analysing international pharmaceutical regulations

Vol.15 No.2 July 2016

gmp revıewanalysing international pharmaceutical regulations

Human error: don't blamepeople – fix the systembecause...if you don’t theerrors will happen againand again...

New EMA draft guidelineon sterilisation of themedicinal product

Counterfeit drugs andproduct serialisation – anoverview of serialisationrequirements

VOL.15 NO.2 JULY 2016 2 GMP REVIEW

Editorial commentPeter Savin 3

Human error: don't blame people – fix thesystem because...if you don’t the errors willhappen again and again...by Martin Lush 4

New EMA draft guideline on sterilisation ofthe medicinal producby Tim Sandle 6

Counterfeit drugs and product serialisation –an overview of serialisation requirementsby Andrew Love and Stephen McIndoe 9

Regulatory updateEU, USA & Internationalby Malcolm Holmes 12

Events 20

Contents

EDITORPeter Savin

ADVISORY PANELElizabeth AllansonMichael AnisfeldMalcolm HolmesHedley Rees

Madhu Saghee

MANAGING EDITORSue Briggs

SUBSCRIPTIONSJill Monk

PRODUCTIONDave Johnson

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GMP REVIEW 3 VOL.15 NO.2 JULY 2016

Editorial comment

Welcome to this latest issue ofGMP Review. As we go toprint, the result of the UKreferendum on our membershipof the EU has just beenannounced and all thediscussions on what it meanshave just started. While thereare some seemingly obviousimpacts on our world ofpharmaceutical goodmanufacturing practice (GMP),such as the probable move ofthe European MedicinesAgency out of its Canary Wharf Londonoffices, it is difficult to see if there will be anysignificant impact on the GMP legislation orthe UK inspectorate processes as weexperience them. I guess that only time willtell, in the meantime, carry on regardlesseveryone.Our Regulatory Update from Malcolm

Holmes contains the usual comprehensive andinformative summary of emergingrequirements and news. One particularlyinteresting topic for all GMP professionals isthe control of compounding pharmacies in theUSA. Are the US FDA in control or are patientsstill at unacceptable risk? So long after the Elixir of Death incident

which resulted in approval of the FederalFood, Drug & Cosmetic Act, the FDA stilldoesn't appear to have the authority todemand recall or suspend manufacture in suchcircumstances. In the UK, the MHRA could(and would) suspend or withdraw a license.While the FDA regularly chases the money andimposes enormous fines on pharmaceuticalcompanies, in cases like this it does notappear to be able to protect the patient. All it

can do is to alert healthcareprofessionals not to use any drugproducts that are intended to besterile and are produced anddistributed nationwide byPharmakon Pharmaceuticals Inc.This particular alert is due to alack of sterility assurance andother quality issues, which areobviously very significant risks.In this issue of GMP Review, we

have a paper on human errorprevention from Martin Lush. Asa pharmaceutical consultant,

‘human error’ is a favourite topic of mine as Istill see far too many companies citing it asthe major cause of deviations, with thesubsequent corrective and preventive action(CAPA) stating that ‘the operator wasretrained’. This raises so many questions aboutthe quality of the initial investigations as wellas the subsequent CAPA and the CAPAeffectiveness review. All this is still happeningdespite the fact that the Eudralex EUGuidelines to Good Manufacturing Practicehave clearly proscribed it since 2013 (just re-read Chapter 1 section 1.4). If this is thesituation with human error in yourorganisation, then I thoroughly recommendthat you read and share Martin’s paper and hisquiz. It is an excellent ‘eye-opener’.We also have papers from some of our

regular contributors, Tim Sandle reviews thenew EMA Draft Guideline on Sterilisation ofthe Medicinal Product and Andrew Love andStephen McIndoe present their second paperin their series of four papers on anti-counterfeiting and the serialisation issue.

Peter Savin, Editor


Ever poured coffee into a tea pot, put petrol in a diesel car,written on a white board with a permanent marker, turned upat the wrong hotel for a conference or forgotten the name ofyour boss? Well, I’ve done them all. I even managed to getonto the wrong flight once. That took some doing. As they say‘To Error is Human’.

Well, if you're serious about error prevention, read on toget your error reduction questions answered, guidance onyour ‘Six to Fix’, access to free ‘error reduction’ resources andadditional support to help drive down errors.

Let’s start with a ‘top ten’ error quiz to getthe neurons firing. Answer with a simple'Yes' or 'No'

1. Are a majority of your deviations or mistakes put downto ‘human error’?

2. Do your preventive actions focus on things like ‘re-training’, additional checks, adding more detail toinstructions or, when all else has failed, disciplinaryaction? Who knows, even promotion (yep, I’ve seenthis as well).

3. Do you think our regulators are happy with errorshappening again and again?

4. Do most of your error investigations focus on yourpeople, not the ‘system’ or working conditions theyhave to endure?

5. Do you believe there is no such thing as a single ‘rootcause’ to any problem?

6. Does a culture of ‘blame’ increase the risk of errors andmistakes?

7. Does complexity increase error rates?

8. Do you think most errors are due to systems,procedures and the leadership who created them?

9. Is your training predicated on the belief in ‘trainedperfectibility’? In other words, once trained you'reexpected to get it right?

10. Do you think people are naturally error prone andwill always make mistakes…and there is nothing youcan do about it? I know what my long suffering wifewould say.

Now the answers:Q1. Lots of ‘human error deviations’? Answer = YesI’m afraid so. In our experience, ‘root cause – human error’ isthe conclusion of convenience for a good few incidentreports. Why? Well, it’s quick and easy for sure. It also satisfies

those who believe in ‘The Person Model’ of human error. Thisis the most widely held view that places the origins ofmistakes squarely between the ears of people at the sharpend. “The product of forgetfulness, inattention, distraction,ignorance and other wayward mental processes” (Prof. JamesReason). The actions that follow usually involve retraining,naming, shaming and writing more procedures. This approachfocuses on the person, not the system or environment.Although quick, easy and emotionally satisfying, it is also verywrong. The illusion of control it creates is false and potentiallydangerous. More later…

Q2. Lots of checks, retraining and the like? Answer =in our experience YesIf you focus prevention purely on ‘The Person’, a few thingsare guaranteed. The incident will happen again, risk willincrease and culture of fear and blame will creep in (thebiggest risk of all). Once blame becomes the norm, mistakesget hidden and go unreported. After all, who likes pain and

It is no longer acceptable to blame HumanError for deviations and incidents. For over3 years the EU GMP regulations have madeit very clear (in Chapter 1, 1.4 (xiv)) that anappropriate level of root cause analysisshould be applied during the investigationof deviations, and that where human error issuspected or identified as the cause, thismust be justified having ensured thatsystem- based problems have not beenoverlooked.The message is simple, do not blame

human error for deviations and do notassign CAPAs that state “the operator wasretrained” as you will have failed toidentified the root cause and your CAPA willbe totally ineffective. The regulatoryinspectors know this, does your company?In this paper Martin Lush provides a simple

quiz that is a highly effective diagnostic touse in your organization to determine if itreally understands the issues around ‘HumanError’ and if so, what to do about them.

Human error: don't blame people – fix the system because...if you don’t the errors will happen again and again...

Martin Lush


embarrassment? As soon as ‘error’ becomes a dirty word,you're on the slippery slope to a potential crisis. It’s not if,more like when. Few set out to create a blame culture (whywould you?) but it can creep in unnoticed. Poor keyperformance indicators (KPIs), ineffective communication,invisible shop floor management all help 'blame' to sneak in.

Q3. Are regulators happy? Answer = emphatically NoRegulators, many of whom have attended our course HumanError Prevention, want you to fix problems and minimise risk.Not treat the symptoms and move on. An increasing numberof companies have been cited for poor investigations andrepeat incidents. If you’ve concluded ‘root cause – humanerror’, you had better have a good reason. If you have lots ofhuman error deviations, you deserve the criticism and 483scoming your way. As one inspector said to me recently "itseems we’re more concerned about the increased risk thanthey are".

