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European Journal of Parenteral & Pharmaceutical Sciences
2015 Volume 20 Number 4
THE JOURNAL OF THE PHARMACEUTICAL AND HEALTHCARE SCIENCES SOCIETY (PHSS) GROW WITH US
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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
M Gerard Lee & Pharmaceutical Hook, Hampshire, UK Bengt Ljungqvist Chalmers University of Technology, Sciences Gothenburg, Sweden Tim Sizer Southmead Hospital, Westbury-on-Trym, 2015 Volume 20 Number 4 Bristol, UK
MANAGING EDITOR Sue Briggs T: +44 (0)1295 688028 E: [email protected] Contents
PUBLISHER Editorial: Qualified person or quivering person 115 Euromed Communications Passfield Business Centre Liphook, Hampshire GU30 7SB Peer-reviewed Papers T: +44 (0)1428 752222 Assessment of degree of risk from sources of microbial F: +44 (0)1428 752223 E: [email protected] contamination in cleanrooms; 2: Surfaces and liquids 118 www.euromedcommunications.com W Whyte and T Eaton INTERNATIONAL REVIEW BOARD Science and Technology Features Rosamund Baird University of Bath, UK Microbial transfer by surface contact in cleanrooms 128 Stephen Denyer W Whyte and T Eaton University of Brighton, UK Gordon Farquharson Risk-based environmental control and process monitoring in Critical Systems Ltd, UK aseptic processing 133 Michael Jahnke James L Drinkwater and Marc Van Laere Haupt Pharma Wulfing GmbH, Gronau/Leine, Germany Regulatory review 144 David Jones Malcolm Holmes Rapid Micro Biosystems, USA Brian Matthews PHSS activity and initiatives report 152 South Croydon, Surrey, UK Simon McEwen ITH Pharma Ltd, UK Instructions for authors in this issue or from our website: www.euromedcommunications.com Didier Meyer DMCompliance, France Stephen Moss University of Bath, UK Gerry Prout Kennet Bioservices Ltd, Swindon, UK The European Journal of Parenteral & Pharmaceutical Sciences is the quarterly journal of the Pharmaceutical and Berit Reinmuller Healthcare Sciences Society (PHSS). The journal provides a forum for publishing original peer reviewed papers, Chalmers University of Technology, editorials, reviews and science & technology articles on all aspects of pharmaceutical and healthcare sciences. Papers will normally be published within six to nine months of acceptance. Gothenburg, Sweden The European Journal of Parenteral & Pharmaceutical Sciences will also contain articles based on the Kirit Sanghani proceedings of the Confederation’s scientific meetings, symposia and workshops. All submissions are subject to Siemens Healthcare, UK peer review by members of the editorial board and external referees. Advice to contributors is available from the managing editor. The journal is published quarterly and is indexed in Scopus (http://info.scopus.com) and Embase David Sherwood (http://www.embase.com). It is provided free of charge to full and associate members of the PHSS. For non- UCB Group, Slough, UK members the annual subscription is £90 (personal rate) or £180 (institutional rate), plus annual postage costs of £12. Back issues are available at £25 each (abstracts of back issues can be viewed on our website at ADVERTISEMENTS www.euromedcommunications.com). Cheques (drawn on a UK bank) should be made payable to Euromed Allan Andrews 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 Tel +44(0)1428 752222 consent of the author and editor, and the usual acknowl edge ments must be made. Authorisation to photocopy items for Fax: +44(0)1428 752223 internal or personal use is granted by the PHSS. Requests for reprints should be made to the publishers, Euromed E: [email protected] Communications. While all reasonable care has been taken in preparing this journal, neither the publishers nor the PHSS can accept PHARMACEUTICAL AND HEALTHCARE any responsibility for the accuracy of the advice or information contained in the journal. SCIENCES SOCIETY Statements and opinions expressed in the articles and communications herein are those of the author(s) 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 © 2015 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 BYTHETIMEYOUHAVE
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Suitable for sporicidal transfer disinfection due to its short contact time and low residue, Contec ProChlor is a new, innovative, sporicidal biocide specifi cally designed for use in pharmaceutical cleanrooms. Available fi ltered and sterile, Contec ProChlor is one of the fastest acting, cleanroom sporicides available. Contact Contec at [email protected] or by calling 0845 652 2582 to request a sample. www.contecinc.com Use biocides safely. Always read the label and product information before use. European Journal of Parenteral & Pharmaceutical Sciences 2015; 20(4): 115-116 © 2015 Pharmaceutical and Healthcare Sciences Society
Editorial: Qualified person or quivering person
The new Annex 16 guidelines have been issued (12 October Prior to any batch certification and release, the marketing 2015) and come into operation on 15 April 2016 authorisation application contains the QP declaration of the (http://ec.europa.eu/health/files/eudralex/vol-4/v4_an16 API. This document provides a declaration of the GMP _201510_en.pdf). While the directives associated with the compliance of the supply chain, manufacture and testing qualified person (QP) certification have not changed, the associated with the API and, therefore, the product that the competent authorities’ interpretation of the directive have API is used for. become more prescriptive. The requirement to risk assess all drug product excipients The certification and release steps are broken down and comes into force at the same time (March 2016). The batch defined. release certification will mean a verification of this. While all of these aspects were implicit in the previous 1. Document review and approval. version of Annex 16, they were not spelt out in quite so much 2. Certification by the QP designated by signature in register detail. or equivalent. Hence the title of this editorial – the person signing the 3. Transfer of stock from not available to available for sale. register (or equivalent) is ultimately accountable for all stages in the process from start in EU Guidelines to Good While the QP only needs to perform step 2, the marketing Manufacturing Practice Part 2, through EU Guidelines to Good Manufacturing Practice authorisation holder (MAH) certification QP is accountable Part 1, to good distribution practice transfer to saleable stock and the Falsified Medicines for the compliance of all these stages and declares this in the Directive. batch certificate of conformance. While the certifying QP can Even in product manufactured in a single EU have a shared responsibility as in 1.4.2, there is still only one country/single company, there will be people who are not signature on the batch conformance certification. familiar with these requirements and not able to comply easily. Where the MAH delegates stages in the process, such 1.4.2 The QP who performs certification of the as the manufacture of the API intermediate, but this is shared finished product batch may assume full responsibility between companies and/or sites, then the QP is often the one for all stages of manufacture of the batch or this requesting information that is “confidential”, not part of the responsibility may be shared with other QPs who technical agreement or not easily available. The situation can have provided confirmation for specified steps in the become more difficult for a QP who has policy makers manufacture and control of a batch. outside the EU where there are differences in interpretation of the EU guidelines. These differences in interpretation may While other QPs may take responsibility for parts of the make the certification process unworkable for the certifying process, the certifying QP is accountable for verification of QP. Above all, the QP is obliged to follow the QP code of all stages from the manufacture of the intermediate of the practice regardless of company policies. active pharmaceutical ingredient (API) to the transfer of the This annex has been revised for just this multi-site saleable stock. Other highlighted responsibilities are as complex situation which now seems to be the norm. The days follows. have long gone where one site delivers the whole process, long and complex supply chains are now universally used. • Batch certification also includes the certification of More than ever, processes now are subcontracted to transportation and storage of the reference samples used to specialists – API here, drug product there, and secondary test the product. The requirements for samples sent at a packaging somewhere else. Hence, the supply chain maps are different time that the product is impossibly stringent. going to be a vital part of the QPs documentation. In these • All activities within a manufacturing and importation situations, the certifying QP can take into account the authorisation require a QP signature. If the contracted documentation of another QP on another EU manufacturer’s activity is a good manufacturing practice (GMP) activity, license (or Mutual Recognition Agreement license) but still e.g. secondary packaging only, this assembly process remains accountable for the whole process in that everything requires a QP signature. needs to be in place prior to batch certification. 116 Editorial
The only way this can work is through strong quality chain conformance. management systems. These must include reference to The process of one person being accountable for batch the marketing authorisation (MA). This is the first version certification was established in the 1970s when of Annex 16 to explicitly state that the QP needs to have manufacturing of pharmaceutical products was a simple access to the relevant parts of the MA. It has always been national operation. Now, with global supply chains of implicit that if the QP certifies that the product is in such complexity, does it still make sense that one person compliance with the MA then the QP has access to the is accountable for the whole supply chain? The annex MA. Does this need to be the MA or a regulatory affairs raises the question of who is accountable if things go summary of the MA? badly wrong and end up in court. The technical agreements and audits of the API, drug What is absolutely clear is the substantial amount of product and packaging sites need to be focused on both support that the QP(s) needs to be able to fulfil this role. the compliance of the sites to current regulations but also access to documents needed for the Annual Product Review, the Qualified Persons Declaration and supply Kay O’Hagan
Allen Stoddart 1928–2015
It is with sadness that we announce the passing of Allen Stoddart. Allen was a founder member of the Parenteral Society (PHSS) over 33 years ago and was a loyal member for a number of years. Allen was a chemist by training and education, but became an excellent self-taught microbiologist during his 39 years of service with Glaxo (Barnard Castle site) and a very early member of the forerunner to the PHSS, the Parenteral Society. Allen joined Glaxo in 1948 and had numerous roles before joining the microbiology department in 1966. He rose to become the head of department which at its peak had 65 people servicing a multi- product site, a significant portion of which were steriles, of 2000 employees. He was an enthusiastic believer in technical progress and invested in his team to ensure technical excellence and development which was recognised by the company. Outside of work, Allen was an enthusiastic sportsman playing cricket, rugby and golf, and prior to his career with Glaxo he served in the RAF. Allen leaves a wife Laura and two daughters Karen and Diane to whom we wish our condolences. Announcement of George Sykes Memorial Award Winner 2015
We are pleased to announce this year’s winner of George Sykes Memorial Award is:
Viability of microorganisms in novel chemical and biopharmaceutical anticancer drug solutions
Iman Sarakbi, Matteo Federici and Irene Krämer Department of Pharmacy, University Medical Center Mainz, Johannes Gutenberg-University, Mainz, Germany
Abstract Most anticancer drug products used in clinical practice lack antimicrobial properties. Therefore, materials and methods utilised to prepare the parenterally administered preparations must ensure sterility and avoid the introduction of contaminants and the growth of microorganisms. The aim of the study was to evaluate the growth potential of four different microorganisms in diluted ready-to use novel chemical and biopharmaceutical anticancer drug preparations. In three consecutive series, 14 different antineoplastic drugs were diluted to the lowest customary concentrations in polyolefin containers prefilled with 0.9% sodium chloride or 5% dextrose solution. Aliquots (9 mL) of each anticancer drug solution were inoculated with 1 mL suspension of bacteria or fungi (Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa and Candida albicans) to achieve approximately 104 microorganisms per mL. Pure vehicle solutions were used as positive controls in each series. The inoculated preparations were stored at room temperature (22°C) and protected from light. Samples (1 mL) were taken immediately and 1, 3, 5, 24, 48 and 144 hours after inoculation, processed and transferred to tryptic soy agar plates. The plates were incubated at 37°C and the colony-forming units counted after 24 hours. The tested microorganisms remained viable in most of the anticancer drug solutions over a period of 144 hours after inoculation. Trabectedin was the only product generating distinct and rapid antibacterial activity. Viability of C.albicans was not affected by trabectedin, but growth of the fungus was retarded in temsirolimus-containing samples. Nab-paclitaxel suspension supported the growth of the selected bacteria and fungus. Most of the novel anticancer drug products showed neither growth-retarding nor growth-supporting properties. Therefore, in pharmacy departments the anticancer drug products for parenteral administration should be prepared under strict aseptic conditions and refrigerated. Lack of antibacterial and antifungal properties should be considered when assigning extended expiry dates. Attention should be paid to the vulnerability of albumin- containing nab-paclitaxel suspensions to microorganism proliferation.
