european Industrial Pharmacy Issue 35 (December 2017) by European Industrial Pharmacists Group (EIPG)

european INDUSTRIAL

PHARMACY

Regulatory consequences of data cata integrity failures Revisions made to European Pharmacopoeia sterilisation chapters Predicting production tablet properties from small scale manufacture Qualification of visual inspection of parenteral products ISSUE 35

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DECEMBER 2017

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REGULATORY CONSEQUENCES OF DATA INTEGRITY FAILURES Data integrity inadequacies can easily lead to a statement of non-compliance, with serious regulatory consequences, and not only for the manufacturer concerned. by David Cockburn

REVISIONS MADE TO EUROPEAN PHARMACOPOEIA STERILISATION CHAPTERS Methods of sterilisation and the assessment of sterilisation using biological indicators represent important areas of regulatory concern. by Tim Sandle

PREDICTING PRODUCTION TABLET PROPERTIES FROM SMALL SCALE MANUFACTURE With growing use of the laboratory press system, the ability to predict production tablet properties from lab scale data becomes important. In this article, Michael Gamlen describes how this can be done. by Michael Gamlen

QUALIFICATION OF VISUAL INSPECTION OF PARENTERAL PRODUCTS Visual inspection of parenteral products is required by both pharmacopoeias and good manufacturing practice. The SFSTPF Commission have described the various methods and apparatuses commonly used in the pharmaceutical industry for visual inspection. by Commission SFSTPF. Caire-Maurisier, F. Dumontier, P. Grel, C. Jolly, É. Levacher, S. Marcq, F. Sliwinski

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MANAGING EDITOR Phoebe Speis PRODUCTION Sue Feather SUBSCRIPTIONS Jill Monk ADVERTISEMENTS Stephanie Painter EDITORIAL BOARD Michael Anisfeld Claude Farrugia Michael Gamlen Ching-Yi Hsu John Jolley Giorgos Panoutsopoulos European Industrial Pharmacy is published four times a year by: Euromed Communications Passfield Business Centre, Lynchborough Road, Passfield, Liphook, Hampshire GU30 7SB Tel: +44 (0)1428 752222 Fax: +44 (0)1428 752223 Email: info@euromedcommunications.com www.eipg.eu/eipg-journal

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editorial The End of the Beginning Dear friends and colleagues, 2017 has come to a close, and as I look back in reflection, I cannot but once again be impressed by the far-reaching effects of events that have occurred in the pharmaceutical world - effects that have not only had an immediate impact but that are likely to command our attention for quite some time to come. We have seen the first medicine approved with a digital ingestion tracking system, the first gene therapy medicines approved against cancer and against inherited disease. The excitement that these scientific advances represent is tempered by sombre contemplation of the long-overdue changes in how healthcare systems and health technology assessment are dealing with the challenging questions surrounding availability and accessibility of these novel medicinal products. In this same year, one must mention two topics particular to the pharmaceutical industry in Europe. The first is the set of impending milestones in the implementation of the Delegated Regulation for the safety features appearing on the packaging of medicinal products for human use. It might seem that there is time to spare, with the deadline more than a year away, but some targets are much closer, not the least of which the six-month full-scale testing period recommended in every country - which effectively means that regulatory notifications and variations need to be submitted, serialised products ready within the supply chain, repositories functional, and all stakeholders on board by August of this year. The second topic is, of course, Brexit. Already we have seen the impact in the decision for the relocation of the

European Medicines Agency, and the effect that this will have on the operations of the Agency and its role in healthcare throughout Europe. Yet this is but a drop in the ocean compared to the changes that the pharmaceutical industry and the professionals within it will need to implement to be prepared for Brexit, even with the transitional period that the industry is calling for. So much is at stake, and above all, the continued supply of medicines to patients who need them, with the peace of mind that professionals within the industry have worked to the best of their abilities to ensure their quality, safety and efficacy. Yes, we are about to see considerable changes in the pharmaceutical world, and we must be prepared for them. Change is inevitable, and it comes even to EIPG, or more specifically, to EIPG's involvement in european Industrial Pharmacy. After more than nine years of collaboration with Euromed, and to whom I extend my thanks for their commitment and hard work over all these years, the General Assembly has decided to explore alternative paths for the future of EIPG's publication portfolio, and we look to the future with courage, for, in the words of the Bard, â&#x20AC;&#x153;Would I wear so fair on my journey! The first stretch is the worst, methinks.â&#x20AC;? I wish you all a serene and fruitful 2018.

Professor Claude Farrugia President, EIPG

We would like to thank Professor Farrugia for his kind words and his valuable service on the EIP editorial board over the years. The European Industrial Pharmacy Journal was first published by Euromed Communications nine years ago. We will continue to publish the Industrial Pharmacy Journal and continue to offer it complimentary to our readers. Please click here to register which will ensure your continued receipt of the Journal.

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REGULATORY CONSEQUENCES OF DATA INTEGRITY FAILURES by David Cockburn

ithout data integrity you cannot have adherence to GMP. Regulators are now focussing more on data integrity in the context of manufacturing. Ultimately, a GMP inspection by an EU authority can only have one of two outcomes. Either the inspected site complies with GMP and receives a GMP certificate or it does not. Data integrity inadequacies can easily lead to a statement of non-compliance, with serious regulatory consequences, and not only for the manufacturer concerned. David Cockburn is an experienced manufacturing quality compliance professional, with a grounding in both the pharmaceutical industry and the regulatory authorities at national and EU level and considerable wider international exposure. David spent the last 15 years of his career at the European Medicines Agency (EMA) where he became head of the Manufacturing and Quality Compliance Service and held the chair of the GMP/GDP Inspectors Working Group. Prior to leaving EMA David was the EU technical lead working with US-FDA on mutual reliance in GMP inspections culminating in the signing of the EU-USA Mutual Recognition Agreement in 2017. This article is based on the author’s own opinions and does not represent the views of EMA.

Data integrity has pre-occupied the pharmaceutical industry for many decades. The US generics scandal in the late 1980s uncovered, in addition to bribery of FDA officials, fabrication of bioequivalence and other data. Despite greater awareness and vigilance among regulators, cases like that involving GVK Biosciences, still emerge. Recently, the data integrity spotlight has increasingly focussed on GMPregulated activities. In 2005 a whistleblower exposed widespread malpractice at Ranbaxy which echoed much of the 1980’s scandal including issues with manufacturing related data. Furthermore, the increasing use of computerised systems provides new challenges to maintaining data integrity. This article will focus on the consequences of data integrity failures in the GMP environment

from an EU regulatory perspective. That is not to say that there are fundamental differences on this topic with other international regulators but authorities have to operate under different regulatory frameworks. First of all, what do I mean by “Data integrity”? There is no definition of the term in EU legislation or GMP guidance. The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) did however publish its own definition in 2015: “The extent to which all data are complete, consistent and accurate throughout the data lifecycle.” This definition shares the core fundamentals of more extensive definitions from the US Food and Drug Administration (FDA) and the World Health Organisation (WHO) in 2016. Those definitions go on to cite the so-

called ALCOA elements (attributable, legible, contemporaneously recorded, original or a true copy, and accurate). The next question is what are the EU’s GMP requirements concerning data integrity? Data integrity is not explicitly mentioned in the GMP directives (2003/94/EC and 91/412/EEC) or the counterpart for active substances, Regulation 1252/2014. This is rectified in Directive (EU) 2017/1752, which will replace directive 2003/94/EC as a consequence of the Clinical Trials Regulation where a specific reference is found in article 9(1): “…The documentation system shall ensure data quality and integrity…” Although this new directive will not come into operation until 2019 at the earliest, it does not mean that the principles of data integrity do not already apply. It should be selfevident that you cannot comply with GMP based on incomplete or inaccurate data. Furthermore, the aforementioned ALCOA elements can be found readily throughout the interpretive GMP guidelines, as illustrated in the European Medicines Agency’s (EMA’s) published Questions and Answers on data integrity in August 2016 (see Q&A number 13). Despite this, there appears to be a desire among some inspectorates, as well as an expectation by the regulated industry, to have more guidance on data integrity. If this is to happen it is critical that international regulators work together on the topic. What are the regulatory consequences of data integrity failures? In this context lack of data integrity is a failure to comply with GMP. This normally comes to light during a GMP inspection. Even if a manufacturer voluntarily reports that it has a data integrity problem, or someone blows the whistle, an inspection would be triggered. EU legislation requires an unambiguous conclusion following a GMP inspection, i.e. either the manufacturer complies with GMP, or it does not. In the former case, within 90 days, a GMP certificate is

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REGULATORY CONSEQUENCES OF DATA INTEGRITY FAILURES

issued and uploaded to the Union’s EudraGMDP database and in the latter case, a statement of noncompliance is uploaded. Perfect GMP compliance is, arguably, an unrealistic expectation. Almost all GMP inspections (or companies’ internal audits) reveal some noncompliance. In practice, a GMP certificate will be issued if the inspector is satisfied that the manufacturer is generally compliant with the principles and guidelines of GMP as laid down in the relevant GMP directive (or Regulation), usually after accepting corrective/preventive actions taken or committed to for any identified failures to comply. The GMP status of a manufacturer relies heavily on documentation, and its supporting data, whether paper or electronic. Any inspection finding that casts doubt on the completeness, consistency or accuracy of data is highly likely, unless the inspector can be convinced that the occurrences noted are isolated and/or all very low risk, to tip the balance towards a non-compliance statement. The uploading of a statement of non-compliance is never undertaken lightly and normally indicates an extreme situation at the site in question, as would be the case where there is serious doubt about the integrity of data. If it is clear that data are wilfully manipulated, then this is fraud and there can be little doubt about the inspection outcome. Moreover, referral to the relevant enforcement authorities and criminal investigation could follow. A non-compliance statement is

the first regulatory step taken to safeguard public health and has serious, far-reaching consequences. In effect it means that the manufacturing authorisation holder has failed to fulfil its legal obligation to comply with GMP and so provides grounds for suspension, variation or revocation of the authorisation. When the noncompliance is connected with a site outside of the EU it is the manufacturing authorisation of the EU importer that is at risk. The Qualified Person, already personally exposed to regulatory action, can no longer certify affected batches prior to their release since the certification would, de facto, be untrue. In addition, any marketing authorisation, listing the noncompliant site as a manufacturer, would not meet the conditions of authorisation so further EU supply would be unlawful unless from an alternative authorised source. A whole range of more specific measures, including batch recalls, are available to regulators and will be recommended to the EU regulatory network by the issuing inspectorate, tailored to the specific circumstances of the inspection findings and as a result of a regulatory risk assessment. Examination of the statements of non-compliance uploaded to EudraGMDP over the last 5 years reveal that well over 60% of them cite data integrity as a main factor. Several refer to deliberate falsification of data. As I have already mentioned a statement of non-compliance represents an extreme situation and so it is likely

continued

that some, (lesser) data integrity problems are being found in inspections that nevertheless ended up with a GMP certificate being issued. In those cases manufacturers need to address those problems with the utmost vigour because if they persist there is a high risk the next inspection will result in a noncompliance statement. Of all the possible compliance topics, persistent data integrity issues will completely undermine trust and increase suspicion of deliberate falsification. Something else stands out from the EudraGMDP data. I mentioned Ranbaxy and GVK Biosciences at the start of this article. The sites involved in both cases were located in India. Non-compliance statements in EudraGMDP, particularly in connection with data integrity, put sites in India at the top of the table with China not far behind, both well ahead of sites in other countries. Exploring that observation is beyond the scope of this article but there may be factors that at least partially explain this skew. Data integrity issues are nevertheless being found everywhere. In conclusion, manufacturing/ quality data is fundamental to everything a manufacturer does so any data integrity issues present a high risk of being the subject of a statement of non-compliance. This will lead to very serious and potentially widespread regulatory problems as well as undermining a manufacturer’s credibility and reputation which could make recovery even more difficult.

The European Industrial Pharmacy Journal will continue to be produced by Euromed Communications and complimentary issues will be available to our readers. Simply click here to register to ensure that you continue to receive your e-version of the journal automatically every quarter.

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REVISIONS MADE TO EUROPEAN PHARMACOPOEIA STERILISATION CHAPTERS by Tim Sandle

ethods of sterilisation and the assessment of sterilisation using biological indicators represent important areas of regulatory concern. The two applicable guidance chapters in the European Pharmacopeia have undergone revisions. This article assesses the main changes. Notably these include reference to the production of sterile products through aseptic processing for the first time; and changes to the assessment of the suitability of biological indicators, including a new recommendation for supplier auditing. Tim Sandle, PhD, CBiol, MSBiol is Head of Microbiology at the UK Bio Products Laboratory overseeing microbiological contamination control policy and investigation and developing programmes for environmental monitoring, cleanroom classification and batch review. In addition, Tim sits on LBI/30, the BSI Cleanrooms Committee, and the Pharmig committee. He also runs a blog: Pharmaceutical Microbiology – http://www.pharmamicroresources.com/

Introduction

Two guidance chapters in the European Pharmacopoeia have been updated. The chapters are effective from July 2017, and are contained within the recently published second supplement to the 9th edition of the pharmacopoeia.1 The revised chapters are: 5.1.1 “Methods of Preparation of Sterile Products” and 5.1.2 “Biological indicators and related microbial preparations used in the manufacture of sterile products”. The changes to the biological indicator chapter are more extensive, although the sterile products chapter introduces aseptic processing to the chapter for the first time. This article summarises and discusses the main changes, highlighting some omissions which will ideally be addressed in future revisions.

Methods of Preparation of Sterile Products

Chapter 5.1.12 has undergone a general revision and, for the most

part, it has been completely rewritten. The chapter covers the manufacture of sterile pharmaceutical products, either by terminal sterilisation or by aseptic processing. Both types of sterile products are prepared in cleanrooms: terminally sterilised products are dispensed into vials within an EU GMP Grade C / ISO 14644 Class 8 (in operation) environment; aseptic dispensing is performed under an EU GMP Grade A / ISO 14644 class 5 environment.3 The most notable change to the chapter is with the sections on the different sterilisation processes. The descriptions of each process now have the same format, which follows the order of: principle, equipment, sterilisation cycle, cycle effectiveness and routine control. This makes the sections more readable. In addition, some specific information has been added pertaining to each sterilisation process. The sterilisation methods addressed in the chapter are:

• • • • •

Steam sterilisation. Dry heat sterilisation. Ionising radiation sterilisation. Gas sterilisation. Membrane filtration.

In addition to these methods of ‘sterilisation’ (which inactivate, destroy or remove microbial contamination), ‘aseptic assembly’ has been added. The most interesting issue with the list is the reference to “gas sterilisation” which has the phrase “vapour phase sterilisation” following it in parentheses. In this section two methods of sterilisation by gas are described: alkylating agents, which is principally ethylene oxide (commonly used to sterilise plastics, especially those that might become embrittled by gamma radiation); and oxidising agents, which is principally hydrogen peroxide in the vapour form. With hydrogen peroxide vapour, which is the most common means of treating the inside environment of an isolator, it is more common to use the term ‘decontamination’ (or biodecontamination) rather than ‘sterilisation’. Indeed, in this author’s experience, regulatory agencies such as the MHRA stress that hydrogen peroxide vapour is not a sterilant (primarily because it cannot penetrate the item being sterilised). This means, with aseptic processing isolators, for instance, product contact parts (such as filling needles and stopper bowls) are sterilised separately and fitted in place prior to running the hydrogen peroxide cycle. With the European Pharmacopoeia description this will no doubt cause some confusion within the pharmaceuticals and healthcare sectors over what is and what is not a ‘sterilisation’ process. With steam sterilisation the approach to validation has been updated and the section on dry heat sterilisation (which is distinct from depyrogenation) has a wider description of the method and details regarding some of the types of process equipment suitable for this method of sterilisation have been added. A note is made about dry heat sterilisation being less effective

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than moist heat sterilisation. With radiation sterilisation the reference to superseded European guidance has been removed. The main addition to the chapter, and of interest to users of cleanrooms in the pharmaceutical and healthcare sectors, is a new section titled ‘Aseptic Assembly’. This is the first direct mention of aseptic processing and, by implication, cleanrooms to appear in the European Pharmacopoeia. Unlike the United States Pharmacopoeia, which has contained a chapter on aseptic processing for a couple of decades (USP <1116>), this important class of sterile products has not featured outside of the pharmacopoeia chapter on sterility testing (chapter 2.6.1). While the new section is welcome it does not offer very much in the way of detail. The section discusses the importance of bringing together a sterile product (which has been sterile membrane filtered) together with sterile bottles and containing closures, and for these to be processed under aseptic conditions. The aseptic section highlights areas of concern in relation to where microbial contamination can arise from (environment, personnel and critical surfaces) and draws the reader’s attention to the risks associated with product transfer and hold times (where longer hold times, if improperly controlled, present opportunities for microbial growth). Reference is also made to the importance of conducting media simulation trials (where a cultured medium is used in place of product) to qualify the aseptic process. There is no reference, however, to the cleanroom standard ISO 14644 and no direct reference to cleanroom design, certification or operation. Given that a poorly designed cleanroom can significantly impact upon aseptic processing, this stands out as a glaring omission. In terms of definitions there is clarification with the term “Sterility Assurance Level”. The core concept of the term remains unchanged: the probability of a single viable microorganism surviving on or in an

item after sterilisation. The change relates to removal of a previous reference to exponential inactivation. This is because this is not appropriate to sterilisation by filtration given that membrane filtration is not a first-order process (that is, it does not destroy microorganisms at a predictable rate as occurs with steam sterilisation). With membrane filtration, detail about the microbial challenge test has been deleted (this now appears in chapter 5.1.2, which is the second chapter reviewed in this article). Biological indicators

Chapter 5.1.24 concerns biological indicators. Biological indicators are preparations of specific microorganisms that have a high resistance towards particular sterilisation methods. In the past, a biological indicator was simply a ‘spore strip’ (a spore population inoculated onto a carrier, such as filter paper). Today biological indicators include spores inoculated onto paper strips, stainless steel discs, held in ampoules in liquid media, and as preparations used to challenge membrane filters. The required and shared characteristics of biological indicators are that: they must have a proven resistance to the sterilisation method; and they must be defined in terms of identity, purity and population.5 Different biological indicators are used for different sterilisation processes. Biological indicators are designed for use with:6

• • • • • •

Ethylene oxide gas (Bacillus atrophaeus). Hydrogen peroxide vapour (Geobacillus stearothermophilus). Dry heat (Bacillus atrophaeus). Moist heat (steam) (Geobacillus stearothermophilus). Radiation (Bacillus pumilus). Membrane filtration (Brevundimonas diminuta)

The opening section of the chapter has been rewritten. With the revised introduction this describes when

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biological indicators are intended to be used (qualification and requalification of sterilisation processes); where they are not used (routine sterilisation runs); as well as what falls outside the scope of the chapter (most of what falls under the heading of alternative methods of sterilisation). The introduction also clarifies that biological indicators can be used to assess the time point between survival and kill. When biological indicators are subject to a full sterilisation process there must be no survivors in order for the sterilisation process to be considered valid. Many operators of sterilisers think it is good practice to understand where in the sterilisation process the dividing line between microbial survival and destruction occurs so that the degree of additional overkill can be understood as well as ensuring that the level of overkill is sufficient. The introductory section further discusses the different formats of biological indicators and distinguishes between those purchased commercially (such as the classic ‘spore strip’) with those that are bespoke designs prepared inhouse. Here the text adds a note of caution that such developed in-house biological indicators will most likely have a higher resistance than the source preparation. For this reason, the resistance of the carrier needs to be independently assessed. A note of caution is added about self-contained biological indicators, such as ampoules of media containing bacterial spores. Such indicators may not be suitable for all sterilisation processes because some self-contained systems cannot directly assess penetration of the sterilisation agent. The substantive part of the revised chapter includes a section on quality assessments of biological indicators. This includes the importance of auditing manufacturers or, alternatively, conducting verification tests upon receipt (and, as part of qualification, at the end of the shelflife).