Q4. Investigations focus on people? Answer = in ourexperience YesA recent report from the highly respected Institute ofMedicine endorsed the opposite approach to ‘The PersonModel’. Namely, ‘The System Model’ approach to errorinvestigations. The premise here is that humans are fallibleand that errors are to be expected. Even in the bestorganisations. Errors are seen as the consequence not thecause. The starting point of any investigation. Rarely itsconclusion. The ‘System’ approach to investigations isadopted by those companies serious about removing the real‘error traps’ that management unintentionally set byintroducing complexity, poor communication, inappropriateKPIs, selecting suppliers on price alone…the list is endless.Ironically, many of these exist in your quality system which ismeant to protect your patients and your legacy. Not increaseerror risk.

Q5. Root cause: Answer = there is no such thing as‘Root Cause’!Every mistake, big and small, is always due to multiplecontributing factors that all come together to form the ‘errorchain’. When investigating errors, you must dig below thesurface to discover, and remove, the many contributing factorsthat exist. So, think error chain and multiple causes and banthe term ‘root cause’ for ever. It’s a myth.

Q6. Does a blame culture make a difference? Answer= you betWe humans are really quite simple creatures. Part of ourmakeup is to feel liked, respected and safe. When criticised,named, shamed and blamed we are conditioned to either

fight or run away. Both career limiting. In a blame culture,there are a few other options to help avoid the pain andignominy of criticism. Just say nothing or tell managementonly the good news or just hide problems that could bepainful. All perfectly understandable really. Leaders are thearchitects of company culture and it is their job is to createone that allows problems to be raised, discussed andsolved…without fear.

Q7. Do complexity and error go hand in hand?Answer = 100% YesOur 21st century brains are virtually identical to those of ourancestors. All they had to worry about was staying alive andreproducing. They didn’t have to endure complex standardoperating procedures (SOPs), overcomplicated batch recordsor operating processes that require multi-tasking which, bythe way, is a neurological impossibility. As complexityincreases, so does confusion, followed by errors. Want toreduce error rate? Just strip out complexity. Want to knowhow?...just carry on reading.

Q8. Do ‘systems’ create most errors? Answer: YesSOPs with just words, batch records with multiple checks,ineffective training, poor change control, overreliance oncontractors, 12-hour shifts, a 20-page SOP for deviationinvestigations are all examples of ‘error traps’ set byleadership, albeit unintentionally. I could have gone on…mylist of system ‘error traps’ reads like ‘War and Peace’. Wantto know how to find these and fix them? Read on…

Q9. Once trained, do you expect people to get itright? Answer = ermm…We all know the correct answer is No. Training alone doesn’twork. However, its effectiveness can be dramatically improvedby taking the 10/20/70 approach and by focusing on the‘habit loop’. More later…

Q10. Should we just accept that people will alwaysmake mistakes? Answer = no, not reallyWe all make mistakes and there is little we can do to changethe neurological processes that created them. However, wecan change the environment, the error ‘catalysts’. We canadopt good user centred design, wage war on complexity,put supervisors back on the line, fix the blame culture,remove the term ‘root cause’ and invest in education nottraining. The key to it all is to focus on the system not theperson. Vital to error reduction is getting leadershipconnected and visible to the shop floor. Maybe, then, theywouldn’t set so many ‘error traps’.

Continued on page 8

Human error: don't blame people continued


Importance of sterile medicinal productsBy ‘sterile products’, this is taken to include the preparationof terminally sterilised products and the aseptic preparationof products through sterile filling. The distinction here is thatsome products can be terminally sterilised in their finalcontainer while others cannot and need to rely on pre-sterilisation of the components and bulk product beforebeing aseptically filled within a cleanroom.

Although the terms ‘sterile manufacture’ or ‘asepticmanufacturing’ are widespread, there is no generic approachto the manufacturing of sterile products. Each plant orprocess will differ in relation to the technologies, productsand process steps. Some processes, for example, use terminalsterilisation which has one level of risk; other processesinvolve filling aseptic products which has an arguably higherlevel of risk. The new guidance attempts to contextualisethese risks and provide the latest regulatory thinking inrelation to product safety.

With the concept of sterility, this cannot be proven throughtesting (the weaknesses of the sterility test are well established);sterility assurance is a factor of a well-maintained and in-controlmanufacturing operation, including the following.

● The bioburden of the formulation components.

● The sterilisation procedure (or aseptic processing, usingsatisfactory aseptic techniques).

● The integrity of the container closure system.

European regulationsThe existing European regulatory guidance for sterile productsis based on European Commission Directive 2003/94/EC,which describes principles and guidelines of goodmanufacturing practice (GMP) with respect to medicinalproducts for human use and investigational medicinalproducts for human use. European GMP is set-out withinEudraLex. The Rules Governing Medicinal Products in theEuropean Union. Volume 4: EU Guidelines to GoodManufacturing Practice – Medicinal Products for Human andVeterinary Use. Annex 12. Annex 1 is currently under review –a process for which a concept paper has been produced3.

In addition, to support Annex 1, there is a documentpertaining to pre-sterilisation bioburden4; and one whichprovides the decision tree for selecting terminal sterilisation oraseptic filling5. The new draft document sets out to replacethese two documents, unifying the content and addingadditional material.

The difference between the new document and Annex 1is that the new guideline focuses on actions to consider

when establishing a new product, including what isrequired for licence submission, and for modifyingprocesses; whereas Annex 1 focuses on maintainingcompliance.

Key points from the draft guidanceThe most important points raised in the new guidance are asfollows.

Sterilisation methodAs with the previous guidance, terminal sterilisation remainsthe process of choice for sterile products. Aseptic processingshould only be followed if it can be demonstrated that anyconventional sterilisation process would destroy, or renderineffective, the medicinal product.

The guidance also reiterates that the sterility assurancelevel is applicable to terminally sterilised products, and that itis not applicable to aseptic processing.

Microbial controlThe document stresses the importance of microbial controlduring processing. The main risk highlighted is levels ofbacterial endotoxin in the finished product. With bioburden,emphasis is placed on filter validation and demonstration thatthe final filter used can remove a ‘high’ bioburden.

Steam sterilisationWith steam sterilisation, the draft guidance states that an F0≥8 minutes is required for all steam sterilisation processes. TheF0 concept concerns equivalent lethality. An F0 of 8 minutesmeans that the process being conducted at whatevertemperature (T°C) and time (� minutes) is equivalent in termsof its lethality to 8 minutes at 121°C. This could be a higher

Given the importance of sterile products, inproviding both a therapeutic medicine andwith regards to the necessity of being freefrom viable microorganisms, pyrogenicsubstances and visible particulates, no newguidance has been issued by a regulatoryauthority in recent years. This has changedwith a new draft guidance document from theEuropean Medicines Agency. Issued in April2016 for public comment, the document istitled Guideline on the Sterilisation of theMedicinal Product, Active Substance,Excipient and Primary Container1. The keypoints are reviewed in this article.

by Tim SandleNew EMA draft guideline on sterilisation of the medicinal product


temperature than 121°C for a shorter time, or a lowertemperature than 121°C for a longer time.

To support a case for steam sterilisation, the following dataneeds to be compiled.

● Load mapping distribution (cold spots) – summary orconfirmation of performance.

● Physical and biological cycle effect confirmationsummary of at least three autoclave runs ensuring:

• Sufficient time at or above nominal temperature inthe whole autoclave.

• Acceptable temperature differences betweenthermocouples in the load.

• Acceptable F0 variability within the load.

• Relationship between physical and biologicalvalidation.

An assessment of pre-sterilisation bioburden is alsorequired, up to a maximum of 100 colony forming units (CFU)per 100mL (or equivalent).

Dry heat sterilisationThe requirements for dry heat sterilisation are similar (in thatboth steam sterilisation and dry heat sterilisation require asterility assurance level of 10-6). The requirements for processdescription and validation are also similar.

● Load mapping distribution (cold spots) – summary orconfirmation of performance.

