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European Journal of Parenteral & Pharmaceutical Sciences

2016 Volume 21 Number 2

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EDITORIAL BOARD CHAIRMAN OF THE PHSS European Journal James Drinkwater F Ziel GmbH, UK

EDITOR-IN-CHIEF of Parenteral Kay O’Hagan Tecmac UK Ltd, UK Bengt Ljungqvist & Pharmaceutical Chalmers University of Technology, Gothenburg, Sweden Tim Sizer Sciences Southmead Hospital, Westbury-on-Trym, Bristol, UK 2016 Volume 21 Number 2 MANAGING EDITOR Sue Briggs T: +44 (0)1295 688028 E: [email protected] Contents PUBLISHER Euromed Communications Editorial: EU and the US – vive la différence? 35 Passfield Business Centre Liphook, Hampshire GU30 7SB Peer-reviewed Papers T: +44 (0)1428 752222 Equations for predicting airborne cleanliness in non-unidirectional F: +44 (0)1428 752223 airflow cleanrooms 38 E: [email protected] W Whyte, N Lenegan and T Eaton www.euromedcommunications.com

INTERNATIONAL REVIEW BOARD Deposition velocities of airborne microbe-carrying particles 45 Rosamund Baird W Whyte and T Eaton University of Bath, UK The use of a single growth medium for environmental monitoring Stephen Denyer University of Brighton, UK of pharmacy aseptic units using tryptone soya agar with 1% glucose 50 Gordon Farquharson John Rhodes, Jennifer Feasby, Wayne Goddard, Alison Beaney and Mike Baker Critical Systems Ltd, UK Regulatory review 56 Michael Jahnke Haupt Pharma Wulfing GmbH, Malcolm Holmes Gronau/Leine, Germany PHSS activity and initiatives report 64 David Jones Rapid Micro Biosystems, USA Brian Matthews Instructions for authors in this issue or from our website: www.euromedcommunications.com South Croydon, Surrey, UK Simon McEwen Consultant, UK Didier Meyer DMCompliance, France The European Journal of Parenteral & Pharmaceutical Sciences is the quarterly journal of the Pharmaceutical and Stephen Moss Healthcare Sciences Society (PHSS). The journal provides a forum for publishing original peer reviewed papers, University of Bath, UK editorials, reviews and science & technology articles on all aspects of pharmaceutical and healthcare sciences. Papers Gerry Prout will normally be published within six to nine months of acceptance. Kennet Bioservices Ltd, Swindon, UK The European Journal of Parenteral & Pharmaceutical Sciences will also contain articles based on the proceedings of the Confederation’s scientific meetings, symposia and workshops. All submissions are subject to Berit Reinmuller peer review by members of the editorial board and external referees. Advice to contributors is available from the Chalmers University of Technology, managing editor. The journal is published quarterly and is indexed in Scopus (http://info.scopus.com) and Embase Gothenburg, Sweden (http://www.embase.com). It is provided free of charge to full and associate members of the PHSS. For non- Kirit Sanghani members the annual subscription is £90 (personal rate) or £180 (institutional rate), plus annual postage costs of Siemens Healthcare, UK £12. Back issues are available at £25 each (abstracts of back issues can be viewed on our website at Khalid Sheikh www.euromedcommunications.com). Cheques (drawn on a UK bank) should be made payable to Euromed University College London, UK Communications. Subscription orders should be sent to the publishers’ office. Reproduction of articles published in the journal, in whole or in part, is not permitted without the previous written ADVERTISEMENTS consent of the author and editor, and the usual acknowl edge ments must be made. Authorisation to photocopy items for Allan Andrews internal or personal use is granted by the PHSS. Requests for reprints should be made to the publishers, Euromed Tel +44(0)1428 752222 Communications. Fax: +44(0)1428 752223 While all reasonable care has been taken in preparing this journal, neither the publishers nor the PHSS can accept E: [email protected] any responsibility for the accuracy of the advice or information contained in the journal. PHARMACEUTICAL AND HEALTHCARE Statements and opinions expressed in the articles and communications herein are those of the author(s) SCIENCES SOCIETY and not necessarily those of the PHSS, the editor or the publishers. Tamsin Marshall The PHSS, the editor and the publishers disclaim any responsibility or liability for such material and do not 6A Kingsdown Orchard, Hyde Road, guarantee, warrant or endorse any product or service advertised or mentioned in the publication nor do they guarantee Swindon SN2 7RR any claim made by the manufacturer of such product or service. Tel: +44 (0) 1793 824254 © 2016 Pharmaceutical and Healthcare Sciences Society Fax: +44 (0) 1793 832551 A publication of the Pharmaceutical and Healthcare Sciences Society E: [email protected]; W: www.phss.co.uk The journal is published quarterly and indexed in Embase and Scopus ISSN: 0964-4679 OUR TEST, YOUR CURE...

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Editorial: EU and the US – vive la différence?

Will the differences in legislation and culture Regulatory Agency (MHRA) inspector for advice between the US and Europe mean that mutual or clarification is common. I have never heard of recognition agreement (MRA) will never happen? this sort of informal discussion with FP batch Mutual recognition is about accepting that the approval within the US industry and the US Food competent authority good manufacturing practice and Drug Administration (FDA) but it is becoming (GMP) standards and expectations leading to batch more common place to approach the FDA for manufacture, testing and approval are equivalent. informal guidance. The difference in approach of If the UK leaves the EU, a UK/US and UK/EU the agencies is often generally described as: the MRA are possible. But what is the value of the FDA are investigators – the MHRA (as an EU MRA? For the company, there are huge financial example) assist towards compliance. benefits. This cost saving is mainly in the With site approval in the US, there is annual laboratory retest requirements. For the competent company registration (once the company has been authorities, there are huge benefits as the global inspected and approved) which is independent of an audit workload is greatly reduced. For the qualified inspection program. FDA inspections are scheduled person (QP), there is not so much benefit. There and based on risk (as with Europe), but typically will always be a spectrum of GMP compliance in short notice or no notice inspections are held. There any country and the existence of an MRA means are differences in approach between the EU and the that each party to the agreement has equivalent US to FP batch release, MA and MIA and GMP standards. It does not mean that each approachability of investigators/inspectors. company invariably meets the standards. However, my understanding of the lack of an The EU situation with batch approval of a MRA between the EU and the US is the US finished product (FP) for market release is about a perception of EU diversity in EU member state personal responsibility. A release site is named on a GMP standards and the enforcement of these marketing authorisation (MA), certifying QPs are standards within the 28 EU member states. While named on the site manufacturing and importation the US would be comfortable with a number of the licence (MIA). The named QP must be approved by member states, they are not happy with the GMP the EU competent authority before being approved standards of all 28. This unhappiness is not only to certify FP batches for release. with some of the new member states, but with some In the US, a person is deemed to be suitably of the founder members of the EU. qualified to approve FP batches by company The same pharmaceutical directives apply to all appointment. However, the 21CFR211 requires the 28 EU member states and although they are locally person to have appropriate training, education and interpreted into law, the same GMP guidelines are experience and this would be verified on audit. In applicable. The European Medicines Agency has the EU, it is both by the company who submit the made it clear that any MRA must be applicable to variation and by the relevant competent authority all countries or not at all. who approve the MIA. In my experience of auditing in the EU member In the EU, QP certification is about personal states, there is a spectrum of site GMP compliance. responsibility and the QP essentially performs the This compliance spectrum is more a function of the task independently of the company. The site ownership and management than the country in certification of batch compliance by a QP is as which it is situated. Small and locally owned much about compliance with the QP code of companies often do not have the experience, practice as it is with compliance to company infrastructure and investment to compete in the processes. Discussion between a QP and the current pharmaceutical world. Local ventures have relevant Medicines and Healthcare Products more manual processes and systems because of the 36 Editorial

amount of investment needed for the currently in batch certification. What the country of accepted good practice systems and processes. manufacture means to the QP is different Manual systems and processes are intrinsically approval process documents and the ability to error prone, and it is this that leads to poor GMP. take the word of an EU QP. If the QP genuinely Large global companies have the systems and believed that any EU member states had poor finances to invest in GMP compliance. Where competent authority oversight of good global companies are situated in the new EU practices, then they could not certify the batch. member states, you will see global compliance This is implicit in the code of practice. standards applied to the sites and consistently The EU–US mutual reliance initiative has met. Where global companies subcontract to started and aims to complete the equivalency local companies for price reasons, they often assessments in 2016. So are we heading towards suffer via poor GMP compliance in any member an EU/US MRA? I think it is still a long way state – old or new. away. For a QP it is the audit, technical agreements and personal knowledge of all the GMP and good distribution practice processes that count Kay O’Hagan

There are a number of aspects to the journal, including CALL FOR PAPERS peer-reviewed scientific papers. Scientific papers should focus on scientific experimentation and reference other scientific literature to create and test a hypothesis. These & ARTICLES are peer reviewed by subject matter experts from the International Review Board. Dear Colleagues, The other section is the Science and Technology Features. We live in a world of change and the pharmaceutical and This includes reviews of regulatory updates, book reviews, healthcare industry is rapidly changing. Regulations, conference reviews, technology reviews, industry reviews, technology, diseases and user expectations mean that what best practice reviews and updates on the PHSS Special was obviously correct years ago is not quite so concrete now. Interest Groups. These are reviewed for publication but do This is your opportunity to drive that change. We need not always require subject matter expert reviews. articles and scientific papers that test, disseminate, validate We call for papers and articles that you would like to see and publicise these changes. The areas that the EJPPS included in your journal. This is your opportunity to drive specialises in are the parenteral and pharmaceutical the changes in the world we work in. sciences. It is about where and how we make pharmaceutical products and medical devices, how and Thank you for your continued support where we test them, how and where we use them and the regulatory environment we work within. It is also about the Kay O’Hagan hospital sector. Increasingly, this is where we make and test Editor-in-Chief, EJPPS products but, more importantly, it is where we use the products we make. European Journal of Parenteral & Pharmaceutical Sciences 2016 21(2): 37 © 2016 Pharmaceutical and Healthcare Sciences Society

Information and Instructions for Authors

The Journal welcomes topical reviews, scientific papers, short D. References communications and readers' letters. The editorial team will References should be numbered sequentially as they appear in do all they can to assist you with the preparation and peer the text, using superscript format, and listed in the same order review where this is necessary. Please feel free to seek advice at the end of the text, as follows: and help if necessary. We look forward to receiving your Journal articles submission. 1. Gibbons D. Greener cleanrooms. European Journal of Parenteral and Pharmaceutical Sciences 2007; 12(3): Kay O'Hagan 75–78. Editor in Chief Books 2. Hodges N. In: Microbiological contamination control in pharma ceutical cleanrooms (ed. Halls N). Boca Raton, A. Presenting the material CRC Press/Sue Horwood Publishing, 2004; 115–136. Reviews and scientific papers are normally of four to six published pages (3000–3500 words approximately); short E. Handling illustrative material communications are one to two pages long (750–1500 Indicate within the text where figures and tables should fall. words). If graphs or tables are presented as an integral part of the Submit your text as an email file to the Managing Editor, text, it is best if they are treated as a self contained addendum Sue Briggs: [email protected] section at the end, following the references and numbered If there are any queries please do not hesitate to to contact according to the order in which they appear in the text. the office by telephone on +44 (0)1428 752222 or email as The source of all graphic or tabular material should be above. provided if possible. Papers may be submitted in languages other than English Legends for diagrams supplied separately should also be but, if accepted, will be translated by Euromed, using a keyed into this addendum, as should captions for specialist translator, and published in English with only the photographs. author's summary published in the original language. Authors For photographs supplied electronically, we prefer to will have the opportunity of checking the translation, if receive the original picture file in print quality (high resolution) requested. tif, jpg or similar format, rather than embedded within the text. The title page should stand separately from the text, to Good quality line drawings are also acceptable, and should allow anonymous review. It should include the title of the include all the relevant details. If facilities for producing line paper and the name(s) and position(s) of the author(s). drawings are not available to the author, figures can be Indicate the principal author where relevant. Also supply the redrawn by the publishers. name, contact address (including email address if possible) and daytime telephone and fax numbers of the person who F. The review process will check the proofs. Papers will be refereed by members of the editorial board and/or their nominees. B. Preparing the text If any questions arise at this point, the paper will be The editorial team will help as much as possible, but you can returned to the author for comment and/or amendment. assist greatly. In preparing the text, only use the space bar to Otherwise, the corresponding author will be sent page provide space between words. For multiple spacing, use the proofs by the due date. The editors' decision is final and tab command. correspondence will not necessarily be entered into regarding The text should be divided into sections and given plentiful reasons for rejection, etc. sub-headings, but avoid section numbering. Give scientific measures in SI units, temperatures in Conflict of interest degrees Celsius and, wherever possible, the generic rather Authors are expected to disclose any commercial or other than the proprietary names of drugs. Abbreviations and associations that might pose a conflict of interest in connection acronyms should be spelt out in full the first time they appear with the submitted article. All funding sources supporting the within the text and, if necessary, defined. work should be acknowledged on the title page, as should institutional or corporate affiliations of the authors. For the full C. Key words set of ethical guidelines please see the main journal page of the Each paper should have up to six key words or phrases that Euromed website characterise the contents of the paper. These will be used for indexing and data retrieval purposes. Thank you for your co-operation. European Journal of Parenteral & Pharmaceutical Sciences 2016; 21(2): 38-43 © 2016 Pharmaceutical and Healthcare Sciences Society

Equations for predicting airborne cleanliness in non-unidirectional airflow cleanrooms

W Whyte1, N Lenegan2 and T Eaton3* 1 School of Engineering, University of Glasgow, Glasgow G12 8QQ 2 Energy and Carbon Reduction Solutions, Ashton-Under-Lyne, Lancashire, OL5 0RF 3 AstraZeneca, Macclesfield, Cheshire, SK10 2NA

Equations are derived in this paper for predicting the airborne concentration of particles and microbe-carrying particles in non-unidirectional airflow cleanrooms during manufacturing. The equations are obtained for a variety of ventilation systems with different configurations for mixing fresh and recirculated air, air filter placements, and number and efficiency of air filters. The variables in the equations are air supply rate, airborne dispersion rate of contamination from machinery and people, surface deposition of particles from air, particle concentration in fresh make- up air, proportion of make-up air, and air filter efficiencies. The equations are amenable to relatively simple modification for the study of different cleanroom ventilation systems. The use of these equations to investigate the effect of different configurations of ventilation systems and the relative importance of the equation variables on airborne concentrations will be reported in a further paper.