REVISIONS MADE TO EUROPEAN PHARMACOPOEIA STERILISATION CHAPTERS

Quality assessments for biological indicators must include: 1.The genus and species of the microorganism. 2.The culture collection reference of the microorganism. 3.The batch number. 4.Logarithm of the spore count (to one decimal value). 5.Recovery method used. 6.Type of carrier. 7.Type of packaging (e.g. outer envelope). 8.Composition of the recovery medium (including medium of self-contained biological indicators). 9.Type of indicator in the medium (if applicable, e.g. some media contain dyes indicating pH colour changes). 10.Sterilisation process and recovery conditions against which the biological indicator has been characterized. 11.Resistance against a specified sterilisation process, expressed as time or dose. 12.Method used to determine the D-value (e.g. fractional negative approach). 13.Z-values (where applicable). This is the temperature difference that leads to a tenfold difference with the D-value. 14.Storage conditions. 15.Expiry time.

The chapter has several changes relating to the specification and use of biological indicators. With steam sterilisation, the D-value range for Geobacillus stearothermophilus widens from 1.5 to 3.0 minutes (previous version) to 1.5 to 4.5 minutes for the reference temperature of 121°C (new version). Similarly the dry heat biological indicator D-value range is extended to between 1 and 5 minutes (with a reference temperature of 160°C). D-value refers to decimal reduction time (or decimal reduction dose) and is the time (or dose) required at a given condition (e.g. temperature), or set of conditions, to kill 90% (or 1 log) of the exposed microorganisms. For sterile products that cannot be sterilised in their final containers (that is, aseptic processing is required instead of terminal sterilisation) the sterilisation of liquid bulks through sterilising grade filters is a necessary step. A new section has been added to cover the validation of membrane filters, and this helps to connect this chapter to chapter 5.1.1 and the new section on aseptic processing. Suitable filters for most processes (removal of bacteria and fungi) have a pore size of not greater than 0.22 μm. The chapter addresses this for the first time and describes the

validation, in line with other guidances, as a microbial challenge of 107 per square centimetre of filter face. The recommended microorganism is Brevundimonas diminuta, for assessing nominal pore sizes of 0.22 μm (with a mycoplasma challenge recommended for pore sizes of 0.1 μm, as would be required for cell culture media). There are some omissions from the chapter. Unfortunately the information relating to gas sterilisation is relatively limited. The use of gas sterilisation for disinfection is stated as falling outside the scope of pharmacopoeia; this process is already complicated through the numbers of different types of gas sterilisation processes and lack of reference cycles. An opportunity to add clarity to users of isolators selecting biological indicators to use with hydrogen peroxide vapour cycles has been lost.

filtration and hydrogen peroxide vapour. The useful parts of the updates include the (albeit brief) sections on aseptic processing and with the validation of membrane filters used for sterilisation. Despite the revisions the chapters do not remain without their problems. As stated above the classification of hydrogen peroxide vapour as ‘sterilisation’ places it at odds with current inspectorate trends (and perhaps with the long-waited EU GMP Annex 1 update). Keeping with the same process, the brief description on the use of biological indicators for assessing hydrogen peroxide cycle efficacy lacks the guidance that many users have been seeking around the characterisation of resistance. Despite the omissions, note needs to be taken of the chapters. Although the status of the chapters, based on their position in the pharmacopoeia, is as ‘general chapters’ and therefore not mandatory, deviating from the chapter content requires a robust rationale and one that must stand-up to regulatory scrutiny. Thus, for those involved with sterile products manufacture becoming familiar with these chapters is recommended. References

Summary 5

Both European Pharmacopoeia chapters – on sterilisation and biological indicators – have been substantially rewritten and they both contain additional content, particularly relating to aseptic processing, sterilisation by membrane

continued

European Pharmacopoeia, Ninth Edition, Supplement 9.2, European Directorate for the Quality of Medicines and HealthCare of the Council or Europe, Strasbourg, France European Pharmacopoeia. Chapter 5.1.1 Methods of Preparation of Sterile Products, Ph. Eur., edition 9.2, pp4333-4336 Tidswell, E. “Sterility.” In Saghee, M.R., Sandle, T. and Tidswell, E.C. (Eds.) (2011) Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices, New Delhi: Business Horizons, pp. 589614 European Pharmacopoeia. Chapter 5.1.2 Biological indicators and related microbial preparations used in the manufacture of sterile products, Ph. Eur., edition 9.2, pp4336-4339 Sandle, T. (2013). Sterility, sterilisation and sterility assurance for pharmaceuticals: Technology, validation and current regulations, Woodhead Publishing, Oxford, pp263-279 Pflug, I.J. and Odlaug, T.E. (1986) Biological indicators in the pharmaceutical and medical device industry. Journal of Parenteral Science and Technology, 40, 242–248

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PREDICTING PRODUCTION TABLET PROPERTIES FROM SMALL SCALE MANUFACTURE by Michael Gamlen

ith growing use of the laboratory press system, the ability to predict production tablet properties from lab scale data becomes important. In this article, Michael Gamlen describes how this can be done. Michael Gamlen studied for a PhD with Professor JM Newton at Nottingham University and was Head of Solid Dosage Form Development at the Wellcome Foundation Ltd for 15 years. He is the inventor of the Gamlen Powder Compaction Analysis System, and works as a consultant and trainer. He is a regular contributor of articles on tableting and powder compaction.

Developing a new tablet formulation is a difficult task based on limited information about many parameters including the drug dose and the desired final tablet shape – round or capsule-shaped, large or small. There is very little published information to enable a formulator to predict the properties of a tablet made at one size using the properties of a tablet made at another (size). For example, small scale tablet development is regularly performed on our laboratory compaction system using punch and die sizes of 4-6 mm. In this article I will be explaining how these measurements are being used to predict Production running hardness and compaction forces based on the material properties measured, providing valuable information to the development process and the tech transfer team. The recent publication of USP <1062>1 has spread the understanding of the key tablet parameters which need to be characterised to understand tablet properties (see Figure 1). The compaction triangle, first proposed by Tye and Amidon2 has greatly assisted this process. The key relationships of compressibility (solid fraction vs compaction pressure),

tabletability (compaction pressure versus tablet tensile fracture stress) and compactibility (tablet tensile fracture stress vs solid fraction) together provide a unique insight into formulation properties. Of these, the most useful for making product comparisons are compactability and tabletability; compressibility has other applications for formulation assessment which we will also discuss.

Pitt et al3 compared the properties of tablets prepared on a laboratory compaction system with the same materials compacted on a production Fette press under production conditions, for both compactibility and compressibility. Two formulations were compared – one wet granulation and one direct compression. The laboratory compaction was using a 100 mg, 6 mm diameter round tablet whilst the production material was the same product compressed using an 800 mg caplet shape. Tablets were compressed at a range of compaction pressures and fractured in diametral compression. The tensile fracture stress of each tablet shape was calculated using the formula of Fell and Newton4 σT = 2P/(πdt) (where P is the fracture stress, and d and t are the tablet diameter and thickness respectively) for the tensile fracture of flat faced circular tablets. The formula of Pitt5 was used for the calculation of the tensile fracture stress of the capsule shaped tablets made under production conditions. Example data are shown in Figures 2 and 3. The compactibility and tabletability of both formulations were found to coincide. Work performed at our in-house facility has also evaluated the effect of tablet size on tablet properties. Studies with pre-gelled starch

Figure 1. The compaction triangle

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compressibility, and microcrystalline cellulose tabletability using 3 and 6 mm punches showed that these systems were also predictable from one size to another. Recent work published by Schiano and Gamlen (AAPS 2017 poster) explored a much broader range of tablet properties (see Figures 4 and 5). Tablets of microcrystalline cellulose from 3 to 8 mm diameter and ranging in weight between 20 and 250 mg showed reproducible compactibility and tabletability relationships which are fully predictive from one size to another.

The implications of these observations are that the measurements of tabletability and compactibility are related to fundamental material properties, and are therefore in a class of measurements such as density and surface area. This opens up a number of exciting possibilities such as whether they can be predicted from molecular structure, and to what extent we can extend the principle to other tablet properties. Also included in Schiano’s poster is the relationship between peak tablet ejection stress and

Figure 2. Compactability comparison - Fette and Gamlen

Figure 3. Tabletability comparison - Fette and Gamlen

continued

compaction pressure (Figure 6). For microcrystalline cellulose, this also gives a strong correlation. The ejection stress increases to a value of 3 MPa at a compaction pressure of 100 MPa, and then levels out with no further increase at compaction pressures up to 350 MPa. It would be interesting to see if the relationship holds for other materials. Based on these observations I have been considering the options for predicting the running hardness of tablets made under production from the tablets made on the laboratory press. For tablets in the normal compaction pressure operating range of 0 – 200 MPa, the tabletability relationship is normally linear, occasionally with a positive xaxis intercept (which indicates that tablets do not form at all below a certain minimum pressure – a reasonable observation). The slope of this line applies independently of tablet size as the tensile fracture stress of the tablet is simply a function of compaction pressure. In this article I will be considering the simple case of predicting the tensile fracture for a round tablet from another round tablet. We will call the weight of the small and large tablets, respectively, w and W, the radius of the tablets respectively, r and R, and the thickness of the tablets respectively, t and T. We need to estimate T, the thickness of the large tablet, and then use the Fell and Newton equation to calculate the tablet breaking load of the large tablet from its thickness. Based on the principle of density independence of tablet size outlined above, the density of the large tablet will be the same as the density of the small tablet at equal compaction pressure. The volume of the small tablet is given by v = π*r2*t and the density of the small tablet by d = π*r2*t/w. The volume of the large tablet is given by V = π*R2*T

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continued

Figure 4. Compactabiliy profile of microcrystalline cellulose

Figure 5. Tabletabiliy profile of microcrystalline cellulose

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PREDICTING PRODUCTION TABLET PROPERTIES FROM SMALL SCALE MANUFACTURE

Figure 6. Ejection stress profile for microcrystalline cellulose

and the density of the large tablet by D= π*R2*T/W. However, we know that d=D as the tablets are compressed under equal conditions so we can rearrange the density equations to find that T = (W/w)*(r2/R2)*t. (Note that a similar relationship can be derived for the capsule shaped products, using the formula developed by Pitt). As an example, let’s assume that a formulator has developed a tablet of 5 mm diameter and a compression weight of 70 mg, and in production he plans to use a 500 mg tablet of 10 mm diameter. If the tablet has a minimum

acceptable tensile fracture strength of 2 MPa, the breaking strength of the 5 mm tablet is 2.4 kg (from the equation of Fell and Newton) which, using the same equation, would give a breaking strength of the 800 mg caplet shaped production tablet of 8.6 kg. If this was achieved at a compaction pressure of 200 MPa, the maximum recommended production tablet pressure, then the compaction force required to produce the tablet would be F = Pressure x Area = 200 * π*52 = 15.7 kN. (Note that use of millimetres instead of metres in this formula corrects for the unit of MPa instead of Pa, keeping the calculation simple).

continued

These types of predictions are important and useful because they help the Production to assess whether the formulation is behaving as expected. For example if, in Production, a force of 20 kN is required to produce the target running hardness of 8.6 kg, then it is clear that the formulation is not performing as well as it would be expected based on the small scale data. The cause of the change would be worth investigating as other changes in the products performance such as dissolution or friability may have also taken place. Making accurate measurement of compaction properties is becoming increasingly important for checking the consistency of products during the scale-up process as well as on a batch- to-batch basis in Production. References

The United States Pharmacopeia, 36th ed. US Pharmacopeia Convention, Rockville, Maryland, 2013. C.K. Tye, C.C. Sun, G.E. Amidon, Evaluation of the effects of tableting speed on the relationships between compaction pressure, tablet tensile strength, and tablet solid fraction, J. Pharm. Sci. 94 (2005) 465–472. Kendal G.Pitt. Compression prediction accuracy from small scale compaction studies to production presses, Powder Technology 270 (2015) 490–493. J.T. Fell and J.M. Newton. Determination of Tablet Strength by the DiametralCompression Test, Journal of Pharmaceutical Sciences 59 (1970) 688691. K.G. Pitt, and M.J. Heasley. Determination of the tensile strength of elongated tablets, Powder Technology 238 (2013) 169-175.

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Qualification de l’inspection visuelle des médicaments injectables Commission SFSTP F. Caire-Maurisier, F. Dumontier, P. Grel, C. Jolly, É. Levacher, S. Marcq, F. Sliwinski

Qualification of visual inspection of parenteral products

L’

inspection visuelle des médicaments injectables est requise aussi bien par les pharmacopées que par les bonnes pratiques de fabrication. La commission s’est proposé de présenter les différentes méthodes et équipements communément utilisés en industrie pharmaceutique pour l’inspection visuelle. Les aspects pratiques de la constitution et de la gestion des « défauthèques », les principes fondamentaux de la qualification des systèmes, le processus de qualification du personnel au mirage manuel et semi-automatique sont également couverts par les travaux de la commission.

isual inspection of parenteral products is required by both pharmacopoeias and good manufacturing practice. The Commission decided to describe the various methods and apparatuses commonly used in the pharmaceutical industry for visual inspection. The Commission’s work also covered practical aspects concerning the constitution and management of defect databases, the basic principles of system qualification, and the process of qualification of personnel in manual and semiautomated visual inspection.

Mots clefs : Inspection visuelle, Mirage, Qualification, Formation, Défauts, NQA, Particules.

Key words: Visual inspection, Qualification, Training, Defects, AQL, Particles.

I Introduction

Parmi les critères fondamentaux de qualité des médicaments injectables répondant aux exigences de pureté, innocuité, efficacité et stérilité, l’inspection des unités remplies est une étape clef dans la maîtrise de nos procédés de fabrication. Quel que soit le pays d’appartenance, les autorités de tutelle exigent que cette opération soit conduite. Les références réglementaires, tant dans la définition des moyens à mettre en œuvre (mode opératoire : cadence, sensibilité, équipement…) que dans les objectifs fixés (« pratiquement exempt de particules »…), placent les industriels pharmaceutiques dans une situation délicate au regard des interprétations possibles. À cet égard, les BPF indiquent : « 124. Après la répartition, les produits à usage parentéral doivent subir un contrôle individuel destiné à détecter tout corps étranger ou autre défaut. Lorsque ce contrôle est effectué visuellement, il doit être fait dans des conditions appropriées de lumière et d’arrière-plan préalablement déterminées. » Les principes d’inspection se déclinent en : - mirage visuel (manuel ou semi-automatique), - mirage automatique.

Among the essential criteria of the quality of parenteral products corresponding to purity, safety, efficacy and sterility requirements, inspection of filled units is a key step in control of our manufacturing processes. This operation is required by regulatory authorities in all countries. Regulatory guidelines concerning the definition of the methods to be used (procedure: rate, sensitivity, equipment, etc.) and the objectives (“practically particle-free”) place pharmaceutical manufacturers in a delicate situation in view of the various possible interpretations.

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For example, GMP indicate: “124. Filled containers of parenteral products should be inspected individually for extraneous contamination or other defects. When inspection is done visually, it should be done under suitable and controlled conditions of illumination and background”. The principles of inspection can be classified as: - visual inspection (manual or semiautomated), - automated visual inspection.

Notre groupe de travail s’est attaché au mirage visuel, où l’homme est au cœur du processus. Les auteurs proposent une méthodologie basée sur les retours d’inspection, les pratiques usuelles et abordent l’ensemble des critères complémentaires nécessaires à la mise en place d’une démarche de qualification de mirage visuel.

The working party examined visual inspection in which man is at the heart of the process. The authors propose a methodology based on inspection feedback, usual practices and discuss all of the complementary criteria required to set up a visual inspection qualification approach.