Congratulations to Iman Sarakbi, Matteo Federici and Irene Krämer! We look forward to receiving the submission of papers for the 2016 award. European Journal of Parenteral & Pharmaceutical Sciences 2015; 20(4): 118-127 © 2015 Pharmaceutical and Healthcare Sciences Society
Assessment of degree of risk from sources of microbial contamination in cleanrooms; 2: Surfaces and liquids W Whyte1 and T Eaton2* 1 James Watt Building South, University of Glasgow, UK 2 AstraZeneca, Macclesfield, UK
The degree of risk from microbial contamination of manufactured products in healthcare cleanrooms has been assessed in a series of three articles. The first article discussed airborne sources, and this second article considers surface contact and liquid sources. A final article will consider all sources and give further information on the application of the risk method. The degree of risk to products from micro-organisms transferred from sources by surface contact, or by liquids, has been assessed by the means of fundamental equations used to calculate the likely number of microbes deposited (NMD) onto, or into, a product. The method calculates the likely product contamination rate from each source and gives a more accurate risk assessment than those presently available. It also allows a direct comparison to be made between microbial transfer by different routes, i.e. surface, liquid and air.
Key words: Risk assessment, degree of risk, source, surface contact, contamination, micro-organisms, microbes, MCPs.
Introduction assessment carried out in this manner may not be accurate, for the following reasons. The requirements for minimising microbial contamination in pharmaceutical cleanrooms are outlined in regulatory • Assigning risk descriptors and risk scores is subjective. documents published by authorities that include the European • The way the risk scores are combined may not reflect the Commission1 and the Food and Drug Administration in the 2 actual mechanism of contamination. USA . These authorities also suggest the use of risk • Differences between the transfer mechanisms of air, management and assessment techniques to identify and 3,4 surface contact and liquid make it difficult for these types control sources of microbial contamination . Risk of risks to be compared. assessment and management methods have been investigated by the authors of this article5–9 and other approaches are 10 It would be beneficial if a risk assessment method was discussed by Mollah et al . available that avoided these short comings, and could calculate Risk assessment methods are used to calculate the degree the contamination rate of products from the various sources in of risk to the product from microbial sources in a cleanroom. a cleanroom. A previous article by Whyte and Eaton11 Factors that influence risk are determined and assigned discussed the application of such a method to airborne sources descriptors of risk, which are of the ‘high’, ‘medium’, and of microbe-carrying particles (MCPs). This article considers ‘low’ type that act as surrogates for actual numerical values. the application of the method to surface and liquid sources. Numerical scores are assigned to these descriptors and the scores combined, usually by multiplication, to obtain a risk assessment for each source of contamination. However, a risk Calculation of microbial deposition onto a product Risk is defined12 as the product of the ‘severity’ (also known as ‘criticality’) of harm and the ‘probability’ of occurrence, *Corresponding author: Tim Eaton, Sterile Manufacturing Specialist, AstraZeneca, UK Operations, Silk Road Business Park, Macclesfield, and its magnitude can be determined by multiplying together Cheshire, SK10 2NA; Email: [email protected]; Tel: +44(0)1625 values assigned to these two variables. 514916. 118 ASSESSMENT OF DEGREE OF RISK FROM SOURCES OF MICROBIAL CONTAMINATION IN CLEANROOMS; 2: SURFACES AND LIQUIDS 119
Equation 1 measured. The proportion of microbes on the donating surface, which are transferred to a receiving surface or Degree of risk = severity of harm × probability of harm product, is known as the transfer coefficient. Whyte and Eaton16 have carried out experiments using skin-derived In the context of microbial contamination of products in a MCPs to obtain transfer coefficients and the following cleanroom, ‘severity’ can be considered as the product of average values were obtained: gloves to stainless steel = the concentration of microbes in, or on, a source of 0.19, stainless steel to stainless steel = 0.10, and clothing to contamination, and the likelihood that these microbes will stainless steel = 0.06. The contact between stainless steel be transferred to a product. The ‘probability’ can usually and glass is between hard surfaces and assumed to have a be considered in (a) airborne contamination as the time the similar value to that between stainless steel and stainless product is exposed to contamination, (b) surface steel. As these coefficients have similar values, and for contamination as the number of contacts, and (c) liquid simplification, a worst case transfer coefficient of 0.2 was contamination as continuous. used in all surface transfers considered in this paper. Fundamental risk factor equations have been derived by Equation 4 can be used to calculate the NMDL from Whyte and Eaton7,11 to calculate the number of microbes that liquid sources. deposit onto, or into, a product from air, surface contact, or liquids. These equations calculate the number of microbes Equation 4; Liquid deposited (NMD) onto, or into, one product unit, and typically give a numerical value well below one. The NMD NMDL = c*p*v in this article uses the format 1 x 10-6 but it can be alternatively given as a product contamination rate of 1 in Where, NMDL = number of liquid-borne microbes 106, or 1 in a million units. It is important to make sure that deposited into a single product, c = concentration of the units of measurement are consistent in the risk equations, microbes in a liquid source, p = transfer coefficient of and those mainly used in this article are centimetres and microbes from source to product, and v = volume of liquid seconds, although metres and seconds are also used. deposited into product. Equation 2 has been derived by Whyte and Eaton7, 11 to calculate the NMDA from air sources. Description of cleanroom studied Equation 2; Airborne In the first article of this series, Whyte and Eaton11 described a method of calculating the NMDA from NMDA = c*p*a*t*sv airborne sources of microbes, and illustrated it with a pharmaceutical cleanroom used to aseptically fill batches Where, NMDA = number of airborne MCPs deposited onto a of pharmaceutical products in a unidirectional air flow single product, c = concentration of microbes in the airborne (UDAF) workstation. The same example will again be source, p = transfer coefficient of MCPs transmitted from used to calculate the NMD from surfaces and liquids. source to product, a = area of product exposed to microbial Cleanrooms that control microbial contamination use a deposition, t = time of exposure to airborne deposition, and variety of designs and manufacturing methods. Increasing sv = settling velocity of MCPs through air. regulatory expectations are leading to designs of pharmaceutical cleanrooms for aseptic filling that include The settling velocity (sv) is the rate that MCPs fall through an isolator or restricted access barrier system (RABS). the air, and has been discussed and used in the previous However, to illustrate the wider application of the risk article11. Microbes do not normally exist in the air as assessment method to more traditional cleanroom designs single cells. They are mainly dispersed on skin particles found in other types of healthcare rooms, the following by personnel and have an average aerodynamic diameter cleanroom and manufacturing method is used as an µ 13,14 of about 12 m , with an average deposition velocity of example. about 0.46 cm/s15. 3 Equation 3 can be used to calculate the NMDSC from 1 Vials are aseptically filled with 2 cm of aqueous surfaces. solution, and sealed with sterile closures. This is carried out in batches of 4000, which take about 4 Equation 3; Surface contact hours to process. 2 Eight litres of an aqueous solution of the active NMDSC = c*p*a*n ingredient is prepared in an adjacent preparation cleanroom and piped from the preparation vessel Where, NMDSC = number of MCPs deposited onto a through a sterilised, sterilising-grade filter, and into single product by surface contact, c = concentration of the filling workstation. An aseptic connection is made MCPs on the surface of a source, p = transfer coefficient in the workstation with the product-filling equipment of MCPs from donating to receiving surface, a = area of before filling starts. contact, and n = number of contacts. 3 The vials are sterilised in a depyrogenation tunnel Equation 3 is used to calculate the NMDSC onto a from which they exit, and are conveyed through a product by surface contact. Much of the information UDAF workstation (EU Guidelines to Good required to solve Equation 3 will be known, or can be Manufacturing Practice (GGMP) Grade A), which is 120 W WHYTE, T EATON
known in this article as the ‘filling workstation’. The solution, and product-contacting surfaces, such as the vials, which have an inner neck area of 2 cm2, are sterile vial closures, storage hopper, forceps, and automatically filled in the filling workstation and track-ways, are sterilised. closed by a stopper. The vials are open in the filling workstation to airborne contamination for 600 s. 4 The filling workstation is situated in a non- Degree of risk from sources of surface unidirectional airflow cleanroom (EU GGMP Grade and liquid microbial contamination in a B) which is known as the ‘filling room’. The filling cleanroom room has a volume of 300 m3 and an air supply of 3.33 Shown in Figure 1 are the main surface and liquid sources m3/s of HEPA-filtered air (40 air changes per hour). of microbial contamination of a product, along with 5 Two people work in the filling cleanroom and one of methods of controlling microbial concentrations and these attends to the filling operation within the transfer. The source of most, if not all, of microbes in a workstation. Access into the filling workstation is cleanroom is people, who are considered the prime source. through plastic-strip curtains that hang round the Also included are sources external to the cleanroom that perimeter and down to just above the floor. may be the cause of contamination in the primary product Interventions may occur when there are problems with and containers. The sources which directly contact product the filling line, and these are normally corrected by are within the UDAF workstation and are known as sterilised long forceps. primary sources. The floor is also included as it is within 6 Vial stoppers are held in a hopper that has a capacity of the workstation, but it is not a primary source, as microbes 1000 stoppers, and replenished every hour. on the floor’s surface are firstly dispersed into the air by 7 Personnel wear cleanroom clothing consisting of a walking, and then transferred by air to product. Also given one-piece polyester coverall with full hood, overboots in Figure 1, for the sake of completeness, are methods of and mask. Sterilised, latex, double sets of gloves are controlling airborne transfer of MCPs to surfaces. worn over disinfected hands. Not shown in Figure 1, or considered in this article, are 8 Hard surfaces, which do not come into contact with the secondary sources, e.g. walls, doors, trolleys, tables, product containers or closures, are disinfected. Hard disinfectant cans, etc., whose surface microbes do not surfaces, such as pipework that contacts the product directly contact the product but do so through an