Key words: Equations, airborne cleanliness, particles, microbe-carrying particles, non-unidirectional airflow cleanrooms.

Introduction specified airborne cleanliness condition. These equations do not consider air mixing and distribution in the cleanroom and When designing a cleanroom to achieve a required airborne this is discussed elsewhere4. cleanliness class or grade, such as specified in the A number of equations have been derived to calculate the International Organization for Standardization (ISO) airborne concentration in a cleanroom5–9. These equations 14644-11, or the European Union Guidelines to Good 2 have been mainly derived for a single type of ventilation Manufacturing Practice (EU GGMP) , designers have a system and are not applicable to all design configurations, and problem in deciding how much filtered air should be supplied an investigation is required to determine whether changes in to the cleanroom. Currently, this is not normally calculated the design of ventilation systems through filter placement, but based on experience or some rule of thumb, and the numbers of filters, and methods of mixing fresh and consequence of this is that designers are over-cautious, and recirculated air within the ventilation plant, will cause many cleanrooms have excessive air supply that is associated differences to the airborne concentrations in the cleanroom. with high capital and running costs, and energy waste. Also, the previously-derived equations have either not Conversely, a low air supply may result in too high a considered the effect of surface deposition of particles, or not concentration of airborne contamination, and major remedial done so in an analytical way. In addition, some of the work to rectify the problem. There is, therefore, a need for a previously reported equations have been derived by assuming method to calculate the air volume supply rate for a required a transient state, and, therefore, the mathematics is relatively concentration of airborne contamination, and information on 3 complicated, and it would be useful if the derivation method such a method has been previously published by the authors . was simplified. The airborne cleanliness of a cleanroom is directly related to This paper derives equations for a variety of ventilation the amount of filtered air supplied to a cleanroom, and plants. These equations provide a means of investigating (a) equations derived to calculate airborne cleanliness can be the influence of different designs of ventilation plants, (b) the rewritten so that the amount of air required is determined for a importance of the different variables that influence the airborne concentration, (c) the possibility of simplification of the equations, and (d) the usefulness of the method suggested *Corresponding author: Tim Eaton, Sterile Manufacturing Specialist, 3 AstraZeneca, UK Operations, Silk Road Business Park, Macclesfield, by Whyte, Whyte, Eaton and Lenegan for calculating the air Cheshire, SK10 2NA; Email: [email protected]; Tel: +44(0)1625 supply rate for a specified airborne concentration in non- 514916. 38 EquAtionS foR PREDiCting AiRboRnE ClEAnlinESS in non-uniDiRECtionAl AiRflow ClEAnRoomS 39 unidirectional airflow (non-UDAF) cleanrooms. These calculations. Therefore, the particle balance in a will be investigated in a further paper. cleanroom is given by Equation 1.

Equation 1 Derivation of equations to calculate airborne cleanliness in a cleanroom Rate of airborne contamination entering the At the start of activity in a cleanroom, personnel will enter room + rate of airborne contamination an empty cleanroom with a low airborne concentration of generated within the room particles and microbe-carrying particles (MCPs). For a = manufacturing operation, equipment will be set-up, and Rate of contamination exiting the room through machinery switched on, and this activity causes a build-up recirculated and exhaust air + particle deposition of airborne contamination. When manufacturing starts and rate onto room surfaces the activity of personnel settles down, the airborne contamination will be reduced a little to a fairly constant Whyte, Agricola and Derks11,12 have investigated the ‘steady-state’ condition, i.e. the operational condition. deposition mechanisms of particles in cleanrooms. Their Equations are derived in this section for calculating the investigation has shown that the following Equation 2 concentration of particles in a non-UDAF cleanroom in can be used for calculating the deposition rate of particles the steady-state condition, such as found during onto a given surface area. manufacturing. However, they should not be used in UDAF systems, as air cleanliness is not dependent on the Equation 2 air supply rate but on its displacement by UDAF. Surface particle deposition rate = C*VD*A The symbols used in the equations are as follows: Where, C is the airborne particle concentration in a C=Concentration of airborne particles or MCPs in a cleanroom, and VD is the deposition velocity of particles cleanroom (no./m3) falling through air onto a surface. A is the surface area onto CF = Concentration of airborne contamination in fresh which the particles deposit, and if the loss of particles by make-up air (no./m3) deposition in the whole cleanroom is considered, the surface area can be assumed to be equivalent to the floor area. CR = Concentration of airborne contamination in 3 In cleanrooms, cumulative particle sizes are counted, recirculated air (no./m ) which includes all particles over a threshold size, and CE = Concentration of airborne contamination in excess 3 the deposition velocities of a range of cumulative or extracted air (no./m ) particle sizes in different ventilation conditions have 3 11 Qs = Total air volume supply rate to cleanroom (m /s) been obtained by Whyte, Agricola and Derks . The 3 QF = Air volume supply rate of fresh make-up air (m /s) deposition velocities of MCPs are reported by Whyte 13 3 and Eaton . QR = Air volume recirculated from cleanroom (m /s) Air filters are normally considered by their removal ηP = Removal efficiency of primary air filter efficiency, which is usually given as a percentage. In this ηS = Removal efficiency of secondary air filter article, the proportion of airborne contamination that ηT = Removal efficiency of terminal air filter penetrates through filters is also used. These quantities are related as follows: DM = Average dispersal rate of airborne contamination from machinery (no./s) Penetration proportion = 1 – {removal efficiency (%)/100} DP = Average dispersal rate of airborne contamination from personnel (no./s) A typical cleanroom ventilation system will recirculate 2 A=Area of deposition (m ) of particles air from the cleanroom, add fresh air, modify the VD = Deposition velocity of particles of a size D (µm) temperature and humidity, filter the air, and supply it to falling through air (m/s) the cleanroom. The airborne concentration in a cleanroom is influenced by the contamination in the air supply, which Cleanrooms are typically maintained at a positive may differ according to the design of the air ventilation pressure with respect to adjacent areas, in order to system. The importance of this was investigated by minimise the entry of airborne contamination. In cases consideration of the following different configurations of where the prevention of the entry of contamination is ventilation systems. important, or the contamination challenge is substantial, air locks can be used. It can, therefore, be assumed that an 1. Type 1: Standard recirculation loop, where fresh air is insignificant amount of contamination enters the introduced into the recirculated air before any cleanroom from adjacent areas. In addition, it has been filtration occurs. shown that in a typical cleanroom, the dispersion of 2. Type 2: The fresh air is filtered before being contamination from a floor during walking contributes a introduced into the recirculated air. small amount to the airborne concentration10 and, 3. Type 3: Part of the recirculated air by-passes the air therefore, need not be included in the following conditioning plant. 40 w whytE, n lEnEgAn, t EAton

Figure 1. Type 1: Standard recirculation loop. AC = air conditioning plant, D = dispersion from machinery and personnel, air filters = .

These three types of ventilation systems were investigated The rate that airborne contamination exits a cleanroom when they had a primary, secondary and terminal filter or, and is recirculated to the air conditioning plant is CRQR. alternatively, a primary and terminal filter. The surplus air that pressurises a cleanroom can be exhausted by means of an extract fan to the outside, or passes through the room’s fabric, doorways, air dampers Type 1: Standard recirculation loop or grilles, at a rate of CE.QE. There is also a loss of Shown in Figure 1 is, possibly, the most common particles within the cleanroom by surface deposition, ventilation system arrangement found in cleanrooms, and the previously discussed Equation 2 can be used to where air is recirculated from the cleanroom, mixed with calculate the rate that they are lost. The total loss of fresh make-up air, and filtered by a primary filter prior to airborne contamination from the cleanroom is, the air conditioning plant. After conditioning, the air can therefore: be filtered by a secondary filter, which is used to extend the life of the terminal filter, and reduce the contamination CRqR + CEqE + C.VD.A risk to products should a leak occur in the terminal filter. The air is finally filtered by a terminal filter in the In the steady-state condition, the particle balance shown in cleanroom ceiling. Equation 1 can be expressed mathematically as follows: The rate that particles enter a cleanroom (no./s) is the 3 product of the air supply rate (m /s) and the associated (Co.qo + CR.qR)(1 – ηP)(1 – ηS)(1 – ηt) + DP + Dm = 3 particle concentration (no./m ). The rate of outdoor fresh CRqR + CEqE + C.VD.A air supplied to the cleanroom is CO.QO, and the recirculated air rate is CR.QR. The mixed air passes The particle concentration in both the recirculated (CR) through primary, secondary (when installed), and terminal and exhaust air (CE) can be assumed to be the same as in filters that have particle penetrations of 1-ηP, 1-ηS and 1- the cleanroom (C) and, to retain the air volume balance, ηT, respectively. The rate that particle contamination the fresh air supply is equal to that exhausted i.e. QE = QO. enters the cleanroom in the supply air is therefore: Therefore, the equation can be rewritten as follows:

퐶푂푄푂 퐶푅푄푅 휂푃 휂푆 휂푇 ( + )(1 − )(1 − )(1 − ) (Co.qo + CqR)(1 – ηP) (1 – ηS)(1 – ηt) + DP + Dm = CqR + Cqo + C.VD.A The filtered supply air enters the cleanroom and mixes with contaminants dispersed from people at a rate of DP, Rearranging and solving for C, which is the required and from machines at a rate of DM. Therefore, particles are airborne concentration in the cleanroom, and assuming the added to the cleanroom air at the following rate: volume of air supplied to the cleanroom is equal to the sum of the recirculated and fresh air supply rate, i.e. Q = 퐶푂 푄푂 퐶푅 푄푅 휂푃 휂푆 휂푇 퐷푃 퐷푀 ( . + . )(1 − )(1 − )(1 − ) + + QR + QO, the following equation is obtained: EquAtionS foR PREDiCting AiRboRnE ClEAnlinESS in non-uniDiRECtionAl AiRflow ClEAnRoomS 41

Equation 3 again used, and the same assumptions made as in the previous section, the following equation is obtained. 퐶푂푄푂 휂푃 휂푆 휂푇 퐷푃 퐷푀 퐶 1111111111111111(1 − )(1 − )(1 − ) + + = Equation 5 푄푆 푉퐷 𝐴 푄푅 휂P 휂푆 휂푇 + . − (1 − )(1 − )(1 − ) 퐶푂푄푂 휂푃 휂푆 휂푇 퐷푃 퐷푀 퐶 11111111111111(1 − )(1 − )(1 − ) + + If a secondary filter is not installed, the following equation = 푄푆 푉퐷𝐴 푄푅 휂푆 휂푇 is obtained: + − (1 − )(1 − )

Equation 4 If a secondary filter is not installed, the following equation

퐶푂푄푂 휂푃 휂푇 퐷푃 퐷푀 applies: 퐶 1111111111111(1 − )(1 − ) + + = 푄푆 푉퐷 𝐴 푄푅 휂P 휂푇 + . − (1 − )(1 − ) Equation 6 퐶 푄 휂 휂 퐷 퐷 Shown in figure below is a variation of the layout of the 푂 푂 푃 푇 푃 푀 퐶 1111111111111(1 − )(1 − ) + + Type 1 ventilation system, in which fresh and recirculated = 푄푆 푉퐷𝐴 푄푅 휂푇 air are filtered before they mix. If the primary filters have + − (1 − ) the same removal efficiency, then Equations 3 and 4 can be used. Or, alternatively, the equation previously reported by Whyte et al.10:

퐶푂푄푂 휂푃 휂푇 퐷푃 퐷푀 퐶 1111111111111(1 − )(1 − ) + + = 푄푆 푉퐷𝐴 푄푅휂푇 + +

A variation on the Type 2 ventilation system is shown in the figure below. Although the air conditioning plant is in a different location, it draws the same mixture of filtered air through the secondary filter, and Equations 5 and 6 are Type 2: Fresh air filtered before mixing applicable. with recirculated air Shown in Figure 2 is another ventilation arrangement used in cleanrooms, where fresh make-up air is filtered by a primary filter, and passed through an air conditioning plant before being mixed with recirculated air. The mixed air is then drawn through a secondary filter (where installed) and directed to the terminal filter in the cleanroom ceiling. If the particle-balance Equation 1 is

Figure 2. Conditioned fresh air system. AC = air conditioning plant, filters = . 42 w whytE, n lEnEgAn, t EAton

Figure 3. Recirculated air by-pass, AC = air conditioning plant, filters = .