● Physical and biological cycle effect confirmationsummary of at least three sterilisation runs ensuring:

• Sufficient time at or above nominal temperature inthe whole dry heat sterilisation cabinet.

• Acceptable temperature differences betweenthermocouples in the load.

• Acceptable lethality variability within the load.

• Relationship between physical and biologicalvalidation.

Sterile filtrationWith sterile filtration, the specification given is for a filter witha pore size of 0.22µm or less, which is consistent with previousguidance. New information is provided about the point offiltration being located as close as possible to filling and thatthis should take place at the end of any hold time (with the aimof ensuring the tested bulk is representative).

A further change is in the bioburden limit. Since the mid-1990s, the bioburden limit has been not more than 10

CFU/100mL. The draft text now reads “bioburden limit ofhigher than 10 CFU/100mL before pre-filtration may beacceptable”. This is based on data relating to productbioburden.

The terminology for the bioburden test is now described as“Total Aerobic Microbial Count”, which is consistent with theterminology used for testing non-sterile products in theEuropean Pharmacopoeia. This replaces the “Total ViableAerobic Count”, which is sometimes used. Interestingly, aspecific agar is referred to for the test: casein soya bean digestagar (which is the non-commercial name for tryptonesoyabean agar).

A key point is made regarding filter validation. Here, itstates that the filter validation must have considered the totalfiltration time, and demonstrate suitable bacterial retention.

Other forms of sterilisationThe draft guidance makes reference to ionising radiation,although this is short on detail and the reader is directedtowards ISO standards (such as EN/ISO 11137: Sterilisation ofHealth Care Products – Radiation). More detail is provided inrelation to gassing. Here, it is emphasised that sterilisation bygas is limited to surface sterilisation only. Key requisites are asfollows.

● Understanding the product bioburden prior tosterilisation.

● The time of exposure to the gas.

● The temperature and humidity prior to and during eachstep of the sterilisation cycle.

● Conditions for the removal of any toxic gas residues.

With the latter point, a caution is made about the toxicityof ethylene oxide.

For any other type of sterilisation method, not described inthe draft guidance, these can be considered. However,scientific advice must be sought.

DepyrogenationThe guidance references the minimum temperature fordepyrogenation by dry heat as at or above 220oC, with therequirement to demonstrate a three-log reduction ofendotoxin. This is different from earlier descriptions ofdepyrogenation, which place the threshold at 180oC (albeitfor a longer run time).

Aseptic processingWith aseptic processing, the draft guidance highlights twopoints of contamination concern: product hold time andprocess run time. Concerns are raised about processes

New EMA draft guideline continued


running for 24 hours or more, and there is a requirement thatprocess simulations (media trials) are used to justify asepticfilling run times.

Other points coveredThe guidance provides a revised series of decision trees forthe sterilisation of aqueous products and non-aqueous liquid,semi-solid or dry powder products. These are designed tohelp the pharmaceutical manufacturer select between terminalsterilisation methods and aseptic processing.

SummaryThe new document provides greater clarification on Europeanregulatory thinking in relation to sterile products manufactureand simplifies access through bringing two existing documentstogether.

Overall, there is little of controversy; although the issue withthe pre-final filtration bioburden being extended to a value about10 CFU/100mL (when justified) may lead to a debate aboutmicrobial controls during manufacturing. A second point ofdiscussion could revolve around media fills and run times. It isoften unclear how long media fills should be. With things notcovered, environmental monitoring – the key measure ofenvironmental control for aseptic processing – is consciouslyabsent, along with cleanrooms and manufacturing environments.

Nevertheless, the document does help to clarify the licencesubmission requirements in relation to sterilisation methods.Comments close in October 2016 and the finalised document isexpected early into 2017.

References1 European Medicines Agency. Guideline on the Sterilisation ofthe Medicinal Product, Active Substance, Excipient andPrimary Container.EMA/CHMP/CVMP/QWP/BWP/850374/2015. London, UK:EMA; 2016. Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/04/WC500204724.pdf (Accessed 1 May2016).

2 European Commission. EudraLex. The Rules GoverningMedicinal Products in the European Union. Volume 4: EUGuidelines to Good Manufacturing Practice – MedicinalProducts for Human and Veterinary Use. Annex 1 –Manufacture of Sterile Medicinal Products. Brussels, Belgium:European Commission; 2008. Available at:http://ec.europa.eu/health/files/eudralex/vol-4/2008_11_25_gmp-an1_en.pdf (Accessed 15 May 2016).

3 European Medicines Agency. Concept Paper on the Revision ofAnnex 1 of the Guidelines on Good Manufacturing Practice –Manufacture of Sterile Medicinal Products.EMA/INS/GMP/735037/2014. London, UK: EMA; February2015. Available at:http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/02/WC500181863.pdf (Accessed 10 May2016).

4 The European Agency for the Evaluation of Medicinal Products,Committee for Proprietary Medicinal Products. Note forGuidance on Manufacturing of the Finished Dosage Form.CPMP/QWP/486/95. London, UK: EMEA; April 1996. Availableat: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002916.pdf

5 The European Agency for the Evaluation of Medicinal Products,Committee for Proprietary Medicinal Products. Decision Treesfor the Selection of Sterilisation Methods (CPMP/QWP/054/98)and Annex to Note for Guidance on DevelopmentPharmaceutics (CPMP/QWP/155/96). London, UK: EMEA;1999. Available at:http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003520.pdf (accessed 10 May2016).

Dr. Tim Sandle is Head of Microbiology at the UK Bio ProductsLaboratory (email: [email protected]). In addition, Tim is a visitingtutor with the School of Pharmacy and Pharmaceutical Sciences,University of Manchester. Tim serves on several national andinternational committees relating to pharmaceutical microbiologyand cleanroom contamination control. Outside of work, Tim runs anon-line microbiology blog (www.pharmamicroresources.com) and hehas written extensively on the subject of pharmaceuticalmicrobiology and contamination control.

New EMA draft guideline continued

Now for your ‘Six to Fix’● Ban the term ‘root cause’. It’s a myth. Focus on

removing the multiple factors that accompany everyerror or mistake. Break the error chain.

● Make sure your investigation focuses on ‘The System’,not ‘The Person’.

● Remove blame and you will be fine. Don’t and youwon’t.

● If you haven’t started your war on complexity already,

start now. You can’t afford to lose it.

● Get your leadership on the shop floor. You can’t affordanymore error traps.

Martin Lush is the President of NSF Pharma Biotech Consulting.He has over 30 years’ experience in the pharmaceutical andhealthcare industry. He has held senior management positions inquality assurance, manufacturing, quality control and supplychain auditing and has conducted audits and educationprograms for many hundreds of companies in over 25 countries.

Human error: don't blame people continued from page 5


Serialisation legislation requires that every product pack isuniquely identified and registered in an external agencydatabase, together with information about the productcontained in the pack. Depending on the particular legislation,it may also be necessary to update the external agencydatabase with product movement and change of ownershipinformation, a significantly more complex requirement.

Whilst some pharmaceutical companies understand thislegislation and have a clear strategy and program of capabilityimplementation under way, others do not.

Unique identificationFirstly, let’s look at the basics of serialisation. To help explainthis, we will break serialisation legislative requirements downinto four elements.

1. Unique identification.2. Product information notification.3. Authentication.4. Track & trace.

1. Unique identificationAll serialisation legislation requires one or more levels ofpackaging to be uniquely identified with some form of“licence plate” or serial number. Furthermore, in all recentlegislation, this identification must be applied to packagingusing some form of machine-readable carrier.

In current legislation, the lowest level of packagingrequiring serialisation is the smallest saleable unit, typically thesecondary pack. As will be discussed later, some legislationalso requires higher levels of packaging and shippers to beserialised as well.

Ultimately, serialisation of primary packaging (e.g. blisterpockets, vials) and in some cases (e.g. tablets) the productitself may be required, as many would argue that this providesthe best protection to the patient. Whist some regulators arediscussing this, few are indicating imminent legislation.