Figure 1. Risk diagram showing sources of surface and liquid microbial contamination along with control methods. ASSESSMENT OF DEGREE OF RISK FROM SOURCES OF MICROBIAL CONTAMINATION IN CLEANROOMS; 2: SURFACES AND LIQUIDS 121 intermediate vector. These secondary sources are too Gloves numerous to be considered, but are usually less important In the cleanroom example, personnel wear disposable than primary sources as their microbes are subject to an double latex gloves. These gloves have been sterilised additional transfer step associated with an intermediate by gamma radiation and, as demonstrated in Annex A, vector. However, the last vector which contacts the the risk from surface microbes on unused gloves can be product will be one of the primary sources, with gloves the ignored. However, there is a low possibility of skin main one, and the degree of risk can therefore be microbes being on glove surfaces because of indirectly ascertained by a risk assessment of the primary punctures17. Glove surfaces may also be contaminated sources, particularly gloves. when donned, and by touching various surfaces during Should it be thought necessary, the NMDSC from the cleanroom manufacturing activities, as well as secondary sources can be calculated. Equation 2 can be deposition of airborne contamination. Gloves are used to calculate the number of source microbes deposited routinely disinfected during manufacture with sterile onto an intermediate vector surface, and the surface 70% isopropyl alcohol (IPA) to control the level of concentration on the vector can then be used to calculate the surface contamination. Personnel are instructed never to NMDSC onto product. The NMD can also be calculated for contact product with gloves, but it is useful to consider mixed routes of transfer, such as surface contact and liquid what may occur if the vulnerable inner neck area of transfer, or surface contact and air transfer, as demonstrated vials is touched by gloves, and the NMDSC can be in the "Pipework, filling tubes and needles" and the calculated as follows. "Microbial dispersion from cleanroom floor" sections, respectively. The microbial sources shown in Figure 1 are tools, Risk factor Assessment gloves, cleanroom garments, product solution, solution 1. Microbial The post-manufacture measurement of pathways (pipework, filling tubes and needles, etc.), concentration on the microbial concentration of five finger -3 2 containers, and floor, and their degree of risk is now glove surface tips gives an average of 3.9 x 10 /cm . (number/cm2) The five finger tips have a total surface assessed. area of approximately 7.5 cm2, and so the glove surface concentration is -4 2 Tools 5.2 x 10 /cm Sterilised tools include items such as long-length forceps 2. Transfer As discussed in the “Calculation of used to correct product vials that are displaced or fall coefficient microbial deposition onto a product” section, the transfer coefficient between over, and the forceps may contact the product. The tools gloves and vials is assumed to be 0.2, will be sterilised and, as demonstrated in Annex A, the and all contamination transferred enters surface concentration of microbes following sterilisation the product and prior to use is negligible, and can be ignored. 3. Area of contact The area of contact between a single (cm2) glove tip and the inner neck of the vial However, the forceps may be contaminated by airborne was measured and estimated to be deposition, or by touching other contaminated surfaces 0.5 cm2 and, if they contact the vulnerable inner neck of the vial, 4. Number of At worst, the glove tip might accidently microbes may be transferred to product. The NMDSC can contacts contact the internal neck area 1 per be calculated as follows. 4000 containers, which is a frequency of 2.5 x 10-4 Using Equation 2, the NMD can be calculated; Risk factor Assessment SC NMD = c*p*a*n = 5.3 x 10-4 * 0.2 * 0.5 * 2.5 x 10-4 = 1.3 x 10-8 1. Microbial The microbial concentration on sterile SC concentration on surfaces was determined by sampling forceps surface after completion of manufacturing and (number/cm2) will, therefore, represent the worst case concentrations. From 38,062 samples, one microbe was recovered. The Cleanroom garments forceps had a contact area with the Garments are sterilised by radiation prior to use and, as sampling media of 1.2 cm2, which shown in Annex A, they will be effectively free of gives a surface concentration of 2.2 x 10-5/cm2 microbes when unused. However, their surface may be contaminated when donned, touched by contaminated 2. Transfer As discussed in the “Calculation of coefficient microbial deposition onto a product” surfaces during manufacturing, or from microbes section, the transfer coefficient depositing from the air. It is expected that the use of between stainless steel and glass long-length sterilised tools and good aseptic practices surfaces is assumed to be 0.2 will prevent garments contacting product. However, if 3. Area of contact The area of the forceps that makes they accidently contact the vial, it is useful to know the (cm2) contact with the inner neck of the vial was measured and found to be 0.3 cm2 degree of risk, and the NMDSC can be calculated as follows. 4. Number of At worst, the internal neck area is contacts contacted 10 times per 4000 containers, which is a frequency of 2.5 x 10-3
Using Equation 2, the NMDSC is: -5 -3 -9 NMDSC = c*p*a*n = 2.2 x 10 * 0.2 * 0.3 * 2.5 x 10 = 3.3 x 10 122 W WHYTE, T EATON
Risk factor Assessment and needles are decontaminated and steam sterilised at 1. Microbial The forearms and chest of garments are 121°C. The internal surface of all these items prior to concentration on sampled after manufacturing using sterilisation has been determined experimentally to have garment surface RODAC plates and an average 2 -2 2 14 microbes and, as calculated in Annex A1, the number (number/cm) concentration is 2.7 x 10 per 24 cm , -19 which is a concentration of of microbes likely to survive steam sterilisation is 10 . If 1.1 x 10-3/cm2 all of these microbes are washed off the pipework by the 3 2. Transfer As discussed in the “Calculation of passage of 8000 cm of product solution, the concentration -23 coefficient microbial deposition onto a product” of microbes in the product solution will be 1.3 x 10 per section, the transfer coefficient between cm3. Such a low concentration can be ignored. the garment and the vulnerable inner neck area of the vial is assumed to be When the flexible pipe is connected to the filter, or 0.2. All contaminants were assumed to needles fitted into the filling machinery, the opening of a enter the product pipe or needle surface may touch a glove, and microbial 3. Area of contact The area of contact between a garment transfer may occur. Any microbes transferred are assumed 2 (cm) and the vulnerable neck area of the to mix with product solution and be subsequently container was measured and estimate to be about 0.5 cm2 dispensed into the vials. The area of the glove that contacts with the pipework is likely to be different from that of a 4. Number of At worst, the contact of the garment with contact the internal neck area of the container is needle opening. However, to avoid multiple calculations, assumed to be 1 contact per 4000 the area of 0.5 cm2, previously used in the “Gloves” section containers, which is a frequency of -4 when a glove touches vials, is again used. 2.5 x 10 The NMD is calculated in two stages, namely, glove to Using Equation 2, the NMD can be calculated; SC pipework or needles, and then from pipework or needles -3 -4 -8 NMDSC = c*p*a*n = 1.1 x 10 * 0.2 * 0.5 * 2.5 x 10 = 2.8 x 10 to product.
Risk factor Assessment Filtered aqueous product solution The solution of primary product is a potential source of 1. Microbial The post-manufacture measurement of concentration on the microbial concentration of five finger microbial contamination and is filtered through a sterilised, glove surface tips gives an average of 3.9 x 10-3/cm2. sterilising-grade filter of the membrane type. Pre- and post- (number/cm2) The five finger tips have a total surface 2 use integrity testing of the filter is carried out using an area of approximately 7.5 cm , and so the glove surface concentration is automated test unit that measures the rate of diffusive gas 5.2 x 10-4 /cm2 flow. This measurement is directly related to a bacterial 2. Transfer As discussed in the “Calculation of challenge test performed by the filter manufacturer, where coefficient microbial deposition onto a product” the filter is challenged with Brevundimonas diminuta, with section, the transfer coefficient between µ 2 a size of approximately 0.3 m. Filters are required to gloves and pipework or needles is assumed to be 0.2 retain a challenge of 1 x 107 bacteria per cm2 of filter area. 3. Area of contact An area of 0.5 cm2 was assumed The number of microbes deposited (NMDL) in product can (cm2) be calculated as follows. 4. Number of The frequency of contact is unlikely to Risk factor Assessment contacts exceed 1 contact per filling batch of 4000 vials, which is a frequency of 1. Microbial The maximum concentration, prior to 2.5 x 10-4 concentration in sterile filtration, is determined 3 the product experimentally to be 10/cm Using Equation 2, the NMDSC onto the pipe or needle opening solution can be calculated as follows: 3 (number/cm) -4 -4 -8 NMDSC = c*p*a*n = 5.2 x 10 * 0.2 * 0.5 * 2.5 x 10 = 1.3 x 10
2. Transfer The filter has a total filtration area of -8 coefficient 1000 cm2, and required to retain a The calculation in the row above shows that 1.3 x 10 MCPs challenge of 1010 bacteria. The transfer are transferred to the pipe and needle openings and these are coefficient across the filter is, therefore, assumed to enter the product solution. The number that will 1 x10-10. Although there may be enter a product by liquid transfer can now be calculated deposition of microbes throughout the 5. Microbial The product solution passes through the pipework from filter to filling point, this concentration in internal areas of pipework and needles, will be very small compared to the product solution all microbes are assumed to be washed removal efficiency of the filter, and is (number/cm3) and mixed into the product solution, and ignored the concentration in the solution of 3 -8 3 8000 cm is 1.3 x 10 ÷ 8000 = 3. Volume of product 2 cm -12 2 solution dispensed 1.6 x 10/cm 3 into vial (cm ) 6. Transfer All microbes introduced by contact are Using Equation 4, the NMD can be calculated; coefficient assumed to be swept by product L solution into the containers and the -10 -9 NMDL = c*p*vc = 10 * 1 x 10 * 2 = 2.0 x 10 transfer coefficient is 1 7 Volume of product 2 cm3 solution dispensed 3 Pipework, filling tubes and needles into vial (cm)
The product solution is transferred from the sterilising- Using Equation 4, the NMDL can be calculated; grade filter to the filling point through a flexible transfer -12 -12 NMDL = c*p*v = 1.6 x 10 * 1 * 2 = 3.3 x 10 pipe that is connected to filling needles. The flexible pipe ASSESSMENT OF DEGREE OF RISK FROM SOURCES OF MICROBIAL CONTAMINATION IN CLEANROOMS; 2: SURFACES AND LIQUIDS 123
Product vials Risk factor Assessment Following decontamination in an automated washing unit, 1. Concentration of The airborne concentration of MCPs in the vials are transferred to the filling workstation through airborne MCPs the filling cleanroom derived from the -12 3 a depyrogenation tunnel, where they are sterilised. The dispersed from the floor is 6.3 x 10 /cm (see calculation filling cleanroom in Annex B) possibility that microbes can survive within the vial after floor (no/cm3) sterilisation can be calculated using the method given in 2. Transfer The transfer coefficient is assumed to Annex A. coefficient of be 1 x 10-4 The maximum microbial concentration on the inner, MCP from filling product-contacting surface of each vial, following cleanroom to product decontamination and prior to depyrogenation, was 2 determined experimentally to be 10. As calculated in 3. Area of product The inner neck area of vial is 2 cm exposed (cm2) Annex A2, a dry heat sterilisation cycle of 170°C for 2 hours would reduce this to a concentration of about 4. Time of The proportion of time that a person -119 deposition (s) works in the filling workstation is 0.1 of 1 x 10 . However, the depyrogenation cycle uses a the total time, and therefore the time temperature of 250°C for 30 minutes and this additional for the transfer of contamination from heat will decrease the microbial concentration to about 1 the filling room (normally 600 s) is reduced to 60 s x10-300000 per vial. As these microbes are within the vial, and there is no transfer coefficient to be considered, the 5. Deposition The average setting velocity of MCPs -300000 velocity through through the air and into the vial is NMDSC will remain at about 1 x 10 . air of MCPs assumed to be 0.46 cm/s (see the (cm/s) “Calculation of microbial deposition onto a product” section). Microbial dispersion from cleanroom floor The transfer of microbes from cleanroom floor to product Using Equation 1, the NMDA can be calculated to be as follows: -12 -4 occurs in two stages. MCPs are dispersed into the air by NMDA = c*p*a*t*s = 6.3 x 10 * 1 x 10 * 2 * 60 * 0.46 = contact of shoes with the floor, and then transmitted 3.5 x 10-14 through the air to the product, where they may deposit. The concentration of airborne microbes in the air of the filling cleanroom and filling workstation that have been Filling workstation dispersed from a floor is calculated in Annex B, and can In the filling workstation, the mechanism of dispersion of now be used to