Type 3: Recirculated air by-pass Equation 9 In some cleanrooms, where there is a large demand for 퐷푃 퐷푀 퐶 11111+ clean air but where the air conditioning requirement is = 푄 푉퐷 𝐴 relatively small, a proportion of the recirculated air is + . designed to by-pass the air conditioning plant and flow directly to the terminal filter. Such an arrangement is If surface deposition is unimportant, then the following shown in Figure 3. Equation 10, which is known as the ‘simple dilution’ Using the same particle-balance Equation 1, and equation, can be used. assumptions used in the previous two sections, the following equation is obtained. Equation 10

Equation 7 퐷푃 퐷푀 퐶 1111+ 퐶푂푄푂 휂푃 휂푆 휂푇 퐷푃 퐷푀 = 푄 퐶 111111111111111(1 − )(1 − )(1 − ) + + = 푄푆 푉퐷 𝐴 푄푅 푥 휂푃 휂푆 + . − . (1 − )(1 − ) 휂푇 푦 휂푇 (1 − ) – qR. (1 – ) Discussion Where, x is the proportion of the recirculated air that goes Equations have been derived in this article to calculate through the air conditioning plant, and y is the proportion the airborne concentration of particles or MCPs in that enters directly into the supply air duct. cleanrooms during the operational state. These equations If a secondary filter is not installed, the following are applicable to non-UDAF cleanrooms and assume a equation is applicable: steady-state condition brought about by a balance between particles introduced into the cleanroom and Equation 8 those removed. Similar equations have been previously

퐶푂 푄푂 휂푃 휂T 퐷푃 퐷푀 derived by research workers but usually apply to a single 퐶 1111111111111111111. (1 − )(1 − ) + + design of ventilation systems, which may differ from = 푄푆 푉퐷 𝐴 푄푅푥 휂푃 휂T 푦 휂푇 other systems in the way fresh air is introduced into the + . − (1 − )(1 − ) – qR. (1 – ) recirculated air, and in the placement and number of air filters. This article derives equations for three Simple dilution equations configurations of ventilation systems, where a secondary filter is, or is not, installed. The variables in these If the air filters installed in the ventilation system have a equations include air supply rate, airborne dispersion sufficiently high removal efficiency to ensure that the rate of contamination from machinery and people, airborne contamination in the filtered air supplied to the surface deposition of particles from the air, particle cleanroom has no practical significance, i.e. the removal concentration in the fresh air, proportion of fresh air, and efficiency (η) is 1, Equations 3 to 8 can all be reduced to air filter efficiencies. It is considered that these equations the following ‘dilution and deposition’ equation. are a useful advance over previously derived equations, EquAtionS foR PREDiCting AiRboRnE ClEAnlinESS in non-uniDiRECtionAl AiRflow ClEAnRoomS 43 and have been obtained in a way that allows the simple 3. Whyte W, Whyte WM, Eaton T and Lenegan N. Calculation of air supply rates for non-unidirectional airflow cleanrooms. European derivation of similar equations for other ventilation Journal of Parenteral and Pharmaceutical Sciences system. 2014;19(4):121–129. Actual values for dispersion and deposition rates, and 4. Whyte W, Hejab M, Whyte WM and Green G. Experimental and CFD airflow studies of a cleanroom with special respect to air for particle concentrations in make-up air, are provided in supply inlets. International. Journal of Ventilation 2010;9(3):197– a paper to be published, and these values will be used with 209. the derived equations to more accurately calculate the 5. Morrison PW. Environmental Control in Electronic manufacturing. New York, USA: Van Nostrand; 1973. ISBN: 0442255640. airborne concentration in non-UDAF cleanrooms. An 6. Brown WK and Lynn CA. Fundamental clean room concepts. investigation into the importance of the variables in the AShRAE transactions 1986;92(1):272–288. equations, and the effect of different efficiencies and 7. Jaisinghani RA. Energy efficient low operating cost cleanroom airflow design. Presentation at the Contamination Control, Design, placement of air filters in the different ventilation systems Test, and Evaluation Product Reliability: the 49th Annual Meeting is also carried out. In addition, by considering the and Exposition of the Institute of Environmental Science and importance of the various equation variables, the derived Technology. Phoenix, Arizona, 18–21 May 2003. 8. Sun W, Mitchell J, Flyzik K, Shih-Cheng H, Junjie L, Vijayakumar equations are simplified. R and Fukuda H. Development of cleanroom required airflow rate Rearranging the equations derived in this paper will model based on establishment of theoretical basis and lab validation. allow the calculation of the air supply needed to obtain a AShRAE transactions 2010;116:87–97. 9. Camfill Farr. CREO: Clean Room Design Standards and Energy specified airborne concentration of contamination in non- optimisation. Stockholm, Sweden: Camfil Farr, 2012. UDAF cleanrooms. The information gathered in the next 10. Whyte W, Whyte WM, Blake S and Green G. Dispersion of article will also enable the validity of the approach microbes from floors when walking in ventilated rooms. 3 international Journal of Ventilation 2013;12(3):271–284. suggested by Whyte, Whyte, Eaton and Lenegan for 11. Whyte W, Agricola K and Derks M. Airborne particle deposition in calculating the air supply rates for non-UDAF cleanrooms cleanrooms: Relationship between deposition rate and airborne to be investigated. concentration. Clean Air and Containment Review 2016;Issue 25:4– 10. 12. Whyte W, Agricola K and Derks M. Airborne particle deposition in cleanrooms: Calculation of product contamination and required References cleanliness class. Clean Air and Containment Review 2016;Issue 1. International Organization for Standardization. iSo 14644-1:2015. 26:4–10. Cleanrooms and Associated Controlled Environments – Part 1: 13. Whyte W and Eaton T. Deposition velocities of airborne microbe- Classification of Air Cleanliness by Particle Concentration. carrying particles. European Journal of Parenteral and Geneva, Switzerland: ISO; 2015. Pharmaceutical Sciences 2016;21(2):45–49. 2. European Commission. Eudralex. the Rules governing medicinal Products in the European union. Volume 4: Eu guidelines to good manufacturing Practice – medicinal Products for human and Veterinary use. Annex 1 – manufacture of Sterile medicinal Products. Brussels, Belgium: European Commission; 2008. PHSS-Q3P UCL Annual Conference 2016 Tuesday 6th September 2016 University College London UCL, School of Pharmacy 29-39 Brunswick Park, London, WC1N 1AX

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Impact of GMP regulation changes on contamination control, cross contamination control and QP certification - batch release.

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Deposition velocities of airborne microbe- carrying particles

W Whyte1and T Eaton2* 1 School of Engineering, University of Glasgow, Glasgow G12 8QQ 3 AstraZeneca, Macclesfield, Cheshire, SK10 2NA

The deposition velocity of airborne microbe-carrying particles (MCPs) falling towards surfaces was obtained experimentally in operating theatres and cleanrooms. The airborne concentrations of MCPs, and their deposition rate onto surfaces, are related by the deposition velocity, and measurements made by a microbial air sampler and settle plates allowed deposition velocities to be calculated. The deposition velocity of MCPs was found to vary with the airborne concentration, with higher deposition rates occurring at lower airborne concentrations. Knowledge of the deposition velocity allows the deposition on surfaces, such as product or settle plates, by a known airborne concentration of MCPs to be predicted, as well as the airborne concentration that should not be exceeded for a specified product contamination rate. The relationship of airborne concentration and settle plate counts of MCPs used in Annex 1 of the EU Guidelines to Good Manufacturing Practice to specify grades of pharmaceutical cleanrooms was reassessed, and improvements suggested.

Key words: Deposition velocities, airborne micro-organisms, microbe-carrying particles, surface deposition, cleanrooms, operating rooms.

3 Introduction MCPs in hospital air is about 12 µm, and Whyte and Hejab have confirmed this during experiments carried out on people In cleanrooms and hospital operating rooms, the high exercising in a dispersal chamber. efficiency filtration of the air supply to the room ensures that MCPs may deposit from the air onto surgical wounds no microbe-carrying particles (MCPs) enter a room in the and products manufactured in cleanrooms and, based on supply air. Also, these ventilated rooms are normally results published by Whyte4, a deposition velocity of positively pressurised with respect to adjacent areas, and this 0.46 cm/s has been used to calculate airborne deposition of ensures that few MCPs enter from outside. Therefore, MCPs onto pharmaceutical products5. However, recent airborne MCPs in ventilated rooms are generated within the research by Whyte, Agricola and Derks6 carried out on room and most, if not all, come from personnel. airborne particles in a cleanroom has shown that the Micro-organisms grow on the cells and glands of the skin, deposition velocity of particles increases as the air and are dispersed into the air on skin detritus. Skin cells have 1 cleanliness increases. It was, therefore, decided that a fresh been reported by Mackintosh et al. to have a top surface area investigation of the values of deposition velocities of MCPs of approximately 33 µm × 44 µm, and 3 to 5 µm thick. They was desirable. Sampling results had been gathered over a may be found in the air either as whole cells, or fragments of number of years in pharmaceutical cleanrooms and cells. Particles found in room air will vary in size, shape and operating theatres, and were available to calculate the density, and their size is normally given as an equivalent deposition velocity of MCPs, and ascertain if it varied with particle diameter, which is the diameter of a sphere of unit airborne cleanliness. density that settles in air at the same velocity as the particle under consideration. Noble, Lidwell and Kingston2 have reported that the average equivalent particle diameter of Deposition of particles onto surfaces The number of MCPs that will deposit onto a surface, such as manufactured products, open surgical wounds, or settle *Corresponding author: * Tim Eaton, Sterile Manufacturing Specialist, 5,6 AstraZeneca, UK Operations, Silk Road Business Park, Macclesfield, plates, can be calculated by use of the following equation . Cheshire, SK10 2NA; Email: [email protected]; Tel: +44(0)1625 514916. 45 46 W WHYTE, T EATON

Equation 1 Experimental methods

Number of MCPs deposited = c*a*t*vD Cleanrooms and operating rooms studied Where c = airborne concentration of MCPs, a = area of Experiments were carried out in three pharmaceutical manufacturing rooms in which the air supply, the number deposition surface, t = deposition time, and vD = deposition velocity of people present, and clothing worn, were varied to obtain a range of airborne concentrations of MCPs. Two If Equation 1 is rewritten in terms of the airborne hospital operating theatres were also studied. The rooms concentration of MCPs, the airborne concentration can be studied were as follows. calculated that should not be exceeded for a specified and acceptable amount of surface deposition. Both these (1) Vial-filling cleanroom: This cleanroom was a non- methods of calculation are described by Whyte, Agricola unidirectional airflow (non-UDAF) cleanroom that and Derks7. However, to complete these calculations, the was supplied with approximately 20 air changes per deposition velocity of airborne particles must be known. hour, and the vial filling carried out in a horizontal A useful approach to the investigation of the surface UDAF cabinet. deposition and deposition velocity of MCPs is use of the microbial deposition rate (MDR), which is the deposition (2) Diagnostics cleanroom: This was a non-UDAF rate of MCPs onto a standard surface area in a standard cleanroom supplied with 18 air changes per hour. The time and can be obtained from counts on settle plates. air quality of the room could be enhanced by use of a Settle plates of 9 cm diameter (64 cm2 surface area) are free-standing UDAF unit of 1.8 m × 0.7 m surface area most commonly used in cleanrooms, but settle plates of 14 with an air supply velocity of 0.3 m/s. cm diameter (154 cm2 surface area) are also used, as they (3) Ampoule-filling cleanroom: This cleanroom had a are more sensitive, as are several 9 cm plates. If the 2 number of MCPs that deposit onto a settle plate of known floor area of 175 m and about 25 air changes per hour. area, exposed for a known time, is ascertained, then the Vertical UDAF units were fitted over two ampoule MDR (no./m2/s) can be obtained by calculating the filling areas. number of MCPs that will deposit onto one square metre in one second. This approach allows Equation 1 to be (4) Non-UDAF operating theatre: This was used for transformed to the following Equation 2. orthopaedic surgery and was 6.1 m × 6.1 m in floor area, with an air change rate of about 22 per hour. Equation 2 (5) UDAF operating theatre enclosure: Orthopaedic MDR = c * vD surgery was carried out within a UDAF enclosure Rearranging Equation 2 gives the following Equation 3. located in a non-UDAF operating room. The UDAF enclosure had a high-efficiency particulate air filter Equation 3 ceiling that was 3 m × 4 m in area and had a downward 111MDR air velocity of 0.3 m/s. vD = c The cleanroom clothing worn in the pharmaceutical cleanrooms was made from a woven polyester fabric and Use of Equation 3 allows the deposition velocity of MCPs consisted of a coverall, hood and knee-length over-boots, in a ventilated room to be ascertained by simultaneously a mask and sterile gloves. When higher airborne microbial measuring, at the same location, the airborne concentration counts were required, either cotton garments or normal with an air sampler and the MDR with a settle plate. indoor clothing was worn. Further increases in the Annex 1 of the European Union Guidelines to Good airborne concentration of MCPs were obtained by Manufacturing Practice (EU GGMP)8 specifies grades of introducing additional personnel into the room. cleanrooms with maximum concentrations of particles In the non-UDAF operating theatre, the surgical and MCPs. These include maximum airborne clothing consisted of sterile cotton gowns worn over concentrations of MCPs/m3 and settle plate counts of cotton shirts and trousers. In the UDAF enclosure, non- MCPs deposited onto a 90 mm diameter plate in 4 hours. woven fabric gowns were worn over cotton shirts and The settle plate counts for a given airborne concentration trousers. Hoods, face masks and sterile gloves were worn of MCPs were based on information published in 1989 in both theatres. by the Parenteral Society (now the Pharmaceutical and Healthcare Sciences Society) Technical Monograph No Air sampling methods 29 that used an equation published by Whyte4 that is Microbial sampling in the pharmaceutical cleanrooms was similar to Equation 1 and used a deposition velocity of carried out during microbial growth media (broth) 0.46 cm/s. A reappraisal of the deposition velocities of experiments for the filling of either vials or ampoules. In MCPs in this article gives an opportunity to reconsider the diagnostics preparation cleanroom, microbial the maximum settle plate counts given in the EU GGMP monitoring was undertaken during normal production for different grades of pharmaceutical cleanrooms. activities, but when the room ventilation was switched off, DEPOSITION VELOCITIES OF AIRBORNE MICROBE-CARRYING PARTICLES 47