There are broadly two approaches to ensuring that serialnumbers are unique that are currently adopted by legislation,market uniqueness and product uniqueness.

Market uniquenessIn this model, an external agency manages all serial numbersfor a particular market or region. They issue serial numberblocks to manufacturers (and potentially other supply chainpartners), who would then manage the application of thosenumbers to product packaging.

UNIQUE IDENTIFICATION = UNIQUE NUMBER ISSUED BYEXTERNAL AGENCY

In this model, a manufacturer will typically require a serialnumber [request and allocation management system] toensure that enough serial numbers are available in the rightlocations to enable manufacture.

Product uniquenessAn alternative model uses a combination of product code andserial number to achieve uniqueness.

UNIQUE IDENTIFICATION = PRODUCT CODE + SERIALNUMBER

Product codes, such as the internationally recognisedGlobal Trade Identifier Number (GTIN) are unique. Therefore,in this type of scheme, the uniqueness of serial numbersneed only be managed across all product of the sameproduct code.

Given that product codes are normally unique to a singlemanufacturer, the management of serial numbers for aproduct can then become the entire responsibility of theindividual manufacturer. Typically this simplifies matters as it isnot necessary to ask an external agency for groups of serialnumbers and it offers the opportunity for simpler rules-basedserial number allocation and management to individualmanufacturing facilities.

Having established which packaging levels need to beserialised and the method of creating and managing uniqueidentifiers or serial numbers, we will now discuss theinformation that needs to be applied to the packaging and themechanism by which this is achieved.

Information applied to packagingOften, the information required to be applied to thepackaging is not limited to the unique identifier or serialnumber described above. Frequently, additional information,

As discussed in our previous article on thethreat of counterfeit drugs, pharmaceuticalproduct serialisation legislation is beingdeveloped and approved across the world toensure patient safety and prevent fraud.Achieving this across the supply chain is amajor and very costly undertaking. Failure tocomply with these legislative requirementswill mean that pharmaceutical companies willnot be able to sell products in the affectedmarkets.

Counterfeit drugs and product serialisation– an overview of serialisation requirements

by Andrew Love andStephen McIndoe

such as [Batch/Lot Identifier] and [Expiry Date] are alsorequired to be included in the machine readable carrier. Often,if not already present, text describing this information mustalso be applied to the packaging.

This additional information allows people in thedownstream supply chain to make use of the information toimprove the efficiency and effectiveness of their processeswithout the need to obtain information from any othersource.

As an example, dispensaries can scan the machine readablecarrier, obtain information about the product contained withinthe carrier and compare this electronically with theprescription to help reduce dispensing errors.

Machine-readable carriersThere are many different ways in which information can beplaced on a pack in order that it is machine readable.

Where serialisation legislation is concerned, two methodsare typically currently mandated: linear barcodes and/or2D/Datamatrix barcodes. Radio Frequency Identification(RFID) tags have also been extensively discussed, but at thetime of writing had not been mandated.

2. Product information notificationTypically, once product packaging of one or more levels hasbeen uniquely identified, this information, together with otherinformation related to the product and manufacturer is passedto an external agency database.

The information in this database is then used by thedownstream supply chain and other agencies as describedlater in this series.

The triggers and grouping of the information transfers willvary according to the specific requirements of the legislationand the local business processes. In the simplest of models,the information can be transferred at, or around the time whenthe product packaging batch has been completed.

3. AuthenticationAuthentication is a term often used to describe the followingprocess of checking the legitimacy of a product using itsserialisation.

One of the primary purposes of serialisation is to enableindividuals in the downstream supply chain to scan a productand compare the information on the product packaging withthe information stored in the external agency’s database. If thetwo sets of information match and it is evident that theproduct has not been tampered with, then it will be highlylikely that that the product is legitimate.

As an example, a patient might scan a product pack with asmart phone using its in-built camera. Using an application,

the smart phone would then request information related tothe unique identifier contained in the machine readable codeand display it to the patient. The patient would then comparethis information to the information contained on thepackaging. If everything matched and the tamper evidentsealing was still intact, the patient could have greaterconfidence that the product was legitimate.

A number of serialisation legislative models stop at therequirement for a means of authentication. It appears that therecent European Union falsified medicines legislation2011/62/EU is one such example. Many would argue that thislevel of serialisation provides an improved level of protectionagainst falsified products and fraud that is sufficient, at leastfor the current round of legislation.

4. Track & traceTrack and trace legislative models attempt to further improvethe protection against the entry of falsified medicines into thelegitimate supply chain.

Typically, this is achieved by also requiring every change ofownership (and potentially location) of product to berecorded in the external agency database. Such legislationthen also requires purchasers to verify the legitimacy of theproduct they are receiving by ensuring that the externalagency database confirms that the seller had legitimateownership of the product prior to sale. Rules are also requiredin the external agency database to ensure that the sameproduct was not introduced illegitimately into the supplychain, or sold more than once from any single owner.

This is a similar model to that used in many countries tocontrol the legitimate buying and selling of motor vehicles,which also present a significant threat to the health and safetyof the public if they are not legitimate. Many such modelsadhere to the following basic principles. Each car is identifiedby a unique licence plate. When a seller sells a motor vehicle,they have to complete a sales transaction which is registeredin the transport agency’s database stating which vehicle(licence plate) they have sold and to whom. When a buyerpurchases the motor vehicle, they register their ownershipwith the same agency and indicate who they purchased thevehicle (licence plate) from. The external agency databasealso contains other information that helps confirm the identityof the vehicle to anyone concerned, such as make, model,colour. This information is also used by buyers and sellers toconfirm the legitimate identity of individual vehicles. If thesale and purchase information matches then all is ok. If not,then investigation activity is triggered.

These additional track & trace requirements necessitatetwo very significant additional elements to be implementedover and above the authentication serialisation model.


Counterfeit drugs and product serialisation continued


1. Many, if not all, supply chain nodes handling productwill need to be equipped to scan product and relatethe unique identifier information to purchase, sales andother transactions and then communicate it to theexternal agency database. If they break productshippers down, they may also be required to serialisenew shippers.

2. To make (1) practical, many if not all levels ofpackaging shippers (e.g. bundles, cases and pallets)need to be serialised, and the physical relationshipbetween a shipper and its serialised contents built,communicated and maintained in the external agency’sdatabase.

Element (1) is required to track the purchase and salestransactions down to the individual uniquely identified pack.For example, whenever a sale is made, all products which arephysically changing ownership would need to be identifiedand the associated sale information updated in the externalagency database. This requires the location in the supplychain handling the product at the point of sale to physicallyidentify all the product being sold, down to its unique

identifier. This is normally achieved by incorporatingserialisation technology into the order processing and pickingactivities at a distribution location.

Element (2) is required to avoid the need for every suchdistribution location to break open all shippers and identifyall uniquely identified packages within. A situation whichwould quickly bring the product supply chain to an effectivehalt.

This completes the second article in this series. In the nextarticle we will look at standards, opportunities presented byserialisation beyond legislative compliance, and what youwould need to do to comply with the legislation.

Stephen McIndoe is a Vice� President at Be4ward and works withglobal healthcare companies to create award-winning world classpackaging labelling and artwork capabilities. He is also co-author,with his colleague Andrew Love, of the book Developing andSustaining Excellent Packaging Labelling and ArtworkCapabilities�.

Andrew Love is also a Vice� President at Be4ward. He waspreviously Head of Global Packaging Design at GlaxoSmithKline.�

Counterfeit drugs and product serialisation continued

PharmacoVigilanceRevıewSupporting the safe use of

medicines and medical devices

Managing Reference SafetyInformation

The EU centralised applicationfrom a pharmacovigilance andrisk management prospective

Post-authorisation aggregatesafety reporting: the new PSUR

New European pharmacovigilancelegislation – an adequateresponse to current challenges?

Volume 7 Number 3/4 Nov 2013

PharmacoVigilanceRevıew

Journal on drug safety issuesEditor – Rob Begnett

This quarterly journal provides informed comment andanalysis of international pharmaceutical regulationsrelating to the safe use of medicines and medicinaldevices. It also carries reviews of current methods ofpharmacovigilance.