calculate the NMDA. MCPs from floor to air by walking is the same as the filling cleanroom. However, the walking activity is Filling cleanroom reduced, as is the microbial concentration on the floor, and The concentration of MCPs dispersed into the cleanroom this information is used in Annex B to calculate the air from the floor is calculated in Annex B. Assuming a dispersion rate from the floor. Because of the downward -4 2 microbial concentration on the floor of 1.2 x 10 /cm , and flow of UDAF, the MCPs dispersed from the floor will not two people walking about for half of the total mix with all of the air in the filling workstation, but only manufacturing time, the number of MCPs dispersed into with air close to the floor. The airborne concentration the air in the filling cleanroom is calculated. These MCPs above the floor has been calculated in Annex B to be 2.3 x mix with room air, and the airborne concentration of 10-7/m3 (2.3 x 10-13/cm3). microbes in the filling cleanroom that is derived from the It is now necessary to consider the transfer of the -6 3 floor has been calculated to be 6.3 x 10 /m (6.3 x airborne MCPs from the area near to the floor to vials at -12 3 10 /cm ). the filling location. The experiments carried out by For the airborne MCPs in the filling cleanroom to reach Ljungqvist and Reinmuller18 did not investigate this exact a product, they have to be transmitted across the curtains situation but found that the proportion that reached a and the UDAF within the filling workstation, and closures hopper from the floor area was about 1 x 10-3. It deposited into a container. People may work through the may seem surprising that the proportion of MCPs that curtain, or enter the workstation to attend to containers reaches the closures or vials against the downflow of air and machinery. Movement through the curtain and within may be greater than that transmitted across the airflow the UDAF allows airborne MCPs from the filling (found to be about 1 x 10-4). However, machinery can cleanroom to be transmitted to product. Experiments disrupt the downward airflow and produce a turbulent 18 carried out by Ljungqvist and Reinmuller have shown wake where particles can flow in the opposite direction to the proportion of airborne particles released outside the the overall flow. The transfer of contamination in such workstation that reached the product when personnel were conditions can be complicated, and it is best determined -4 working, was about 1 x 10 ; this proportion is the transfer experimentally in the individual situation. However, it has coefficient. The NMDA dispersed from the floor of the been assumed that in the worst condition, the transfer filling cleanroom and deposited into the vial by the coefficient is 1 x 10-3. airborne route can be calculated as follows. 124 W WHYTE, T EATON
Risk factor Assessment To illustrate the method, a pharmaceutical cleanroom is 1. Concentration of The airborne concentration of MCPs used in which batches of vials are aseptically filled in a airborne MCPs just above the floor that is derived from UDAF workstation. Cleanrooms used for aseptic filling are derived from filling the workstation floor by walking is now being designed with isolators and RABS but the workstation floor 2.3 x 10-13 /cm3 (no/cm3) cleanroom used in the example allows the demonstration of the risk assessment in a wider spectrum of cleanroom 2. Transfer The transfer coefficient is assumed to coefficient of be 1 x 10-3 design and manufacturing methods. However, if a different MCP from around cleanroom or manufacturing process is to be considered, the floor to vial the risk assessment must be carried out for that cleanroom. 3. Area of product The inner neck area of vial is 2 cm2 The equations used to calculate the NMD from exposed (cm2) surface contact or liquids are fundamental, and if the 4. Time of airborne The proportion of time that a person input into the equations is correct then the result will be deposition (s) works in the filling workstation is 0.1 of the total time, and therefore the time for exact. Some of the equations variables (risk factors) will the transfer of contamination from the be known, e.g. the horizontal area of product exposed to filling room (normally 600 s) is reduced airborne contamination, and others may need an to 60 s additional collection of information, such as the 5. Settling velocity The settling velocity through air and into of MCPs through a vial is 0.46 cm/s concentration of MCPs on surfaces and in liquids. The air (cm/s) transfer coefficient is a more difficult variable to ascertain, as information is not readily available. The Using Equation 1, the NMDA can be calculated to be as follows:
-13 -3 values of the airborne transfer coefficient used in this NMDA = c*p*a*t*s = 2.3 x 10 * 1 x 10 * 2 * 60 * 0.46 = 1.3 x 10-14 article are obtained from the results of Ljungvist and Reinmuller18, but we recommend further experiments to extend this knowledge. The surface transfer coefficients are based on our experimental results16, which determined that in the worst case situation the surface Relative importance of sources of transfer coefficient was unlikely to be greater than 0.2. contamination in a typical The values of the transfer coefficients are, therefore, pharmaceutical cleanroom reasonable estimates. However, if the required risk The NMDs from surface contact and liquid routes found variables cannot be obtained, and estimates based on an in the example cleanroom are given in Table 1. informed estimate, the resulting risk assessment is almost certain to be more accurate than a risk assessment based on descriptors and risk scores. Discussion and conclusions It can be seen in Table 1 that the highest degree of The method of ascertaining the degree of risk from risk from surface contact and liquid sources in the sources of microbial contamination in a cleanroom is cleanroom example occurs if the vulnerable area of the carried out by calculating the number of MCPs deposited product is touched by the gloves or garments worn by (NMD) into, or onto, a product by means of equations the cleanroom personnel. Personnel are trained to avoid 11 presented in the introduction. A previous article has such contact but the calculation shows what can occur if considered the degree of risk from airborne sources and mistakes are made, and the NMDSC is in the region of this article ascertains the risk from surface and liquid 10-8, i.e. one product in every 108 may be contaminated sources. by microbes. However, if contact is made with an
Table 1. Importance of sources of surface contact and liquid contamination in a pharmaceutical cleanroom.
Risk importance Source of microbial contamination NMD from surface contact and liquids
-8 1 Contact of product with cleanroom garments* 2.8 x 10
-8 2 Contact of product with double gloves* 1.3 x 10
-9 3 Contact of product with ‘sterile’ tools, e.g. forceps with container neck 3.3 x 10
-9 4 Filtered aqueous product solution 2 x 10
-12 5 Liquid contamination through contact of gloves with pipework and filling needles* 3.3 x 10
-14 6 Floor in the UDAF filling workstation EU GGMP grade A 1.3 x 10
-14 7 Floor in the non-unidirectional airflow filling room EU GGMP grade B 3.5 x 10
-300000 8 Sterilised product containers 1 x 10
*Under normal control conditions, the risk will be much smaller. However, it is useful to determine the degree of risk when normal control measures have been breached and these contamination rates relate to this. ASSESSMENT OF DEGREE OF RISK FROM SOURCES OF MICROBIAL CONTAMINATION IN CLEANROOMS; 2: SURFACES AND LIQUIDS 125 inanimate item, such as a sterilised tool or ancillary 8 Whyte W and Eaton T. Risk Management of Contamination During -9 Manufacturing Operations in Cleanrooms. Parenteral Society item, e.g. forceps, the NMDSC will be about 10 . If the Technical Monograph No 14. Swindon, UK: The Parenteral Society personnel’s gloves make contact with vulnerable areas and The Scottish Society for Contamination Control; 2005. ISBN of pipework or needle assembly, during the set-up of the No. 1-905271-12-3. -12 9 Whyte W. Operating a Cleanroom: Managing the Risk from filling equipment, the NMDSC is likely to be about 10 . Contamination. In: Cleanroom Technology: Fundamentals of When the primary solution of product is filtered by a Design, Testing and Operation, 2nd Edition. Chichester, UK: John Wiley & Sons; 2010, Chapter 16. ISBN 978-0-470-74806-0. single sterilised sterilising grade filter, the NMDL is -9 10 Mollah H, Baseman H and Long M (editors). Risk Management likely to be less than about 10 . The NMD from the Applications in Pharmaceutical and Biopharmaceutical floor in both the filling cleanroom and the filling Manufacturing. Chichester, UK: John Wiley & Sons; 2013. ISBN workstation is negligible and about 10-14. The risk from 978-0-470-55234-6. 11 Whyte W and Eaton T. Assessment of degree of risk from sources of sterilised (depyrogenation cycle) containers is infinitely -300000 microbial contamination in cleanrooms; 1: airborne. European low (1 x 10 ). Journal of Parenteral and Pharmaceutical Science 2015;20(2):52– In a previous article, Whyte and Eaton11 discussed and 62. 12 International Standards Organization. ISO/IEC Guide 51:2014. calculated the NMDA from airborne sources. A further Safety Aspect – Guidelines for their Inclusion in Standards. Geneva, article will consider all sources of microbiological Switzerland: ISO; 2014. contamination in various types of cleanrooms, i.e. those 13 Noble WC, Lidwell OM and Kingston D. The size distribution of airborne particles carrying micro-organisms. Journal of Hygiene transferred by air, surface contact, and liquid routes. Also 1963;61:385–391. discussed will be methods used to reduce the degree of 14 Whyte W and Hejab M. Particle and microbial airborne dispersion risk, where it is considered too high. from people. European Journal of Parenteral and Pharmaceutical Science 2007;12(2):39–46. 15 Whyte W. Sterility assurance and models for assessing airborne bacterial contamination. Journal of Parenteral Science and References Technology 1986;40:188–197. 1 European Commission. EudraLex. The Rules Governing Medicinal 16 Whyte W and Eaton T. Microbial transfer by surface contact in Products in the European Union. Volume 4: EU Guidelines to Good cleanrooms. European Journal of Parenteral and Pharmaceutical Manufacturing Practice – Medicinal Products for Human and Sciences 2015;20(4):128–132. Veterinary Use. Annex 1 – Manufacture of Sterile Medicinal 17 Eaton T. A safe pair of hands – how secure are your gloves used for Products. Brussels, Belgium: European Commission; 2008. aseptically prepared pharmaceutical products? European Journal of 2 Food and Drug Administration. Guidance for Industry: Sterile Drug Parenteral and Pharmaceutical Sciences 2005;10(3):35–42. Products Produced by Aseptic Processing – Current Good 18 Ljungqvist B and Reinmuller B. Chapter 8: Risk assessment with the Manufacturing Practice. Silver Spring, MD, USA: FDA; 2004. LR-method. In: Practical Safety Ventilation in Pharmaceutical and 3 European Commission. EudraLex. The Rules Governing Medicinal Biotech Cleanrooms. Bethesda, MD, USA: PDA; 2006. ISSN: 1- Products in the European Union. Volume 4: EU Guidelines to Good 930114-89-3. Manufacturing Practice – Medicinal Products for Human and 19 Parenteral Drug Association. Validation of Moist Heat Sterilisation Veterinary Use. Annex 20 – Quality Risk Management. Brussels, Processes. PDA Technical Report No. 1 (Revised 2007). Bethesda, Belgium: European Commission; 2009. MD, USA: Parenteral Drug Association. 4 Food and Drug Administration. Pharmaceutical cGMPs for the 21st 20 Parenteral Drug Association. Validation of Dry Heat Processes Used Century – a Risk-Based Approach. Silver Spring, MD, USA: FDA; for Depyrogenation and Sterilization. PDA Technical Report No. 3 September 2004. (Revised 2013). Bethesda, MD, USA: Parenteral Drug Association. 5 Whyte W. A cleanroom contamination control system. European 21 International Organization for Standardization. ISO 11137-2: 2012. Journal of Parenteral Sciences 2002;7(2):55–61. Sterilisation of Health Care Products – Radiation – Part 2: 6 Whyte W and Eaton T. Microbial risk assessment in pharmaceutical Establishing the Sterilization Dose. Geneva, Switzerland: ISO. cleanrooms. European Journal of Parenteral and Pharmaceutical 22 Whyte W, Whyte WM, Blake S and Green G. Dispersion of Sciences 2004;9(1):16–23. microbes from floors when walking in ventilated rooms. 7 Whyte W and Eaton T. Microbiological contamination models for use International Journal of Ventilation 2013;12(3):271–284. in risk assessment during pharmaceutical production. European Journal of Parenteral and Pharmaceutical Sciences 2004;9(1):11–15.