Figure 1. Relationship of MDR and airborne concentration of MCPs. or additional personnel wearing indoor clothing were of 10 cm diameter flexible tubing was added that was introduced, production activities were suspended, and bent through 90° to the horizontal, and connected to a monitoring undertaken with personnel moving about and sterile metal cone which converged to a 4 cm opening active within the cleanroom. In the operating theatres, through which air samples were drawn. This allowed sampling was carried out during routine orthopaedic airborne MCPs to be efficiently sampled at the locations surgical operations. where containers were filled or close to the surgical Airborne MCPs were sampled by means of a slit wound, but where the sampler was too large to be placed. sampler (Casella Ltd) that sampled 700 litres of air per Sampling times varied from 0.5 minutes to 15 minutes, minute onto Petri dishes containing tryptone soya agar depending on the expected MCP counts, and sampling (Oxoid Ltd). After use, the Petri dishes were incubated was carried out over 2 and 5-hour periods in the same for 36 to 48 hours at 37°C and the microbial colonies day. In the case of pharmaceutical manufacturing, counted. To the air intake of the sampler, a 60 cm length samples were taken at both the vial and ampoule turntable

Table 1. Experimental conditions and results. Number Cleanroom/ Room UDAF Type of MCP Settle plate MDR Deposition 2 operating ventilation clothing volumetric count 14 cm (no./m /s) velocity theatre count diameter (cm/s) 3 application (no./m ) (no./h)

1 Vial filling On Horizontal – on Cleanroom 0.4 0.76 0.014 3.43

2 Vial filling On Off Cleanroom 85 8.5 0.15 0.18

3 Vial filling Off Off Cotton 186 42.6 0.77 0.41

4 Diagnostics On None Cleanroom 15.9 1.3 0.023 0.15

5 Diagnostics On Free-standing Cleanroom 1.8 3.3 0.060 3.31 UDAF

6 Diagnostics Off None Indoor* 1116 106 1.9 0.17

† 7 Ampoule filling Off Off Indoor 118 14.6 0.26 0.22

8 Ampoule filling On Off Indoor 15 6 0.11 0.72

9 Orthopaedic On None Cotton 539 128 2.3 0.43 surgery

10 Orthopaedic On On Non-woven 3.8 1.3 0.023 0.62 surgery

† * 10 people present; 8 people present. 48 W WHYTE, T EATON and filling point, and an average calculated. During fits the results. The equation of this line is as follows. surgical operations, samples were taken within 20 cm of the open wound. Equation 4 Settle plate sampling was carried out at the same time y = 0.0161 x0.6571 as sampling with an air sampler, using 14 cm diameter Petri dishes containing tryptone soya agar, which were Where y = MDR (no/m2/s), and x = airborne MCP incubated after use for 36 to 48 hours at 37°C and the concentration/m3 microbial colonies counted. The settle plates were laid out in the pharmaceutical cleanrooms on the filling machine Equation 4 was used to calculate the expected MDR for a close to the filling area. Plates were exposed when filling range of airborne MCP concentrations, and from these started and the lids replaced when filling stopped; this results the deposition velocity (cm/s) was calculated by exposure time varied from between 2 and 5 hours. During means of Equation 3. These results are given in Table 2. the surgical operations, the open settle plate was placed Shown in the first two columns of Table 3 are the within 20 cm of the wound for the time between incision maximum airborne concentrations and settle plate and closure, and, depending on the operation, exposed for counts given in Annex 1 of the most recent edition of the between about 1 and 2 hours. EU GGMP (2008) for different grades of cleanrooms. Using the deposition velocities given in Table 2, the number of MCPs expected to deposit onto a settle plate of 9 cm diameter (area = 0.0064 m2) during an exposure Experimental results time of 4 hours, was calculated for the airborne Given in Table 1 are the type of cleanrooms and operating concentrations given in Table 3. Finally, in the last theatres studied. Also included are the MCP air column of Table 3 are the required settle plate results, concentrations/m3, the number of MCPs that deposited given as the MDR, using the base units of the onto a 14 cm diameter settle plate per hour, and the MDR International System of Units (SI units), i.e. no./m2/s. (number/m2/s). The average deposition velocity of MCPs The MDR allows the number of MCPs deposited onto calculated by Equation 3 is also included but given in the any size of settle plate, in any time of exposure, to be more commonly used units of cm/s. calculated. Shown in Figure 1 is the relationship of the airborne concentration to the MDR, with a regression line that best Discussion and conclusions Knowledge of the deposition velocity of MCPs as they fall Table 2. Deposition velocities for airborne concentrations of through the air onto cleanroom surfaces allows the MCPs. calculation of the amount of deposition on a surface such Airborne Deposition as a product, as well as the airborne concentration that 3 concentration/m velocity (cm/s) should not be exceeded for a specified amount of product contamination. These two calculation methods are 0.1 3.55 7 described by Whyte, Agricola and Derks . 0.5 2.04 The deposition velocity of a range of particle sizes in 1 1.61 a cleanroom was ascertained by Whyte, Agricola and Derks6 who reported that as the concentration of 5 0.93 airborne particles in the cleanroom decreased, the 10 0.73 deposition velocity increased. The reason for this was not clear but it was suggested that as lower particle 50 0.42 concentrations were associated with higher air supply 100 0.33 rates, smaller particles would be quickly swept from the 200 0.26 cleanroom with little time to deposit, but larger particles would still be deposited by gravity. This effect was 500 0.19

Table 3. EU GGMP recommended limits for air concentrations and settle plate counts. Present and corrected information. Grade Air sample Settle plates Settle plates Corrected settle 3 cfu/m (diameter 90 mm) (diameter 90 mm) plate counts 2 cfu/4 hours cfu/4 hours as MDR (cfu/m /s)

Current requirements Corrected requirements

A <1 <1 <1.5 0.016

B 10 570.073

C 100 50 30 0.33

D 200 100 48 0.52 DEPOSITION VELOCITIES OF AIRBORNE MICROBE-CARRYING PARTICLES 49 expected to increase as the average residence time of the deposition velocity of 0.46 cm/s. Using the set of more air reduces owing to an increase in air supply rates. It accurate deposition velocities, the EU GGMP maximum was also thought that an increase in the turbulent concentrations can be revised to provide more accurate intensity of the air, caused by an increase in the air settle plate counts. Table 3 shows the settle plate counts supply, would also increase the amount of surface currently specified by the EU GGMP and those based on deposition. the information obtained in this article. It is suggested that It is known that MCPs in cleanroom air do not the EU GGMP should be revised to take account of these normally exist as single-celled organisms but are findings. commonly found on skin cells dispersed by personnel and have an equivalent particle size of about 12 µm. The deposition velocity of these MCPs had been reported by References Whyte4 to be about 0.46 cm/s, and this velocity has been 1. Mackintosh CA, Lidwell OM, Towers AG and Marples RR. The dimensions of skin fragments dispersed into air during activity. used in several articles, such as that published by Whyte Journal of Hygiene 1978;81:471–479. 5 and Eaton to calculate the contamination rate of products 2. Noble WC, Lidwell OM and Kingston D. The size distribution of in cleanrooms. However, the results of the investigation airborne particles carrying micro-organisms. Journal of Hygiene 6 1963;61:385–391. carried out by Whyte, Agricola and Derks has questioned 3. Whyte W and Hejab M. Particle and microbial airborne dispersion the accuracy of the use of a single deposition velocity from people. European Journal of Parenteral and Pharmaceutical over a range of the cleanliness conditions found in a Sciences 2007;12(2):39–46. 4. Whyte W. Sterility assurance and models for assessing airborne cleanroom. bacterial contamination. Journal of Parenteral Science and The measurement of airborne concentrations and settle Technology 1986;40:188–197. plate counts was carried out in a wide variety of 5. Whyte W and Eaton T. Assessment of degree of risk from sources of microbial contamination in cleanrooms; 1: Airborne. European cleanrooms and operating theatres. This data was Journal of Parenteral and Pharmaceutical Sciences analysed and the deposition velocities of MCPs obtained. 2015;20(2):52–62. These results showed that the deposition velocity 6. Whyte W, Agricola K and Derks M. Airborne particle deposition in cleanrooms: relationship between deposition rate and airborne increased as the airborne concentration in the rooms concentration. Clean Air and Containment Review 2016;Issue decreased, and the use of these deposition velocities 25:4–10. should improve the accuracy of the calculation of surface 7. Whyte W, Agricola K and Derks M. Airborne particle deposition in cleanrooms: Calculation of product contamination and required contamination, as well as the calculation of the cleanroom class. Clean Air and Containment Review 2016;Issue concentration of airborne MCPs required to ensure that 26:4–10. 8. European Commission. EudraLex. The Rules Governing Medicinal microbial deposition of surfaces is not greater than Products in the European Union. Volume 4: EU Guidelines to Good specified. Manufacturing Practice – Medicinal Products for Human and The EU GGMP specifies grades of cleanroom for use Veterinary Use. Annex 1 – Manufacture of Sterile Medicinal in pharmaceutical manufacturing, and gives suggested Products. Brussels, Belgium: European Commission; 2008. 9. Parenteral Society. Parenteral Society Technical Monograph Number limits of the airborne concentrations and settle plate 2. Environmental Contamination Control Practice. Swindon, UK: counts of MCPs. The settle plate counts that correspond to Pharmaceutical and Healthcare Sciences Society; 1989. the airborne concentrations were derived from data originally published in the Parenteral Society9 and based on the equation published by Whyte4, which used a single European Journal of Parenteral & Pharmaceutical Sciences 2016; 21(2): 50-55 © 2016 Pharmaceutical and Healthcare Sciences Society

The use of a single growth medium for environmental monitoring of pharmacy aseptic units using tryptone soya agar with 1% glucose John Rhodes1*, Jennifer Feasby1, Wayne Goddard1, Alison Beaney2 and Mike Baker3 1 North Tees and Hartlepool NHS Foundation Trust, Stockton-on-Tees, UK 2 Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK 3 Pharma Quality Consulting, Cheshire, UK

The suitability of tryptone soya agar, Sabouraud dextrose agar and tryptone soya agar with 1% glucose plates for general environmental monitoring was compared. Plates were incubated at three different temperatures to assess an optimal temperature for growth. Results indicated that there are benefits from using tryptone soya agar with 1% glucose incubated at 25°C as an all-purpose medium for environmental monitoring.

Key words: Tryptone soya agar, Sabouraud dextrose agar, tryptone soya agar with 1% glucose, environmental monitoring of aseptic rooms, settle plates, finger dabs.