II Définitions

II Definitions

L’inspection visuelle (mirage) : on entend par inspection visuelle ou mirage l’opération de contrôle de présence de tout corps étranger ou autre défaut pour chaque unité remplie. Bien que ce contrôle concerne 100 % des unités remplies, il ne peut garantir l’absence de défauts qu’avec une certaine probabilité. L’inspection visuelle dite « manuelle » est réalisée par l’œil humain sur un poste approprié où les opérations sont entièrement assurées par l’opérateur. L’inspection visuelle semi-automatique est réalisée par l’œil humain avec un équipement permettant l’alimentation, le défilement et l’agitation par rotation ou retournement à vitesse contrôlée. L’inspection automatique est réalisée par des systèmes de vision en dehors de toute intervention humaine. Contrôle visuel “in-process” : contrôle réalisé au cours du process en vue d’optimiser les paramètres d’exploitation des équipements en production (charbonnage, particules, casse…). NQA (niveau de qualité acceptable) : niveau de qualité qui, pour le contrôle par échantillonnage sur une série continue de lots, constitue la limite acceptable pour la qualité moyenne d’une fabrication (définition issue de la norme ISO 2859-1). En d’autres termes, le recours à un contrôle statistique sur un lot est possible dès lors qu’il appartient à une série de lots ayant le même niveau de qualité. La constitution de l’échantillon sur ce lot doit être menée de manière représentative et répondre à une taille définie par la norme ISO 2859-1, fonction notamment de la taille du lot. Cet échantillon doit être évalué et le lot concerné sera accepté si cet échantillon comporte un nombre d’unités avec défauts inférieur à un nombre limite. Ce nombre limite est basé notamment sur le NQA et la taille du lot. Ainsi, le NQA est le niveau de qualité acceptable pour le lot ; il est défini par l’industriel et est fonction de la criticité du défaut. Imperfection cosmétique : défaut d’aspect ne mettant pas en cause la qualité intrinsèque du produit. La détection de ces défauts est hors périmètre de cet article dans la mesure où les exigences sont variables en fonction des clients. Particules visibles : il serait confortable de se réfugier derrière le seuil communément admis des 80 à 100 µm, mais il s’agit plutôt d’une probabilité de détecter des particules à l’œil nu en fonction de plusieurs variables : environnement, temps d’observation, opérateur, nature du produit. Tendances : suivi régulier d’indicateurs permettant de mettre en évidence une dérive progressive du

Visual inspection: visual inspection is defined as the control operation designed to detect the presence of any foreign matter or any other defect for each filled unit. Although this control concerns 100 % of filled units, it can only guarantee the absence of defects with a certain probability. Manual visual inspection is performed by the human eye at an appropriate viewing station, where all operations are ensured by the operator. Semiautomated visual inspection is performed by the human eye with equipment comprising a feeder, conveyor and agitation by rotation or inversion at a controlled speed. Automated inspection is performed by vision systems in the absence of any human intervention. In-process visual inspection: control test performed during the process to optimize manufacturing equipment operating parameters (carbonization, particles, breakage, etc.). AQL (acceptance quality level): quality level that is the worst tolerable process average when a continuing series of lots is submitted for acceptance sampling (definition derived from ISO 2859-1). In simple terms, a statistical control can be performed on a lot when it belongs to a series of lots with the same quality level. Constitution of the sample of this lot must be conducted according to a representative process and must comply with a sample size defined by ISO 2859-1, essentially depending on the lot size. This sample must be evaluated and the lot concerned will be accepted if this sample comprises a number of defective units less than a defined limit. This limit is essentially based on the AQL and the lot size. The AQL is therefore the acceptance quality level for the lot; it is defined by the manufacturer and varies according to the criticality of the defect. Cosmetic imperfection: defects of appearance with no impact on the intrinsic quality of the product. The detection of these defects is beyond the scope of this article, as cosmetic requirements vary according to the customer. Visible particles: it would be tempting to use the commonly accepted cut-off of 80 to 100 µm, but this cut-off corresponds to a probability of detecting particles with the naked eye, depending on several variables: environment, observation time, operator, nature of the product. Trends: regular monitoring of indicators allowing demonstration of a progressive drift of the quality

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niveau de qualité (rendement mirage, pourcentage de rebuts par type de défauts…). Limite de confiance : « risque statistique » permettant d’évaluer la précision de l’estimation d’un paramètre statistique sur l’échantillon (UCL, upper confident level). Méthode Knapp : approche statistique visant à comparer le mirage manuel à une méthode alternative afin d’en déterminer l’efficacité, dans le cadre de la recherche de particules en solution. Kit de référence : ensemble de spécimens ou photographies représentant chaque défaut ainsi que sa criticité. Objectif : servir d’étalon primaire, approuvé par les utilisateurs et l’assurance qualité (AQ). Kit de formation : ensemble de spécimens représentatif qualitativement de la production. Objectif : servir d’outil à la formation. Kit de qualification : ensemble de spécimens représentatif qualitativement et quantitativement de la production. Objectif : servir d’outil à la réalisation de la qualification.

level (visual inspection yield, percent rejects by type of defect, etc.). Limit of confidence: statistical risk used to evaluate the precision of an estimate of a statistical parameter on the sample (UCL, upper confidence level). Knapp method: in the context of testing for particles in solution, a statistical approach designed to compare manual visual inspection to an alternative method in order to determine its efficacy. Reference kit: set of specimens or photographs representing each defect and its criticality. Objective: to be used as a primary standard, approved by users and quality assurance (QA). Training kit: set of specimens qualitatively representative of production. Objective: to be used as a training tool. Qualification kit: set of specimens qualitatively and quantitatively representative of production. Objective: to be used as a qualification tool.

III Textes réglementaires

III Regulatory texts

1. Liste de textes

1. List of texts

1.1. Textes réglementaires

1.1. Regulatory texts

Bonnes pratiques de fabrication. Good Manufacturing Practices européennes, Annexe 1. Pharmacopée européenne : - formes pharmaceutiques/0520 préparations parentérales/préparations injectables, - monographie EP 2.9.20, contamination particulaire : particules visibles, - monographies générales 0153 vaccins pour usages humains. FDA : - GMP Guidance on Sterile Drug Products produced by Aseptic Processing, - cGMP (2004), Chapter VI B.2, Inspection of Container Closure System. Pharmacopée américaine (US Pharmacopoeia) : - General Chapter 1 Injections, Foreign and Particulate Matter (USP 36), - USP 788 Particule matters in injection, - USP 790 Visible particules in injections (draft). Japanese Pharmacopoeia XVI (6.06 Foreign insoluble matter).

Good Manufacturing Practice. European Good Manufacturing Practice, Appendix 1. European Pharmacopoeia: - dosage forms/0520 Parenteral preparations/Injections, - Ph. Eur. Monograph 2.9.20, Particulate contamination: visible particles, - general monographs 0153 Vaccines for human use.

1.2. Recommandations

1.2. Recommendations

WHO, Regulation, guidance annexe 6. ANSM, fiche n° 2, signalements « particules de verre dans les injectables », éléments d’investigations à prendre en compte et mesures préventives (juin 2009).

WHO Regulation, guidance appendix 6. ANSM, notification form No. 2 “Glass particles in injections” elements of investigations to be taken into account and preventive measures (June 2009).

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FDA: - GMP Guidance on Sterile Drug Products produced by Aseptic Processing, - cGMP (2004), Chapter VI B.2, Inspection of Container Closure System. United States Pharmacopoeia (USP): - General Chapter 1 Injections, Foreign and Particulate Matter (USP 36), - USP 788 Particulate matters in injections, - USP 790 Visible particles in injections (draft). Japanese Pharmacopoeia XVI (6.06 Foreign insoluble matter).

1.3. Norme

1.3. Standard

ISO 2859-1, avril 2000.

ISO 2859-1, April 2000.

2. Tableau de synthèse des exigences

2. Summary table of requirements

Le tableau 1 synthétise les principales exigences réglementaires. Remarque : on peut noter l’absence d’harmonisation sur le sujet…

The main regulatory requirements are summarized in Table 1. Note the absence of harmonisation on this subject.

Tableau 1. Principales exigences réglementaires.

BPF/GMP Eu

FDA cGMP

Ph. Eur.

USP

Objectifs

- Contrôler 100 % des contenants, contaminations étrangères ou autres défauts

- N'importe quelles unités endommagées ou défectueuses devraient être détectées et enlevées, pendant l'inspection finale

- Claires et pratiquement sans particules

- Chaque contenant sera inspecté autant que possible afin de détecter la présence de corps étranger et de particules de matières - Garantir le produit “pour l’essentiel” avec absence de particules visibles

- Claire et libre de par ticules étrangères aisément détectables

Méthodes

- Contrôler individuellement, pauses répétées - Si autres méthodes, validation obligatoire

- Pas d’étiquettes, lavage, séchage de l'extérieur, retournement du contenant, s’assurer qu’il n’y a pas de bulles d'air, observation environ 5 s devant le panneau blanc, répétez la procédure devant le panneau noir, enregistrez la présence de n'importe quelles particules

- Méthode d’inspection décrite et qualifiée - Qualification avec particules “représentatives” de la production réelle - Si le contenu ou contenant ne permet pas une totale inspection, il sera complété par le contrôle sur un échantillon soit reconstitué (lyophilisat) soit transféré (verre brun)

Matériels

- Conditions appropriées d’éclairage et d’arrière-plan - Si autres méthodes, procédé validé et équipement qualifié périodiquement

- Panneau noir, mat, de taille appropriée en position verticale - Panneau blanc anti-reflet de taille appropriée en position verticale - Support de lampe réglable, non directe, avec source de lumière blanche et diffuseur adapté, (2 tubes de 13W avec longueur d’onde de 525 nm, intensité entre 2000 et 3750 lux mais possibilité de monter pour des contenants plastiques ou verres colorés)

Main d’œuvre

- Contrôle régulier de la vue avec verres correcteurs si portés

Résultats

- À enregistrer

- N'importe quels défauts ou résultats en dehors des spécifications établies pour les contrôles en cours et l’inspection finale doivent être investigués avec § 211.192.

- Pas d’élément grossissant - Intensité lumineuse à environ 1000 lux avec lampe incandescente - Intensité environ 8000 à 10 000 lux pour les contenants en plastique

- Tracer la présence de toutes particules

IV Retours d’inspections

IV Inspection feedback

Dans la cadre de la publication, une enquête réalisée auprès des industriels (2013) permet de noter que les principaux écarts et remarques relevés au cours des dernières inspections de l’ANSM portent sur les items suivants.

In the context of the publication, a survey conducted among manufacturers (2013) revealed that the main defects and comments noted during the last ANSM inspections concerned the following items.

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Table 1. Main regulatory requirements. BPF/GMP Eu

FDA cGMP

Ph. Eur.

Objectives

- Inspection of 100 % of containers, foreign contaminations or other defects

Methods

- Individual inspection repeated breaks - Validation is required for other methods

- Remove any adherent labels from the container and wash and dry the outside. Gently swirl or invert the container, ensuring that air bubbles are not introduced, and observe for about 5 s in front of the white panel. Repeat the procedure in front of the black panel. Record the presence of any particles

Materials

- Appropriate lighting and background conditions, if other methods process must be validated and equipment must be periodically qualified

- A matt black panel of appropriate size held in a vertical position - A non-glare white panel of appropriate size held in a vertical position - An adjustable lampholder fitted with a suitable, shaded, white-light source and with a suitable light diffuser (a viewing illuminator containing two 13 W fluorescent tubes, each 525 mm in length, is suitable). The intensity of illumination at the viewing point is maintained between 2000 lux and 3750 lux, although higher values are preferable for coloured glass and plastic containers

Manpower

- Regular vision testing with corrective glasses when needed

Results

- Record results

USP

- A ny d a m a g e d - Clear and practically par- - Each container will be inspecor defective units ticle-free ted as far as possible to detect should be detecthe presence of foreign matter ted, and removed and particles to essentially guaduring inspection rantee the product for absence of the final sealed of visible particles product

JP - Clear and free of easily detectable foreign particles

- Method of inspection described and qualified - Qualification with particles representative of real production - If the content or container does not allow total inspection, it will be completed by inspection on a reconstituted (freeze-dried powder) or transferred sample (brown glass) - No magnifying element Intensity of illumination of about 1,000 lux with incandescent lamp - Intensity of about 8,000 to 10,000 lux for plastic containers

- Any defects or - Record the presence of any re s u l t s o u t s i d e particles the specifications established for inprocess and final inspection are to be investigated in accord with § 211.192

1. Habilitation des opérateurs et conditions de maintien

1. Qualification of operators and maintenance conditions

- S’assurer de la mise en place d’un kit représentatif de la production contenant des défauts en quantité définie et permettant d’habiliter le personnel. - Critères d’acceptation préalablement définis et procédurés selon criticité des défauts et cela de manière reproductible. - Demande de vérification et de surveillance de l’acuité visuelle des opérateurs. - Conditions de maintien de l’habilitation et notamment la gestion des (longues) absences (de pratique) ainsi que la fréquence de réhabilitation. - Rendre accessible l’état des habilitations (affichage de matrice…).

- Ensure the presence of a kit representative of the production containing a defined quantity of defects, allowing qualification of personnel. - Reproducible acceptance criteria previously defined in a procedure according to criticality of defects.

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- Verification and monitoring of the operators’ visual acuity. - Conditions of maintenance of qualification, especially management of (long) absences (of practice) as well as requalification frequency. - Make the qualification status accessible (display of the matrix, etc.). 17

2. Conditions de réalisation du mirage

2. Visual inspection conditions

Au-delà des exigences définies dans les pharmacopées européenne, japonaise et américaine décrivant les fonds noirs et fonds blancs ainsi que les valeurs d’intensité lumineuse appliquées au poste, d’autres éléments doivent être envisagés : - les intervalles entre temps de travail et temps de pause ; - les cadences, qui doivent permettre de nous assurer que le mirage reste efficace au cours du temps ; - d’autre part l’éclairage de l’espace environnant, la disposition et l’ergonomie du poste qui doivent favoriser la concentration de l’opérateur et ainsi éviter tout risque de confusion.

Apart from the requirements defined in the European, Japanese and American Pharmacopoeias describing black and white panels as well as intensity of illumination applied for inspection, other elements must also be considered: - intervals between work times and break times; - inspection rates must ensure that visual inspection remains effective over time; - illumination of the environment, organisation and ergonomy of the viewing station must also promote the operator’s concentration and therefore avoid any risk of confusion.

3. Documentation et défauthèque de référence

3. Documentation and reference defect database

- Opérations de mirage décrites dans des procédures détaillées (méthode, matériel, conditions opératoires, les prérequis du poste). - Défauthèque physique (les photos ne sont pas jugées suffisantes), tenue à jour régulièrement et maîtrisée, doit permettre aux opérateurs de visualiser les défauts et servir de référence en cas de doute.

- The visual inspection operations described in detailed procedures (method, material, operating conditions, viewing station prerequisites). - Physical defect database (photographs are not considered to be sufficient), regularly kept up-to-date and mastered, must allow operators to visualize defects and must constitute a reference when in doubt.

4. Contrôle final et analyse des tendances

4. Final control and trend analysis

- Valider chaque opération de mirage par un contrôle a posteriori (contrôle statistique selon plan d’échantillonnage établi, double mirage…).

- Attente de suivi des tendances des défauts détectés au mirage afin de permettre des investigations et la mise en place d’actions préventives et/ou correctives.

- Validate each visual inspection operation by a retrospective control (statistical control according to an established sampling plan, double visual inspection, etc.). - Trend analysis of the defects detected on visual inspection to allow investigations and implementation of corrective and/or preventive actions.

V Retours d’experiences

V Experience feedback

1. Contexte/discussion

1. Background/discussion

L’évaluation visuelle de la qualité des solutions parentérales, en ce qui concerne les particules visibles, peut s’appuyer sur des méthodes de contrôle alternatives à la Pharmacopée. Ces méthodes doivent néanmoins être aussi performantes que celles décrites à la monographie (2.9.20) de la Ph. Eur. Le tableau 2 identifie les principaux paramètres des modes opératoires susceptibles d’être ajustés. La profession est convaincue que le zéro défaut ne pourra jamais être atteint par le caractère probabiliste de la détection. Néanmoins, au vu de la disparité des approches des industriels, des spécifications réglementaires et des exigences des inspections de nos autorités de tutelle, un compromis alliant pragmatisme et souci de la qualité des produits mis sur le marché doit être trouvé.

Visual evaluation of the quality of parenteral solutions in terms of visible particles can be based on alternative methods to those described in the Pharmacopoeia. These methods must nevertheless be as efficient as those described in the European Pharmacopoeia monograph (2.9.20). Table 2 identifies the main parameters of the operating procedures that can be adjusted. The profession is convinced that zero defect can never be achieved due to the empirical nature of detection. Nevertheless, in view of the various approaches used by manufacturers, regulatory standards and regulatory authority inspection requirements, a compromise must be reached comprising a pragmatic approach ensuring quality of the products released onto the market.

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Tableau 2. Principaux paramètres des modes opératoires susceptibles d’être ajustés. Thèmes

Impact qualité

Impact industriel

Temps d’observation

Probabilité de détection augmentée au regard du Variable sur la productivité temps d’observation

Nbre unités mirées simultanément

Possibilité de comparaison (entre unités d’une même Augmentation de cadence série observée)

Equipements

Conception : optiques grossissantes, miroirs, éclai- Rejets/rebus plus nombreux, conception d'équiperage optimisé en fonction de la nature du produit ments spécifiques (prototype), transfert ou sous-traimiré peuvent améliorer sensiblement le seuil de dé- tance complexe tection ou élargir le champ des défauts détectables

Tendances - Seuil bas

Détection de défaillance d’un opérateur ou d’un équipement Détection de défauts avérés (problème process amont) ou de défauts non avérés (défaillance opérateur et/ou équipement) Réaction immédiate

Taux de rejet usuel de 2 à 3%, trop bas pour définir un seuil d’alerte et nécessité de remirer l’ensemble du lot Notion de remirage

Remirage de la totalité du lot

Garanties supplémentaires

Retraitement identique et/ou ciblé coûteux

Remirage partiel

Ciblage sur une population à risque / sur un défaut identifié

Moins de manipulation (diminution du risque de générer des défauts lors des opérations de contrôle) Retraitement plus rapide

NQA

Si mis en œuvre, moyen de mesure objectif de la Echantillonnage supplémentaire pour contrôle qualité du lot par classification des défauts

Personnel

Gestion des habilitations

Kit de formation

Révision régulière des défauthèques, maintien des Gestion lourde des défauthèques (stockage, mise à jour, compétences des experts, évite la mémorisation des gestion des casses et usures) défauts du kit de qualification

Kit de référence

Pas d’ambiguïté sur la criticité des défauts

Gestion du kit

Kit de qualification

Vérifications régulières de sa validité

Gestion du kit

- Seuil haut - En continu

Arrêt pour investigation et décision de la suite

Table 2. Main parameters of the operating procedures that can be adjusted. Themes Observation time

Quality impact

Industrial impact

Increased probability of detection with increasing observation time

Number of units inspected Possibility of comparison (between units of the same simultaneously series inspected) Equipment

Trends - Low threshold - High threshold - Continuously

Variable impact on productivity Increased inspection rate

Design: magnifying lenses, mirrors, lighting opti- Greater number of rejects, design of specific equipment mized according to the nature of the product inspec- (prototype), complex transfer or outsourcing ted can considerably improve the limit of detection or broaden the range of detectable defects Detection of operator or equipment failure

Usual rejection rate of 2 to 3%, too low to define an alert threshold and the need to reinspect all of the lot Reinspection concept

Detection of documented defects (problem in upstream process) or non-documented defects (operator and/or equipment failure) Immediate reaction Process stopped for investigation and decision concerning continuation

Reinspection of the entire lot

Additional guarantees

Expensive identical and/or targeted reprocessing

Partial reinspection

Targeted to a risk population/an identified defect

Decreased handling (decreased risk of generating defects during control operations) More rapid reprocessing

AQL

When used, objective measurement of the quality Additional sampling for controls of the lot by classification of defects

Personnel

Qualification management

Training kit

Regular revision of defect databases, maintenance of Complex management of defect databases (storage, the experts’ skills, avoids memorization of defects of update, management of breakages and wear and tear) the qualification kit

Reference kit

No ambiguity concerning the criticality of defects

Kit management

Qualification kit

Regular verifications of its validity

Kit management

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En prenant en compte l’ensemble des éléments, le groupe de travail est parvenu à un compromis à considérer comme un outil d’aide à la décision, dans vos industries respectives et avec vos spécificités.