Annex A: Calculation of the reduction of Equation A1 surface microbial concentrations by sterilisation Log B = Log A – (F0 /D) In the main body of this article, it has been assumed that Where, A = number of microbes at the start of sterilisation, surfaces of microbial sources, such as gloves, tools and B = number of microbes at the end of sterilisation, F0 = garments, which are unused and sterilised by steam, dry equivalent exposure time, and D = D-value heat and radiation, have no surface micro-organisms, or such an extremely small number that it will make no The values of F0 and D are ascertained as follows. significant contribution to microbial contamination of product. The justification of this assumption is contained Fo: For steam sterilisation, 121°C is the reference in this annex. With knowledge of sterilisation kinetics, the temperature used to calculate the effectiveness of number of microbes likely to survive sterilisation can be sterilisation at other temperatures, and calculated by calculated for the three sterilisation processes. Equation A2:
Steam sterilisation Equation A2 The number of microbes that survive steam sterilisation 19 can be calculated by means of the following equation . F0 = L x t 126 W WHYTE, T EATON
Where, L = lethal rate, and t = sterilisation time. Where, TO = sterilisation temperature utilised, Tb = base temperature, and Z = z value. At 121°C, the lethal rate (L) has a value of 1 and, therefore, for sterilisation at 121°C for 20 minutes, the F0 The z-value is the temperature coefficient of microbial value is 20 minutes. destruction and is the number of degrees Centigrade required to cause a 10-fold increase in the sterilisation 20 D value: The D-value is the time required, at a specified rate, and is assumed to be 20°C . Utilising a Tb value of temperature, to reduce the microbial population by one 170°C, the lethal rate at 250°C is calculated to be 104. The logarithmic value (90% reduction). The D-value varies FH value for a 30 minute cycle at this temperature is then according to the type of micro-organism but at 121°C, calculated by Equation A4 and found to be 3 x105. Under most microbes die instantly. However, bacterial spores these conditions, the number of surviving microbes in have a much greater thermal resistance, and a D-value of 1 each container can then be calculated using Equation A3. minute is often assumed19. This is a reasonable value, as As an example, if the D-value at a dry heat temperature of spores isolated in cleanrooms are likely to be the 250°C for 1 minute is considered with a microbial mesophilic type that is more susceptible to heat treatment concentration on the internal surface of a vial of 10, the and are likely to be less than 5% of the microflora found in number of surviving organisms is 10-299999. cleanrooms. If appropriate values of F0 and D are used in Equation Radiation sterilisation A1, the number of surviving organisms can be calculated. Cleanroom garments are normally sterilised by gamma For example, if the number of microbes in the internal radiation, using a minimum radiation dose of 25 kGy. The surfaces of pipework and needles is 14, the number of number of microbes on a cleanroom garments prior to surviving microbes is 10-19. sterilisation can be determined by immersing and agitating the garment in liquid, filtering the liquid, and Dry heat sterilisation incubating the filter. A one-piece coverall is the item of The number of microbes remaining after dry heat cleanroom clothing with the largest area and, therefore, sterilisation can be calculated by means of the following the highest bioburden, and shown to have a bioburden equation20. prior to sterilisation of 190 microbes. The radiation dose required to achieve a given Equation A3 sterility assurance level up to 1 x 10-6, for a range of average bioburdens of microbes with a standard Log B = Log A – (FH /D) distribution of resistance against radiation, is given in table 5 of ISO 11137-221. For a bioburden of 190 Where, FH = equivalent exposure time in dry heat. microbes, this is represented graphically in Figure A1. By extrapolation of the graph, it can be seen that the For dry heat sterilisation, 170°C is the reference number of surviving microbes after exposure to 25 kGy temperature from which the effectiveness of sterilisation is approximately 1 x 10-7. As the one-piece coverall has at other temperatures can be calculated by means of an external surface area of about 16,000 cm2, and hence a Equation A4.
Equation A4
FH = L x t
For dry heat sterilisation at 170°C, the lethal rate (L) is 1. Therefore, using Equation A4, the FH value for a cycle of 120 minutes at 170°C is 120. At a dry heat temperature of 170°C, a D-value of 1 minute is assumed20. Using Equation A3, the number of surviving micro-organisms, when the maximum number on the internal surface of an object such as a container is 10, can be calculated to be 10-119. However, containers that are subjected to the depyrogenation conditions of 250°C for 30 minutes will have an increased lethal rate at this temperature that can be calculated from use of Equation A5.
Equation A5 Figure A1. Radiation dose required to achieve a sterility assurance level for an [(To-Tb)/Z] L = 10 average bio-burden of 190, extrapolated for a dose of 25 kGy. ASSESSMENT OF DEGREE OF RISK FROM SOURCES OF MICROBIAL CONTAMINATION IN CLEANROOMS; 2: SURFACES AND LIQUIDS 127 total internal and external area of about 32,000 cm2, the is assumed: two people walk about the filling cleanroom concentration of surviving micro-organisms on the for a proportion of 0.5 of the time, at a rate of 1.5 steps per garment surface can be assumed to be 1 x 10-7 ÷ 32,000 = second, and have shoes with a contact area of 110 cm2 3.1 x 10-12/cm2. (0.011 m2). The redispersion fraction is 0.0012, the air supply rate is 3.33 m3/s, and the floor area is 100 m2 with a microbial surface concentration of 1.2/m2. The airborne Annex B: Number of MCPs dispersed concentration of MCPs in the filling cleanroom in the from cleanroom floor steady-state condition during manufacturing (C) is, To calculate the risk to product from MCPs dispersed by therefore, as follows. personnel walking on a floor, it is necessary to know the concentration of MCPs in the air of a clean zone that are 1.2*0.011 0.0012 2 1.5 0.5 111111111111* * * * -6 3 -12 3 derived from the floor. These are calculated in this annex. C = = 6.3x10 /m = 6.3x10 /cm The number of MCPs dispersed from a floor by 3.33+(0.0046×100) walking has been investigated by Whyte et al22 who showed it to be dependent on the total number of steps per This concentration is used in the “Filling cleanroom” second taken by all of the personnel in the room, the shoe subsection of the “Microbial dispersion from cleanroom area, and the ‘redispersion fraction’ (RF), which is the floor” section to calculate the NMDA when the source is fraction of MCPs on the floor surface that is dispersed by the filling cleanroom floor. one step. The dispersion rate can be calculated as follows. Filling workstation Equation B1 In the filling workstation, the mechanism of dispersion of MCPs from the floor into air is the same as the filling DF = CF x AS x RF x N x W x P cleanroom, and the number of MCPs dispersed per second can also be calculated by Equation B1. However, only one Where, DF = microbial dispersion rate, CF = concentration person attends to the filling line, and spends a smaller of microbes on floor surface, AS = area of shoe in contact proportion of their total time (0.1) working and walking in with floor, RF = redispersion fraction, N = number of the filling workstation. Their walking rate is again 1.5/s people in room, W = walking rate (number of steps/s), and with a shoe area of 0.011 m2. The microbial concentration P = proportion of time spent walking. on the floor of the filling workstation is lower than the filling room, and 0.42/m2. The microbial dispersion rate Knowing the dispersion rate of MCPs from the floor by (DF) is therefore as follows. walking, the airborne concentration of MCPs in both the filling cleanroom and filling workstation can be calculated DF = CF x AS x RF x N x W x P = as follows. 0.42*0.011*0.0012*1*1.5*0.1 = 8.3 x 10-7/s
Filling cleanroom Because of the downward UDAF in the filling When MCPs are dispersed from the cleanroom floor, they workstation, the MCPs dispersed from the floor will not will mix with the air in the non-unidirectional airflow mix with all of the air in the workstation but only with the filling cleanroom to give a reasonably constant air above the floor. The area of the air supply filters is 3 m concentration across the room. The airborne concentration x 3 m, and air is discharged from the filters at a velocity of of MCPs can be calculated by Equation B2 derived by 0.4 m/s; there is, therefore, an air supply volume of Whyte et al22 to take account of dilution by the air supply 3.6 m3/s. As the UDAF does not pass through the floor, the to the cleanroom and the loss by gravitational re- UDAF will change to non-unidirectional airflow above deposition onto the floor. the floor and turbulently mix with the dispersed MCPs. The concentration of MCPs close to the floor can, Equation B2 therefore, be calculated in the steady-state condition by use of Equation B2 but, as the floor area is so small, the 퐷 퐶 퐴 푅 𝑁 푊 푃 Airborne 𝐹 𝐹 푆 𝐹 MCP deposition on the floor area is ignored. 1111 11111111∗ ∗ ∗ ∗ ∗ concentration of = 푄 푉 퐴 = 푄 푉 퐴 3 퐷 퐷 floor-derived MCPs/m +( ∗ ) +( ∗ ) Airborne concentration of floor-derived MCPs close to floor = −7 3 111111111111111microbial dispersion rate from floor/s 11111 8.3 x 10 /s Where, Q is the rate of air supply volume (m /s), VD is the = deposition velocity of MCPs (0.0046 m/s), and A is the air supply volume rate (m3/s) 3.6m3/s deposition area (m2) in the room (normally the floor). = 2.3 x 10-7/m3 = 2.3 x 10-13/cm3 The meaning and the value of the deposition velocity of MCPs, which is 0.0046 m/s, is discussed in Part 1 of these The NMDA is calculated in the “Filling workstation” articles11 and the experiment to determine the redispersion subsection of the “Microbial dispersion from cleanroom factor, which was 0.0012, is described by Whyte et al22. floor” section from this concentration. In the cleanroom example being studied, the following European Journal of Parenteral & Pharmaceutical Sciences 2015; 20(4): 128-132 © 2015 Pharmaceutical and Healthcare Sciences Society
Science and Technology Feature
Microbial transfer by surface contact in cleanrooms W Whyte1 and T Eaton2 1 James Watt Building South, University of Glasgow, UK 2 AstraZeneca, Macclesfield, UK
Experiments were carried out to ascertain the proportion of microbes that would be transferred from a contaminated surface to a receiving surface in a cleanroom. To simulate transfers, microbe-carrying particles (MCPs) were sampled from the skin onto donating sterile surfaces, which were latex gloves, stainless steel and clothing fabric. A contact was made between these surfaces and a sterile receiving surface of stainless steel, and the proportion of MCPs transferred ascertained. The proportion of MCPs transferred, i.e. the transfer coefficient, was 0.19 for gloves, 0.10 for stainless steel, and 0.06 for clothing fabric. These transfer coefficients would vary in different conditions and the reasons are discussed.
Key words: Microbial transfer, surface contact, cleanrooms.
Introduction The MSTC of materials used in hospital metal, and plastic surfaces, were found operating rooms has been investigated to vary from about 0.05 to 0.45. A major route of transfer of microbial 1 by Knobben et al , who showed that contamination in cleanrooms is by Cleanrooms are supplied with filtered they varied according to (a) the type of surface contact. This occurs when a air and there should normally be no microbes, (b) surface properties that contaminated donating surface, such as external source of airborne microbes. a gloved hand, comes into contact with included roughness and hydrophobicity, The main source of airborne microbes a receiving surface, and microbes are (c) whether the contact was dry or moist, is the people in the room who disperse transferred. By this means, microbial and (d) whether the surfaces were microbes carried on skin cells and, to a contamination can be transferred rubbed together or not. Their lesser extent, on particles of clothing between various surfaces, or directly to experiments were carried out on fabric. These are known as microbe- surfaces that were artificially seeded carrying particles (MCPs). Macintosh a product being manufactured in a 2 cleanroom. The proportion of microbes with suspensions of different species of et al studied the dimensions of skin transferred from a donating to a microbes. The transfer coefficients of cells and skin fragments dispersed receiving surface is the microbial contacts that are directly applicable to during activity of people. It was surface transfer coefficient (MSTC) this investigation, i.e. simple dry reported that the outer layer of skin is that is calculated using Equation 1. contacts made between gloves, clothing, made up of cells that have a flake-like shape with a maximum length of about µ 44 m, a minimum length of about Equation 1 µ µ 33 m, and about 4 m thick. These MCPs are dispersed into the air as 1111111111111111111111Concentration of microbes donated to receiving surface MSTC = microbes carried on whole skin cells, or on fragments of cells. The number of Concentration of microbes on donating surface MCPs dispersed varies between individuals, their activity, and the type of clothing they wear, but is in the region of 1–230/s3,4 and account for *Corresponding author: Tim Eaton, Sterile Manufacturing Specialist, AstraZeneca, UK Operations, most, if not all, of the MCPs found in Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA; Email: [email protected]; the air of cleanrooms. Tel: +44(0)1625 514916 MICROBIAL TRANSFER BY SURFACE CONTACT IN CLEANROOMS 129
Due to their size, and the effect of Experimental methods dabber was manufactured in a gravity, MCPs easily deposit from lathe from a solid piece of metal. the air onto surfaces. When The overall approach to these The contact face was then deposited, they firmly adhere to experiments was to contaminate a smoothed and electropolished. surfaces, and are not removed by the donating surface with MCPs from The surface roughness and air currents found within ventilated human skin, and then press the flatness of the contact surfaces rooms, but are transferred by contact surface onto a sterile receiving were measured by a Taylor with surfaces such as gloves. surface. The number of microbes on Hobson TalySurf Form Intra 50 the donating and receiving surfaces by scanning across the two MCPs on surfaces in cleanrooms and was then determined and the transfer diagonals in each dabber. This operating theatres differ in size and coefficient calculated. The transfer showed that the surface shape from the unicellular microbes surfaces used, and the methods of roughness, as measured by the deposited from suspensions and measuring and calculating surface Ra, gave an average distance studied by Knobben. Also, skin has a concentrations and transfer between the peaks and valleys of mixed microbial flora, and surface µ coefficients, are now described. the surface of about 0.15 m. transfers are likely to involve a The flatness across the 28 mm of variety of microbial species. It 2.1 Donating and receiving the two diagonals of each dabber would, therefore, be interesting to surfaces find if the transfer coefficients of was also measured using the MCPs gave similar results to those Metal surfaces Talysurf and the result from one determined by Knobben. In addition, Two types of metal ‘dabbers’ were of the diagonals is shown in we wished to find the values of used as donating and receiving Figure 2; the other three diagonal surface transfer coefficients in the surfaces, and a photograph of these is profiles were very similar. shown in Figure 1. following three situations to advance Figure 2 shows that the flatness our research into the degree of risk (a) The two dabbers in the of the contact surface fell away associated with the various microbial foreground of Figure 1 were about 1.5 mm from the outer 5,6 µ sources in cleanrooms . used to transfer microbes edge, and dropped by about 8 m. a. Contact between a gloved finger, between a latex glove and However, as shown in Figure 2, and a hard surface such as stainless steel, and between two the main part of the surface stainless steel. stainless steel surfaces, and were (about 80%) had a surface in made from 316 L stainless steel. which the peaks and valleys of b. Contact between two hard The contact area was a 2 cm x the surface lay within boundaries surfaces, such as between µ 2 cm square with a thickness of of about 2 m. stainless steel and stainless steel. 3 mm, and the handle was (b) For use with clothing fabric, a c. Contact between clothing, and a 6.5 cm long. To obtain a smooth slightly larger and circular dabber hard surface such as stainless steel. and flat contact surface, the was used, which was easier to wrap, tape, and present an unwrinkled fabric surface. This is shown in the background of Figure 1. It had a round stainless steel surface of 2.5 cm diameter that was 1 cm thick and attached to a handle 8 cm long. When the fabric was fitted to the dabber, the fabric’s surface contact area was 5 cm2. The contact surfaces of the dabbers were placed, prior to the tests, in 70% isopropyl alcohol (IPA). When needed, a dabber was removed and, to finalise the sterilisation and ensure a completely dry surface, the 70% IPA was ‘flamed off’ and the dabber allowed to cool.