Introduction any test methods or suitable media. For cleanroom monitoring of UK National Health Service (NHS) aseptic services, more The choice of a microbiological growth medium is not simple. detailed guidance has been provided4 for environmental settle The Difco Manual has proven to be a comprehensive source of plate agars. It indicates that the media recommended is: information since the first edition appeared in 1927. The tenth edition was published in 1984 and found its way into most 1 “standardised on tryptone soya for bacterial count (this microbiology laboratories . The guide for the selection of will also detect yeasts and moulds to an extent) and culture media formed a 9-page table and contained many agars Sabouraud dextrose medium for the selective and broths for isolation, differentiation and propagation of determination of yeasts and moulds.” 4 different classes of micro-organisms. The most ubiquitous propagation agars were tryptone soya agar (TSA) for aerobic This advice was based on the experience of the authors over bacteria and Sabouraud dextrose agar (SDA)/Sabouraud several years in NHS pharmaceutical quality control, maltose agar (SMA) for yeasts and moulds. however, the extent that fungi grow on TSA had not been The media supplied by Difco and similar companies were published. formulated for specific applications, namely clinical, Sabouraud agar medium was developed by a French serology, water, foods, beverages and pharmaceutical dermatologist Raymond JA Sabouraud in the late 1890s to microbiology. Pharmaceutical microbiology was based on 5,6 2 support the growth of fungi . J Hare provides a history and formulations provided by Pharmacopoeias for testing the theory of Sabouraud agar7: products. Little was published for environmental microbiology. “The available means of inhibiting bacterial growth in European Union Guidelines to Good Manufacturing Sabouraud’s pre antibiotic era was an acidic medium Practice Annex 1 describes the manufacture of sterile (pH 5.6)…Glucose is present at the high level of 4% in medicinal products and contains recommended limits for 3 Sabouraud’s formulation to assist in vigorous environmental microbial contamination . It provides a fermentation and acid production of any bacteria maximum number of colonies for settle plates, contact plates, present, inhibiting future bacterial growth. In 1977, airborne viable counts and finger dabs, but does not reference Emmens formulated an alternative version of Sabouraud’s agar which contains half the amount of glucose (2%) and a neutral pH of 6.8–7.0. The neutral *Corresponding author: John Rhodes, Stockton Quality Control pH seems to enhance the growth of some pathogenic Laboratory, University Hospital of North Tees, Hardwick, Stockton-on-Tees, 7,8 UK, TS19 8PE. Email: [email protected]. Tel: +44(0)1642 614194 fungi.”

50 USE OF TSA + 1% GLUCOSE FOR THE ENVIRONMENTAL MONITORING OF PHARMACY ASEPTIC UNITS 51

The ideal medium for environmental monitoring is broad Table 1. Agar plates prepared by Oxoid UK and Cherwell spectrum and encourages the growth of sub-lethally Laboratories UK used in the tests. damaged organisms and spores. In the 1930s, Bowers and 9 Medium Oxoid catalogue Cherwell catalogue Hucker developed tryptone glucose skim milk agar, a number number medium for detecting bacteria in milk and other dairy TSA+G PO0330B 104466 products. TSA PO0241B 104131 In 1932, Norton recommended the incorporation of 0.5 to 1% dextrose10 and the Becton Dickinson updated Difco SDA PO0410B 104066 manual11 indicates the following for dextrose agar:

“Dextrose is an energy source used by many of nine plates, three of each type of agar on different organisms. The high concentration of this surfaces in the laboratory in order to collect environmental ingredient makes dextrose agar a suitable medium organisms. The plates were incubated at 22.5°C, 25°C and for the production of early, abundant organism 32.5°C in such a way that each type of media was growth and shortening the lag periods of older incubated at each temperature per location. The plates cultures.” were read over 5 days. Oxoid plates were exposed in a laboratory with no air conditioning. Cherwell plates were Tryptone glucose extract medium, used as a standard plate exposed in a laboratory supplied with air filtered through count agar for dairy products and water, and plate count an EU8 filter. agar, used for obtaining microbial plate counts from milk and dairy products, foods, water and other materials of sanitary importance, were developed from the Bowers and Results Hucker formulation11. These media were formulated using The plates for the ten locations were read and the number 1% glucose and a pH of 7.0 ± 0.2 in contrast with SDA of bacteria and fungi recorded. The total number of formulated with 4% dextrose and pH 5.6 ± 0.22. organisms identified as bacteria for the ten locations were The optimal pH range for growth for the majority of presented as a bar chart for each manufacturer of plates in bacteria is between 6.5 and 7.5 which is in line with Figures 2 and 3. The total number of organisms identified Emmons philosophy8. A plate incorporating the general as fungi (moulds and yeasts) are presented as a separate purpose formulation of TSA and 1% glucose (TSA+G) bar chart for each manufacturer of plates in Figures 4 and has been formulated at pH 7.0 ± 0.2 for general use in 5. Oxoid plates were read daily over the 5 days of cleanrooms as indicated in Figure 1. Stockton Quality incubation. Control Laboratory has been using TSA+G since 1973 for plates used for routine environmental monitoring. The aim of the study was to validate the use of TSA+G Discussion by comparing the effect of typical environmental The tests were carried out using pre-poured and irradiated organism growth on TSA, SDA and TSA+G settle plates plates prepared by Oxoid and Cherwell Laboratories. from two different suppliers when incubated at three Oxoid plates were being purchased at the time of the different temperatures, 22.5°C, 25°C and 32.5°C. initial validation. The repeat tests were carried out as part of a revalidation study when the laboratory was located in an air conditioned building and at that time plates were Pancreatic digest of casein 15 g purchased from Cherwell Laboratories. Both sets of plates Enzymatic digest of soya bean 5 g were exposed in a general laboratory environment under turbulent air. Staff wore laboratory coats over personal Sodium Chloride 5 g clothing and, therefore, a challenge by human Agar 15 g commensals was expected. The laboratory did not control the cleanliness of items brought into the test areas and, Glucose 10 g therefore, a range of environmental organism challenge is Water 1000 mL not unusual. It is known that the chance of particles carrying organisms landing on a plate is poor and pH at 25°C 7.0 ± 0.2 12 determined by particle size, air flows and eddies . Figure 1. Formulation of TSA+G plates. Therefore, the total number of organisms for the ten locations were added together to reduce this variation. The total number of bacteria recovered on the Oxoid and Cherwell plates were similar as shown when comparing Materials and methods Figures 2 and 3, however, the total number of fungi Agar plates prepared by Oxoid UK and Cherwell obtained for the Cherwell plates were significantly lower Laboratories UK were used in the tests and detailed as in as shown when comparing Figures 3 and 4. It is believed Table 1. that the difference arises because the Cherwell plates were Plates were exposed for between 1 and 4 hours to exposed in an air conditioned laboratory and not a simulate different challenges. They were placed in groups variation in quality of the product. 52 JOHN RHODES, JENNIFER FEASBY, WAYNE GODDARD, ALISON BEANEY, MIKE BAKER

Figure 2. Total number of bacteria recovered from the three formulations of Oxoid agars incubated at three temperatures after 5 days.

It was not possible to control the challenge size as the 219 bacteria which corresponded to 74% of the total count number of organisms landing on the plate depended on the for the study. The corresponding plates incubated at activity in the room and the airflow around the different 22.5°C and 32.5°C gave counts of 96 and 100, group sites. Plates were grouped closely together to respectively. A Grubbs outlier test13 indicated that the 219 minimise variations due to location and exposed for up to result was an outlier (p < 0.01). This suggests that this 4 hours to average out the number of particles landing on a result introduced a bias into the statistics. When all the plate in the group. Figure 2 implies that TSA+G plate results for this location were removed from the plots, incubated at 25°C recovered twice as many organisms as Figure 6 replaces Figure 2 and Figure 7 replaces Figure TSA plates or the TSA+G incubated at a higher or lower 4. The removal of entrance area plates did not change the temperature. However, when the individual plate counts shape of the fungi plot but did alter the TSA+G profile in were examined, one Oxoid plate exposed on the floor in line with the TSA and SDA profiles. the laboratory entrance area for 3 hours gave a count of Clearly, the SDA plates from Oxoid or Cherwell did

Figure 3. Total number of bacteria recovered from the three formulations of Cherwell agars incubated at three temperatures after 5 days. USE OF TSA + 1% GLUCOSE FOR THE ENVIRONMENTAL MONITORING OF PHARMACY ASEPTIC UNITS 53

Figure 4. Total number of fungi recovered from the three formulations of Oxoid agar incubated at three temperatures after 5 days.

Figure 5. Total number of fungi recovered from the three formulations of Cherwell agar incubated at three temperatures after 5 days.

Figure 6. Total number of bacteria recovered from the three formulations of Oxoid agar incubated at three temperatures after removal of the entrance set of results after 5 days. 54 JOHN RHODES, JENNIFER FEASBY, WAYNE GODDARD, ALISON BEANEY, MIKE BAKER

Figure 7. Total number of fungi recovered from the three formulations of Oxoid agar incubated at three temperatures after removal of the entrance set of plates after 5 days.

not support the growth of bacteria (Figures 6 and 3) to any TSA plates especially when growth is observed in SDA great extent which was not unexpected as the pH of the plates. 8 formulation is low . The bacteria that settled on all the The comparative data for each of the three media Oxoid plates grew better at the higher temperature (see indicates that either 22.5°C or 25°C would be an Figure 6), however, the bacteria that settled on the appropriate incubation temperature for fungi, but not Cherwell plates appeared to grow equally well at any of 32.5°C. TSA+G gave similar total fungal counts to SDA the incubation temperatures. and a greater recovery than TSA for both Oxoid and Incubating at 32.5°C reduced the recovery of fungi for Cherwell plates. Either 25°C or 32.5°C would be an all three media from both suppliers as shown in Figures 5 appropriate incubation temperature for bacteria on TSA or and 7. It is well established that lower temperatures 14 TSA+G plates. The TSA gave slightly better recovery than encourage the growth of filamentous fungi . However, TSA+G for both bacteria and fungi but this was not dermatophytes or dimorphic fungi prefer the higher 7 significant (p > 0.1) temperature but take 2 to 4 weeks for growth . As test Dual temperature incubation has not been considered14 results are required to establish whether a cleanroom in this study, however, 25°C does appear to be a good remains microbiologically in control, timely results are compromise for single temperature incubation of TSA+G. essential in the event of a high count exceeding an alert or It gave the best recovery of bacteria on Cherwell plates action level to ensure an investigation is undertaken and and the best recovery of fungi on Oxoid plates. Slightly appropriate action is taken in order to minimise the risk of better results were obtained for fungi on Cherwell plates at preparing a microbially contaminated product. Extending 22.5°C and for the recovery of bacteria on Oxoid plates at the incubation time to permit the growth of slow-growing 32.5°C. The authors believe that there would be little organisms will delay the commencement of an benefit from changing incubation temperatures. investigation and potentially allow faster growing The use of a single media to monitor clean air devices organisms to overgrow a plate. The British Pharmacopoeia total viable count test for has the advantage of taking up less space in critical areas, non-sterile preparations2 has separate limits for bacterial such as isolators or laminar flow cabinets. Finger dabs can counts and fungal counts. It utilises TSA incubated at only be carried out once at the end of a work session and a 32.5°C for 3 days and SDA incubated at 22.5°C for 5 days single general purpose agar will allow the culture of a for mould and yeast count. In order to allow fungi to be broad range of organisms. It is a requirement that environmental monitoring results are trended on a counted independently from bacteria, SDA inhibits the 15 growth of bacteria. When a total viable count is not monthly basis . Results from a single plate at a given performed by filtration, molten agar is poured over the position will be easier to record and manipulate than from sample and growth appears as small discrete colonies two plates. There will be no possibility of mix up if the embedded in the agar. The agar is incubated at 22.5°C to wrong media is exposed, especially if SDA plates are encourage mould growth and the incubation time is 5 days exposed less frequently. If different temperatures are used as growth is slow. Bacteria are grown on TSA as it is not for the TSA and SDA plates, there is a possibility of inhibitive of bacterial growth. Bacteria tends to grow incubating agar at the wrong temperature if they are sufficiently well for the visual counting of colonies after 3 wrapped together, mislabelled in error or simply placed in days at 32.5°C. However, experience has shown that the wrong incubator, organism numbers could then be occasionally yeast or mould contamination is observed in underreported. USE OF TSA + 1% GLUCOSE FOR THE ENVIRONMENTAL MONITORING OF PHARMACY ASEPTIC UNITS 55