By taking all of these elements into account, the working party reached a compromise that can be considered to be an aid to decision tool in your respective industries and with your specificities.

2. Défauts

2. Defects

Un défaut est un élément de nature à impacter l’identité, l’efficacité, la pureté, l’usage et l’image du produit. Les critères de sélection des défauts peuvent être : - visibilité, - historique, - nature du produit et du contenant, - exigences des clients (donneurs d’ordre).

A defect is an element likely to impact the identity, efficacy, purity, use and image of the product.

2.1. Sources

Au-delà du contrôle particulaire, l’inspection visuelle permet également la détection d’autres défauts, provenant de sources multiples : - défauts article (fournisseur), - produit, - process de fabrication, - process de remplissage, - convoyage, - lyophilisation, - stérilisation, - stockage, - mirage.

Apart from testing for particles, visual inspection also allows the detection of other defects, derived from multiple sources: - packaging material defects (supplier), - product, - manufacturing process, - filling process, - conveyor system, - freeze-drying, - sterilization, - storage, - visual inspection.

2.2. Typologie

2.2. Typology

Les défauts observés lors de l’inspection visuelle sont de différentes natures et de caractères différenciés (tableau 3, liste non exhaustive). Une partie de ces défauts est illustrée en annexe.

Different types of defects with differentiated characters are observed during visual inspection (Table 3, non-comprehensive list). Some of these defects are illustrated in appendix.

Defect selection criteria can be: visibility, history, nature of the product and the container, customer requirements.

Tableau 3. Principaux défauts observés lors de l’inspection visuelle. Table 3. Different types of defects observed during visual inspection. Famille Family

Type

Critères et remarques Criteria and comments

Particules endogènes Endogenous particles

Suspension, protéine… Suspension, protein…

Particules exogènes Exogenous particles

Verre / Glass Fibre / Fibre Colorée / Coloured Métalliques / Metal Plastique / Plastic Silicone / Silicone Poils / Hair Nuisibles / Pest

Taille*, position et comportement Size*, position and behaviour

Volume

Haut / High Bas / Low Vide / Empty

Ces défauts seront observés par comparaison et non par mesure, le contrôle du volume n’étant pas un objectif du mirage These defects are observed by comparison and not by measurement, as visual inspection is not designed to control volume

Défaut produit Product defect

Couleur / Colour Opacité/limpidité / Opacity/clarity Aspect du lyophilisat / Appearance of the freeze-dried powder

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Tableau 3. Principaux défauts observés lors de l’inspection visuelle (suite). Table 3. Different types of defects observed during visual inspection (continued). Famille Family Bouchage / Crimping Sertissage / Stoppering Scellage / Sealing

Type

Critères et remarques Criteria and comments

Absence et nombre / Absence and number Capsule non-conforme / Non-conforming capsule Scellage / Sealing

Position / Position

Etirement verre gros « picot », affaissement verre, trou Stretching of large blob of glass, glass weakness, hole Mal positionné (haut –bas), mal posé (à l’envers, de travers, quantité, …) Incorrectly positioned (high-low), incorrectly applied (upside down, askew, quantity, etc.)

Présence de liquide dans le joint / Presence of liquid in the seal Erreur d’AC / Packaging material error Défaut contenant Container defect

Eclat intérieur (larme calcinée…) / Internal chip (burnt defect…) Dimension / Dimensions Eclat extérieur / External chip Fêlure (incisé…) / Crack (incised...) Rayure / Scratch Couleur / Colour Excroissance intérieure (aiguille de verre, ailette, perchoir…) Internal excrescence (glass splinter, rib, ledge…) Excroissance extérieure (bavure) External excrescence (smudge) Collé coupant (suite au collage de deux contenants) Sharp joint (following gluing of two containers) Bulle (bouillon) / Bubble (broth) Pli vertical / Vertical fold Pli horizontal / Horizontal fold Tache intérieure / Internal spot Tache extérieure / External spot Inclusion / Inclusion Eléments d’intégrité abîmés (joint de piston, protège-aiguille, site de perfusion, bouchon, aiguille…) Damaged elements (piston seal, needle cover, infusion site, stopper, needle…)

*Afin de faciliter la définition d’une taille de particule, il est possible de se limiter à deux familles (petites/grosses) selon l’exemple donné en figure 1. *To facilitate the definition of particle size, two families (small/large) can be defined according to Figure 1. Figure 1. Exemple de détermination de seuil : médiane 50% (fondée sur la distribution réelle des tailles de particules de plusieurs lots de production). Le principe de l’exemple consiste à mesurer l’ensemble des particules observées sur une population choisie (par exemple un nombre de défauts ou de lots défini) afin de déterminer la médiane entre les grandes et les petites particules. Figure 1. Example of determination of the limit: median 50 % (based on the real distribution of particle size of several production lots). The principle of this example consists of measuring all particles observed in a chosen population (for example a number of defects or defined lots) in order to determine the median between large particles and small particles.

2.3. Analyse de criticité des défauts

2.3. Defect criticality analysis

Tous les défauts caractérisés doivent être évalués. Exemple de rationnel et de critères permettant d’établir/évaluer la criticité des défauts (tableau 4) : - un impact en termes d’efficacité/identité/sécurité (rouge) détermine un niveau critique ; - un impact d’utilisation/réclamation (orange) détermine un niveau majeur ; - un impact d’image/productivité (jaune) détermine un niveau mineur ; - le niveau le plus critique l’emporte. L’évaluation de la criticité des défauts se fera au regard de la connaissance du produit, de l’historique et de la politique de l’entreprise, et de données

All defects identified must be evaluated. Example of the rationale and criteria used to establish/evaluate the criticality of defects (Table 4): - impact in terms of efficacy/identity/safety (red) determines a critical level; - impact of use/complaint (orange) determines a major level; - impact of image/productivity (yellow) determines a minor level; - the most critical level is adopted. Evaluation of the criticality of defects is based on knowledge of the product, product history and the company’s policy, and analytical data, and should

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Tableau 4. Rationnel et critères. Table 4. Rationale and criteria. Défaut constaté

Efficacité Efficacy

Identité

Sécurité patient (stérilité, pureté)

Identity

Patient safety (sterility, purity)

Particule en solution Particle in solution

Capsule abîmée Damaged cap

Rayure Scratch Fêlure Crack

Defect observed

Aspect gâteau inhabituel Unusual appearance

Utilisation Use

Réclamation

Ternit image

Productivité

Rationnel

Criticité

Complaint

Impaired image

Productivity

Rationale

Criticality

O/Y

Risque de réclamation à évaluer selon destination/clients Risk of complaint to be evaluated according to destination/customer

M /m

m Défaut d’intégrité avéré Documented defect of integrity

C C

O : oui. N : non. C : critique. M : majeur. m : mineur. Un score rouge oriente une classification critique. Un score orange oriente une classification majeure. Un score jaune oriente une classification mineure. Le score le plus critique l’emporte. Y: yes. N: no. C: critical. M: major. m: minor. A red score indicates a critical classification. An orange score indicates a major classification. A yellow score indicates a minor classification. The most critical score is adopted.

analytiques, de préférence par un groupe multidisciplinaire. Ainsi un défaut pourra être catégorisé différemment d’une entreprise à l’autre, l’important étant de justifier la démarche de manière rationnelle.

preferably be performed by a multidisciplinary group. A defect may therefore be classified in different ways from one company to another; however, it is important to rationally justify the approach used.

2.4. Criticité/NQA

2.4. Criticality/AQL

Défaut critique : défaut pouvant directement affecter l’identité, l’efficacité ou la pureté du médicament dont l’usage peut entraîner des dommages sur la santé du patient ou l’efficacité du traitement. Défaut majeur : défaut entraînant l’impossibilité – ou un problème – d’utilisation du produit. Ne présente pas de risque patient mais expose à des réclamations. Défaut mineur : ne présente aucun risque sur la qualité du produit, ni de risque utilisateur (infirmière, patient). Défaut pouvant impacter la productivité, l’image du produit ou du laboratoire. Les NQA appliqués pour ces différentes classifications sont variables en fonction des industriels et des clients. Les NQA les plus observés sont les suivants : - défaut rédhibitoire : -, - défaut critique : 0,025 à 0,1, - défaut majeur : 0,25 à 0,65, - défaut mineur : 1 à 4.

Critical defect: defect that may directly affect identity, efficacy or purity of the drug product for which use of the product can cause damage to the patient’s health or decrease the efficacy of treatment. Major defect: defect that makes the product difficult or impossible to use. Does not present a risk for the patient, but may be the subject of complaints.

2.5. Défauthèque

2.5. Defect database

La notion de défauthèque recouvre les kits de référence, de formation et de qualification (tableau 5). Ces kits sont déterminés pour des objectifs différents mais pour des raisons de facilité pratique et de coûts ils peuvent cependant se substituer les uns aux autres.

The concept of defect database includes reference, training and qualification kits (Table 5). These kits are determined for various objectives, but for practical reasons and cost, they can be interchanged.

Minor defect: does not present any risk in terms of product quality or for the user (nurse, patient). Defect that may impact productivity or the product or company image. AQL applied to these various classifications vary as a function of the manufacturer and the customer. The most commonly used AQL are as follows: - prohibitive defect: -, - critical defect: 0.025 to 0.1, - major defect: 0.25 to 0.65, - minor defect: 1 to 4.

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Tableau 5. Trois types de kits. Table 5. Three types of kits. Kit de référence Reference kit Présence de tous les défauts rencontrés Presence of all defects encountered

Kit de formation Training kit

Kit de qualification Qualification kit

Présence de tout ou partie des défauts, Présence des défauts sélectionnés, en proportion représentative de la production, mélangés à des conformes mélangés à des conformes Presence of all or some defects, mixed with Presence of a proportion of selected defects conforming elements representative of production, mixed with conforming elements

Apprentissage de leur typologie & criticité

Apprentissage de l’élimination des défauts

Learning of their typology & criticality

Learning of defect elimination

Validation de l’aptitude à éliminer les défauts en condition de production Validation of the ability to eliminate defects under production condition

La sélection des défauts à détecter lors de l’opération de mirage repose sur : - la criticité (critique et majeure a minima, mineure), - l’occurrence d’apparition des défauts, - des spécificités clients. Dans le cas de production multiproduits, il conviendrait idéalement de constituer des kits par référence (format/produit) mais l’établissement d’un rationnel par la notion de regroupement (limpidité, type de verre, viscosité, taille, volume…) peut justifier la réduction du nombre de kits. La constitution des kits doit être assurée par des équipes habilitées et approuvés par l’assurance qualité.

Selection of the defects to be detected during the visual inspection operation is based on: - criticality (critical and minimal major, minor), - defect frequency, - customer specificities. In the case of multi-product productions, kits should ideally be established by reference (format/ product), but a rationale based on a grouping concept (clarity, glass type, viscosity, size, volume...) can justify a smaller number of kits.

2.5.1. Kit de référence

2.5.1. Reference kit

Utilisation : - formation d’un nouvel arrivant ou sensibilisation (apprentissage des défauts, de leurs terminologies et criticités) ; - aide à la construction des kits de formation et de qualification ; - aide à l’investigation lors de litiges ; - limiter autant que faire se peut les manipulations des échantillons. Constitution : - établir la liste la plus exhaustive en se basant sur les essais de qualification, l’historique du process, la connaissance du produit (contenu/contenant), les réclamations, etc., afin de figer la terminologie des défauts ; - associer à chaque défaut soit un échantillon soit une représentation iconographique (photos et schémas) ; - évaluer la criticité de chaque défaut selon modalités décrites au V.2 avec approbation finale par l’assurance qualité. Gestion : - les conditions de stockage doivent nous garantir l’absence d’altération et l’intégrité physique des échantillons (à l’abri de la lumière, accès contrôlé, conditions de conservation du produit à respecter…). NB : Attention, certains défauts peuvent disparaître et/ou apparaître au cours du temps ; de plus, la péremption du produit est à prendre en compte dans la durée de conservation du kit. Le kit devant servir d’étalon primaire, les représentations iconographiques sont à privilégier afin de s’affranchir de ces difficultés.

Use: - training of a new arrival or to increase the awareness of personnel (learning of defects, of their terminologies and criticalities); - aid to the constitution of training and qualification kits; - aid to investigation in the event of litigation; - limit handling of samples as far as possible.

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Constitution of kits must be ensured by qualified teams and must be approved by quality assurance.

Constitution: - establish the most comprehensive list on the basis of qualification trials, process history, knowledge on the product (content/container), complaints, etc., in order to define the terminology of the defects; - associate with each defect either a sample or a graphic representation (photographs and diagrams); - evaluate the criticality of each defect according to the modalities described in § V.2 with final approval by quality assurance. Management: - storage conditions must ensure the absence of alteration and the physical integrity of samples (protected from light, controlled access, compliance with the product’s storage conditions, etc.). NB: As some defects may disappear and/or appear over time, the product’s expiry date must also be taken into account to determine the kit’s shelf life. As the kit is used as a primary standard, graphic representations are preferable in order to avoid these difficulties.

L’opportunité de rajouter de nouveaux défauts doit s’appuyer sur une évaluation périodique (selon une fréquence adaptée) des défauts apparus et des réclamations.

The decision to add new defects must be based on regular evaluation (according to an appropriate frequency) of the defects observed and complaints.

2.5.2. Kit de formation

2.5.2. Training kit

Utilisation : - formation du personnel (développer l’aptitude à différencier les unités conformes des non conformes et les classifier selon leur terminologie dans les conditions de mirage de la production) ; - l’utilisation de ce kit peut être substituée par une mise en situation au poste de travail encadré par un référent (par exemple, tutorat). Constitution : - présence a minima de tous les défauts sélectionnés dans le kit de référence sans contrainte quantitative parmi des unités conformes. Gestion : - les conditions de stockage doivent nous garantir l’absence d’altération et l’intégrité physique des échantillons (à l’abri de la lumière, accès contrôle, conditions de conservation du produit à respecter…) ; - avant utilisation, s’assurer que l’aspect visuel du kit n’a pas évolué par rapport à l’état initial (présence de tous les défauts et marquage lisible).

Use: - training of personnel (to develop their capacity to differentiate conforming from non-conforming units and to classify them according to their terminology under manufacturing visual inspection conditions); - use of this kit can be replaced by viewing station exercises supervised by an expert (tutorial, for example). Constitution: - presence of at least all defects selected in the reference kit with no quantitative constraints among conforming units. Management: - storage conditions must ensure the absence of alteration and the physical integrity of samples (protected from light, controlled access, compliance with the product’s storage conditions…);

2.5.3. Kit de qualification

2.5.3. Qualification kit

Utilisation : - habilitation du personnel dans les conditions réelles de mirage. Constitution : - présence a minima des défauts critiques et majeurs ; - la distribution des défauts peut s’appuyer sur les taux de rejets moyens ou les dépasser afin de garantir pour un même défaut ses différentes formes (localisation sur l’unité, taille, intensité, comportement...) ; - dans la mesure du possible, le dimensionnement doit être suffisant afin de correspondre au temps de mirage continu et la cadence prévue en production. Cependant, il peut être adapté si le volume du kit est trop important à gérer et/ou selon les spécificités du produit ; - il peut être intéressant de constituer plusieurs kits afin de prévenir la mémorisation de défauts et des casses. Gestion : - les conditions de stockage doivent nous garantir l’absence d’altération et l’intégrité physique des échantillons (à l’abri de la lumière, accès contrôlé, conditions de conservation du produit à respecter…) ; - identification unitaire aléatoire limitant le plus possible la mémorisation des défauts et ne gênant pas l’observation ; - avant utilisation, s’assurer que l’aspect visuel du kit n’a pas évolué par rapport à l’état initial (présence de tous les défauts et marquage lisible) ; - après utilisation, effectuer une réconciliation par une personne habilitée.

Use: - qualification of personnel under real visual inspection conditions. Constitution: - presence of at least critical and major defects; - the distribution of defects can be based on mean rejection rates or higher rates in order to ensure the presence of various forms of the same defect (site on the unit, size, intensity, behaviour…); - as far as possible, kit dimensions must be sufficient to correspond to continuous visual inspection times and the planned production rate. However, kit dimensions can be adapted when the kit is too large to manage and/or according to product specificities; - it may be useful to constitute several kits in order to avoid memorization of defects and allow for breakages.

- before use, ensure that the visual appearance of the kit has not changed from its initial state (presence of all defects and legible labelling).

Management: - storage conditions must ensure the absence of alteration and the physical integrity of samples (protected from light, controlled access, compliance with the product’s storage conditions…); - random unit identification limiting memorization of defects to a minimum and not interfering with observation; - before use, ensure that the visual appearance of the kit has not changed from its initial state (presence of all defects and legible labelling); - after use, reconciliation should be performed by a qualified person.

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À titre d’exemple, le kit de qualification peut être constitué de la manière suivante : considérant une cadence de 3 000 unités/h, un temps de mirage de 30 min et un taux de rejet moyen de 5 %, le nombre d’unités constitutives du kit sera de 3 000/2 = 1 500 unités. Le nombre de défauts à intégrer sera alors de 1 500 unités × 5 % = 75 défauts (représentatifs selon C/M/m).

For example, the qualification kit can be composed in the following way: considering a rate of 3,000 units/h, a visual inspection time of 30 min and a mean rejection rate of 5 %, the number of constitutive units of the kit will be 3,000/2 = 1,500 units. The number of defects to be included will then be 1,500 units x 5 % = 75 defects (representative according to C/M/m).

3. Environnement et conditions de mirage

3. Visual inspection environment and conditions

3.1. Environnement

3.1. Environment

Objectif : favoriser la concentration du personnel en éliminant toutes sources d’interférences telles que bruits, mouvements, éclairages divers… Plusieurs solutions peuvent être envisagées afin de confiner l’opération : - salle dédiée et/ou physiquement séparée des autres opérations et opérateurs (rideaux, cloisons…) ; - bouchons d’oreille pour les environnements bruyants ; - musique d’ambiance ; - limiter au maximum les allées et venues ; - entretenir une intensité lumineuse faible de l’environnement pendant le temps de mirage ; - etc. Exemples : - dans le cas d’une salle dédiée, une programmation automatique de la luminosité et de la musique permettrait de déterminer les phases de mirage et de pause, - de même, une visite de personnes extérieures devrait interrompre les opérations de mirage car susceptible d’altérer la concentration du personnel.