Gloved finger The tip of the first finger of a fresh sterile glove was used as the donor Figure 1. Dabbers used for transferring MCPs. surface. The gloves were powder- 130 W WHYTE, T EATON
Figure 2. Surface flatness of a dabber. free latex surgical gloves (Monlycke surface. It has been reported by the donating and receiving surfaces. ‘Biogel’). The roughness (Ra) of the Knobben et al1 that a typical pressure This was carried out by pressing finger of a glove was measured by when people touch a surface is these surfaces onto the surface of the Talysurf Form Intra 50 and found 2 µ 1 kg/cm . However, experiments nutrient agar (Difco TSA) in a Petri to be 1.3 m. carried out with a simple kitchen dish and counting the microbial scale showed that a pressure of 1 kg colonies after incubation. Cleanroom fabric was reasonable but when this If a surface was pressed once onto The cleanroom fabric was a woven pressure was transferred to a surface nutrient agar, the microbial count Selguard polyester fabric used in the of 4 cm2, a pressure of 250 g/cm2 was too variable to be acceptable. manufacture of cleanroom seemed more appropriate, and this To obtain an exact count, sequential garments. The cleanroom fabric was pressure was used. The application pressings would have to continue sterilised prior to the start of the time was 2 seconds. experiments by gamma radiation, until all the MCPs were deposited and its sterility maintained When using a finger, it is not possible on the nutrient agar and a total throughout the tests by careful to reproduce an identical pressure on count from all counts obtained; this aseptic technique and storage in a each experiment. However, would require a large number of sterile plastic bag. variability occurs in normal nutrient agar plates and much situations in a cleanroom, and this tedious work in counting the 2.2 Contact transfer method experimental variability was microbial colonies. An alternative To prepare the stainless steel dabber, considered acceptable. To provide was investigated in which the two latex glove, and clothing fabric confidence in the results, 10 tests methods suggested by Whyte, 7 surface, as a donating surface, they were carried out on each type of Carson and Hambraeus for were contaminated with skin surface contact. obtaining the initial microbial count microbes by rubbing their surface 10 on a surface, were used. These times over the face (cheek) of the 2.3 Measuring the microbial employed either a two, or multiple- person who carried out the concentration on surfaces press, sequential sampling method. experiments (WW). The To calculate the MSTC, it was The former method did not give contaminated surface was then necessary to ascertain the sufficiently accurate results, and the pressed against the sterile receiving concentration of microbes on both latter method could not be used
Table 1. MSTC between different surfaces.
Transfer type Individual transfer coefficients Mean Standard deviation Range
Glove to electropolished stainless 0.29, 0.11, 0.27, 0.24, 0.10, 0.19 0.06 0.10 to steel 0.14, 0.19, 0.18, 0.19, 0.23 0.29
Electroplated stainless steel to 0.15, 0.10, 0.09, 0.10, 0.04, 0.10 0.05 0.03 to electropolished stainless steel 0.06, 0.05, 0.14, 0.03, 0.19 0.19
Clothing to electropolished 0.08, 0.14, 0.04, 0.06, 0.13, 0.06 0.04 0.02 to stainless steel 0.10, 0.05, 0.02, 0.03, 0.03 0.14 MICROBIAL TRANSFER BY SURFACE CONTACT IN CLEANROOMS 131 when there were zero counts. Results cleanrooms, the donor surface was However, it was found that a single rubbed on a person’s face and pressed Table 1 140 mm diameter nutrient agar plate Shown in are the MSTCs against a receiving surface. The could accommodate seven from each individual test result, along microbial concentration on the donor sequential pressings from both the with the mean, median, standard and receiving surfaces were obtained donor and receiving surfaces (total deviation and range of the counts by pressing the surfaces in a of 14 pressings), while still leaving from each type of surface contact. sequential manner onto nutrient agar sufficient space between the contact The difference between the results surface, and ascertaining the total areas to ensure the microbial from the three transfer types were counts. The transfer coefficient was colonies were attributed to the analysed statistically by means of then calculated and the average correct contact area. This method Tukey’s pairwise comparison. This values found to be as follows. was used and a total count from the showed that, at a 95% confidence level, Gloves to stainless steel = 0.19 seven sequential counts from both the glove-to-stainless steel transfer Stainless steel to stainless steel = 0.10 donor and receiving surfaces was results were statistically different from Clothing fabric to stainless steel = 0.06 obtained, and the MSTC calculated. the other two transfer results. However, Knobben et al1 showed that during All nutrient agar plates used to no statistical difference was found between the results of the stainless dry contact with no rubbing, the measure the microbes on the transfer coefficients of glove-to- donating and receiving surfaces steel-to-stainless steel transfers and the clothing fabric-to-stainless steel stainless steel contact were between were incubated at 37ºC and the about 0.3 and 0.5, and in clothing-to- transfers. microbial colonies counted. The hard surfaces were between about commonly accepted maximum 0.10 and 0.15. Our experiments, concentration of microbial colonies Discussion and therefore, gave a transfer coefficient on an agar plate that allows easy and that was approximately half the value 2 conclusions accurate counting is 5/cm . obtained by Knobben. No stainless However, the concentration of The experiments described in this steel-to-stainless steel experiments MCPs on the donor surface had to be article were carried out to ascertain the were reported by Knobben. higher to ensure suitably high counts proportion of microbes that were were obtained on the receiving likely to be transferred from one It was expected that the type of surface surfaces. The acceptable surface to another in a cleanroom, i.e. would influence the transfer concentration on the donating the transfer coefficient. Knobben et coefficient found in the present 1 surfaces was, therefore, increased to al had carried out experiments that experiments and this appears to be 2 correct. The transfer coefficient about 20/cm . To ensure that the showed the transfer coefficient was between latex gloves and metal had colonies did not crowd each other dependent on the type of bacteria, type the highest value, and it was assumed out, a short incubation time of 24 of surface, whether surfaces were that this was caused by the softness of hours was used, and the colonies rubbed together, and whether the the latex glove allowing good contact viewed under good illumination transfer occurred in moist or dry with the stainless steel surface. The with 2.5 magnification. Any conditions. The experiments reported 2 clothing fabric gave the lowest concentrations above 25/cm were in this paper were confined to transfer coefficient. The reason for discarded. The concentration was situations most likely to occur in a 2 this is likely to be caused by the fabric calculated from the 4 cm stainless cleanroom, i.e. dry conditions with no being woven from threads of polyester steel dabber surface, and with the rubbing. The transfers were between and, as the threads are circular, it fabric surface (5 cm2) the count was the following three surfaces (donating would be expected that only a small adjusted proportionally downwards. surface first): (a) latex gloves to surface area would make contact with Also, the area of a glove finger that stainless steel, (b) stainless steel to the stainless steel surface. made contact with the agar surface stainless steel, and (c) clothing to varied and, therefore, the microbial stainless steel. The experiments Hard surface-to-hard surface contacts colonies within an area of 2 cm2 was differed from Knobben’s experiments between different surfaces were likely ascertained and recalculated for in that microbe-carrying skin particles to give a variation in their transfer 4 cm2. were used in place of suspensions of coefficient that would be related to the different species of bacteria. smoothness and overall flatness of the From these donating and receiving surface. The surface of the stainless surface counts, the MSTC was To simulate the naturally-occurring steel used in the experiments was µ calculated as follows: MCPs found in occupied smooth with a Ra of about 0.15 m. The deviation from perfect flatness Equation 2 across about 80% of the surface was shown to vary from the highest to µ 1111111111111111111111 Number of microbes on receiving surface lowest point by no more than 2 m. MSTC = However, if two of these stainless steel Number on donating surface + number remaining on surfaces were pressed together, there receiving surface would be spaces between the two 132 W WHYTE, T EATON
µ surfaces that could be 4 m apart. If the 3. Whyte W and Hejab M. Particle and Acknowledgement microbial airborne dispersion from particles were smaller than this size, as We would like to thank Michael people. European Journal of Parenteral would occur if a microbe was present and Pharmaceutical Science in a unicellular form and, therefore, in Perreur-Lloyd and Liam 2007;12(2):39–46. µ 4. Whyte W. The effect of mechanical the size range of between about 0.5 m Cunningham of the School of µ Physics and Astronomy, University ventilation and clothing on airborne to 2 m, the microbe is less likely to be microbes and wound sepsis in hospital contacted and transferred. However, of Glasgow for carrying out the operating rooms, Part 2. Clean Air and Containment Review 2015;Issue 22:4–11. MCPs carried on skin cells, fragments measurements of roughness and flatness of the stainless steel dabbers. 5. Whyte W and Eaton T. Assessment of of skin cells, or clothing fragments, degree of risk from sources of microbial could be transferred, depending on contamination in cleanrooms; 1: Airborne. European Journal of their size and position on the surfaces. References Parenteral & Pharmaceutical Sciences Although it is not possible to predict 1. Knobben, BA, van der Mei HC, van Horn 2015;20(2):52–62. from the information gathered, what JR and Bussher HJ. Transfer of bacteria 6. Whyte W and Eaton T. Assessment of degree of risk from sources of microbial proportion of the MCPs will be between biomaterial surfaces in the operating room – an experimental study. contamination in cleanrooms; 2: Surface transferred, it is clear that surfaces that Journal of Biomedical Materials and liquid contact. European Journal of are rough and uneven are more likely Research 2007;Part A, 80A:790–799. Parenteral & Pharmaceutical Sciences 2015;20(4):118–127. to give low transfer coefficients. 2. Mackintosh C, Lidwell OM, Towers AG and Marples RR. The dimensions of skin 7. Whyte W, Carson W and Hambraeus A. Transfer experiments were carried out fragments dispersed into the air during Methods for calculating the efficiency of activity. Journal of Hygiene bacterial surface sampling techniques. using MCP concentrations in the 1978;81:471–479. Journal of Hospital Infection region of 5 to 20/cm2, which is higher 1989;13:33–41. than the concentrations found on surfaces in cleanrooms4, which might range from practically sterile to about 0.001/cm2. If the experimental contact surfaces were so dirty that microbes and skin particles were piled on top of t.01536 403815 each other, or were close enough to www.sglab.co.uk influence the transfer, the transfer coefficient might differ from when contamination was sparse. However, QUALITY PRODUCTS FOR MICROBIOLOGY the concentration of MCPs found on AGARS • BROTHS • REAGENTS • STAINS • BESPOKE MEDIA the donating surface, as determined by contact with nutrient agar, was not greater than about 25/cm2 and this appeared too low to have an influence on the transfer coefficient. Also, a microscopic investigation of a slide drawn over the face in the same manner as the contact experiments showed that skin cells were present at a low concentration, and relatively difficult to find on the slide and a distance apart that was unlikely to influence the surface transfer. Although the transfer coefficients found in these experiments were likely to be similar to those found in cleanrooms, to obtain an accurate transfer coefficient it would be necessary to carry out experiments of the type reported in this article. However, consideration of the experimental results, the differences Convenience between the results, and the variables that affect the magnitude of the you can trust... transfer coefficients suggests that a value of 20% could be used as a general transfer coefficient for the types of transfers found in the situations studied in this article. 4356 European Journal of Parenteral & Pharmaceutical Sciences 2015; 20(4): 133-142 © 2015 Pharmaceutical and Healthcare Sciences Society
Science and Technology Feature
Risk-based environmental control and process monitoring in aseptic processing James L Drinkwater1 and Marc Van Laere2 1 Head of Aseptic Processing Technologies and GMP Compliance, F Ziel GmbH, Billerbeck, Germany 2 Mithra Pharmaceuticals Belgium, Liege, Belgium
Risk-based environmental control, delivered by technical and organisational good manufacturing practice (GMP) control measures, are inherently linked to risk-based environmental monitoring (EM) and trend data analysis. Process monitoring is reported as a developing requirement in the revision of the EU Guidelines to Good Manufacturing Practice Annex 1 which combines all EM programs through classification/characterisation, media fills/process simulations, routine EM and batch/shift end surface sampling as one plan. This article considers the control measures for environmental control in different aseptically processed product types together with requirements in risk-based EM.