5. Sabouraud R. La question des teignes. Annales de Dermatologie et Conclusion de Vénéréologie (Series 3) 1896;7:87–135. The choice of medium and incubation temperature for 6. Sabouraud R. Recherche des milieux de culture propres a la microbiological environmental monitoring must be a différenciation des espèces trichophytiques a grosse spore. In: Les Trichophyties Humaines. Paris, France: Masson et Cie; 1896, pp. compromise. The results indicate that the optimal 49–55. conditions for incubating plates for the recovery of both 7. Hare JM. Sabouraud agar for fungal growth. In: Laboratory fungi and bacteria at a single temperature is about 25°C. Protocols in Fungal Biology: Current Methods in Fungal Biology. SDA is inappropriate as a general purpose Gupta VK and Tuohy MG, Eds. New York, USA: Springer Science; environmental medium and should only be used to 2012, pp. 211–216. 8. Emmons CW, Binford CH, Utz JP and Kwon-Chung KJ. Medical quantify moulds and yeasts. TSA incubated at 25°C will mycology, 3rd edition. Philadelphia, PA, USA: Lea & Febiger; 1977, recover moulds and yeasts and the inclusion of 1% p. 535. glucose does appear to have benefits in improving their 9. Bowers CS and Hucker GJ. The composition of media for the recovery to the same level as SDA. The use of a single bacterial analysis of milk. Technical Bulletin 228. Geneva, NY, USA: medium also confers practical benefits in busy New York State Agricultural Experiment Station; 1935, p. 228. 10. Norton JF. The bacteria of pus. Journal of Laboratory and Clinical pharmaceutical units. Medicine 1932;17:558–585. 11. Zimbro MJ, Power DA, Miller SM, Wilson GE and Johnson JA, Eds. Difco & BBL Manual. Manual of Microbiological Culture References Media, 2nd Edition. Sparks, MD, USA: Becton Dickinson 1. Difco Laboratories. Difco Manual: Dehydrated Culture Media and Diagnostics; 2009, p. 190. Reagents for Microbiology, 10th Edition. Detroit, MI, USA: Difco 12. Whyte W. Cleanroom Technology: Fundamentals of Design, Testing Laboratories; 1984. and Operation, 2nd Edition. Chichester, UK: Wiley; 2010, pp. 197– 2. British Pharmacopoeia Commission Secretariat. British 198. Pharmacopoeia. London, UK: The Stationary Office; 2015. 13. Miller JN and Miller JC. Statistics and Chemometrics for Analytical 3. European Commission. EudraLex. The Rules Governing Medicinal Chemistry, 6th Edition. Upper Saddle River, NJ, USA: Prentice Products in the European Union. Volume 4: EU Guidelines to Good Hall; 2010, pp. 49–51. Manufacturing Practice – Medicinal Products for Human and 14. Sandle T. Optimal conditions for the recovery of bioburden from Veterinary Use. Annex 1 – Manufacture of Sterile Medicinal pharmaceutical processes: a case study. European Journal of Products. Brussels, Belgium: European Commission; 2008. Parenteral and Pharmaceutical Sciences 2013;18(3):84–90. http://ec.europa.eu/health/files/eudralex/vol-4/2008_11_25_gmp- 15. Medicines and Healthcare Products Regulatory Agency. MHRA an1_en.pdf [Accessed 9 April 2015]. Questions and Answers for Specials Manufacturer’s. London, UK: 4. Beaney AM, Ed. Quality Assurance of Aseptic Preparation Services, MHRA; 2015. https://www.gov.uk/government/uploads/system/ 4th Edition. London, UK: Pharmaceutical Press; 2006, pp. 65–74. uploads/attachment_data/file/400232/Guidance_for__specials__ma nufacturers.pdf [Accessed 21 September 2015]. European Journal of Parenteral & Pharmaceutical Sciences 2016; 21(2): 56-63 © 2016 Pharmaceutical and Healthcare Sciences Society

Regulatory Review

Introduction • Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products Developments in the “regulation” of the pharmaceutical • Contents of a Complete Submission for the Evaluation of industry since our last review include the following. Proprietary Names – Guidance for Industry • Data Integrity and Compliance with CGMP [current GMP] Europe • Food and Drug Administration (FDA) alerts healthcare • Potential presence of mutagenic alkyl sulfonates in active professionals not to use sterile drug products from substances Pharmakon Pharmaceuticals, Inc., Noblesville, Indiana • Pharmacopoeial Discussion Group (PDG) November 2015 • Pharmaceutical distribution supply chain pilot projects; • European Formulary for paediatric medicines request for information • Revised European Pharmacopoeia (Ph. Eur.) General • Facility definition under Section 503B of the Food, Drug Chapter on Raman Spectroscopy and Cosmetic (FD&C) Act • High performance thin-layer chromatography (HPTLC) of • Prescription Requirement Under Section 503A of the herbal drugs and herbal drug preparations FD&C Act • Delegated Regulation 2016/161 and its applicability to UK • Hospital and Health System Compounding • First year’s work of the UK stakeholders’ reclassification • FDA approves a second bio-similar platform • Improvements to the change of ownership application International (COA) process for medicines marketing authorisations • Good manufacturing practice (GMP) and good distribution Canada practice (GDP) • Post-Notice of Compliance (NOC) Changes Guidance • GDP – qualification of suppliers – 3 steps needed to assure Document supply chain integrity • Government response to the consultation on statutory fees China for producers of e-cigarette products • China Food and Drug Administration (CFDA) requires generics to obtain brand-name drug quality USA • Completeness assessments [CA] for Type II API [active India pharmaceutical ingredient] DMFs [drug master files] under • Proposal to replace gelatine in capsules GDUFA [Generic Drug User Fee] – Guidance for Industry • Guidelines on Similar Biologics Regulatory Requirements • Characterization of Ultrahigh Molecular Weight for Marketing Authorization Polyethylene (UHMWPE) Used in Orthopedic Devices • Recommendations to reduce the risk for Zika virus blood WHO transmission in USA • Prequalification of quality control laboratories (QCLs) for • Donor Screening Recommendations to Reduce the Risk of use by United Nations (UN) agencies – proposal for change Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products – Guidance for Industry Products • Immunogenicity-Related Considerations for Low Molecular • Medicines and Healthcare Products Regulatory Agency Weight Heparin [LMWH] – Guidance for Industry (MHRA) letter to the Editor of the Sunday Post in response • Environmental Assessment: Q&A Regarding Drugs With to article on faulty equipment Estrogenic, Androgenic, or Thyroid Activity – Guidance • New toolkit supports better understanding of the risks of for Industry valproate and pregnancy • Implementation of the “Deemed to be a License” Provision • FDA Advisory Committee recommends approval of first of the Biologics Price Competition and Innovation [BPCI] biosimilar monoclonal antibody (mAb) medication Act – Guidance for Industry • Fusafungine nose and mouth sprays are no longer marketed • Evaluating the Abuse Deterrence of Generic Solid Oral in the EU Opioid Drug Products • Labeling for Biosimilar Products Documents • Safety Considerations for Product Design to Minimize • The Responsible Person [RP] for GDP – Code of Practice Medication Errors – Guidance for Industry • Annex 16: Certification by a Qualified Person and Batch • Comparability Protocols for Human Drugs and Biologics Release Q&As REGULATORY REVIEW 57

Europe pharmaceutical applications. It is nowadays used regularly for the identification and characterisation of material in the laboratory environment. European Directorate for the Quality of Medicines Newer Raman technologies have become available and existing ones have been developed further. Hand-held Potential presence of mutagenic alkyl sulfonates in instruments are now available which are suitable for active substances identification purposes even though requiring different The last of five general methods, elaborated by the Ph. tolerances for the wavenumber scale verification than Eur.’s Mesilate Working Party, were implemented on 1 benchtop models. April 2016 (Supplement 8.7). This working party had been In addition, Raman spectroscopy is increasingly used appointed by the Ph. Eur. Commission in 2008 to assist for process analytical technology (PAT) or for chemical users in determining mutagenic impurities potentially imaging applications. One focus of the revision was, present in mesilate-, besilate- or tosilate- salts of active therefore, to ensure full applicability of the chapter to the substances. In addition to the elaboration of these methods, potential use of this technique in a PAT environment. the Ph. Eur. Commission had also decided to revise the This general revision also covers an update of the production section of the monographs to inform users of reference standards or reagents used for verification of the the risk related to the potential presence of such mutagenic wavenumber scale. impurities. New Ph. Eur. General Chapter (2.8.25) High PDG hosted by US Pharmacopiea (USP) in Rockville, Performance Thin-Layer Chromatography (HPTLC) Maryland, USA, 3–4 November 2015 of Herbal Drugs and Herbal Drug Preparations Twenty nine of the 36 General Chapters and 48 of the 62 This new general method was established to improve the excipient monographs on the current work programme have reproducibility of identification methods and tests on been harmonised. Sign-offs at this meeting include a adulteration by better standardising HPTLC. Together with revision to Uniformity of Content/Mass. In-depth the general chapter, the monographs on Birch leaf (1174), discussions on a number of additional items currently on Roman Chamomile flower (0380), St. John’s wort (1438) the work programme took place with a view to resolving and St. John’s wort dry extract, quantified (1874) were outstanding issues and advancing the items toward sign-off. adopted showing the practical application of the new chapter. To support the user, pictures of sample chromatograms will European Formulary for paediatric medicines: rules be published in the knowledge database showing the natural and criteria approved variability of the herbal drugs and herbal drug extracts. The European Committee on Pharmaceuticals and Pharmaceutical Care (CD-P-PH) adopted the detailed European Commission framework of a project for a European Paediatric Formulary. Delegated Regulation 2016/161 The future online publication will give hospital and The European Parliament and Council has approved and retail pharmacies across Europe easy access to a formulary published this Delegated Regulation in the Official Journal for the preparation of unlicensed formulations of paediatric of the European Union. This supplements the Falsified medicines. Although there have been significant efforts to Medicines Directive (FMD) and introduces two mandatory increase the number of available licensed medicines for safety features that will allow medicines to be verified and children, there is still a shortfall, especially of those authenticated. containing well-known active substances. These safety features comprise of a unique identifier (a The European Paediatric Formulary is intended to 2D data matrix code and human readable information) and provide clinicians and pharmacists with a compilation of tamper-evident features on the pack. appropriate formulations, easily and freely accessible all (For relevance and implementation dates to the UK, see over Europe, in case no appropriate licensed product is MHRA below.) available. It is neither intended to be mandatory, nor to replace, nor hinder the market entry of, licensed products. MHRA Medicines which have been authorised for use in the paediatric population by a regulatory authority and which Delegated Regulation 2016/161 (applicability to UK) are manufactured at an industrial scale are the preferred The delegated regulation comes into force in the UK in 2019. option and the ultimate goal. Marketing authorisation holders will be required to place:

Revised Ph. Eur. General Chapter on Raman • a unique identifier (a 2D data matrix code and human Spectroscopy readable information) on medical products that can be The revised chapter is published in Supplement 8.7 and scanned at fixed points along the supply chain; entered into force on 1 April 2016. The chapter has been • tamper-evident features on the pack. completely rewritten and has been given a new structure. The General Chapter 2.2.48 was first presented in the 4th These safety features on the packaging of medicines which edition of the Ph. Eur. in 2002. Since then, Raman fall within the remit of the delegated regulation must be spectroscopy has received more and more attention in applied in the UK no later than 9 February 2019. 58 REGULATORY REVIEW

First year’s work of the UK stakeholders’ USA reclassification platform The platform has been established by the MHRA to maximise healthcare professional and patient involvement FDA in the reclassification of non-prescription medicines. The MHRA anticipates that this initiative will help to enable Completeness assessments for Type II API DMFs under more medicines to be made available without GDUFA – Guidance for Industry prescription, either as a Pharmacy Medicine (P) or a This guidance is intended for holders of Type II API DMFs General Sales List Medicine (GSL) through increasing that are, or will be referenced in an abbreviated new drug engagement with patients and healthcare professionals in application (ANDA), an amendment to an ANDA, a prior the switch process. approval supplement (PAS) to an ANDA, or an amendment to a PAS (generic drug submissions) under the GDUFA Improvements to the COA process for medicines amendments of 2012. marketing authorisations The MHRA aims to grant all COAs within 42 days. To • DMF holders are required to pay a DMF fee when first facilitate this, the application form now has advice to help authorising the reference of their DMF in a generic fill in the COA form with a revised list of supporting application. documentation. If there are no outstanding issues that result • Type II API DMFs must undergo an FDA CA. in a request for further information, the COA can be granted within 30 days. The guidance makes recommendations about the information that should be included in the DMF to facilitate GDP and GMP a GDUFA CA. The guidance does not apply to Type II API The MHRA has updated its December 2014 Guidance on DMFs used to support new drug applications (NDAs), GDP and GMP and how to prepare for an inspection, which biologics license applications (BLAs), other submissions forms part of its guidance on manufacturing, wholesaling, that are not generic drug submissions, or any other types importing and exporting medicines good practice, of DMFs. inspections and enforcement, and patient safety. Although the requirement for a CA for Type II API DMFs is new, the FDA has previously evaluated DMFs in GDP – qualification of suppliers – the 3 steps needed to accordance with the criteria set out in the GDUFA assure supply chain integrity Completeness Assessment Checklist for Type II API Recently, the MHRA has had a number of situations where DMFs (CA Checklist), In order to ensure adequate time for companies have not understood the obligations placed on the CA, the FDA strongly encourages the DMF holder to them by the Human Medicines Regulations 2012 submit a complete DMF and pay the DMF fee at least 6 Regulation 44 (2) and (3) and Good Distribution Practice months prior to the submission of an ANDA or PAS that in relation to qualification of suppliers. It has, therefore, will rely on the DMF. published a Blog to remind companies of the requirements When submitting a DMF, the DMF holder should also and give tips on ways to ensure the system of qualification submit Form FDA 3794, the Generic Drug User Fee Cover is robust. Sheet, which includes the minimum information necessary for the FDA to determine whether a DMF holder has Government response to the consultation on statutory satisfied all relevant user fee obligations. The CA does not fees for producers of e-cigarette products replace the full scientific review, which determines whether The MHRA has now publicised its response to the the information contained in the DMF is adequate to consultation on statutory fees for these products. The responses to the consultation show that respondents were support an ANDA regulatory action. largely against proposals to introduce statutory fees to The FDA will undertake a CA to determine the cover regulatory activity relating to e-cigarette products. following. Some respondents agreed in principle with the charging of fees but expressed concerns about the impact. New • Is the DMF active? information was provided at consultation that previous • Has the fee been paid? volume estimates had been too low. Based on calculations • Has the DMF been previously reviewed? and estimates provided by industry and trade associations, • Does the DMF pertain to a single API? it is now estimated that the MHRA may expect as many as • Does the DMF contain certain administrative 14,000 notifications in the first year (20 May 2016 to 31 information? March 2017). • Does the DMF contain all the information necessary to Based on the new higher volume estimates provided by enable a scientific review? industry, the fees as proposed at consultation are judged to • Is the DMF written in English? be high and could run the risk of over recovery against costs. Using the new volume estimate, along with an If the DMF passes the CA, it will be found complete and appreciation of the remaining significant uncertainty, it has the DMF number will be made publicly available on the been possible to reduce the fees. FDA’s website. REGULATORY REVIEW 59