Objective: facilitate the personnel’s concentration by eliminating all sources of interference, such as noise, movements, various light sources… Several solutions can be considered to ensure good operating conditions: - dedicated visual inspection room and/or separated physically from the other operations and operators (curtains, partitions…); - ear plugs for noisy environments; - background music; - limit personnel movements to a minimum; - maintain low background lighting during visual inspection; - etc. Examples: - in the case of a dedicated visual inspection room, automated programming of luminosity and music can be used to determine visual inspection phases and breaks; - similarly, visual inspection operations must be interrupted by the arrival of other personnel, which can alter the personnel’s level of concentration.

3.2. Conditions de production

3.2. Production conditions

Les conditions de mirage doivent être identiques à celles définies lors de la qualification : - appliquer le temps de cycle mirage/pause visuelle comme imposé dans les textes réglementaires, ce qui implique l’obligation d’en apporter la preuve en routine. Exemples de cycle en mirage manuel : - 45 min de mirage/15 min de pause, - 30 min de mirage/10 min de pause, - 20 min de mirage/5 min de pause ; le temps de pause est à ajuster en fonction de l’importance de la cadence et/ou de l’intensité lumineuse élevée ; - respecter la cadence ou le temps d’observation défini ; - respecter la manipulation nécessaire à l’observation : - retournements, - alternance noir/blanc, - zone spatiale de mirage, - respect d’une chronologie (par exemple, haut/bas, contenant/contenu...) ; - respecter le nombre d’unités à mirer simultanément dans le cadre du mirage manuel ;

Visual inspection conditions must be identical to those defined during qualification: - apply the visual inspection cycle/visual break time as required by regulatory texts, which implies the obligation to routinely provide proof of these times. Examples of manual visual inspection cycle: - 45 min of visual inspection/15-min break, - 30 min of visual inspection/10-min break, - 20 min of visual inspection/5-min break; the break time should be adjusted according to the production rate and/or intensity of illumination; - comply with the defined rate or observation time; - comply with the handling necessary for observation: - inversions, - alternating black/white panels, - visual inspection spatial zone, - compliance with a defined chronology (for example, high/low, container/content, etc.); - comply with the number of units to be inspected simultaneously in the context of manual visual inspection; - categorize defects in order to analyse trends: this

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- catégoriser les défauts afin de gérer les tendances : cette opération pourra se faire en temps réel ou à l’issue de l’opération de mirage.

operation could be performed in real-time or after completing visual inspection operations.

4. Matériel

4. Equipment

4.1. Postes manuels

4.1. Manual viewing stations

Les postes d’inspection visuelle manuelle ou tables de mirage sont décrits dans la monographie 2.9.20 (figure 2) de la Pharmacopée européenne.

Manual visual inspection viewing stations are described in monograph 2.9.20 (Figure 2) of the European Pharmacopoeia.

Figure 2. Ph. Eur. 2.9.20 1, appareillage pour les particules visibles.

Figure 2. Eur. Ph. 2.9.20 1, apparatus for visible particles.

Pour rappel, la monographie 2.9.20 précise que cet appareillage est une « méthode simple d’évaluation visuelle de la qualité des solutions parentérales en ce qui concerne les particules visibles. D’autres méthode validées peuvent être utilisées ». La figure 3 montre un poste de mirage en mode manuel.

Note that monograph 2.9.20 indicates that this “test is intended to provide a simple procedure for the visual assessment of the quality of parenteral solutions as regards visible particles. Other validated methods may be used”. A manual visual inspection viewing station is illustrated in Figure 3.

4.1.1. Descriptif des postes manuels

4.1.1. Description of manual viewing station

Il consiste en un panneau noir mat et un panneau blanc non réfléchissant disposés verticalement en face du poste d’observation. Une rampe d’éclairage, indirect, orientable, diffuse une lumière de λ = 525 nm, d’une intensité comprise entre 2 000 et 3 750 lux, à l’aide de tubes de lampe de type néon d’une puissance de 13 W. Des intensités lumineuses plus importantes sont préconisées pour l’inspection visuelle des contenants en matière plastique.

It consists of a matt black panel and non-glare white panel held in a vertical position in front of the viewing station. An adjustable, indirect light source diffuses light with λ = 525 nm, with an intensity ranging between 2000 lux and 3750 lux, using 13 W fluorescent tubes. Higher intensities of illumination are preferable for the visual inspection of plastic containers.

4.1.2. IQ/OQ of manual viewing stations

4.1.2. QI/QO des postes manuels La qualification de ces systèmes repose avant tout sur la vérification des éléments d’éclairage en qualification d’installation en veillant à leur conformité aux spécifications aux dif-

Figure 3. Poste de mirage manuel. Figure 3. Manual visual inspection viewing station.

Qualification of these systems is essentially based on verification of the light source in the context of installation qualification by ensuring their compliance with the standards of the various pharmacopoeias

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férentes pharmacopées et, le cas échéant, au cahier des charges. En qualification opérationnelle, l’intensité lumineuse sera contrôlée à l’aide d’un luxmètre dûment étalonné.

and, when necessary, user requirement specifications. In the context of operational qualification, the intensity of illumination is controlled by an appropriately calibrated lux meter.

4.1.3. Métrologie des postes manuels

4.1.3. Metrology of manual viewing stations

Vérification de la luminosité à l’aide un luxmètre 4. Exemple de mapping. et validation de la zone de Figure Figure 4. Example of mapping. mirage. Fréquence à définir (usuellement une fois par an). Les spécificités des fournisseurs de lampe seront à prendre en compte afin d’ajuster la fréquence de métrologie. La réalisation d’un mapping tridimensionnel du poste de travail (figure 4) permettra de vérifier la conformité de l’intensité lumineuse dans la zone d’inspection. Dans le cas de lampes halogènes, il conviendra de respecter le temps de chauffe.

Verification of the intensity of illumination with a lux meter and validation of the visual inspection zone. Frequency of metrology testing must be defined (usually annually). The specificities of lamp suppliers should be taken into account to adjust the frequency of metrology testing. Three-dimensional mapping of the viewing station (Figure 4) can be used to verify compliance of the intensity of illumination in the visual inspection zone. Heating times must be observed when halogen lamps are used.

4.2. Postes semi-automatiques

4.2. Semiautomated viewing stations

4.2.1. Descriptif

4.2.1. Description

Ces équipements (figure 5) sont classiquement These apparatuses (Figure 5) are classically comcomposés : posed of: - d’un module de chargement, - a loading module, - d’un poste de mirage, - a viewing station, - d’un système d’éjection et d’une table d’accumula- an ejection system and an accumulation table. tion. Ils répondent aux besoins des industriels pour They comply with the manufacturer’s needs for l’inspection visuelle des ampoules, flacons et autres visual inspection of ampoules, vials, and other carcartouches, notamment en termes de cadence. tridges, especially in terms of rate. La vitesse de défilement des unités inspectées est la The conveyor speed of inspected units correrésultante du meilleur compromis entre l’efficacité de sponds to the best compromise between efficacy of l’inspection visuelle et les contraintes de productivité. visual inspection and productivity constraints. Le poste de mirage est équipé d’un pupitre pour The viewing station is equipped with a control la mise en œuvre et le parapanel for operation and adjustmétrage de la machine, d’un ment of the machine, adapted éclairage adapté, d’un jeu de lighting, and a set of mirrors miroirs pour permettre l’obserto allow observation of all vation du récipient sur toutes surfaces of the container. ses faces. Les unités sont mises en Units are rotated rapidly to rotation rapide pour décrocher mobilize any particles on their d’éventuelles particules de leur walls, then rotated slowly in paroi, puis en rotation lente, au the viewing zone to allow sediniveau de la zone d’inspection, mentation of these particles pour permettre la sédimentaand observation of all of their tion de ces particules et l’obsersurface. vation de toute leur surface. Un système de faisceau An infrared beam system infrarouge permet l’éjection allows the ejection of defecdes unités défectueuses par tive units by interruption of interruption de celui-ci, une the beam and an audio alarm alarme sonore signale la prise Figure 5. Mireuse semi-automatique. indicates that the units have en compte de l’éjection. been ejected. Figure 5. Semiautomated viewing station. european INDUSTRIAL PHARMACY December 2017

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Généralement, des compteurs sont positionnés en entrée et sortie de la zone d’inspection ainsi qu’au niveau du système de recueil des unités éjectées.

Counters are generally positioned at the entry and exit of the viewing zone and at the level of the ejected unit recording system.

4.2.2. Qualification initiale

4.2.2. Initial qualification

Lors de l’installation de l’équipement dans son environnement, veiller à vérifier la lumière, le bruit et la position dans la zone.

At the time of installation of the equipment in its environment, check lighting, noise and position in the zone.

4.2.3. Qualification opérationnelle

4.2.3. Operational qualification

En qualification opérationnelle, une attention In the context of operational qualification, more plus particulière sera portée aux aspects suivants, particular attention is paid to the following aspects, préalablement révélés par une analyse de risque previously identified by functional risk analysis: fonctionnelle : - levels of access (administrator, maintenance, - les niveaux d’accès (administrateur, maintenance, user…) of the operator-machine interface; utilisateur…) de l’interface opérateur-machine ; - conveyor speeds; - les vitesses de transport ; - unit rotation speeds (rapid and slow); - les vitesses de mise en rotation des unités (rapide - activation of all light sources necessary for effecet lente) ; tive visual inspection (three possible light sources, - l’activation de tous les éclairages nécessaires à un Figure 6); mirage efficace (trois sources possibles, figure 6) ; - measurement of the intensity of light sources; - la mesure de l’intensité des sources lumineuses ; - counting function; - la fonction de comptage ; - ejection system including counting; - le système d’éjection incluant le pointage ; - stop (emergency, on de- les fonctions d’arrêt (d’urmand, automated on saturagence, à la demande, autotion of ejection systems and/ matique lors de la saturaor accumulation of units) tion des systèmes d’éjection Figure 6. Trois sources d’éclairage sur poste semi-automatique. and re-start functions (lot et/ou d’accumulation des Figure 6. Three light sources for semiautomated viewing stations. data storage, systematic and unités) et de redémarrage preventive ejection of units (conservation des données du lot, éjection systémain the viewing zone when the machine is stopped…). tique et préventive des unités dans la zone d’inspection lors de l’arrêt…). 4.2.4. Regular control 4.2.4. Contrôle périodique - Verification of the intensity of illumination with a - Vérification de la luminosité à l’aide un luxmètre. lux meter. - Fréquence à définir (usuellement une fois par an). - Frequency to be defined (usually annually). - Vitesse de défilement. - Conveyor speed. - Vitesse de rotation rapide puis lente. - Rapid and slow rotation speeds. - Contrôle des niveaux d’usure (courroie d’entraîne- Control of the degree of wear (conveyor belts, rotament, caoutchouc de rotation…). tion rubber, etc.).

La qualification de performance de l’opération de mirage manuel et semi-automatique est réalisée par le biais de la qualification du personnel sur équipement manuel et semi-automatique de production.

Performance qualification of manual and semiautomated visual inspection is performed by qualification of personnel on manual and semiautomated production equipment.

5. Qualification du personnel

5. Personnel qualification

5.1. Prérequis

5.1. Prerequisites

A minima, un certificat médical d’aptitude au poste est nécessaire. Il s’appuie, entre autres, sur des tests portant généralement sur la vision des couleurs, la vision de près et de loin, la myopie, le sens stéréoscopique, les défauts de convergence, l’astigmatisme, la fatigue visuelle (phories). Le code du travail imposant une visite médicale

At least a medical certificate of aptitude for the workstation is required. This certificate of aptitude is based, among other things, on tests assessing colour vision, near and distant vision, myopia, stereoscopic perception, defects of convergence, astigmatism, visual fatigue (phorias). As a regular medical visit is required by French

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périodique, c’est la qualification annuelle de l’opérateur qui permettra de détecter l’apparition d’une dérive. Pour autant, il est important de sensibiliser les opérateurs au fait de déclarer toute évolution de leur vision. De plus, les GMP EU nous incitent à vérifier régulièrement l’acuité (avec correction si nécessaire) des opérateurs, ce qui peut être fait par exemple avec un visiotest (figure 7). 5.2. Processus 5.2.1. Apprentissage

law, the operator’s annual qualification is used to detect any changes in his/ her visual capacities. However, operators must be encouraged to report any changes in their vision. EU GMP also require regular verification of operators’ visual acuity (with correction if necessary), for example by means of a visiotest (Figure 7).

Figure 7. Exemple d’équipement visiotest. Figure 7. Example of visiotest equipment.

5.2. Process 5.2.1. Learning

L’apprentissage des défauts est réalisé à l’aide du kit de référence. Cette opération est réalisée sous la responsabilité d’une personne habilitée puis validée par un test (oral, écrit…) avant de passer à l’étape suivante.

Learning of defects is performed by means of the reference kit. This operation is performed under the responsibility of a qualified person and is then validated by a test (oral, written...) before proceeding to the next step.

5.2.2. Formation

5.2.2. Training

L’apprentissage de la conduite de l’opération de mirage est réalisé sur ligne ou sur un équipement dédié, à l’aide du kit de formation, toujours sous la responsabilité d’une personne habilitée (tuteur). Une notion de temps de formation maximal doit être définie, au-delà duquel l’efficacité du processus peut être mise en question. La formation peut comporter une étape de mirage en double. Une évaluation – orale, écrite, pratique – entre le tuteur et la personne formée valide le passage à l’étape de qualification.

Training in visual inspection operations is performed on line or on dedicated equipment, using the training kit, always under the responsibility of a qualified person (tutor). A maximum training time must be defined, beyond which the efficacy of the process appears to be doubtful. Training can comprise a double visual inspection step. Oral, written, or practical evaluation between the tutor and the trained person validates passage to the qualification step.

5.3.3. Qualification

La qualification est sous la responsabilité de l’AQ. L’évaluation met en œuvre le kit de qualification, en conditions réelles de production, idéalement en tenant compte de l’amplitude horaire du poste et des temps de pause (prise en compte de la fatigabilité de l’opérateur). En qualification initiale, trois tests consécutifs conformes valident cette étape, mais, au regard de la spécificité de l’opération, on admet usuellement que trois tests conformes sur cinq suffisent à valider l’opérateur. Le résultat d’un test conforme : - correspond à la détection de 100 % des défauts critiques et majeurs et selon les usages à environ 75 % des autres défauts ; - est lié à un temps de mirage et/ou à une cadence préalablement définis ; - doit intégrer un taux maximal de faux rejets (2-7 %). En qualification périodique (à renouveler usuellement une fois par an), un test conforme est validant. Une non-conformité doit déclencher une investigation dont les résultats peuvent invalider, ou non, le résultat du test.

Qualification is performed under the responsibility of QA. Evaluation is based on use of the qualification kit, under real production conditions, ideally by taking into account the viewing station working time and break times (to take operator fatigue into account). In the context of initial qualification, three consecutive satisfactory tests validate this step, but, in view of the specificity of the operation, it is generally accepted that three out of five satisfactory tests are sufficient to validate the operator. The result of a satisfactory test: - corresponds to the detection of 100 % of critical and major defects and about 75 % of other defects, depending on local practices; - is related to a previously defined visual inspection time and/or inspection rate; - must include a maximum false-rejection rate (2-7 %). In the context of periodic qualification (usually renewed annually) one satisfactory test is validated. An unsatisfactory test must trigger an investigation, the results of which can validate or invalidate the test result.

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Motifs de remise en cause de la qualification : - échec à la qualification après investigation afin de valider la décision ; - absence d’activité de mirage supérieure à trois mois (un processus de requalification partielle ou totale est alors à envisager) ; - signalement d’un problème de vue ; - récurrence de déviation émise lors d’investigation ciblée sur un individu.

Reasons for refusal of qualification: - failure of qualification after investigation to validate the decision; - absence of visual inspection activity for more than three months (a process of partial or total requalification may then be considered); - report of a vision problem; - recurrent deviation revealed by targeted investigation of an individual.

5.3. Stratégie de qualification

5.3. Qualification strategy

Dans le cas d’une configuration de plusieurs équipements équivalents, la qualification d’une personne sur un équipement peut être étendue à l’ensemble du parc. Dans le cadre de l’intégration d’un équipement équivalent, la qualification de performance peut être couverte par la validation du procédé (comparaison aux tendances observées historiquement). Dans le cadre d’un nouveau produit, il convient d’évaluer la similarité à un kit existant (limpidité, type de verre, viscosité, taille, volume…) afin éventuellement de s’affranchir de la mise en œuvre d’un processus de qualification. En cas de non-similarité, la mise en œuvre d’un processus de qualification avec un nouveau kit devra être réalisée.

In the context of configuration of several equivalent apparatuses, personnel qualification on one apparatus can be extended to the whole range of apparatuses. In the context of installation of an equivalent apparatus, performance qualification can be covered by process validation (comparison with historically observed trends). In the context of a new product, the similarity with an existing kit (clarity, type of glass, viscosity, size, volume, etc.) should be evaluated to possibly avoid the need for a qualification process.

6. Amélioration continue

6. Continuous improvement

6.1. Tendances inter-lots

6.1. Inter-lot trends

L’analyse de tendance des taux de rejet de mirage est un critère d’alerte important pour la maîtrise de la qualité du lot mais aussi pour le suivi des équipements de process et de répartition. Ces tendances doivent être analysées tant d’un point de vue quantitatif que qualitatif. D’un point de vue quantitatif, le pourcentage par catégories de défauts identifiés, couvrant les trois niveaux de criticité, doit être suivi régulièrement. Il appartient à chacun de définir ces catégories pour établir son plan de surveillance. Les valeurs d’alerte (calculées par exemple sur la base de l’UCL) doivent être réévaluées régulièrement (au moins une fois par an). Cette réévaluation doit être documentée. Le dépassement du seuil d’alerte devra déclencher une investigation pour identifier la cause de la dérive. La détermination de la root-cause permettra d’envisager des actions correctives et préventives. Dans le même esprit, un contrôle visuel in-process du lot peut permettre de rétablir une éventuelle dérive de process en temps réel. L’aspect qualitatif du rejet est également important : en effet, les opérateurs habilités à l’inspection visuelle peuvent mettre en évidence des défauts atypiques ou différents de ceux trouvés habituellement. Ils devront être pris en considération et faire l’objet d’une enquête, même si le taux de rejet ne dépasse pas le seuil d’alerte.

