time I have manage to contribute from alternative angles (eg NHS, small scale IMP manufacturing) which hopefully has increased the awareness of other areas of practice for callers.

Summary


Teleconferences, either 1 to 1 or multiple person, can offer a great forum for discussion surrounding new GMP updates, scenarios or just to hear someone else's point of view other than your sponsor!  In this age of email communication don't forget the faithful old telephone still has a huge part to play in your QP training journey.

Study Toolbox Part 1:  The Onion
Study Toolbox Part 2:  Introduction to Mindmaps 
Study Toolbox Part 3:  Keeping up to date 
Study Toolbox Part 4:  Training Courses
Study Toolbox Part 5:  Visits

Friday's Round Up

Wockhardt 483

Following on from my previous post regarding the multi product recall of Wockhardt products.  This informative warning letter really opens your eyes to the observed actions within the factory.  You have to ask where the QP oversight was and how these issues were not picked up during routine self inspection

GSK trial data issues

Yet more problems for GSK's China operations.  In addition to the well publicised bribery case issues have now been raised with clinical trial activity within China.  Namely the lack of pre-clinical data before products were given to human subjects.

Fresenius 483

Another revealing warning letter regarding an Indian manufacturing site.  The attempt at hiding documents by stuffing them into pockets is a particular highlight.  As with all these warning letters it is useful to get into the habit of using them as possible scenarios and how you would tackle them as a QP

TOC for Cleaning Validation

A useful 30min presentation/webinar on the benefits of using TOC for cleaning validation.  You'll need to submit details to access the presentation (there is no confirmation email so you can put any email in the box)

Top 20 Orphan Products

As mentioned previously orphan drugs are rarely out of the news.  Here is a great list showing the potential behind these lucrative drugs.

One for the Coffee Connoisseurs
Hence the reason copious amounts of coffee are available during DBA courses!


Happy Reading!

Friday's Round Up

API Importation Flow Chart

A good overview of the written confirmation requirements of API imports and a useful flowchart which outlines the process

CEP Update

The EDQM has updated the CEP certificate with regards to the listing of manufacturing sites.  From the 15th July the CEP certificate will carry details of all manufacturing sites involved in the manufacture of the API.  This includes sites performing packaging, micronisation, sterilisation & QC. 

Diovan Data Fabrication
Genentech Data Issues

Yet more reports of falsified data relating to drug development.  Repeated reports should be making you think of potential viva scenario questions relating to this and how you would tackle it.

Certificates of Medicinal Products

I came across the term CMPs for the first time this weeks.  CMPs are issued by the EMA to confirm the marketing authorisation status and the GMP status of the manufacturing site.   The appear to be primarily used for export to 3rd countries to support regulatory approval within that 3rd country.

Supplement Recall (FDA)

A recall for supplements containing medicinal active ingredient sildenafil.  A good example of how API supply chains are being compromised but will the FMD prevent this from happening in the UK?

Orphan Updates

Orphan drugs are rarely out of the news.  The EMA has updated its guidance on orphan applications and sponsorship transfer.  This document provides a good overview of the expectations of the EMA for orphan applications. 

Insects in vials (FDA 483)

More issues highlighted by the FDA relating to an Indian & New York CMO.  Insects within vials is certainly something I haven't come across before.  When you read about deficiency reports such as this it is good to get into the habit for thinking through your response if this was a potential QP scenario. 

FDA guidance on Technical Agreements

The FDA provide a good guideline on the requirements of TAs and scenarios where TAs have been deficient.

Lucentis & Avastin Equal in Efficacy

A study by the UK government to determine if these two treatments are equally effective for macular degeneration.  This is likely to further the debate between the NHS & pharma  where use of a drug off-label (Avastin) instead of the approval licensed product (Lucentis) has been justified on cost despite questions over the legality of this approach.

Happy reading!

GMP Principles in Principalities

Following on from my previous post on the entry of Croatia to the EU this post aims to give an overview of how the small principalities within Europe are integrated within the EU.  As a trainee QP you will need to know how the EU operates and importantly know sufficient information to enable you to provide answers to the round-the-world supply chain viva scenario questions.  These scenarios often involve complex virtual supply chains throughout and outside the EU. 

I'm sure many of you are aware of the EFTA & EEA countries but how would you handle a scenario question that included importing medicines from Monaco, San Marino or Andorra?  This post will aim provide you with the information required to answer that potential scenario.

Monaco 

Famous for its grand prix, casino and tax exiles, Monaco is a small principality on the Mediterranean coast bordered by France.  It is the most densely populated country in the world with a population of ~36,000 squeezed into a land area of 2sqKm.  

Monaco is not a member of the EU, EFTA or EEA and has no MRA in place with the EU.  Hence it can be considered, at face-value, to be a 3rd country with regards to medicine legislation.  However, since 2003 Monaco has a formal agreement with the EU regarding legislation for medicines for human & veterinary use as well as medical devices and cosmetics.   The formal agreement stipulates that certain EU legislation shall apply within the principality of Monaco and includes a number of familiar EU directives.  

EU directives relevant to QP that are incorporated into Monaco law:

• 2001/83/EC
• 2001/82/EC
• 2001/20/EC
• 2002/98/EC (blood directive)
• 91/356/EEC (previous GMP directive, 2003/94/EC not explicitly stated)
• 91/412/EEC (Vet GMP) 

These EU directives should be familiar to you all.  In general terms this means that Monaco complies with EU medicines legislation with regards to both commercial and clinical trial products as if they were a member of the EU.  Therefore the rules surrounding marketing, manufacture or importation of medicines will apply in Monaco as per other member states.  There are manufacturing companies within Monaco (Monegasque companies) that produce pharmaceuticals and cosmetics and some have valid GMP certificates listed on the EudraGMP database. Monaco also has a bilateral agreement with France that covers customs/importation legislation.  As a result when France adopt specific EU directives into national law Monaco will directly apply this French legislation into their own legislative framework.  

It is important to remember that these agreements with Monaco do not remove the requirement for auditing any relevant site within Monaco to determine compliance with EU GMP.  

Andorra & San Marino

 











Both the Principality of Andorra and the Republic of San Marino are 3^rd countries.  They are not part of the EEA or EFTA therefore access to the EU internal-market is limited.  They each have bilateral agreements in place with their immediate neighbours but they do not cover any EU medicine legislation.  The EU has produced a concept paper stating that inclusion of Andorra & San Marino to the EFTA and then EEA is a viable option that should be explored in order to better integrate both countries into the EU framework. 

Currently Andorra and San Marino does not have any mutual recognition with regards to pharmaceuticals.  As a result movement of pharmaceuticals between the EU and San Marino is restricted and importation requirements as for other 3^rd countries will apply.

Summary

Understanding the intricacies of the EU is a vital part of your law & admin module of the study guide.  Expanding your knowledge into very specific areas & countries such as Monaco should give you more confidence during your viva supply chain scenarios.  

Of the 3 countries mentioned only Monaco has implemented EU legislation regarding medicines and hence can be deemed as a 'quasi-EEA' member.  Both Andorra & San Marino have not implemented any relevant EU legislation and are therefore true 3rd countries.