Characterization of Ultrahigh Molecular Weight counterparts, including immunogenicity, this guidance Polyethylene (UHMWPE) Used in Orthopedic Devices also provides recommendations on meeting the There are currently three types of UHMWPE materials in requirement for active ingredient sameness for ANDAs wide-spread clinical use in orthopaedics: conventional for LMWHs as well as addressing impurities and their UHMWPE, highly crosslinked UHMWPE, and vitamin E- effect on forming complexes with PF4 and eliciting an containing highly crosslinked UHMWPE. A fourth type, immune response. non-conventional UHMWPE, consists of any other UHMWPE material not currently in widespread use. Environmental Assessment: Q&A Regarding Drugs This draft guidance addresses the characterisation and with Estrogenic, Androgenic, or Thyroid Activity testing of orthopaedic devices that use UHMWPE Guidance for Industry materials. It is applicable to Class II and Class III devices This guidance is intended to supplement the FDA’s intended for orthopaedic applications and outlines the guidance for industry on Environmental Assessment of information the FDA recommends be included in a Human Drug and Biologics Applications, issued in July submission to characterise the UHMWPE material (e.g. 1998 (the EA Guidance), by addressing specific material description, sterility, biocompatibility, mechanical considerations for drugs that have potential estrogenic, properties, and chemical properties). androgenic, or thyroid hormone pathway activity (E, A, or T activity) in the environment. Recommendations to reduce the risk for Zika virus The FDA regulations at 21 CFR part 25 specify that blood transmission in USA Environmental Assessments (EAs) must be submitted as As a safety measure against the emerging Zika virus part of certain NDAs, ANDAs, BLAs, supplements to outbreak, the FDA has issued new recommendations such applications, and investigational new drug suggesting the deferral of individuals from donating blood applications (INDs), as well as for various other actions, if they have been to areas with active Zika virus unless the action qualifies for a categorical exclusion. transmission, potentially have been exposed to the virus, Failure to submit either an EA or a claim of categorical or have had a confirmed Zika virus infection. exclusion is sufficient grounds for the FDA to refuse to file or approve an application (21 CFR 25.15(a), Donor Screening Recommendations to Reduce the Risk 314.101(d)(4), and 601.2(a) and (c)). This guidance of Transmission of Zika Virus by Human Cells, Tissues, focuses on the categorical exclusion for actions on NDAs and Cellular and Tissue-Based Products – Guidance for and NDA supplements that would increase the use of an Industry active moiety, but the estimated concentration of the The FDA has issued new guidance for immediate substance at the point of entry into the aquatic implementation providing recommendations to reduce the environment would be below 1 part per billion. Although potential transmission risk of Zika virus from human cells, an action that qualifies for this exclusion ordinarily does tissues, and cellular and tissue-based products (HCT/Ps). not require an EA, the FDA will require “at least an EA” The guidance addresses donation of HCT/Ps from both if “extraordinary circumstances” indicate that the specific living and deceased donors, including donors of umbilical proposed action (e.g. the approval of the NDA) may cord blood, placenta, or other gestational tissues. significantly affect the quality of the human environment.

Immunogenicity-Related Considerations for Low Implementation of the “Deemed to be a License” Molecular Weight Heparin – Guidance for Industry Provision of the Biologics Price Competition and This guidance discusses immunogenicity-related Innovation Act – Guidance for Industry considerations for LMWH products and finalises the draft This guidance describes the FDA’s approach to guidance published on 9 April 2014. implementation of the provision of the BPCI Act of 2009 Treatment with heparin or LMWH products can be under which an application for a biological product associated with a potentially fatal adverse event, heparin- approved under Section 505 of the Federal Food, Drug, and induced thrombocytopenia (HIT). This occurs when the Cosmetic (FD&C) Act (21 U.S.C. 355) on or before 23 patient produces antibodies to heparin or LMWH in March 2020, will be deemed to be a license for the complex with the hemokine platelet factor (PF4), leading biological product under Section 351 of the Public Health to irreversible aggregation and depletion of blood platelets. Service (PHS) Act (42 U.S.C. 262) on 23 March 2020. In general, clinical trials are used to assess the risk of Specifically, this guidance describes the FDA’s immunogenicity for products approved under original interpretation of the “deemed to be a license” provision NDAs. Clinical trials are also used in some cases to address in Section 7002(e) of the BPCI Act for biological the risk of immunogenicity following post-approval products that have been or will be approved under Section source-material or manufacturing changes for NDAs. 505 of the FD&C Act on or before 23 March 2020. This This guidance discusses an alternative approach that guidance also provides recommendations to sponsors of can be used, once the risk of immunogenicity has been proposed protein products intended for submission in an evaluated through clinical trials in the first instance, to application that may not receive final approval under assess the effect of certain changes (including post- Section 505 of the FD&C Act on or before 23 March approval changes) on the product’s immunogenicity risk. 2020, to facilitate alignment of product development Because it is important that generic versions of LMWHs plans with the FDA’s interpretation of Section 7002(e) of are as safe and effective as their brand name the BPCI Act. 60 REGULATORY REVIEW

Evaluating the Abuse Deterrence of Generic Solid Oral Under FDA regulations, prescription drug labelling must Opioid Drug Products provide adequate information to enable healthcare This draft guidance is intended to assist a potential applicant practitioners to use the drug safely and for the purposes for who plans to develop and submit an ANDA to seek approval which it is intended and, to this end, the approved of a generic version of a solid oral opioid drug product that prescribing information summarises the essential scientific has the potential for abuse and which references an opioid information needed by healthcare practitioners for the safe drug product with abuse-deterrent properties described in its and effective use of a drug. This labelling reflects the labelling. The guidance recommends studies, including FDA’s finding of safety and effectiveness for the drug comparative in vitro studies, which should be conducted by under the labelled conditions of use and facilitates the potential ANDA applicant and submitted to the FDA in prescribing decisions, thereby enabling the safe and an ANDA to demonstrate that a generic solid oral opioid drug effective use of drugs (including biological products) and product is no less abuse-deterrent than its reference listed drug reducing the likelihood of medication errors. (RLD) with respect to all potential routes of abuse. Safety Considerations for Product Design to Minimize Labeling for Biosimilar Products Medication Errors – Guidance for Industry This draft guidance is intended to assist applicants in This guidance focuses on minimising risks associated with developing draft labelling for submission in applications the design of the drug product and its container closure for proposed biosimilar products under Section 351(k) of system, and is the first in a series of three planned the PHS Act (42 U.S.C. 262(k)). The recommendations for guidances to minimise or eliminate hazards contributing to prescription drug labelling in this guidance pertain only to medication errors at the product design stage. The second the prescribing information (commonly referred to as the guidance focuses on minimising risks associated with the package insert), except for recommendations in Section V design of drug product container labels and carton pertaining to FDA-approved patient labelling (e.g. Patient labelling, and the third focuses on minimising risks when Information, Medication Guide, and Instructions for Use). developing and selecting proposed proprietary names. Specific labelling recommendations for interchangeable To avoid safety issues and costly redesigns after a biological products are not provided. product enters the market, it is important to consider the To meet the standard for interchangeability, an applicant end user(s) in their environments of use early in the must provide sufficient information to demonstrate development and design of a drug product. The FDA biosimilarity and also to demonstrate that the biological recommends the use of risk assessments early and product can be expected to produce the same clinical result throughout the development and design of a drug as the reference product in any given patient and, if the product. Identification of clinically relevant biological product is administered more than once to an characteristics of the drug product during development individual, the risk in terms of safety or diminished efficacy will highlight potential areas for risk assessment. Risk of alternating or switching between the use of the biological assessments also are valuable for identifying potential product and the reference product is not greater than the medication errors that may result from post-marketing risk of using the reference product without such alternation changes or additions to an already marketed drug product or switch (see Section 351(k)(4) of the PHS Act). throughout its lifecycle. Interchangeable products may be substituted for the reference product without the intervention of the Comparability Protocols for Human Drugs and prescribing healthcare provider (see Section 351(i)(3) of Biologics the PHS Act). An application submitted under Section This draft guidance provides recommendations to holders 351(k) of the PHS Act must contain, among other things, of applications for human drugs and biologics on information demonstrating that “the biological product is implementing a chemistry, manufacturing, and controls biosimilar to a reference product” based upon data derived post-approval change through the use of a comparability from the following. protocol. It replaces the draft guidance published in February 2003. • Analytical studies that demonstrate that the biological This draft guidance is intended to establish a framework product is highly similar to the reference product to promote continuous improvement in the manufacturing notwithstanding minor differences in clinically inactive of quality products by encouraging applicants to employ components. the following. • Animal studies (including the assessment of toxicity). • A clinical study or studies (including the assessment of • Effective use of knowledge and understanding of the immunogenicity and pharmacokinetics or product and manufacturing process. pharmacodynamics) that are sufficient to demonstrate • A robust control strategy. safety, purity and potency in one or more appropriate • Risk management activities over a product’s lifecycle. conditions of use for which the reference product is • An effective pharmaceutical quality system. licensed and intended to be used and for which licensure is sought for the biological product. Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products The FDA has the discretion to determine that an element This draft guidance provides recommendations to described above is unnecessary in a 351(k) 72 application. facilitate industry’s development and validation of REGULATORY REVIEW 61 immune assays for assessment of the immunogenicity of FDA alerts healthcare professionals not to use sterile therapeutic protein products during clinical trials. drug products from Pharmakon Pharmaceuticals, Inc., Specifically, this document includes guidance regarding Noblesville, Indiana the development and validation of screening assays, The FDA is alerting healthcare professionals not to use any confirmatory assays, titering assays, and neutralisation drug products that are intended to be sterile and are assays. For the purposes of this guidance, produced and distributed nationwide by Pharmakon immunogenicity is defined as the propensity of the Pharmaceuticals Inc. in Noblesville, Indiana, due to a lack therapeutic protein product to generate immune responses of sterility assurance and other quality issues. to itself and to related proteins or to induce The FDA recently inspected Pharmakon’s facility immunologically related adverse clinical events. The following the company’s voluntary recall of super-potent recommendations for assay development and validation morphine sulfate 0.5 mg/mL preservative free in 0.9% provided in this document apply to assays for detection sodium chloride, 1 mL syringe, for intravenous use. The of anti-drug antibody(ies). This draft guidance may also FDA test results showed the product to be nearly 2500 apply to some combination products on a case-by-case percent of the labelled potency. During the inspection, basis. investigators observed insanitary conditions, including poor sterile production practices, and other deficiencies, Contents of a Complete Submission for the Evaluation which raise concerns about Pharmakon’s ability to assure of Proprietary Names – Guidance for Industry the sterility and quality of drug products that it produces. This guidance describes for industry the information that Additionally, the FDA testing confirmed environmental the FDA uses to evaluate proposed proprietary names for contamination on multiple sites within the cleanrooms, certain drugs, including biological products, under the including the critical ISO 5 area. traditional review process within the time frames set out The FDA recommended that Pharmakon cease sterile in Prescription Drug User Fee Act (PDUFA IV) operations until appropriate corrective actions have been performance goals. The review clock for the performance implemented by the facility and recall all non-expired drug review goals begins when the Agency receives a complete products that are intended to be sterile. However, submission. Pharmakon informed the FDA that it would neither initiate Accurate identification of medications is critical to a recall nor cease sterile production. preventing medication errors and potential harm to the public. This guidance is intended to assist industry in the Pharmaceutical distribution supply chain pilot submission of a complete package of information that the projects; request for information FDA will use in the assessment of: The FDA is soliciting information regarding issues related to utilising the product identifier for product tracing, • the safety aspects of a proposed proprietary name to improving the technical capabilities of the supply chain, reduce medication errors; and and identifying system attributes that are necessary to • promotional implications of a proposed proprietary implement the requirements established under the Drug name, to ensure compliance with other requirements for Supply Chain Security Act (DSCSA). The information labelling and promotion using the FDA’s traditional gathered from public comments will assist with the design review methods. and development of the pilot project(s) that the FDA establishes under the DSCSA. As part of its premarket review of products that are the subject of an NDA, BLA, or ANDA, the FDA evaluates Facility definition under Section 503B of the FD&C Act both safety and promotional aspects of the product’s The FDA has received questions from outsourcing facilities proposed proprietary name. For tools and methods the and other stakeholders about the meaning of this term, such FDA uses for its analysis, see the FDA concept paper as whether multiple suites used for compounding human entitled “PDUFA Pilot Project Proprietary Name drugs at a single street address constitute one or multiple Review”. facilities, or whether a single location where human drugs are compounded can be subdivided into separate operations Data Integrity and Compliance with CGMP compounding under different standards. The FDA is The purpose of this draft guidance is to clarify the role of issuing this draft guidance to answer these questions. data integrity in CGMP for drugs, as required in 21 CFR parts 210, 211, and 212. Prescription Requirement Under Section 503A of the In recent years, the FDA has increasingly observed FD&C Act CGMP violations involving data integrity during CGMP This draft guidance describes the FDA’s proposed policies inspections. This is troubling because ensuring data concerning certain prescription requirements for integrity is an important component of industry’s compounding human drug products for identified responsibility to ensure the safety, efficacy, and quality of individual patients under Section 503A of the FD&C Act. drugs. These data integrity-related CGMP violations have It addresses compounding after the receipt of a prescription led to numerous regulatory actions, including warning for an identified individual patient, compounding before letters, import alerts and consent decrees. This draft the receipt of a prescription for an identified individual guidance contains a set of Q&As clarifying FDA patient (anticipatory compounding), and compounding for requirements. office use (or “office stock”). 62 REGULATORY REVIEW