Trend analysis of visual inspection rejection rates is an important alert criterion for mastery of quality of the lot, but also for monitoring of manufacturing and filling equipment. These trends must be analysed quantitatively and qualitatively.

In the context of non-similar apparatuses, a new qualification process should be performed with a new kit.

From a quantitative point of view, the percentage of categories of defects identified, covering the three levels of criticality, must be regularly monitored. Each manufacturer must define these categories to establish their surveillance plan. Alert values (for example, calculated on the basis of the UCL) must be regularly re-evaluated (at least annually) and re-evaluation of these values must be documented. When an alert threshold is exceeded, an investigation must be carried out to identify the cause of the drift. Determination of the root-cause will allow the proposal of corrective and preventive actions. Similarly, in-process visual inspection of the lot may allow real-time correction of a possible process drift. The qualitative aspect of rejection is also important, as operators qualified in visual inspection may detect atypical defects or defects different from those usually found. These aspects must be taken into consideration and investigated, even when the rejection rate does not exceed the alert threshold.

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6.2. Tendance intra-lots

6.2. Intra-lot trends

Un même lot peut être miré par plusieurs opérateurs et ou plusieurs machines. Dans le cas de la mise en évidence d’un écart significatif des résultats, il peut être pertinent de comparer les pourcentages de défauts retrouvés par opérateur et/ou par machine et de comparer ces valeurs. Si ces écarts ne sont pas expliqués par le process, cela peut mettre en lumière une variabilité dans la capacité de chacun à détecter les défauts. Au même titre que précédemment, la détermination de la root-cause permettra d’envisager des actions correctives et préventives.

A same lot can be inspected by several operators and/or several machines. When a significant difference of the results is demonstrated, it may be relevant to compare the percentages of defects detected by each operator and/ or by each machine. When these differences cannot be explained by the process, they may correspond to the variable capacity of each operator to detect defects. As described above, determination of the rootcause will allow the proposal of corrective and preventive actions.

7. Contrôles statistiques

7. Statistical control

Le contrôle statistique en fin de mirage n’est pas requis par les textes réglementaires. Cependant, les inspecteurs s’attendent à une opération de vérification de l’efficacité du mirage. Les industriels recourent très souvent au contrôle statistique basé sur la norme ISO 2859-1, qui définit par type de défauts le nombre d’unités défectueuses acceptables au sein d’un échantillon représentatif du lot. Les niveaux de qualité acceptable (NQA) sont fixés par les industriels en fonction du risque pour la santé publique mais aussi des exigences de leurs clients. Il en découle une variabilité dans la classification des défauts et des NQA associés. Les NQA applicables au contrôle statistique sur le produit fini doivent être cohérents avec ceux appliqués par les fournisseurs pour les composants du conditionnement primaire. Niveau de contrôle : le plan normal est conduit selon la norme ISO 2859-1 choisie en première intention. Cependant, il existe des cas/situations où l’industriel peut recourir à des contrôles spécifiques, notamment pour les produits onéreux. Contrôle réduit, normal ou renforcé : l’étape de mirage cumule l’ensemble de la variabilité de chacune des phases amont du processus. Dans ce contexte, le contrôle réduit ne nous semble pas adapté. L’absence d’expérience sur la mise en route d’un nouveau produit/procédé devrait orienter vers la mise en place d’un contrôle statistique de type renforcé. Selon la norme : - le contrôle normal ne peut être conduit que sur un processus stable ; - le contrôle renforcé doit être institué à l’apparition d’un deuxième résultat non conforme du contrôle normal sur une série de cinq lots consécutifs d’un même produit ou d’une même présentation. L’industriel doit donc être capable de gérer les échecs récurrents au contrôle, qui sont le signe d’une dérive du process ; - le dépassement du contrôle renforcé (cinq résultats non conformes) entraîne un arrêt du contrôle et la mise en place d’une action d’amélioration du process ; - le retour en contrôle normal peut être envisagé lorsque cinq lots consécutifs satisfont aux normes du NQA.

Statistical control at the end of visual inspection is not required by regulatory texts. However, inspectors expect a verification operation of the efficacy of visual inspection. Manufacturers very often use statistical control based on ISO 2859-1, which defines the number of acceptable defective units per type of defect in a representative sample of the lot.

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Acceptance quality levels (AQL) are defined by manufacturers as a function of the public health risk, but also their customers’ requirements. This results in variability in the classification of defects and associated AQL. AQL applicable to statistical control on the finished product must be consistent with those applied by suppliers for primary packaging material. Level of inspection: the normal sampling plan is primarily conducted according to ISO 2859-1. However, there are cases/situations in which the manufacturer may prefer to use a specific sampling plan, especially in the case of expensive products. Reduced, normal or tightened inspection: the visual inspection step combines all of the variability of each upstream phase of the process. Reduced inspection does not appear to be appropriate in this context. In the absence of experience when launching a new product/process, tightened inspection should be ensured. According to ISO 2859-1: - normal inspection can only be conducted on a stable process; - tightened inspection must be performed when a second non-conforming result is observed on the normal inspection of a series of five consecutive lots of a same product or a same presentation. The manufacturer must therefore be able to manage recurrent inspection failures, which indicate the presence of process drift; - failure of tightened inspection (five non-conforming results) requires interruption of inspection and implementation of a process improvement action; - return to normal inspection can be considered when five consecutive lots meet AQL specifications. 31

Le contrôle renforcé peut être institué devant un résultat inattendu, par exemple en cas de nouveaux défauts, de fréquence inhabituelle (dépassement de seuil d’alerte…) ou d’événements particuliers en cours de production (casse importante lors de la répartition). Les notions de fréquence, détectabilité et gravité seront évaluées pour justifier ou non du recours à ce type de contrôle. L’échantillonnage doit suivre les règles de représentativité définies dans la norme NF ISO 2859-1.

Tightened inspection can be instituted in the case of an unexpected result, for example new defects, an unusual frequency (exceeding the alert threshold…) or unusual events during production (major breakage during filling). The concepts of frequency, detectability and severity will be evaluated to justify or reject the use of this type of inspection.

8. Schéma décisionnel

8. Decisional flowchart

En termes de logique décisionnelle, le groupe de travail propose la stratégie globale représentée dans la figure 8.

The working party proposes the global strategy for the decisional flowchart shown in Figure 8.

VI Conclusion

Au regard du niveau d’exigence croissant de l’étape d’inspection visuelle et de la disparité des méthodologies appliquées, il nous paraissait important d’établir une approche commune. Dans cette perspective, le groupe de travail propose une approche la plus pragmatique possible basée sur les retours d’expérience des industriels et des autorités. Cette démarche a pour objectif de présenter au lecteur l’ensemble des points essentiels à la maîtrise de cette étape complexe. Pour autant, rappelons-nous que le zéro défaut ne reste qu’un objectif…

In view of the growing importance of the visual inspection step and the various methodologies applied, it appeared important to establish a common approach. From this perspective, the working party proposes the most pragmatic possible approach based on feedback from manufacturers and authorities.

Sampling must comply with the rules of representativity defined in NF ISO 2859-1.

This approach is designed to provide the reader will all of the essential points to master this complex step. Nevertheless, it must be remembered that zero defect only remains an objective...

MIRAGE DU LOT Analyse du % des défauts par rapport à nos tendances

Inves ga on maintenance, produc on, analy que

dépassée

Prélèvements du lot pour test sta s que classique selon plan d’échan llonnage défini (procédure)

oui

Défaut facilement détectable

Examen visuel de l’échan llon

non

Inves ga on oui

Ensemble des données conformes

non

Destruc on Mirage conforme

Remirage avec condi ons par culières de type élément grossissant, intensité ajustée et focalisa on sur le défaut

Cas par culier des par cules de verre : recons tu on selon procédure sur échan llonnage représenta f

Test sta s que renforcé

Figure 8. Schéma décisionnel.

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VISUAL INSPECTION OF THE LOT Analysis of the % of defects compared to trends

Inves ga on maintenance, produc on, analysis

exceeded

Sampling of the lot for sta s cal tests according to the defined sampling plan (procedure)

yes

Easily detectable defect

Visual examina on of the sample

Inves ga on yes

All data comply

Destruc on Inspec on complies

Repeat inspec on with special condi ons in terms of magnifying element, adjusted intensity focussing on the defect

Special case of glass par cles Recons tu on according to the procedure on a representa ve sample

Tightened inspec on

Figure 8. Decisional flowchart.

Annexe 1. Exemples de défauts Appendix 1. Examples of defects Ce descriptif peut être associé aux éléments suivants : origine, impact/risque, niveau de criticité. This description can be associated with the following elements: origin, impact/risk, level of criticality. Type de défaut/Type of defect

Photo/Illustration

Type de défaut/Type of defect

Collerette de seringue fissurée Fissured syringe cuff

Pli dans le verre Fold in the glass

Protège-aiguille tordu Twisted needle cover

Particule dans un lyophilisat Particle in freeze-dried powder

Bulle d’air dans le verre (bouillon) Air bubble in the glass (broth)

Capsule abîmée Damaged cap

Fissure

Particule exogène claire (mobile, flottante, fixe) Clear exogenous particle (mobile, floating, fixed)

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Photo/Illustration

Annexe 2. Exemple d’analyse de risque équipement Appendix 2. Example of risk analysis equipment Actual conditions

Resulting conditions

Timing screw feeding

Broken syringes

Visual eye naked + visual inspection

Trained operators

SOP + Training

SOP + Maintenance

Bad finger grip position

Timing screw feeding

Broken syringes

Minimum sensor failure or bad adjustment

Timing screw feeding

Broken syringes

Play in timing screw

Timing screw feeding

Broken syringes

Timing screw synchronizatio n

Timing screw feeding

Broken/Cracks/ Scratches syringes

Damaged timing screw by w earing

Timing screw feeding

Dirts/Scratches on syringes

Damaged timing screw by glass fragments

Rollers and Setting dow n timing screw of syringes on are not rollers synchronzied

Bad syringe positioning

Sensor failure

19 Tim ing screw conveying

Preventive Alarm message maintenance + + visual eye Trained naked operators Preventive Visual maintenance + inspection Trained operators Preventive maintenance + Visual Trained inspection operators Preventive Visual maintenance + inspection Trained operators Preventive Visual maintenance + inspection Trained operators

Alarm message

Preventive maintenance

Actions

Responsable and target date

Actions in progress

RPN

Prevention

Détectability

Detection

Cause of the failure mode

Occurrence

Failure defect

RPN

Failure mode

Detectability

Process function

Occurrence

Part of process

Classification

Severity

Actual controls

Adresses des auteurs/Authors’ addresses Q François Caire-Maurisier, Pharmacie centrale des Armées, TSA 30004, F-45404 Fleury-les-Aubrais Cedex. Q Franck Dumontier, Aspen, 1, rue de l’Abbaye, F-76960 Notre-Dame-de-Bondeville. Q Philippe Grel, Intertek, Ecoparc 2, F-27400 Heudebouville. Q Céline Jolly, Recipharm, 18, route de Montbazon, F-37260 Monts. Q Éric Levacher, Groupe IMT, 38-40, avenue Marcel-Dassault, F-37206 Tours*. Q Sophie Marcq, Merck Serono, 2, rue du Pressoir-Vert, F-45400 Semoy. Q Florence Sliwinski, Delpharm, Rue Paul-Langevin, BP 90241, F-37172 Chambray-les-Tours. *Correspondance : e.levacher@groupe-imt.com

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regulatory review The current review period has seen a number of changes in the regulation of medicines and regulatory guidance in the EU, International markets and the USA.

USA Biosimilars - statistical approaches to evaluate analytical similarity

This draft guidance is intended to provide advice on the evaluation of analytical similarity to sponsors interested in developing biosimilar products for licensure. This evaluation is to support the demonstration that a proposed biosimilar product is highly similar to a licensed reference product. Specifically, this guidance describes the type of information a sponsor of a proposed biosimilar product should obtain about the structural / physicochemical and functional attributes of the reference product, how that information is used in the development of an analytical similarity assessment plan for the proposed biosimilar, and the statistical approaches recommended for evaluating analytical similarity.

Advancement of emerging technology applications for pharmaceutical innovation and modernization

This guidance provides recommendations to pharmaceutical companies interested in participating in a program involving the submission of chemistry, manufacturing, and controls (CMC) information containing emerging technology to FDA. The program is open to companies that intend to include the technology as part of a regulatory submission including investigational new drug applications (IND), original or supplemental new drug applications (NDA), abbreviated new drug applications (ANDA), biologic license applications (BLA), or application-associated Drug Master Files (DMF) reviewed by the Center

for Drug Evaluation and Research (CDER), and where that technology meets other criteria described in this guidance. This program does not cover products reviewed by the Center for Biologics Evaluation and Research. (CBER) Strengthening FDA’s inspection and oversight of drug manufacturing

FDA previously announced restructuring field activities, to direct focus and organization around the programs it regulates, instead of being based on geographic regions. This allows FDA to better align the expertise of staff and make more efficient use of resources. As another key step the FDA’s CDER and the Office of Regulatory Affairs (ORA) are implementing a new agreement to more fully integrate the drug review programs with the facility evaluations and inspections for human drugs. This new collaboration is a model for modernization of other parts of FDA’s organization to better achieve its mission. This new agreement leverages two efforts to ensure alignment between FDA’s field professionals and the agency’s review staff.

ANDAs for certain highly purified synthetic peptide drug products that refer to listed drugs of rDNA origin

This draft guidance is intended to assist potential applicants in determining when an application for a synthetic peptide drug product that refers to a previously approved peptide drug product of recombinant deoxyribonucleic acid (rDNA) origin should be submitted as an abbreviated new drug application (ANDA) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) rather than as a new drug application (NDA) under section 505(b) of the FD&C Act. Specifically, this guidance covers the following five peptide drug products: glucagon, liraglutide, nesiritide, teriparatide, and teduglutide.

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ANDA submissions–refuse-toreceive standards: Q&A

This draft guidance is intended to assist applicants preparing to submit to FDA ANDAs and certain prior approval supplements (PASs) to ANDAs. This guidance provides answers to questions FDA has received from applicants regarding the guidance for industry, ANDA Submissions—Refuseto-Receive Standards (RTR Standards guidance) and the filing review process, in general.

Determining whether to submit an ANDA or a 505(b)(2) application.

This guidance is intended to serve as a foundational guidance to assist applicants in determining which one of the abbreviated approval pathways under the FD&C Act is appropriate for the submission of a marketing application to FDA. It also provides direction to potential applicants on requesting assistance from FDA in making this determination.

Generic Drug User Fee Amendments (GDUFA)

Recently issued amendments relate to:• Formal meetings between FDA and ANDA applicants of complex products under GDUFA This guidance describes an enhanced pathway for discussions between FDA and a prospective applicant preparing to submit, or an applicant that has submitted an ANDA for a complex product to FDA. Specifically, it provides information on requesting and conducting product development meetings, presubmission meetings, and midreview-cycle meetings with FDA. • ANDA Submissions – Prior Approval Supplements (PASs) Under GDUFA This guidance is intended to assist applicants preparing to submit to FDA PASs and amendments to PASs for

REGULATORY REVIEW

•

ANDAs under section 505(j) of the FD&C Act (21 U.S.C. 355(j). Specifically, this guidance describes how the GDUFA performance metric goals apply to: – A PAS subject to the refuseto-receive (RTR) standards – A PAS that requires an inspection – A PAS for which an inspection is not required – An amendment to a PAS – Other PAS-related matters ANDA Submissions — amendments to abbreviated new drug applications under GDUFA This draft guidance is intended to explain to applicants how the review goals established as part of the GDUFA Reauthorization of 2017 (GDUFA II) apply to amendments to either abbreviated new drug applications (ANDAs) or prior approval supplements (PASs) submitted to the FDA under section 505(j) of the (FD&C Act) (21 U.S.C. 355(j)). This guidance describes amendment classifications and categories and explains how amendment submissions may affect an application’s review goal dates. Post-complete response letter meetings between FDA and ANDA applicants. This guidance provides recommendations to industry on post-complete response letter (CRL) meetings between FDA and ANDA applicants for the purpose of clarifying deficiencies identified in a CRL to an ANDA submitted under section 505(j) of the FD&C Act (21 U.S.C. 355(j)) This guidance will assist applicants in generating and submitting a request for a post-CRL meeting and the associated meeting package to FDA as contemplated in

continued

the 2017 (GDUFA II). This guidance is intended to provide procedures that will promote well-managed postCRL meetings

Europe EDQM Updated guidelines on the quality and safety of tissues and cells for human application

The EDQM has published the 3rd Edition of its guidelines ensuring the quality and safety of tissues and cells for human application, be it for transplantation or clinical use (including insemination and fertilisation). This document is aimed at supporting healthcare and transplant professionals on a practical level and improving the rate of successful safe clinical use of tissues and cells. In this 3rd Edition, all the chapters have been updated thoroughly and new chapters have been added to cover novel therapeutic approaches, most of which are still under development.

Memorandum of Understanding (MoU) on use of CEPs in Brazil

EDQM and ANVISA, the Health Surveillance Agency of Brazil, have signed an MoU which lays the foundation for ANVISA to consider the use of Certificates of Suitability to the monographs of the European Pharmacopoeia (CEPs) for their evaluation of marketing authorisation applications (MAAs) for medicinal products.

EMA EU/US MRA enters operational phase.

From 1 Nov 2017 further aspects of the MRA between the European Union and the USA to recognise inspections of manufacturing sites for human medicines conducted in their respective territories come into force. This agreement, which updates the agreement from 1998, allows for recognition of each other’s inspection outcomes.

ATMPs

DG SANTE and the EMA have published a joint action plan to foster the development of ATMPs. The main aims are to streamline procedures and to better address the specific requirements of ATMP developers. The plan contains 19 actions in different key areas.