Order online at www.euromedcommunications.comOr email: [email protected] Tel: +44 (0)1428 752222 Fax: +44 (0)1428 752223


IntroductionWithin this summary, readers will note anexample of a USA compounding companyrefusing to cease steriles manufacture andperform a recall despite Food and drugadministration (FDA) “advice” to do so. Thereis also a letter from the Medicines andHealthcare Products Regulatory agency (MHRA)to a UK newspaper indicating that a recentlypublished article is misleading and could leadto an increase in concern amongst healthcareprofessionals and patients. Developments inthe “regulation” of the pharmaceuticalindustry since our last review include thefollowing.

EuropeEuropean Medicines Agency (EMA)Improving safety of first-in-human clinical trialsThe EMA has started a review of the guidelines that describefirst-in-human clinical trials and the data needed to enabletheir appropriate design and allow initiation. This is beingdone in cooperation with the European Commission and theMember States of the European Union (EU). The review willidentify which areas may need to be revised in light of thetragic incident which took place during a Phase I first-in-humanclincial trial in Rennes, France in January 2016. The trial led tothe death of one participant and hospitalisation of five others.

The aim of the review is to agree a concept paper by July2016 identifying areas for change and proposals to furtherminimise the risk of similar accidents. The concept paper willform the basis for an EU-wide review of the guidelines. Thisprocess will include targeted discussions with stakeholdersand a public consultation on proposed changes later in 2016.

EU Good Manufacturing Practice (GMP) Q&A – datarequired for sterilisation processes of primarypackaging materials subsequently used in an asepticmanufacturing process.Terminal sterilisation of the primary packaging, usedsubsequently during aseptic processing of the finishedproduct, is a critical process and the sterility of the primarycontainer is a critical quality attribute to ensure the sterility ofthe finished product. Both need to be assured for compliancewith relevant pharmacopoeial requirements for the finishedproduct and product approval.

The site where sterilisation of the packaging materials takesplace may not have undergone inspection by an EU authorityand consequently may not hold an EU GMP certificate inrelation to this activity.

When GMP certification is not available, certification that

the sterilisation has been conducted and validated inaccordance with specific International Organization forStandardization (ISO) standards would be considered toprovide an acceptable level of sterility assurance for the emptyprimary container.

Eudralex Volume 3 Sterilisation of the MedicinalProduct, Active Substance, Excipient and PrimaryContainerThis draft guideline, which is open for comment until 13October 2016, provides guidance on the documentationexpected for sterile products in the quality dossier for amarketing authorisation application or a variation applicationfor a medicinal product (called quality dossier throughout theguideline), and the selection of appropriate methods ofsterilisation for sterile products.

Although, terminal sterilisation using a reference conditionof the European Pharmacopoeia (Ph. Eur.) is the method ofchoice whenever possible, this guideline provides informationon when other terminal sterilisation processes, sterilisingfiltration or aseptic processing (either alone or when combinedwith an additional terminal microbial reduction process), couldbe accepted as an alternative to a reference terminalsterilisation process.

This guideline replaces the previous Annexes topharmaceutical development decision trees for the selectionof sterilisation methods (human and veterinary). In addition,the information on methods of sterilisation previouslydescribed in note for guidance on manufacture of the finisheddosage form (human and veterinary) has been revised andincluded in this guideline.

Implementation plan for the introduction of thesafety features on the packaging of centrallyauthorised medicinal products for human use Certain aspects of the implementation of the FalsifiedMedicines Directive (Directive 2011/62/EU FMD) and the newdelegated act on the safety features (Commission DelegatedRegulation (EU) 2016/161 – "the Delegated Regulation") mayimpact on the product information and the marketingauthorisation dossier; in particular, the placing of safetyfeatures, a unique identifier (UI) carried by a 2-D barcode andan anti-tampering device (ATD), on the packaging ofprescription medicines and certain non-prescriptionmedicines for the purposes of authentication andidentification.

The EMA and the European Commission have preparedthis implementation plan to guide applicants and MarketingAuthorisation Holders (MAHs) through the regulatorychanges necessary to accommodate the new legislativerequirements. The EMA and the Quality Review of Documents

Regulatory Update by Malcolm Holmes


Regulatory Update continued

Group (QRD) have revised the Human Product Informationtemplates. The updated QRD template will facilitate theimplementation of the relevant standard statements on the UIand its carrier under Sections 17 and 18 of Annex IIIA, in orderfor the MAHs to implement the safety features by 9 February2019 as required by the Delegated Regulation.

The inclusion of the safety features standard statementsunder Sections 17 and 18 of Annex IIIA does not indicate thatthe safety features have been actually implemented on thepackaging placed on the market, but rather that the productinformation has been updated to confirm that the safetyfeatures will be implemented on the marketed packaging inline with the provisions of the Delegated Regulation (i.e. by 9February 2019). The implementation of the ATD is notexpected to impact the product information. However, whenthe ATD is placed on the immediate packaging because thereis no outer packaging, certain section(s) of the marketingauthorisation dossier may be impacted.

European Directorate for the Quality of Medicines(EDQM)Potential presence of mutagenic alkyl sulfonates inactive substances The last of five general methods, elaborated by the EuropeanPharmacopoeia’s Mesilate Working Party, were implementedon 1 April 2016 (Supplement 8.7). This working party hadbeen appointed by the Ph. Eur. Commission in 2008 to assistusers in determining mutagenic impurities potentially presentin mesilate-, besilate- or tosilate-salts of active substances. Inaddition to the elaboration of these methods, the Ph. Eur.Commission had also decided to revise the productionsection of the monographs to inform users of the risk relatedto the potential presence of such mutagenic impurities.

New Ph. Eur. general chapter on host-cell proteinassays This general chapter provides guidance on the selection,development and validation of a host-cell protein assay anddescribes specific considerations for process-specific, platformand generic assays.

Survey on microbiological control of tissuesThe aim of the survey is to gather information from relevantstakeholders to enable the Ph. Eur. experts in charge of theelaboration of this chapter to have a clear vision on thecurrent situation regarding the characteristics of tissuepreparations used in Europe and how they are monitored withregard to microbiological control. Completing the surveyshould only take 5–10 minutes and should be done by 2September 2016.

MHRAMHRA BlogThe latest edition of the MHRA Blog covers the followingtopics.

● Qualification of customers, what wholesalers need toknow.

● Manufacture of investigational medicinal products –frequently asked questions.

● Enforcement Group – tackling the illegal trade inmedicines.

● Refrigerated medicinal products, part 2: Transportation,packing, temperature management, the use of thirdparty couriers and returns – some things to consider.

(Note: previous topics which may also be of interest are stillavailable on the blog site – MH).

Good Manufacturing Practice and Good DistributionPracticeThe MHRA has updated its December 2014 guidance on GMPand GDP and how to prepare for an inspection, which formspart of its guidance on manufacturing, wholesaling, importingand exporting medicines good practice, inspections andenforcement and patient safety.

GDP – Qualification of suppliers – the 3 steps neededto assure supply chain integrityRecently, the MHRA has had a number of situations wherecompanies have not understood the obligations placed onthem by the Human Medicines Regulations 2012 Regulation44 (2) and (3) and Good Distribution Practice in relation toqualification of suppliers. It has, therefore, published on itsblog a reminder to companies of the requirements and givestips on ways to ensure the system of qualification is robust.

USA

FDAManual of Policies and Procedures (MAPP) – ApplyingICH Q8(R2), Q9 and Q10 principles to chemistry,manufacturing, and controls (CMC) reviewThe number of new drug applications (NDAs), investigationalnew drug applications (INDs), abbreviated new drugapplications (ANDAs) and biologics license applications(BLAs) and their supplements containing quality-by-design(QbD) approaches has increased. Because of this increase, theCenter recognises the need for reviewers to consistentlyimplement the International Conference on Harmonisation(ICH) guidances in their reviews. As a result Office of


Pharmaceutical Quality (OPQ) product quality reviewers willconsider ICH Q8(R2), Q9, and Q10 recommendations whenreviewing applications that may or may not include QbDapproaches.