Hospital and Health System Compounding India Pharmacies located within a hospital or standalone pharmacies that are part of a health system frequently Proposal to replace gelatine in capsules provide compounded drug products for administration India’s Central Drugs Standards Organisation is requesting within the hospital or health system. Some of these comment on a proposal for the above. compounders have registered with the FDA as outsourcing facilities under Section 503B of the FD&C Act and others Guidelines on Similar Biologics Regulatory are state-licensed pharmacies subject to Section 503A. This Requirements for Marketing Authorization draft guidance describes how the FDA intends to apply The Guidelines on Similar Biologics: Regulatory Section 503A of the FD&C Act to drugs compounded in Requirements for Marketing Authorization in India, state-licensed hospital or health system pharmacies for use published in 2012, are in the process of revision. within the hospital or health system. Stakeholders were requested to submit their suggestions or comments to the Office of Drugs Controller General (India) FDA approves a second biosimilar by 30 April 2016. The FDA has approved Inflectra (infliximab-dyyb) for multiple indications. Inflectra is administered by WHO intravenous infusion. This is the second biosimilar approved by the FDA. Inflectra is biosimilar to Janssen Prequalification of QCLs for use by UN agencies – Biotech, Inc.’s Remicade (infliximab), which was proposal for change originally licensed in 1998. Recently, there has been a lot of interest in laboratories that belong to or are located or linked to manufacturers making enquiries as to whether or not they should submit expressions International of interest. They have been discouraged after being informed that consideration of their application will not be prioritised. Canada As the number of enquiries has been increasing, yet there is no agreed policy on how to handle them, there is a need for Post-Notice of Compliance (NOC) Changes Guidance a clear public and transparent policy. Accordingly, WHO Document proposes the principal new wording (in italics below) to this This guidance document applies to sponsors intending to Annex 12 of WHO Technical Report Series, No. 961, 2011. make changes to new drugs that have received an NOC pursuant to Section C.08.004 of the Food and Drug • “If, due to insufficient resources and time constraints, Regulations. This may include pharmaceuticals, biologics WHO has to set priorities in the assessment of interested and radiopharmaceuticals for human use and laboratories, then priority will be given to QCLs in areas pharmaceutical, radiopharmaceutical and certain where UN agencies identify the need for testing of the biotechnological products for veterinary use. In the absence quality of pharmaceutical products, and to national of a guidance specific to quality changes to drugs which QCLs and laboratories providing testing services to were approved through a Drug Identification Application – governments. For example, applications from Biologics (DIN-B), the quality guidance document applies laboratories that belong to or are linked to a to those products. This guidance also applies to those manufacturer of pharmaceutical products, particularly submissions for which an NOC has been recommended but those that have an interest to have such products issuance of the NOC has been placed on hold. prequalified or are prequalified, are discouraged and will be given low priority.” China • “WHO may suspend or withdraw a prequalified quality CFDA requires generics to obtain brand-name drug control laboratory from the list of prequalified QCLs quality when there is evidence of non-compliance with the Pharmaceutical companies have been ordered to make sure WHO-recommended quality standards for such the quality and efficacy of their drugs are on par with brand laboratories and/or this procedure. In addition WHO name drugs, a move that aims to improve the nation's pharma may suspend or withdraw a prequalified QCL if the industry. According to a circular issued by the State Council laboratory is considered to no longer serve the General Office, generic drugs already available on the objectives of prequalification including, but not limited market should be assessed on whether they are consistent to, failure to provide regular services to UN agencies with brand name drugs, and if they could be used clinically. and their partners for a continuous period of more than This circular strengthens the previous 2013 three years.” requirements for bioequivalence. It now requires bioequivalence to be determined against the brand name Products version of the generic drug or, should this no longer be available, against an imported, internationally recognised MHRA letter to the Editor of the Sunday Post in generic version. response to article on faulty equipment The MHRA has written to the Editor of the Sunday Post stating that the article ‘Deadly toll of dodgy NHS gear. REGULATORY REVIEW 63

Thousands killed or seriously injured by faulty equipment’ Annex 16: Certification by a Qualified Person and (24 April 2016) is not only misleading but could lead to an Batch Release Q&A increase of concern not just amongst healthcare The EU Guidelines to Good Manufacturing Practice – professionals but also amongst patients. Medicinal Products for Human and Veterinary Use Annex 16 Certification by a Qualified Person and Batch Release New toolkit supports better understanding of the risks was published in October 2015, and came into effect on 15 of valproate and pregnancy April 2016. Maas & Peither have published in their GMP Valproate (Epilim, Depakote and other generic brands) is a Logfile, eight Q&As from an interview by their editor Dr. treatment for epilepsy and bipolar disorder and is prescribed Sabine Paris with GMP Inspector Dr. Rainer Gnibl of to thousands of women. It is associated with a risk of birth Regierung von Oberbayern, Munich (Government of defects and developmental disorders in children born to Upper Bavaria , Munich). These Q&As make interesting women who take valproate during pregnancy. reading and cover topics relating to: Developed in consultation with stakeholders, the toolkit includes a credit card-sized patient card to be issued by • clarity of the Annex, pharmacists, booklets for healthcare professionals and for • globalisation of the supply chain, patients together with a checklist of important questions and • third party audits, discussion points to be kept with the patient’s file. Warnings • imports from third countries, will appear on the medicine’s packaging later this year. • parallel imports/distribution, The MHRA is asking general practitioners, pharmacists, • unexpected deviations. neurologists, psychiatrists, and other relevant healthcare and mental health professionals to use the toolkit to help Further information on these and other topics can be found facilitate discussion of the risks with their patients. in recent versions of the “Regulatory Update” on the PHSS website and on the websites of the relevant regulatory FDA Advisory Committee recommends approval of bodies and international organisations. first biosimilar mAb medication In addition, a list of useful websites can be obtained The FDA’s Arthritis Advisory Committee has voted in from: [email protected] favour of recommending the mAb CT-P13 as a biosimilar. Regulatory review is prepared by Malcolm Holmes, an The reference biologic is Janssen’s Remicade (infliximab). independent consultant with over 40 years’ experience in If finally approved, the biosimilar will be marketed in the senior roles within the pharmaceutical industry. USA by Pfizer.

Fusafungine nose and mouth sprays are no longer marketed in the EU t.01536 403815 The European Medicines Agency’s Pharmacovigilance www.sglab.co.uk Risk Assessment Committee (PRAC) has recommended that the marketing authorisation for fusafungine-containing medicines be revoked, so the medicines can no longer be QUALITY PRODUCTS FOR MICROBIOLOGY marketed in the EU. This follows a review by the PRAC AGARS • BROTHS • REAGENTS • STAINS • BESPOKE MEDIA which concluded that the benefits of fusafungine did not outweigh its risks, particularly the risk of serious allergic reactions. Fusafungine is an antibiotic and anti- inflammatory nose and mouth spray used to treat upper airway infections, such as rhinopharyngitis (common cold). The majority of the serious allergic reactions occurred soon after the use of the medicine and involved bronchospasm (excessive and prolonged contractions of the airway muscles leading to difficulty breathing). Although the PRAC review found that serious allergic reactions are rare, they can be life-threatening, and the PRAC considered that no measures had been identified to sufficiently reduce this risk.

Documents The Responsible Person for GDP – Code of Practice Convenience A Task Force initiated by the European Compliance Academy (ECA) Foundation has developed a guidance you can trust... document which aims to support RPs for GDP. The Code of Practice Version 01 is available on the ECA GDP Group webpage. The document is available at no cost after registration. 4356 European Journal of Parenteral & Pharmaceutical Sciences 2016; 21(2): 64 © 2016 Pharmaceutical and Healthcare Sciences Society

PHSS Activity and Initiatives Report

At the last management meeting of the PHSS, the publication. team reviewed the successes and lessons learned Together with the monographs that are free to from implementing the new PHSS operating download on the PHSS website to members, there strategy, where the focus is on just two major is an increasing pipeline of reviews, GMP conferences per year and the website interaction updates and their impact plus topical discussions, with members offering important reviews, impact e.g. the review of the EU BREXIT impact on the statements and monographs on best practice all as pharmaceutical industry and regulatory free downloads. authorities. We are pleased to report that the initiative is The PHSS continues to move from strength to working well with great conference attendance, strength driven by an experienced and committed increasing PHSS membership and much management team with great support from the improved interaction with members. MHRA on our initiatives in best practice The two major conferences will be diary events guidance in GMP. in June and September. In June, the conference on For the members, the PHSS is now far more challenges in sterile product manufacturing with accessible with value provided by the scientific, risk-based good manufacturing practice (GMP) technical and regulatory communications to keep will be held in the Manchester area. In up-to-date with developments. The free-of- September, the PHSS Annual Conference will be charge conferences are major events attracting held in London at the University College London over 100 attendees providing a great chance for (UCL) School of Pharmacy in association with interaction, networking together along with the the UCL-Q3P course. The PHSS remains open to knowledge exchange from conference reactive hot topic conferences if there is a need to presentations and the regular discussion panel bring important new information to members, e.g. sessions. after the European Union Guidelines to Good Our thanks also go to the conference exhibitors Manufacturing Practice Annex 1 revision is and sponsors who facilitate the free-of-charge released. conferences for members so the not-for-profit There is also an important focus on special constitution of the PHSS can be truly delivered. interest groups to bring key industry and healthcare sectors together to discuss and prepare best practice guidance, typically monographs that are subject to Medicines and Healthcare Products James L Drinkwater Regulatory Agency (MHRA) review before Chairman of the PHSS ON SALE NOW

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over 25 years of advancing pharmaceutical and and best practice guidance: healthcare sciences the pharmaceutical & healthcare sciences society Technical monograph no. 20 Bio-contamination CHARACTERISATION, Bio-contamination RISK PROFILING, CONTROL, MONITORING Technical Monograph No.20 AND DEVIATION MANAGEMENT. Bio-contamination characterisation, control, monitoring and deviation PREPARED BY A PHSS SPECIAL INTEREST GROUP management in controlled / GMP classified areas. FROM THE PHARMACEUTICAL INDUSTRY, NHS, SUPPLIERS AND SPECIALIST CONSULTANTS. REVIEWED BY THE MHRA. APPLIES TO CONTROLLED ENVIRONMENTS IN GMP AND NON STERILE APPLICATIONS WHERE BIOBURDEN CONTROL IS REQUIRED.

Prepared by the PHSS Bio-contamination Special Interest Group

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Section 1. Introduction and scope includes Section 3. Bio-contamination control principles a review of the challenges and requirements and best practice guidance considering Quality for Bio-contamination control and cross by Design, different processes, control attributes, contamination control with a holistic approach background environments and Barrier technologies. to monitoring and proactive investigations in response to increased risk from changes in bio- Section 4. Bio-contamination monitoring including contamination profiles. classical and Rapid Micro Methods (RMM). Section 2. Bio-contamination characterisation Section 5. Bio-contamination Deviation and risk profiling. Methodologies and strategies management including considerations and guidance that profile bio-contamination through in completing investigations and undertaking establishing control, in operations and holistic corrective and preventative actions (CAPA). monitoring. To back order this monograph please go to PHSS Publications on www.phss.co.uk Some things IT’S SAFER INSIDE are better in ... safer plastic inside

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