Key words: Aseptic processing, EU Guidelines to Good Manufacturing Practice Annex 1, process monitoring, environmental monitoring.
Introduction the status of control when appropriate (CQAs) and, by doing so, understand responses can be taken on deviation the risks to product quality and patient Manufacture of sterile medicinal and from the defined control state. Risk- safety in manufacturing. With risks therapeutic products with aseptic based environmental control and understood, risk control measures can processing requires an approach monitoring can be risk assessed via be applied together with monitoring following risk-based initiatives and formats, including the failure modes and detection of deviations that are good practice set out in International and effects analysis (FMEA), but such reported as trend metrics to provide an Conference on Harmonization (ICH) risk assessments needed adapting to ongoing status on control. Q9 and Q10 and associated good meet GMP requirements. As straight forward as these principles manufacturing practice (GMP) Classification is not risk assessed as seem, firms find it difficult to meet guidances. Quality risk management there are set requirements to achieve, risk-based expectations in regulatory (QRM) is based on designing the but all qualification and operational process properly, understanding where requirements with tangible process process stages require risk assessment solutions and supportive risk the weaknesses are, proceeding to to verify the control measures have the assessments. explore those weaknesses and applying outcome that the process can be appropriate control measures (technical operated at low or medium-low risk. There are difficulties often because of and organisational). Medium-high or high risks may new product types, including new biological products that have unique Control measures set out in a control require additional control measures processing challenges with increasing strategy should deliver risk mitigation to mitigate risks to low/medium-low or process design change and requirements for cross-contamination to acceptable levels, recognising all control together with new technologies risks cannot be avoided but can be process improvement (under change control). for manufacturing and environmental assessed and managed so process monitoring (EM), e.g. single operations are at low or medium-low In principle, this is relatively straight use/disposable systems and rapid risk. Control measures are supported forward; understand the process, microbiological methods (RMM). by process monitoring to inform on including critical quality attributes Contamination and cross- *Corresponding author: James L Drinkwater, Chairman of the PHSS and Head of Aseptic Processing contamination control starts with good Technologies and GMP Compliance, F Ziel GmbH, Josef-Suwelack-Str. 20, 48727 Billerbeck, Germany; process design; it is better to engineer a email: [email protected] 134 JAMES L DRINKWATER MARC VAN LAERE
Figure 1. Different types of aseptic processing by product type. solution which does not allow an control with use of separation more consideration to the 1 operator to do something you do not barrier technology – isolators and challenges of processing smaller want them to do, and hence reduce restricted access barrier systems batches with different aseptic the risks of human error. Facilities (RABS). Where cross- processing needs2 leading to should be moving away from designs contamination control is required, multiple products in the same where operator failure is a huge risk this often means a form of facility and a greater emphasis on and exposure of gowned operators, containment is required and this has cross-contamination control. that generate contamination, to led to the increased specification of In processing of bio-products, there processes and potentially sterile isolators over RABS. To manage is a transition through ‘closed system products that may as a result be cross contamination, it is important processing’ where the product is compromised is an unacceptable risk. a product stays within a set process zone boundary with control of inside a closed system, e.g. This article considers some essential material entry and exit to the process fermenter, reactor, etc., into ‘open principles of risk-based zone and it is possible to system processing’ where the environmental control and process decontaminate up to the boundary product is openly exposed to the monitoring to help apply risk control avoiding un-cleanable mechanical Grade A processing environment, measures and EM methods that meet spaces or dead legs in design. Three e.g. during filling open containers. requirements in classification, types of aseptic processing have Although there are still qualification/media fills, routine risk- developed based on different based monitoring and end of product types (see Figure 1). contamination risks in closed system shift/batch or end of aseptic processing, at aseptic connections, • Aseptic processing of sterile processing campaign. sampling interventions and product medicines that are non- transfers, there is a significant hazardous, e.g. pharmaceuticals contamination risk escalation in open Overview of challenges or non-pathogenic biologic system processing. products that require protection Sterile medicinal and therapeutic from contamination in Surrounding environments of closed product efficacy is increased by use manufacturing/filling. systems require some level of of biological ‘delivery systems’, bioburden control and associated • Aseptic: toxic processing of including antibodies and viral monitoring with a much greater sterile medicines including vectors. In addition, some conjugate extent of environmental control and products use a biological delivery cytotoxics that require product protection and operator monitoring applied as risks escalate system for targeted delivery of a when products are open to the Grade toxic component for oncology protection (and possibly cross- contamination) control measures. A environment. The Grade A treatment. Such products require processing environments where aseptic processing as they typically • Aseptic: bio-hazard processing sterile products are exposed require a cannot be terminally sterilised (in the (including biologics, live viruses) high level of control, monitoring and final product container). that require product protection, data trending to provide assurance operator protection and cross- Aseptic processing to meet today’s that the ongoing state of control is as contamination control. regulatory requirements apply the specified and meets required measure of contamination risk As product profiles change, there is regulatory compliance. RISK-BASED ENVIRONMENTAL CONTROL AND PROCESS MONITORING IN ASEPTIC PROCESSING 135
Balancing technical and processing environment for in-leakage and do not fully support organisation control corrective and inherent process patient safety in requirements to interventions including material aseptically process sterile products. measures in sterile transfers into and out of the In addition, unidirectional airflow is product manufacturing separation barrier (isolator or a key GMP control attribute in Grade RABS). Good process design requires a A environments and this is not fully balance between technical and The more sterile products that are consistent with requirements of once organisational control measures to processed in the open format, the through airflow for controlled areas meet requirements of specific higher the risks of exposure to due to the extent of plant required product quality, efficacy and patient contamination. Closed systems may and energy consumption. safety. The approach to sterile include single-use disposable bags, Pharmaceutical ‘containment’ has to product manufacturing should be set product lines and connections that 3 be interpreted with GMP compliance out in a control strategy which forms are assembled/exposed as a sterile so sterile product quality and patient part of GMP requirements. A key system in the Grade A process safety are not compromised. The part of process design is the extent environment. In this case, single-use Pharmaceutical and Healthcare and balance between open system systems require supply chain Sciences Society details a containment processing and closed system management and good aseptic hierarchy in the Bio-contamination processing. technique in assembly. Technical Monograph 20 that Closed system processing is where Requirements in GMP increasingly facilitates balancing containment and sterile products and components are have to be balanced with GMP. Process design also has to take processed in closed containment (Figure 2); balancing account of capacity/product containers/process equipment and control measures provided for throughput, available resources and transfer pathways where risks to operator safety and/or cross- return of investment to ensure the contamination are mainly at aseptic contamination control. Biological process solution is sustainable. connections. safety level containment is typically Technical and organisational control for pathogens where operator and Open system processing is when measures will change to meet environmental protection is sterile products are openly exposed different aseptic processing types. paramount. to the Grade A processing Figure 3 indicates the types of environment. During filling of open Negative pressure enclosures, where technical and organisational systems, there are increased risks of once through air changes are measures that should be considered contaminating a sterile product as a specified for containment and in contamination and cross- result of intrusions into the Grade A operator protection, have potential contamination control.
Figure 2. Balancing control measures. 136 JAMES L DRINKWATER MARC VAN LAERE
Technical control measures Organisation control measures Quality by design: process design combining contamination Pharmaceutical quality system and cross-contamination control attributes with cGMP, product quality and patient safety requirements. QRM
Open or closed system processing Procedures: standard operating procedures – graphical (best practice)
Training: knowledge exchange between vendors and quality assurance/production/operators
Zoning of controlled areas and pressure differential regimes; Dedicated facilities 1) product protection, 2) preventing cross contamination Dedicated equipment (full or part)
Gowning strategy including use of personal protective equipment
Airflow; product protection/containment Shared equipment with cleaning/decontamination between product types and/or batches Barrier technology to separate operators from process/ products: barrier leak integrity Outsourcing/supply chain management
Single-use disposable systems Campaigning of products, e.g. seasonal with cleaning/ decontamination between campaigns Closed material transfers, e.g. rapid transfer port alpha/beta Aseptic/sterile holds for batch production
Material transfers with decontamination step, e.g. vH202 Fast turnaround (short down time) Decontamination processes: cleaning, sterilisation, surface sterilisation, disinfection, chemical decontamination Disaster/major deviation recovery planning
Figure 3. Example of technical and organisational GMP control measures.