Review of grouped product quality supplementsThis MAPP outlines the policies and procedures for groupingsupplements submitted concurrently that provide for thesame CMC changes to multiple approved NDAs, ANDAs andBLAs and are submitted by the same applicant. The goal is toimprove efficiency and provide consistency when reviewingthese grouped supplements.

● When applicants make identical CMC post-approvalchanges that affect multiple approved applications,the Center needs procedures for reviewing thesegroups of supplements. Implementing theseprocedures helps the OPQ manage the review ofthese changes in an efficient manner and ensuresconsistency.

● This MAPP has been revised to replace the term“bundled supplements” with “grouped supplements”.

● The previous version of this MAPP applied only tosupplements to NDAs/supplements to NDAs. A relatedMAPP applied only to supplements to ANDAs

Environmental Assessment: Question and AnswersRegarding Drugs with Estrogenic, Androgenic, orThyroid Activity – Guidance for Industry This guidance is intended to supplement FDA’s guidance forindustry on Environmental Assessment of Human Drug andBiologics Applications, issued July 1998 (the EA Guidance),by addressing specific considerations for drugs that havepotential estrogenic, androgenic, or thyroid hormonepathway activity (E, A, or T activity) in the environment.

FDA regulations at 21 CFR part 25 specify that EAs mustbe submitted as part of certain NDAs, ANDAs, BLAs,supplements to such applications, and INDs, as well as forvarious other actions, unless the action qualifies for acategorical exclusion. Failure to submit either an EA or aclaim of categorical exclusion is sufficient grounds for theFDA to refuse to file or approve an application (21 CFR25.15(a), 314.101(d)(4), and 601.2(a) and (c)).

This guidance focuses on the categorical exclusion foractions on NDAs and NDA supplements that would increasethe use of an active moiety, but the estimated concentrationof the substance at the point of entry into the aquaticenvironment would be below 1 part per billion. Although anaction that qualifies for this exclusion ordinarily does notrequire an EA, the FDA will require “at least an EA” if

“extraordinary circumstances” indicate that the specificproposed action (e.g. the approval of the NDA) maysignificantly affect the quality of the human environment.

General Principles for Evaluating the AbuseDeterrence of Generic Solid Oral Opioid Drug ProductsThis draft guidance is intended to assist a potentialapplicant who plans to develop and submit an ANDA toseek approval of a generic version of a solid oral opioiddrug product that has the potential for abuse and whichreferences an opioid drug product with abuse-deterrentproperties described in its labelling. The guidancerecommends studies, including comparative in vitro studies,should be conducted by the potential ANDA applicant andsubmitted to the FDA in an ANDA to demonstrate that ageneric solid oral opioid drug product is no less abuse-deterrent than its reference listed drug with respect to allpotential routes of abuse.

Labeling for Biosimilar ProductsThis draft guidance is intended to assist applicants indeveloping draft labelling for submission in applications forproposed biosimilar products under Section 351(k) of the PHSAct (42 U.S.C. 262(k)). The recommendations for prescriptiondrug labelling in this guidance pertain only to the prescribinginformation (commonly referred to as the package insert),except for recommendations in Section V pertaining to FDA-approved patient labelling (e.g. Patient Information,Medication Guide, and Instructions for Use). Specific labellingrecommendations for interchangeable biological products arenot provided.

To meet the standard for interchangeability, an applicantmust provide sufficient information to demonstratebiosimilarity and also to demonstrate that the biologicalproduct can be expected to produce the same clinical resultas the reference product in any given patient and, if thebiological product is administered more than once to anindividual, the risk in terms of safety or diminished efficacy ofalternating or switching between the use of the biologicalproduct and the reference product is not greater than therisk of using the reference product without such alternationor switch (see Section 351(k)(4) of the PHS Act).Interchangeable products may be substituted for thereference product without the intervention of the prescribinghealthcare provider (see Section 351(i)(3) of the PHS Act). Anapplication submitted under Section 351(k) of the PHS Actmust contain, among other things, informationdemonstrating that “the biological product is biosimilar to areference product” based upon data derived from thefollowing.




● Analytical studies that demonstrate that the biologicalproduct is highly similar to the reference productnotwithstanding minor differences in clinically inactivecomponents.

● Animal studies (including the assessment of toxicity).

● A clinical study or studies (including the assessment ofimmunogenicity and pharmacokinetics orpharmacodynamics) that are sufficient to demonstratesafety, purity and potency in one or more appropriateconditions of use for which the reference product islicensed and intended to be used and for whichlicensure is sought for the biological product.

The FDA has the discretion to determine that an elementdescribed above is unnecessary in a 351(k) 72 application.Under FDA regulations, prescription drug labelling mustprovide adequate information to enable healthcarepractitioners to use the drug safely and for the purposes forwhich it is intended, and to this end the approved prescribinginformation summarises the essential scientific informationneeded by healthcare practitioners for the safe and effectiveuse of a drug. This labelling reflects the FDA’s finding ofsafety and effectiveness for the drug under the labelledconditions of use and facilitates prescribing decisions,thereby enabling the safe and effective use of drugs(including biological products) and reducing the likelihood ofmedication errors.

Donor Screening Recommendations to Reduce theRisk of Transmission of Zika Virus by Human Cells,Tissues, and Cellular and Tissue-Based Products –Guidance for IndustryThe FDA has issued new guidance for immediateimplementation providing recommendations to reduce thepotential transmission risk of Zika virus from human cells,tissues, and cellular and tissue-based products (HCT/Ps). Theguidance addresses donation of HCT/Ps from both living anddeceased donors, including donors of umbilical cord blood,placenta, or other gestational tissues.

Safety Considerations for Product Design to MinimizeMedication Errors – Guidance for IndustryThis guidance focuses on minimising risks associated withthe design of the drug product and its container closuresystem, and is the first in a series of three plannedguidances to minimise or eliminate hazards contributing tomedication errors at the product design stage. The secondguidance focuses on minimising risks associated with thedesign of drug product container labels and cartonlabelling, and the third focuses on minimising risks when

developing and selecting proposed proprietary names.To avoid safety issues and costly redesigns after a product

enters the market, it is important to consider the end user(s)in their environments of use early in the development anddesign of a drug product. The FDA recommends the use ofrisk assessments early and throughout the development anddesign of a drug product. Identification of clinically relevantcharacteristics of the drug product during development willhighlight potential areas for risk assessment. Riskassessments also are valuable for identifying potentialmedication errors that may result from post-marketingchanges or additions to an already marketed drug productthroughout its lifecycle.

Comparability Protocols for Human Drugs andBiologics: Chemistry, Manufacturing, and ControlsInformationThis draft guidance provides recommendations to holders ofapplications for human drugs and biologics on implementinga CMC post-approval change through the use of acomparability protocol. It replaces the draft guidance thatwas published in February 2003. This guidance is intended toestablish a framework to promote continuous improvementin the manufacturing of quality products by encouragingapplicants to employ the following.

● Effective use of knowledge and understanding of theproduct and manufacturing process.

● A robust control strategy.

● Risk management activities over a product’s lifecycle.

● An effective pharmaceutical quality system.

Contents of a Complete Submission for the Evaluationof Proprietary Names – Guidance for IndustryThis guidance describes for industry the information thatthe FDA uses to evaluate proposed proprietary names forcertain drugs, including biological products, under thetraditional review process within the time frames set out inthe Prescription Drug User Fee Act (PDUFA IV)performance goals. The review clock for the performancereview goals begins when the Agency receives a completesubmission.

Accurate identification of medications is critical topreventing medication errors and potential harm to thepublic. This guidance is intended to assist industry in thesubmission of a complete package of information that theFDA will use in the assessment of:

● the safety aspects of a proposed proprietary name toreduce medication errors, and

● promotional implications of a proposed proprietaryname, to ensure compliance with other requirementsfor labelling and promotion using the FDA’s traditionalreview methods.