Update on EMA relocation preparedness

The EMA has been working on a business continuity plan aimed at ensuring that the assessment of medicines is not disrupted and that patients in Europe continue to have access to high quality, safe and effective medicines. Since November 2016, EMA carried out several staff surveys to help the Agency prepare for staff losses and to improve planning for succession and knowledge transfer. Some staff losses can be absorbed with EMA’s business continuity plan, but beyond a critical threshold the Agency will no longer be able to fulfil its mandate to protect the health of European citizens. Internal surveys have indicated that for certain locations staff retention rates could be significantly less than 30%. This would mean that the Agency is no longer able to function and, as there is no backup, this would have important consequences for public health in the EU. In a best-case scenario, EMA could keep up to 81% of its workforce. EMA has published the information it submitted to the European Commission in support of its assessment of the 19 Member States’ bids to host the Agency. (Even with a best fit scenario it appears that it will take 2-3 years to achieve parity with current performance. mbh)

Strategic inquiry into presubmission activities organised by the EMA (EU Ombudsman)

EMA has responded to this request stressing that the Agency has robust

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REGULATORY REVIEW

and rigorous assessment processes in place, which separate the advice function from the final decision. No single person has the final say on a medicine’s approval. In addition, it notes the Agency is facing an exceptional situation and will be extremely busy in the next 18-24 months in connection with its necessary relocation as a consequence of Brexit. To be able to prepare for the move and work on necessary operational changes, it has already had to free up staff by reducing or temporarily suspending certain, less essential tasks and will need to limit what it undertakes and plan its activities with extreme care to ensure that the huge disruptions linked to Brexit, affecting both the Agency as a whole and staff individually, do not have an adverse impact on public health. As a first step, a meeting was proposed take place in the last week of September with the Ombudsman services so as to have an initial exchange on the concrete scope of the initiative and agree on a reasonable timeline for the provision of further information potentially helpful for the enquiry. Raising awareness of the perils of antimicrobial resistance

EMA hosted a meeting with key stakeholders on the work of international health authorities and how to optimise collaboration on this topic. The objectives of the meeting were to: • raise awareness of the work of EU institutions, Member States and WHO in the fight against antimicrobial resistance; • enhance understanding of how EMA and ECDC can support the European and global fight against antimicrobial resistance; • discuss how to coordinate efforts on awareness and empowerment of patients, consumers and healthcare professionals. A report on the meeting will be

continued

published on the EMA website in due course.

tool which assist Australian sponsors to prepare GMP clearance applications.

Better labelling of excipients for safe use of medicines

China China to accept overseas trial data

The EMA and the European Commission have updated the annex to the guideline on excipients. The updated annex includes five new excipients and new safety warnings for ten existing excipients. The main aim of this update is to take into account safety concerns which are not currently addressed in the existing annex to the guideline.

MHRA International regulators inspecting in the UK

MHRA has had an increasing number of trade associations and individual companies come to them where the outcome of an inspection in the UK, conducted by an international inspectorate, has differed from the company's own expectations. Going forward the MHRA requests that UK companies inform MHRA if they are hosting an inspection from another medicines regulator.

Potential supply issues

Recent catastrophic weather conditions across the globe can have a significant impact upon the pharmaceutical supply chain. Companies that have sites within their supply chain that could be at risk due to recent weather events should take steps to identify any potential supply issues and licence holders must notify the MHRA of any interruption in supply. MHRA also welcomes assurances that there are no issues.

International Australia Updated GMP Clearance application forms

The TGA have published redesigned e-forms to be used by Australian sponsors when applying for GMP Clearances. Also published are updated guidance on GMP clearance and a clearance application assistance

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China is reported (reuters) to have said it plans to accept data from overseas clinical trials to speed up approvals of drugs. This is a potential boon for international drugmakers as well as patients

ICH ICHQ11 Q&As

Since the ICH Q11 guideline was finalised, worldwide experience with implementation of the recommendations on the development and manufacture of drug substances has given rise to requests for clarification relating to the selection and justification of starting materials. This Q&A document is intended to provide additional clarification and to promote convergence and improve harmonisation of the considerations for the selection and justification of starting materials and of the information that should be provided in marketing authorisation applications and/or Master Files. The focus of the Q&A document is on chemical entity drug substances.

PIC/S Sept 2017 - Meeting / training report

Highlights of the report include:New PIC/S chairman, new executive bureau and new sub-committee members for 2018-2019 • Iran / IFDA, Turkey / TMMDA and Mexico / COFEPRIS join PIC/S • PIC/S seminar on "quality control laboratories: how to inspect" • Saudi Arabia / SFDA as well as Russian Federation / MINPROMTORG & FSI SID&GP apply for preaccession; Armenia / SCDMTE applies for accession • PIC/S vision and perspectives for 2018-2020

•

REGULATORY REVIEW

• • •

continued

New tool and framework to strengthen reliance and maximise resources for GMP compliance of overseas facilities Continued concerns with draft EU GMP guidelines for ATMPS latest PIC/S developments in the field of GM(D)P harmonisation

Switzerland Cross border inspections

The entry into force of the new Article 64a of the revised Therapeutic Products Act has been brought forward to 1 January 2018. The new article governs crossborder inspections, and entails changes affecting inspections carried out in Switzerland by foreign authorities, as well as inspections by the Swiss authorities abroad. The changes mean that a foreign authority is entitled to carry out its

inspection if the establishment to be inspected gives its consent. Authorisation by the State Secretariat for Economic Affairs (SECO) is no longer required. In all cases, foreign authorities must notify the Agency in advance of their intention to perform an inspection and provide the Agency with a copy of the inspection report after they have performed their inspection. Swiss companies and foreign authorities will therefore have to make arrangements for inspections with each other. Swissmedic will notify establishments in good time if it intends to accompany the inspection.

Documents Points to Consider for Ageing Facilities

This Parenteral Drug association (PDA) document covers :• How to recognize that a facility is ageing

•

Impediments to modernization • The business case for modernization • Strategies for modernization • The impact of changing standards • How to slow the ageing process • The regulatory landscape It is available for electronic download as a PDF document at separate rates for PDA members or non members. For further information on these and other topics, we suggest you refer to the websites of relevant regulatory bodies and to current and past editions of “GMP Review News” published by Euromed Communications. To subscribe to this monthly news service contact info@euromedcommunications.com

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european INDUSTRIAL PHARMACY December 2017

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PHARMA IN PLENARY A proposal for a proportionality test by Dr Nicola Davies

The European Commission has proposed a so-called Service package1 including Directive (COM (2016) 822 final) that introduces a general approach towards assessing professions in order to simplify the implementation of regulations and promote cross-border trading of professional services. Specifically, the proposal introduces a framework for a proportionality test designed to scrutinise new provisions for managing regulated professions in Member States.2 Currently, in compliance with the general principle of proportionality, which is a general principle of EU law emanating from the European Court of Justice’s case law requiring Member States to strike the right balance between preserving the fundamental freedom guaranteed by the Treaty and their margin of discretion to decide on how to protect a public interest objective, and with Article 59 of Directive 2005/36/EC3 on the recognition of professional qualifications, Member States follow national proportionality tests before adopting new or amending existing regulations for professions, to consider whether such regulation is justified, necessary and proportionate. However, under the proposed provisions of the Service package, Member States would have to carry out an ex ante assessment mechanism prior to the adoption of new regulations or amendments to existing ones that affect access to – and pursuit of – regulated professions, including those healthcare.4 The healthcare industry, however, is distinct, in that, its economy does not behave in a similar manner as most other regulated industries. Access to healthcare is touted as a

basic human right hence governments in most Member States finance their healthcare services. Without strict regulations, patients and service providers may demand or supply, respectively, more services than the amount that would constitute cost-efficiency. Furthermore, certain regulations are specifically in place in the healthcare industry to ensure the quality and safety and access to healthcare services.5 Now, debates abound on whether healthcare professions should fall within the confines of the proposal Directive, which in some way disregards special nature of healthcare services and health professional regulation. Critiques demand clarity regarding the proportionality test’s potential repercussions on the access to and quality of healthcare services. Specifically, critiques argue for the exclusion of healthcare professions from the scope of the proposal Directive.

The proportionality test

The proposal aims to provide guidance on how Member States should assess professional regulations or requirements based on an alignment with the proportionality principle. Basically, the proposal’s purpose is to ensure that Member States demonstrate consistent and coherent compliance with the obligation to adopt national professional requirements that are suitable, necessary and justified.6 Parts of the proposed Directive contain information on what constitutes justification of public health, public safety, public policy and other aspects of public

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interest, as well as the regulatory criteria and procedures of the proportionality test.7 The creation of the proposal, the Commission argues, is geared towards removing antiquated provisions and reducing burden that make the pursuit of regulated professions, including those in healthcare, more difficult than it needs to be. This general approach to assessing the proportionality of such regulations is intended to nurture an economic environment that supports businesses, jobseekers and customers.8 Essentially, proportionality testing aims to assess whether regulations or amendments to existing ones are crucial to attain public interest goals and are neither underwhelming or in excess of the regulatory strictness deemed necessary to achieve those goals.9 On the other hand, critics argue that while proportionality testing is a useful tool and even needed, in the case of healthcare professionals this should be the competence of the Member States, which in the case of healthcare professionals should be allowed a broader margin of discretion compared to other professions, in undertaking such a test, taking into consideration national specificities and resources. Adopting the general approach to assessing regulated professions could potentially limit access to healthcare employment and quality healthcare services.10

The proposal Directive as a separate legal Act

As one Honourable Member explained, some of the requirements on regular professions

PHARMA IN PLENARY

‘The Commission’s proposal for the Directive on a proportionality test establishes a EU-wide legally binding framework for Member States’ competent authorities to assess the proportionality of the regulation of more than 700 professions including healthcare professions. This is highly surprising given the fact that the European legislator has recognised the special nature of healthcare professions on many occasions in the past, including in the Professional Qualifications Directive and the Falsified Medicines Directive1. This was equally recognised by the European legislator during the preparation of the Services Directive which excludes health are already included in the Professional Qualifications Directive and the Services Directive. A portion of Article 59 in the Directive 2005/36/EC also pertains to basic criteria for adopting new regulations on professions and contains a directive for a proportionality requirement.11 The amended Directive (2013) also contained the obligation for Member States to assess for proportionality.12 The Commission argues that the outcome of a mutual evaluation exercise, wherein they found insufficient proportionality in the measures imposed on various regulated professions, demonstrated

continued

professions from its scope, by explicitly stating that such a horizontal instrument is not appropriate for health services2. PGEU believes that it is not appropriate to address the regulation of health professions, including pharmacists, in a general manner, together with other professions which perform professional activities of varying natures and which are subject to different legislative rules and have completely different safety implications. Healthcare policy decisions relating to the regulation of professions must serve the objective of attaining the best possible quality of care for every patient. Under no circumstance, may quality of care, access to care or patient safety be put at risk by decisions driven by other agendas, in particular economic concerns. We therefore advocate for the exclusion of health professions from the scope of this proposal.’

References 1

See Recital 26 of Directive 2005/36/EC “This Directive does not coordinate all the conditions for access to activities in the field of pharmacy and the pursuit of these activities. In particular, the geographical distribution of pharmacies and the monopoly for dispensing medicines should remain a matter for the Member States (…)”, and Recital 22 of Directive 2011/62/EU “When examining the compatibility with Union law of the conditions for the retail supply of medicinal products, the Court of Justice of the European Union (‘the Court of Justice’) has recognised the very particular nature of medicinal products, whose therapeutic effects distinguish them substantially from other goods. The Court of Justice has also held that health and life of humans rank foremost among the assets and interests protected by the TFEU and that it is for Member States to determine the level of protection which they wish to afford to public health and the way in which that level has to be achieved (…)”.

Ju-rateė ˙ Švarcaite˙ Secretary General, Pharmaceutical Group of the European Union (PGEU)

See Recital 22 of Directive 2006/123/EC “The exclusion of healthcare from the scope of this Directive should cover healthcare and pharmaceutical services provided by health professionals to patients to assess, maintain or restore their state of health where those activities are reserved to a regulated health profession in the Member State in which the services are provided” and Article 2.2 (f) of the same Directive.

a need to establish a more transparent and structured manner of scrutinising regulations.13 Article 59 also accounts for the creation of a separate Directive if there is a need to do so based on the results of the evaluation exercise. The proposal integrates stakeholder involvement, procedural issues and transparency, all of which are important to an effective assessment of new regulations or amendments.14 Furthermore, it is important to point out that health professions are excluded from the scope of the existing Services Directive. The creation of a proposal Directive that is a separate legal Act from the

existing Professional Qualifications Directive and the Services Directive suggests an attempt to subject health providers to the same level and degree of scrutiny as other regulated service providers.15 Other than the explicit exclusion from the existing Directives, Court of Justice case laws (C-570/07 and C-571/07 Blanco Perez [2010]) also highlight the discretion afforded to healthcare professions to prioritise patient safety over other concerns.16 In what is known as the precautionary principle, Member States are entitled to introduce provisions to prevent harm and decide on situations that pose a risk

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PHARMA IN PLENARY

continued

to patient health and safety despite the lack of evidence to inform such a decision. The proposal Directive, however, requires Member States to provide a comprehensive body of evidence supporting measures taken, including evidence to support the economic impact, which, at times, does not align with or completely goes against the objective of preserving human life.17

Opinion of the Committee on the Environment, Public Health and Food Safety The Environment, Public Health and Food Safety (ENVI) have issued an opinion document providing amendments to the proposal Directive. According to the document, some Member States struggle with the implementation of some aspects of the existing Directive. Implementation of the proportionality principle is expected to be much more complex when applied to the healthcare profession and hence counter-productive to the objective of promoting public health.18 It is argued in the ENVI document that while the Commission’s proposal Directive encompasses multiple professions, it is insufficient when applied to the management of the healthcare profession. Furthermore, the healthcare profession exhibits a public service nature that existing directives and the current proposal are unable to account for.19 In the long term, subjecting healthcare professions could lead to a regulatory chill, wherein, due to costs, time, energy and potential repercussions associated with proposed proportionality testing, authorities will be dissuaded from introducing new or amended regulations. Such a future would be beneficial neither to healthcare providers nor patients.20 The ENVI Opinion thus excludes health professions from the scope of the proposal Directive.21

Editorial note On Monday 4th December, the Internal Market and Consumer Protection Committee (IMCO) voted, with 33 votes in favour and 3 against, to adopt a Report that did not call for the exclusion of regulated health professions from the Directive, but instead proposed amendments that recognize the special nature of healthcare professions, as well as granting Member States a margin of discretion that is sufficient to ensure a high level of human health protection, when regulating healthcare professions. The report was subsequently tabled in the The ongoing debates around the proposal Directive underscore the ambiguity associated with the proportionality test, particularly, what measures will be able to withstand the test. This ambiguity may jeopardise the established regulations in healthcare that are specifically articulated to promote and preserve high quality healthcare services and access to care. While regulating healthcare providers is intended to protect public interest objectives, doing so may also require the preservation of the precautionary principle and a margin of discretion for regulations governing health professions. References

http://europa.eu/rapid/press-release_IP17-23_en.htm 2 FEDCAR (2017). The EU proposal for 2 different Tests of Proportionality applied to health professions. Retrieved from http://fedcar.eu/en/news/europe/2017/03/ public-health-the-proposal-of-2-differenttests-of-proportionality/ 3 Directive 2005/36/EC as amended by Directive 2013/55/EU 4 Bieńkowska (2017). Answer given by Ms Bieńkowska on behalf of the Commission. Retrieved from http://www.europarl.europa.eu/sides/getA llAnswers.do?reference=E-2017003590&language=EN 5 Baeten, R. (2017). New Draft EU Directive Submits The Regulation of Health Professions to a Proportionality Test, Eurohealth incorporating Euro Observer, 23(2 |), 2017, pp. 24-27. 6 Bieńkowska (2017). Answer given by Ms Bieńkowska on behalf of the Commission. Retrieved from http://www.europarl.europa.eu/sides/getA llAnswers.do?reference=E-2017003554&language=EN 1

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FEDCAR (2017). The EU proposal for 2 different Tests of Proportionality applied to health professions. Retrieved from http://fedcar.eu/en/news/europe/2017/03/ public-health-the-proposal-of-2-differenttests-of-proportionality/ 8 European Commission (2017). A services economy that works for Europeans. Retrieved from: http:// europa.eu/rapid/press-release_IP-1723_en.htm 9 Baeten, R. (2017). New Draft EU Directive Submits The Regulation of Health Professions to a Proportionality Test, Eurohealth incorporating Euro Observer, 23(2 |), 2017, pp. 24-27. 10 Ibid. 11 Grossetête, F. (2017). Opinion of the Committee on the Environment, Public Health and Food Safety for the Committee on the Internal Market and Consumer Protection on the proposal for a directive of the European Parliament and of the Council on a proportionality test before adoption of new regulation of professions (COM(2016)0822 – C8-0012/ 2017 – 2016/0404(COD)). Retrieved from http://www.europarl.europa.eu/sides/getD oc.do?pubRef=%2f%2fEP%2f%2fNONSGML%2bCOMPA RL%2bPE604.870%2b02%2bDOC%2bPDF%2bV0% 2f%2fEN 12 Sulik, R. (2017). Subject: Proposal for a directive on a proportionality test. Retrieved from http://www.europarl.europa.eu/sides/getD oc.do?pubRef=%2f%2fEP%2f%2fTEXT%2bWQ%2bP-2017004909%2b0%2bDOC%2bXML%2bV0%2f %2fEN&language=EN 13 European Commission (2017). Commission staff working document; impact assessment accompanying the document: Proposal for a Directive of the European Parliament and of the Council on a proportionality test before adoption of new regulation of professions, SWD (2016) 463, Brussels, 2017. 7

14 Bieńkowska

(2017). Answer given by Ms Bieńkowska on behalf of the Commission. Retrieved from http://www.europarl.europa.eu/sides/getA llAnswers.do?reference=P-2017004909&language=EN 15 Joint CED, CPME and PGEU Q&A Document (2017). Questions and Answers on Proportionality and Commission Proposal for a Directive on a Proportionality Test for Adoption of New Regulations for Professions (COM(2016) 822 Final). 16 Bieńkowska (2017). Answer given by Ms Bieńkowska on behalf of the Commission. Retrieved from http://www.europarl.europa.eu/sides/getA llAnswers.do?reference=P-2017004909&language=EN 17 Joint CED, CPME and PGEU Q&A Document (2017). Questions and Answers on Proportionality and Commission Proposal for a Directive on a Proportionality Test for Adoption of New Regulations for Professions (COM(2016) 822 Final).

18 Grossetête,

F. (2017). Opinion of the Committee on the Environment, Public Health and Food Safety for the Committee on the Internal Market and Consumer Protection on the proposal for a directive of the European Parliament and of the Council on a proportionality test before adoption of new regulation of professions (COM(2016)0822 – C8-0012/ 2017 – 2016/0404(COD)). Retrieved from http://www.europarl.europa.eu/sides/getD oc.do?pubRef=%2f%2fEP%2f%2fNONSGML%2bCOMPA RL%2bPE604.870%2b02%2bDOC%2bPDF%2bV0% 2f%2fEN 19 Ibid. 20 Baeten, R. (2017). New Draft EU Directive Submits The Regulation of Health Professions to a Proportionality Test, Eurohealth incorporating Euro Observer, 23(2 |), 2017, pp. 24-27.