As part of its premarket review of products that are thesubject of an NDA, BLA or ANDA, the FDA evaluates bothsafety and promotional aspects of the product’s proposedproprietary name. For tools and methods the FDA uses for itsanalysis, see the FDA concept paper entitled “PDUFA PilotProject Proprietary Name Review”.

Data Integrity and Compliance with CGMPThe purpose of this draft guidance is to clarify the role of dataintegrity in current good manufacturing practice (CGMP) fordrugs, as required n 21 CFR parts 210, 211, and 212.

In recent years, the FDA has increasingly observed CGMPviolations involving data integrity during CGMP inspections.This is troubling because ensuring data integrity is animportant component of the industry’s responsibility toensure the safety, efficacy and quality of drugs. These dataintegrity-related CGMP violations have led to numerousregulatory actions, including warning letters, import alertsand consent decrees. This draft guidance contains a set ofQ&As clarifying the FDAs requirements.

FDA alerts healthcare professionals not to use steriledrug products from Pharmakon Pharmaceuticals, Inc.,Noblesville, IndianaThe FDA is alerting healthcare professionals not to use anydrug products that are intended to be sterile and areproduced and distributed nationwide by PharmakonPharmaceuticals, Inc. in Noblesville, Indiana, due to a lack ofsterility assurance and other quality issues.

The FDA recently inspected Pharmakon’s facilityfollowing the company’s voluntary recall of super-potentmorphine sulfate 0.5mg/mL preservative free in 0.9%sodium chloride, 1mL syringe, for intravenous use. The FDAtest results showed the product to be nearly 2500 percentthe labelled potency. During the inspection, investigatorsobserved insanitary conditions, including poor sterileproduction practices, and other deficiencies, which raiseconcerns about Pharmakon’s ability to assure the sterilityand quality of drug products that it produces. Additionally,FDA testing confirmed environmental contamination onmultiple sites within the cleanrooms, including the criticalISO-5 area.

The FDA recommended that Pharmakon cease sterileoperations until appropriate corrective actions have beenimplemented by the facility and recall all non-expired drugproducts that are intended to be sterile. However,

Pharmakon informed the FDA that it would neitherinitiate a recall nor cease sterile production.

Pharmaceutical distribution supply chain pilotprojects; request for information The FDA is soliciting information regarding issues related toutilising the product identifier for product tracing, improvingthe technical capabilities of the supply chain, and identifyingsystem attributes that are necessary to implement therequirements established under the Drug Supply ChainSecurity Act (DSCSA). The information gathered from publiccomments will assist with the design and development ofthe pilot project(s) that the FDA establishes under theDSCSA.

Facility Definition Under Section 503B of the FederalFood, Drug, and Cosmetic Act The FDA has received questions from outsourcing facilitiesand other stakeholders about the meaning of this term, suchas whether multiple suites used for compounding humandrugs at a single street address constitute one or multiplefacilities, or whether a single location where human drugs arecompounded can be subdivided into separate operationscompounding under different standards. The FDA is issuingthis draft guidance to answer these questions

Prescription Requirement Under Section 503A of theFederal Food, Drug, and Cosmetic ActThis draft guidance describes the FDA’s proposed policiesconcerning certain prescription requirements forcompounding human drug products for identified individualpatients under Section 503A of the FD&C Act. It addressescompounding after the receipt of a prescription for anidentified individual patient, compounding before the receiptof a prescription for an identified individual patient(anticipatory compounding), and compounding for office use(or “office stock”).

Hospital and Health System Compounding Under theFederal Food, Drug, and Cosmetic ActPharmacies located within a hospital or standalonepharmacies that are part of a health system frequentlyprovide compounded drug products for administrationwithin the hospital or health system. Some of thesecompounders have registered with the FDA as outsourcingfacilities under Section 503B of the FD&C Act and others arestate-licensed pharmacies subject to Section 503A. Thisdraft guidance describes how the FDA intends to applySection 503A of the FD&C Act to drugs compounded instate-licensed hospital or health system pharmacies for usewithin the hospital or health system.




FDA approves a second biosimilarThe FDA has approved Inflectra (infliximab-dyyb) for multipleindications. Inflectra is administered by intravenous infusion.This is the second biosimilar approved by the FDA. Inflectra isbiosimilar to Janssen Biotech, Inc.’s Remicade (infliximab),which was originally licensed in 1998.

International

CanadaPost-Notice of Compliance (NOC) ChangesThis guidance document applies to sponsors intending tomake changes to new drugs that have received a NOCpursuant to Section C.08.004 of the Food and DrugRegulations. This may include pharmaceuticals, biologics andradiopharmaceuticals for human use and pharmaceutical,radiopharmaceutical and certain biotechnological productsfor veterinary use. In the absence of a guidance specific toquality changes to drugs which were approved through aDrug Identification Application - Biologics (DIN-B drugs), thequality guidance document applies to those products. Thisguidance also applies to those submissions for which a NOChas been recommended but issuance of the NOC has beenplaced on hold.

ChinaChina Food and Drug Administration requiresgenerics to obtain brand-name drug qualityPharmaceutical companies have been ordered to make surethe quality and efficacy of their drugs are on par with brand-name drugs, a move that aims to improve the nation’s pharmaindustry.

According to a circular issued by the State Council GeneralOffice, generic drugs already available on the market shouldbe assessed on whether they are consistent with brand-namedrugs, and if they could be used clinically.

This circular strengthens the previous 2013 requirementsfor bioequivalence. It now requires bioequivalence to bedetermined against the brand name version of the genericdrug or should this no longer be available then against animported, globally recognised generic version.

IndiaProposal to replace gelatine in capsulesIndia’s Central Drugs Standard Control Organization isrequesting comment on a proposal for the above. Guidelines on similar biologicsThe Guidelines on Similar Biologics: Regulatory Requirementsfor Marketing Authorization in India, 2012 are in the process ofrevision. Stakeholders were requested to submit their

suggestions or comments to the Office of Drugs ControllerGeneral (India) by 30 April 2016.

Pharmaceutical Inspection Cooperation Scheme(PIC/S)2016 PIC/S Seminar, Manchester (July 2016)This seminar which is open only to member and non-memberauthorities of the PIC/S will explore the current landscape withregard to inspection findings and trends, with a particularfocus on data integrity issues and then look to see whatchanges Industry have on the horizon.

PIC/S–PDA API (Q7) Training, Puerto Rico (US),August 2016Active pharmaceutical ingredient (API) suppliers are subject toregulatory oversight, and need to know what regulators arelooking for. ICH Q7 is the international standard that manyregulators use to define GMP requirements for APIs. Thisseminar which is open to all offers the opportunity to learn fromregulatory and industry experts on how these requirements arebeing interpreted and enforced. Additionally, there is anevening session on “What is Data Integrity?”.

World Health Organisation (WHO)WHO Technical Report Series, No. 996WHO Technical Report Series, No. 996 successfully passedthe 139th session of the Executive Board on Tuesday 31 May2016. The following guidelines, as contained in the Annexesto the Expert Committee’s fiftieth report, are nowrecommended for use.

● Annex 1: Good pharmacopoeial practices (new)

● Annex 2: International PharmaceuticalFederation–WHO technical guidelines: points toconsider in the provision by healthcare professionals ofchildren-specific preparations that are not available asauthorized products (new)

● Annex 3: Guidance on good manufacturing practicesfor biological products (revision), following its adoptionby the Expert Committee on Biological Standardizationon 16 October 2015

● Annex 4: Guidance on good manufacturing practices:inspection report, including a model report (revision)

● Annex 5: Guidance on good data and recordmanagement practices (new)

● Annex 6: Good trade and distribution practices forpharmaceutical starting materials (revision)

● Annex 7: Guidelines on the conduct of surveys of thequality of medicines (new)



● Annex 8: Collaborative procedure between WHO’sPrequalification Team and national regulatoryauthorities in the assessment and accelerated nationalregistration of WHO prequalified pharmaceuticalproducts and vaccines (revision)

● Annex 9: Guidance for organizations performing in vivobioequivalence studies (revision)

● Annex 10: WHO general guidance on variations tomultisource pharmaceutical products (new).

Supplementary Guidelines on GMP for HVAC Systemsfor Non-sterile Pharmaceutical Dosage FormsQAS/15.639/rev.1A copy of this document was released to a restricted audiencefor comment – MH.

Products

Proposed reduction of use in animals of “last resortantibiotic” colistin to manage risk of resistanceThe EMA has launched a public consultation on the advicedrafted by its Antimicrobial Advice Ad Hoc Expert Group(AMEG), and endorsed by the Committee for MedicinalProducts for Veterinary Use and Committee for MedicinalProducts for Human Use, to minimise sales of colistin for usein animals and restrict its use in animals to last resort treatmentonly. The deadline to provide comments is 26 June 2016.

The new advice is an update to AMEG’s 2013 opinion,which was requested by the European Commission followingthe recent discovery of a new mechanism of resistance inbacteria to colistin (caused by the mcr-1 gene), which has thepotential for rapid spread. The gene can easily be transferredbetween different types of bacteria, potentially leading torapid development of resistance.

Documents

The Responsible Person for GDP – Code of PracticeA Task Force initiated by the European Compliance Academy(ECA) Foundation has developed a guidance document whichaims to support responsible persons for GDP. The Code ofPractice Version 01 is available on the ECA GDP Group webpage.The document is available at no costs after registration.

Annex 16: Certification by a Qualified Person andBatch Release Q&A The EU Guidelines to Good Manufacturing Practice – MedicinalProducts for Human and Veterinary Use Annex 16 Certificationby a Qualified Person and Batch Release was published inOctober 2015, and came into effect on 15 April 2016. Maas &

Peither have published in their GMP Logfile, eight Q&As froman interview by their editor Dr. Sabine Paris with GMP InspectorDr. Rainer Gnibl of Regierung von Oberbayern, Munich(Government of Upper Bavaria , Munich). These Q&As makeinteresting reading, they cover topics relating to:

● clarity of the Annex,

● globalisation of the supply chain,

● third party audits,

● imports from third countries,

● parallel imports/distribution,

● unexpected deviations.

Can regulators influence the affordability ofmedicines?The growing problem of high medicine prices and its impacton the sustainability of healthcare systems is getting more andmore attention in many countries around the globe.Regulators are willing to play their part in solving the problemand in facilitating continued access to patients of safe andeffective medicines. In an article recently published in the NewEngland Journal of Medicine, two representatives of the EMA,i.e. the Executive Director and Senior Medical Officer, as wellas heads of two national agencies discuss possible regulatoryinterventions. Even though the pricing of medicines is clearlyout of their remit, medicine regulators cannot ignore thecurrent debate on the cost of medicines and can make acontribution to affordable care, explain the authors.

Guide to Information on Human Medicines Evaluatedby EMAThe EMA publishes information on human medicinal productsat various stages of their life cycles, from the earlydevelopmental stages through to the EMA’s evaluation ofauthorisation applications, post-authorisation changes, safetyreviews and withdrawals of authorisation. This guide describesthe different types of information the Agency currentlypublishes for both centrally and non-centrally authorisedmedicines, as well as publication times and location on theEMA’s website. It aims to help stakeholders know what kind ofinformation to expect on medicines undergoing evaluationsand other regulatory procedures.

Further information on these and other topics can be found inrecent versions of the “GMP Review News” circulated tosubscribers by Euromed Communications and on the websitesof the relevant regulatory bodies and internationalorganisations. In addition a list of useful websites can beobtained from [email protected]


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August 20164–6 August 2016 – Manchester, UK2nd World Congress on Biopolymershttp://biopolymers.conferenceseries.com/

12–13 August 2016 – Toronto, Ontario, Canada5th International Summit on GMP, GCP & Quality Control http://gmp-gcp-quality-control.pharmaceuticalconferences.com/

15–16 August 2016 – Toronto, Ontario, Canada5th International Summit on GMP, GCP & Quality Controlhttp://gmp-gcp-quality-control.pharmaceuticalconferences.com/

22–24 August 2016 – New Orleans, LA, USA7th Annual Global Pharma Summithttp://american.pharmaceuticalconferences.com/

22–24 August 2016 – Vienna, AustriaGlobal Pharmaceutical Industry Summit http://industry.pharmaceuticalconferences.com/

22–24 August 2016 – New Orleans, LA, USA7th Annual Global Pharma Summit http://american.pharmaceuticalconferences.com/

28 August–1 September 2016 – Buenos Aires, Argentina 76th FIP World Congress of Pharmacy and PharmaceuticalSciences 2016www.fip.org

September 20165–7 September 2016 – Glasgow, UKAPS 7th International PharmSci Conference 2016www.apsgb.co.uk

5–7 September 2016 – Beijing, ChinaDrug Formulation & Bioavailability Congress http://drugformulation-bioavailability.pharmaceuticalconferences.com/

8–9 September 2016 – Washington, DC, USAWorld Anti-Microbial Congress US 2016 www.terrapinn.com

12–14 September 2016 – Washington, DC, USA2016 PDA/FDA Joint Regulatory Conferencewww.pda.org

12–14 September 2016 – Berlin, Germany6th International Conference on Genomics &Pharmacogenomicshttp://genomics.conferenceseries.com/

18–21 September 2016 – Atlanta, GA, USA2016 ISPE Annual Meeting www.ispe.org

19–21 September 2016 – Vienna, AustriaGlobal Pharmaceutical Industry Summit http://industry.pharmaceuticalconferences.com/

27–28 September 2016 – Strasbourg, FrancePharmaceutical Freeze Drying Technologywww.pda.org

28–30 September 2016 – Toronto, Ontario, Canada6th Pharmacovigilance Congress http://pharmacovigilancecongress.pharmaceuticalconferences.com/

October 20164–6 October 2016 – Barcelona, SpainCPhI Worldwidewww.cphi.com

10–12 October 2016 – Barcelona, SpainWorld Vaccine Congress Europe www.terrapinn.com

11–12 October 2016 – Amsterdam, The Netherlands2016 Pharmaceutical Cold & Supply Chain Logisticswww.pda.org

13 October 2016 – London, UKQuality and stability in the distribution chainwww.jpag.org

13–15 October 2016 – Manchester, UK2nd World Congress and Exhibition on Antibiotics andAntibiotic Resistance http://antibiotics.omicsgroup.com/

17–18 October 2016 – Huntington Beach, CA, USA 2016 PDA Universe of Pre-filled Syringes and InjectionDeviceswww.pda.org

18–20 October 2016 – Berlin, GermanyGlobal Pharmaceutical Regulatory Affairs Summitwww.informa-ls.com

19–21 October 2016 – Houston,TX, USA6th International Conference and Exhibition on Biologicsand Biosimilars http://biosimilars-biologics.pharmaceuticalconferences.com/

24–26 October 2016 – Arlington, VA 11th Annual PDA Global Conference on PharmaceuticalMicrobiology www.pda.org

25–26 October 2016 – Berlin, GermanyVisual Inspection Forum www.pda.org

26–27 October 2016 – Cambridge, UKBioData World Congress 2016www.healthnetworkcommunications.com

27–28 October 2016 – Rome, Italy 2nd International Conference and Expo on Drug Discovery& Designinghttp://drug-discovery.pharmaceuticalconferences.com/

November 20163–4 November 2016 – Washington, DC2016 PDA Outsourcing/CMO Conference www.pda.org

7–9 November 2016 – Istanbul, Turkey2nd International Conference and Expo on Drug Discoveryand Designinghttp://drug-discovery.pharmaceuticalconferences.com/

7–9 November 2016 – Istanbul, Turkey2nd International Conference and Expo on Parenterals andInjectableshttp://drug-discovery.pharmaceuticalconferences.com/http://parenterals-injectables.pharmaceuticalconferences.com/

Events