21 Grossetête,

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european INDUSTRIAL PHARMACY December 2017

â&#x20AC;˘ Issue 35

european INDUSTRIAL PHARMACY December 2017

â&#x20AC;¢ Issue 35

bottled brown Robots only Humans have an astonishing breadth of qualities and abilities. Humans can invent antibiotics, manufacture medicines, change nappies allowing for the mood of junior, comfort a bereaved relative and write poetry. However, 99% of human qualities and abilities are not required for modern jobs. At least, the historian Harari so wrote in 2016 in “Homo Deus: A Brief History of Tomorrow”. Machines can perform that 99% better, faster and cheaper than human muscles and minds. Within decades, many humans, a teaming “under caste”, will be unemployed and unemployable so have little economic or political, power. I suspect industrial pharmacy is not exempt. Perhaps younger staff in particular should ponder. Algorithms

In future, humans need not apply for any occupation routine, repetitive, enough to describe with an algorithm. Self-learning robots with artificial intelligence will reign. They seldom need payment, leave or sleep. They are never grumpy. Any human in the pharmaceutical industry works on borrowed time. Research, development and “helicopter” oversight roles such as marketing, quality assurance and senior management, may linger longest. Jobs will survive. They will be those so poorly paid that humans undercut machines, so few that writing an algorithm is non-

economic, or innovative in mixing knowledge within the algorithm with a wide range of excluded human understandings. Think archeologist. This technological tidal wave may sweep humans through all five famous stages of Kubler-Ross’s change curve. Stages are shock, denial, anger, depression, and then, perhaps, acceptance and integration. In early stages, future decade Luddites may destroy machines and sabotage systems, fearful of a future that the Terminator / Skynet film franchise imagined. If Marxist theory is accepted, when the difference between the wealth of two groups is large enough, revolution will result. Groups are top management that robots have made rich and ex-shop floor workers that robots made unemployable and poor. Strategy

If the potential riches are evenly distributed, such as by the state paying every citizen (working and unemployable), a similar wage, detonation should not occur. In 2016, the Swiss government proposed offering everyone, working or not, a basic monthly wage of £1,800. Interestingly, Swiss citizens rejected this idea. Politicians know how to solve social problems; they seldom know how to solve problems and to be re-elected. Many readers of this journal, I suspect, enjoy their work more than paid leisure. One strategy to survive as a member of the tiny portion of useful workers is to use your crystal

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ball to choose the expertise required and then to bag its highest possible credentials. You should also be ready to re-invent yourself to undertake a profoundly different role about every decade. Above all, you will need emotional resilience and flexibility. To indicate whether you have it, consider this question. Would you prefer your life to be paid leisure doing what you most want to do, and only if you felt like it dabbling in industrial pharmacy as a hobby? It is perhaps unnecessarily pessimistic to suggest that you also hone up on the Cambridge Declaration of Consciousness (2012). This matters to the treatment of sentient laboratory animals, including those in the pharmaceutical industry. One day, artificial intelligence may be to us as we are to our laboratory animals. All this is speculation. As the physicist Niels Bohr said, “Prediction is very difficult, especially if it’s about the future”. Many events, for example, war or environmental collapse may influence. States may enable development of medicines at frontiers in enormous new areas. Such projects include human space travel or immortality. We may find there challenges so prodigious that more humans are needed. Humans remaining, unlike robots, would still need medicines and industrial pharmacy.

Malcolm E Brown

news from the EIPG Update on EMVO

In October, Toms Bluzmanis, (IPS, Latvia) attended a Conference in Tallinn, Estonia on behalf of EIPG. This was chaired by Jevgeni Ossinovski, Estonian Minister of Health and Labour and Maris Jesse, Deputy Secretary General of the Ministry of Social Affairs. The keynote speaker was Andrzej Rys, Director of Health Systems and Products, DG SANTE, European Commission. Speakers pointed out that the biggest challenge to the stakeholders is to connect approximately 2 500 manufacturing companies to the European Medicines Verification System (EMVS), establish national systems in 32 countries, connect many thousands of pharmacies and wholesalers and serialise all appropriate pharmaceutical packs. To date, 26 countries have created their National Medicines Verification Organisation (NMVO), 15 contracts with the IT providers for the new system have been signed and 7 additional NMVOs have already chosen the company. Although 50% of the NMVOs are currently somewhat delayed with starting the project’s implementation phase, the goal is still achievable. Close cooperation of the European Medicines Verification Organisation (EMVO) and all NMVOs is mandatory for success of the project. Alignment across countries has to be achieved. NCAs have to ensure the supervision of the repository systems and, together with the European Commission, help to simplify implementation requirements, provide clarity and harmonisation across Europe. The influence of the new requirements to the availability of medicines was discussed by the stakeholders. The impact of EMVS on medicines availability is difficult to assess, continuity of supply for most of the medicines should not be adversely affected by the EMVS

implementation. However, as pointed out by some of the stakeholders, the EMVS could in their view be of use for prevention of shortages by improving available information for authorities, manufacturers and the supply chain, but the process needs to be elaborated further together with respective agreements to be made between all stakeholders. The conclusion of the conference was that Europe can be ready to implement the safety features if all stakeholders make a strong commitment and effort. Thus, EIPG feels the entire system is extremely challenging with the deadline of February 2019. As six months full scale testing in any country is needed, the effective deadline is August 2018, by which time serialised packs should be on the market and regulatory approval obtained. However, the European scenario is not harmonised: in Italy and Greece, the Delegated Regulation will not come into force till 2025, meaning that emergency supplies from these countries will not necessary be compliant with the provisions of the Regulations, and that manufacturers supplying the domestic and European markets will need to package products differently. Moreover, in terms of the extension of the scope of the Delegated Regulation, some countries (France, Belgium, Spain and Portugal) have expressed an intent to extend the scope to all reimbursed products, while other countries either have no such intent or are still considering the possibility. At the same time, the industry is dealing with the redimensioning of the supply chain because of Brexit.

EIPG Webinar on Paediatrics

On 1st November, John Watson, Executive Director, Regulatory

Affairs Europe, Zogenix International, made an excellent presentation on “Development and regulatory approval of new medicines for children”. The presentation was recorded and is available as a video or slide presentation in the Members Area of the EIPG website under “Webinars” (passwords are available from your EIPG national delegate).

EPSA

EPSA is relaunching their Careers web page and EIPG has assisted them in the collection of biographies to showcase examples of careers available in the pharmaceutical industry. A successful EIPG-EPSA Webinar entitled “Insight to a new Medical Device EU legislation” was held in November. Amon Wafelman (NIA, Netherlands) will assist with EIPG representation at the 41st annual EPSA Congress in April 2018 to be held in Baarlo, Netherlands.

MOGLYNET

This is a Horizon 2020 joint doctoral project for training in Drug Discovery and Development for 12 early stage researchers with which EIPG is involved. An article on Moglynet has been successfully published in the Impact magazine http://www.ingentaconnect.com/con tent/sil/impact/2017/00002017/0000 0008/art00010

EMA Meeting with Interested Parties

Claude Farrugia and Piero Iamartino attended the meeting of EMAGMDP/Inspectors Working Group with Interested Parties, held at the European Medicines Agency (EMA) on 6th December .The agenda had been discussed and agreed in advance with the partners, including the contribution of EIPG. Esther Martinez (EMA Scientific Administrator-Manufacturing and

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NEWS FROM THE EIPG

Quality Compliance) presented an overview of the achievements in 2017, responding to the requests for clarification raised by Interested Parties. In particular, she announced the upcoming publication of the revised version of Annex 1, which will incorporate the new classification as defined by ISO 14644, and the ongoing preparation of a guideline replacing Annex 13. She also reported that Annex 21 is still under development, considering that the European Commission has still to solve issues involving the separation of physical and financial flow of goods, particularly where importation is concerned. As far as the Mutual Recognition Agreement (MRA) with the US is concerned, she reported that the whole process is expected to be finalised by July 2019, with the extension of the agreement to all European countries and the inclusion of veterinary products, vaccines, and blood products. Amongst the main objectives for 2018, EMA has announced further efforts on harmonisation, clarification on GMP compliance and responsibilities of Marketing Authorisation Holders and revision of Annex 4, 11 and 12. Brendan Cuddy (Head of Manufacturing and Quality Compliance of EMA) replied to a few questions raised by the attendees. The clarification requested by EIPG on the QP responsibilities in checking the application of the safety features (as requested by the Falsified Medicines Directive) for an imported product when an MRA is in place (reference was made to Switzerland), EMA replied that in the absence of any specific legislation, QPs should be guided by Annex 16 and therefore, checks on the presence of safety features would have to be performed by the QP performing the release in the European Union. Most of the meeting was taken up by EMA explaining the initiatives aimed at preparing a smooth Brexit transition in 2019. As well as

continued

webinars, EMA is ready to answer any question coming from industry or organising meetings on request. In the first quarter 2018, a survey will be launched by EMA to all MAHs in Europe to verify their preparedness for Brexit, in order to prevent, as far as possible, any issues (e.g. shortage). In March 2019, the UK will be a third country and the trade position between the EU and UK is still to be negotiated. Although an MRA could be expected to be achieved eventually, it is to be remembered that an MRA represents a trade agreement with a third country, and therefore could only be established, and even then not within short timeframes, after the position of trade between the UK and EU in general is established. Moreover being a trade agreement, MRA’s do not cover issues of GMP, and therefore these would need to be considered separately. In the final part of the meeting, following a presentation of the issue of ID sampling of sterile biological products, in relation to a different interpretation of Annex 8 by inspectors, EMA recommended always applying risk assessment as a tool for discriminating the best procedure to follow.

BREXIT

In December, a webinar with members of the European Medicines Agency was attended by Claude Farrugia and Jane Nicholson and the Agency’s responses to questions are summarised as follows: In March 2019, the UK becomes a third country. Therefore, all pharmaceutical legislation has to be interpreted in terms of the relevant legislation of dealing with a third country. Unfortunately this means that in the cases of Active Pharmaceutical Ingredient certification, a request to treat the UK as a third country (for the purposes of a statement and application to put UK on the list of third countries whose GMP statements are accepted) cannot be made before March 2019, because

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until then the UK is not legally a third country. With regards to the discussion of Mutual Recognition Agreements (MRAs), it was made quite clear that an MRA is a trade agreement with a third country therefore GMP is not part of an MRA and furthermore such an agreement cannot be negotiated before one knows under what terms and conditions the UK will interact with the EU in terms of trade. It was warned that these MRA’s take a long time to negotiate, and the same goes for any agreements similar to the recently negotiated EU-US mutual recognition of inspections of medicines manufacturers, so companies should not be considering these as the basis for any continuity plans. It was noted that these are ultimately political issues, and therefore any lobbying has to be done with the politicians forming part of the negotiating team on both sides, rather than with the EMA. However, EMA wants companies to be proactive and to contact EMA with any specific problems. An EMA survey will be held in January (with feedback requested within 2-3 weeks) on centrally approved products but some of the points may also be appropriate for locally approved products. If there is a possibility of shortages, the EMA should be advised and they will deal with the needed industry variations as fast as possible. On the question of QP release of batches, it was emphasised that even if an MRA is in place there will still be a need for QP certification. Therefore if bulk product is manufactured and tested in the EU, shipped to the UK for packaging and then returned to the EU, there will be a requirement for full retesting if there is no MRA in place and if there is an MRA, QP certification will be needed because the UK will be a third party country. It was felt that goods placed on the market before the UK withdrawal date should not be restricted. Also, GMP certificates issued by the MHRA for third party

NEWS FROM THE EIPG

continued

sites would be expected to remain valid for the 3 years but this latter point will need confirmation by the European Commission. Any future acceptance of GMP will depend on the future relationship and whether an MRA is in place. Early inspection in third countries is under consideration. The EMA is trying to obtain granular information on possible shortages in Europe of essential products. The Heads of Medicines Agencies have a task force in place which includes a representative of the Commission and therefore the

Commission is fully aware of any problems being faced by industry. The EMA will also provide clarification on what opportunities will be available for the use of already printed stocks of artworks. In answer to a question on whether industry will be asked to change existing labelling of medicines destined for the UK market, the response was to please contact the MHRA. On the issue of GxP it was noted that because stability studies and pre-clinical studies are not part of an MRA, there should not be problems and clinical trials should

continue to follow the provisions of the Directive. On the GCP agreement with the FDA, it was said that the agreement for inspections was a risk based approach and inspections are made, irrespective of whether the company is in or outside the EU. It would be up to the MHRA if they wished to inspect for a second time but the EMA's current approach will remain the same.

Jane Nicholson (jane@nicholj.plus.com)

PharmacoVigilanceRevıew PharmacoVigilance Revıew Supporting the safe use of medicines and medical devices

Managing Reference Safety Information The EU centralised application from a pharmacovigilance and risk management prospective Post-authorisation aggregate safety reporting: the new PSUR New European pharmacovigilance legislation – an adequate response to current challenges?

Journal on drug safety issues Editor – Rob Begnett

This quarterly journal provides informed comment and analysis of international pharmaceutical regulations relating to the safe use of medicines and medicinal devices. It also carries reviews of current methods of pharmacovigilance.

Volume 7 Number 3/4 Nov 2013

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gmp revÄąew editor: Peter Savin

gmp review is a quarterly newsletter dedicated to the analysis of international pharmaceutical regulations and informed comment on good manufacturing practice. It interprets regulations and related standards and educates organisations in current best GMP practices, technical, operational and strategic to enable sound quality risk management and deliver business benefit. . Order online at www. euromedcommunications.com Or email: publisher@euromedcommunications.com Tel: +44 (0)1428 752222 Fax: +44 (0)1428 752223

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events JANUARY 2018 22-24 January 2018 – Washington, DC, USA 8th Annual Pharmacovigilance and Risk Management Strategies Conference www.diaglobal.org/pharmacvigila nce 22-23 January 2018 – London, UK Pharmaceutical Microbiology 2018 www.pharma-microbiology.com 23-24 January 2018 – Alexandria, VA, USA 13th Biosimilars Summit www.biosimilardevelopment.com 29 January – 1 February 2018 – London, UK 7th Annual Cool Chain Temperature Controlled Logistics Europe www.coolchaineurope.com 30-31 January 2018 – London, UK Festival of Genomics www.festivalofgenomicslondon.com

27-28 February 2018 – Munich, Germany Disposable Solutions for Biomanufacturing www.disposablebiomanufacturing. com 27 February-2 March 2018 Toronto, Ontario, Canada 16 Annual Cold Chain GDP and Temperature Management Logistics Summit www.coldchainpharm.com

MARCH 7-8 March 2018 – Stuttgart, Germany Medical Devices Meeting www.medical-devices-meeting

FEBRUARY

14-15 March 2018 – Milan, Italy 19th Annual Clinical Trial Supply Europe www.arenainternational.com/ctseurope

8 February 2018 – London, UK Cleaning Validation www.jpag.org

15 March 2018 – London, UK Continuous Manufacturing www.jpag.com

9 February 2018 – London, UK Dissolution testing: current and future considerations www.jpag.org

15-16 March 2018 – London, UK ICMDDD 2018: 20th Int Conference on Medical Device Development and Design www.waset.org

15-16 February 2018 – Manchester, UK 13th Annual Biomarkers Congress www.biomarkers-congress.com 19-22 February 2018 – Munich, Germany Software Design for Medical Devices Europe www.sdmdglobal.iqpc.co.uk 26-27 February 2018 – London, UK 12th World Congress on Pharmaceutical Sciences and Innovations in Pharma Industry www.industry.pharmaceuticalconf erences.com

27-28 February 2018 – Rome, Italy Parenteral Packaging www.pda.org

19-20 March 2018 – London, UK 3rd World Congress and Expo on Pharmaceutics and Drug Delivery Systems www. scientificfederation.com 19-21 March 2018 – Rome, Italy 2018 ISPE Europe Annual Conference www.ispe.org 19-21 March 2018 – Orlando, FL, USA 2018 PDA Annual Meeting www.pda.org

19-21 March 2018 – Berlin, Germany 16th International Conference and Exhibition on Pharmaceutics & Novel Drug Delivery Systems www.novel-drugdeliverysystems.pharmaceuticalconferenc es.com 19-22 March 2018 – Granada, Spain 11th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology www.worldmeeting.org 20-21 March 2018 – Loughborough, UK APS Parenteral Drug Development Meeting www.apsgb.co.uk 20-21 March 2018 – London, UK World Pharma Pricing and Access 2018 www.terrapinn.com/conference 21-23 March 2018 – Gothenburg, Sweden 23rd Congress of the EAHP www.eahp.eu

APRIL 3-5 April 2018 – Bethesda, MD, USA 15th Annual Medical Device Quality Congress www.fdanews.com 10-11 April 2018 – Philadelphia, PA, USA World Drug Safety Conference Americas 2018 www.terrapinn.com 24-25 April 2018 Dusseldorf, Germany 2018 Pharma Congress production and technology www.pharma-kongress.com 25-27 April 2018 – Oxon Hill, MD, USA World Orphan Drug Congress USA 2018 www.terrapinn.com

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NOTICE european INDUSTRIAL

PHARMACY

europ INDUSean PHA TRIAL

RMAC Y

Why pharmacists should study compaction: Part 1 – Introduction Joint Supply Chain Actors statement on information and medicinal products shortages What Brexit means for British qualified persons Compatibility of materials in contact with parenteral preparations: risk analysis and strategy

ISSUE 32 • APRIL 2017 www.industrialpharmacy.eu www.eipg.eu

Why ph arma should cists study com Part 2 – paction: m better aking tablets Raising awaren the da nger s o ess of f fa medic ke ines Cybera ttacks on th phar m a indu e str y

european INDUSTRIAL

ISSU E 33 • JUN www .i n d u E 20 st ri al 17 p h ar www .e ip g .e m ac y. eu u

PHARMACY If you have enjoyed reading the broad range of articles in European Industrial Pharmacy journal over the last What a Qualified Person few years then the good news is must know about the recent cleaning that the European Industrial validation updates Seizing the biosimilar Pharmacy Journal will still be opportunity available to our readers. To Pharmacopoeial compaction! continue with access to the Start-up of cleanrooms, initially and after a journal you simply need to click worst-case event here, where you will be able to obtain future editions of European Industrial Pharmacy. ISSUE 34 • SEPTEMBER 2017 www.industrialpharmacy.eu www.eipg.eu

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