Aseptic filling of non- monitoring plates, transferring • Filling zone positive pressure to hazardous products – into/out of the Grade A surround but less positive than processing zone. any additional adjacent Grade A principle requirements isolator modules to provide a • Ready to use (RTU): pre-sterilised • Aseptic processing in barrier containment measure. product containers (vials, syringes isolator technology providing or cartridges) may enter the Grade • At container exit from the Grade A/International A filling zone via de-bagger/no- isolator, an ‘active’ mouse hole Organization of Standardization touch-transfer (NTT) systems4 may be required to contain air (ISO) 5 controlled environments using a combination of pressure discharge and prevent isolator air with integrated risk-based EM differentials and aerodynamic mixing with the surrounding systems and data trending systems. protection contamination control environment. • Cleanroom background measures. Such technology can • An external surface product environment to isolator barrier replace other methods that require container washer/ Grade C (best practice) for ‘open a decontamination step of the decontamination system may be processing’ of pharmaceutical outer surfaces of the container required to prevent contamination products. Filling zone positive ‘tubs’, e.g. ebeam. spread into the downstream areas. pressure to surround. • Cleanroom HVAC configured for • Cleanroom heating, ventilation Aseptic filling of toxic part recirculation and fresh air and air-conditioning (HVAC) exchange. Terminal high- configured for part recirculation (cytotoxic) products – efficiency particulate air (HEPA) and fresh air exchange. principle requirements filters required at the room air • Aseptic processing in barrier • Isolator air-handling system may supply and (depending on risks) isolator technology providing be configured for part at the barrier wall exhaust. Grade A/ISO 5 controlled recirculation and air exchange environments with integrated • Isolator air-handling system that can take air from the risk-based EM systems. configured for part recirculation surrounding environment and and air exchange: air supply can discharge back to the same • Barrier leak integrity applied to be taken from surrounding environment. all zones. environment (or dedicated air • Secure/non-contaminating closed • Cleanroom – isolator background handling unit (AHU)) and vent material transfer devices required environment: Grade C for ‘open discharge must be ducted to for all process support materials, processing’ of pharmaceutical outside via double HEPA including environmental products. filtration with safe change bag- RISK-BASED ENVIRONMENTAL CONTROL AND PROCESS MONITORING IN ASEPTIC PROCESSING 137
in/bag-out filters on primary configured for part recirculation to Industry Sterile Drug Products containment boundary. and air exchange to meet Grade A Produced by Aseptic Processing – requirements for aseptic Current Good Manufacturing • Secure ‘closed’ material transfer processing, in the case of aseptic Practice. devices required for all process filling biological safety cabinets support materials (including EM) For classification, total particulate would not be considered good entering and leaving the Grade A levels are defined for a one cubic practice. processing zone. metre sample at each monitoring • Secure ‘closed’ material transfer • RTU: pre-sterilised containers location. Not to exceed cfu levels are devices required for all process may enter the Grade A filling set for each zone class with the active support materials entering and environment via de-bagger/NTT air (volumetric) measure of one cubic leaving the Grade A process device together with additional metre and settle plates per 4 hour zone. isolator modules (each side of fill maximum exposure together with zone) to provide a higher pressure • Isolator air supply can be taken contact plates (colonies per plate). differential hence containment. from surrounding environment (or ISO14644-1/2 indicates the amount dedicated AHU) and vent of minimum sample locations based • Clean-in-place systems required discharge ducted to outside via on unit area. for barrier/equipment surfaces double ULPA/HEPA filtration: For monitoring in pharmaceutical that become contaminated during safe change bag-in/bag-out filters processing with waste control facilities for total particulate inside on primary containment boundary Grade A zones, continuous monitoring measures applied for all filters. Clean-decontamination in- contaminated waste. is required and, to maintain a better place systems provided for picture of environmental status, data is • Gaseous vaporised hydrogen primary containment boundary of processed over one cubic foot sample peroxide (vH202) surface isolator and enclosed equipment. sizes with continuous run charts that decontamination used for isolator • RTU: pre-sterilised containers consider a ‘rolling’ one cubic metre of barrier, non-contact machine may enter the Grade A filling results. surfaces, surface sterilisation of environment via de-bagger/NTT Microbiological monitoring has stopper bowls/guides, packaging device together with additional known limitations in both recovery difficult to manually disinfect. isolator modules (each side of fill and sample size considering the zone) to provide a high pressure small proportion of actual air volume barrier so air flows into Grade A Aseptic filling of bio- processed or surface area sampled of and isolator buffer zone (without hazard products (including the controlled zone and associated mixing). 5 biologics/live viruses) – equipment . To provide a fuller principle requirements • Gaseous vH202 surface picture of contamination control decontamination to be used for status, trend data from sample • Aseptic processing in barrier isolator barrier, non-contact programs are required. isolator technology providing machine surfaces, surface Grade A/ISO 5 controlled sterilisation of stopper Trend metrics may include incidence environments with integrated bowls/guides and packaging rates above alert and action levels in risk-based EM systems. difficult to manually disinfect. an EM program, incidences of out of specification deviations, e.g. • Cleanroom background Gaseous vH202 may also be recurring alarms indicating the environment to isolator barrier: specified for environmental viral process does not have robust control, Grade C for ‘open processing’ of clearance if required. and out of trend deviations. pharmaceutical products – best practice cGMP. Risk-based environmental There is a necessity to monitor critical control parameters (CCPs) • Cleanroom HVAC configured for classification and and detect with appropriate response once through air exchange with monitoring – overview to any deviations. Today CCPs and terminal HEPA filters at In principle, we classify EM are combined to provide process cleanroom barrier air supply and environmental control by ‘total monitoring. Environmental process double exhaust filters with particulate’ levels of two reference monitoring may include (but not primary exhaust barrier filter of µ particle sizes in Europe of 0.5 m and restricted to) the following. ultra-low penetration air (ULPA) µ µ 5.0 m, and only 0.5 m for USA grade, considering biological • Environmental Food and Drug Administration safety requirements. There is a pressures/differentials. (FDA) requirements together with requirement to balance monitoring colony forming unit (cfu) • Airflows/velocities that support containment with cGMP without microbiological levels to not exceed unidirectional flows. compromise to patient safety or levels/limits set out in the EU product quality. • Temperatures. Guidelines to Good Manufacturing • Isolator air-handling system Practice Annex 1 and FDA Guidance • Humidity. 138 JAMES L DRINKWATER MARC VAN LAERE
Figure 4. Relationship of sampling points.
• Isolator and glove leak integrity at-risk locations, e.g. open product an activity (operators entering gloves monitoring. containers or filled product. during aseptic processing) to capture any particles that may deposit as a • Environmental risk-based Sample locations need to be set result of the activity, or 2) monitor monitoring. between the possible contamination the air flow that has passed over a source and the at-risk location. This • RABS open door access critical surface then over the plate to sounds basic but it is surprising how monitoring. capture microbe carrying particles many times these basics are not that may deposit if challenged. A In the clean air environments of considered or applied. good example would be a feeder Grade A inside isolator barriers, it is bowl where a settle plate cannot be highly unlikely there is homogeneous positioned inside the bowl during distribution of contamination such Positioning settle plates processing but the airflow that that a single sample location will To define risk-based sample exits/overspills from the bowl can be represent generally the locations, a review of the process monitored via a settle plate. contamination status of the zone. flows are required together with any Typically, unidirectional down- potential intervention into the barrier flow ‘first-air’ is protective system, inherent or corrective. There Active air sampling providing a clean column of air that also has to be an assessment of air Active air sampling is required at the is delivered via HEPA filters and air movements and possibility of commencement of set-up for diffuser screens with the first carrying a contamination source to a production operations to provide contact of the air being the critical point at risk, e.g. exposed product or evidence that the starting conditions surfaces, e.g. product containers open container before filling. Such were compliant. Depending on the and product (see Figure 4). In assessment of air movements require length of the production period, it monitoring, it is important to smoke studies that may include may also be useful to undertake control or detect any compromise of visualisation studies or a active air sampling during processing the ‘first-air’ that would put critical combination of smoke as a particle and at shift or day ends so no surfaces or products at risk of challenge and particle counter to extended periods of operation are at contamination. monitor particle movements, e.g. risk of non-compliant monitoring 4 limitational risk method . Such data that would require investigation Risk-based sample locations are studies are essential when verifying if later found to deviate outside discussed in literature and in specific positioning of settle plates. specified or regulatory levels. terms this means sample locations take consideration from possible Settle plate positioning can be Active air samplers need to monitor generation/sources of contamination considered in two ways: 1) position at-risk locations at positions of and the pathway from the source to plate in a possible pathway between activity inside isolators as a result of RISK-BASED ENVIRONMENTAL CONTROL AND PROCESS MONITORING IN ASEPTIC PROCESSING 139 operator glove access. Additional needles at the end of batch production zone. There are two principle tub active air sampling may be specified is considered good practice. transfer methodologies5. during media fills to assess operator If in-process surface sampling is 1) Outer tub surface decontamination interactions either under barrier required, defined by risk assessment, method, e.g. ebeam or plasma conditions in isolators or particularly growth media contact plates are before entry into Grade A de- in justified open barrier door replaced by non-contaminating lidding/filling zones. In principle, interventions of RABS. End of swabs that have been qualified for tubs are removed from the shift/campaign active air sampling is recovery at least equal to that of protective bag and exposed to the best practice in all cases to verify contact plates. Grade C (or D minimum) continued state of control. background environment before loading into the ebeam where the Risk-based environmental Contact plates, finger process requires tub outer surfaces control – example: pre- to be exposed to the prints (dabs) and swabs sterilised container tub decontamination process. As the Surface sampling is something that is transfer into filling zone outer tub surfaces are firstly completed at the end of a One of the key challenges in risk- exposed to a lower grade batch/campaign as, generally, the based environmental control is the background environment by sampling process contaminates transfer of materials in and out of a default, a decontamination step is surfaces and is difficult to recover controlled area. required before transfer to Grade (unacceptable risk) during A zones. processing. Swabs are used on An example is that increasingly pre- 2) An alternative de-bagging/NTT complex surface shapes that are not sterilised containers in tubs are being method prevents the sterile tub suitable for surface plate sampling. used in syringe, vial and cartridge formats, that require tub and nested outer surface from contamination In isolators, it is typically acceptable container transfer into Grade A zones with protective Grade A air supply to only sample finger prints for gloves starting with a de-lidding zone where at bag opening and transfer from that have been used in production. In the tub Tyvek lid cover is removed the de-bagging zone into the de- aseptic filling, the swabbing of before transfer into a Grade A filling lidding Grade A zone. This method
Figure 5. De-bagging/NTT process steps. 140 JAMES L DRINKWATER MARC VAN LAERE
EM sampling plan qualification stage Risk-based EM sampling plans Characterisation at start up and classification at rest (operation qualification). EM sampling plans and associated Performance qualification (PQ) in establishing environmental control: setting of sample locations are process simulation/media fills (PQ) required through different qualification and production stages Routine EM in operation risk-based sampling locations: EM results and deviation (see Figure 6). There may be more incidence rates trended sample locations in characterisation and classification to fully assess a End of batch/campaign EM including surface sampling (trended) controlled area but, when it comes to routine monitoring, sampling should be reduced to key risk areas as the Figure 6. Processing monitoring: combined monitoring. process of sampling can in fact be a risk in its own right so ‘over sampling’ has more risk than benefit. requires pre-sterilised containers to room where the filler in a RABS is be sterilised (ethylene oxide or installed. moist heat) as an assembly of Sterile product filling using open Setting sample locations Tyvek sealed tub and two closed system aseptic processing in isolator A full review of process flows and steri-bags as protective layers. barriers would, following best associated risks of contamination of As no decontamination step is practice, have a Grade C background critical points is required to study 6 applied in the NTT method on entry environment . Typically starting sampling positions as ‘risk based’ of the pre-sterilised containers into with double bagged tubs with both through a Failure Modes and the Grade A filling zone, the protective steri-bags remaining in- Effects Analysis (FMEA) risk sterilised containers–tub–steri bags place on entry to the Grade C filling assessment process. Clear diagrams unit requires supply chain room where bagged tub transfer (see Figure 7) are needed of sample management and risk-control includes a manual wipe disinfection locations categorised by sample measures that apply as soon as the at transfer from a Grade D method/type. Such diagrams should bagged units are removed from the environment through a material indicate the path open product carton packaging, typically in a transfer hatch into the Grade C filling containers take and where operators facility warehouse. Control measures room. interact with the barrier system, including the isolator surrounding apply through the de-bagging Stepwise de-bagging is then environment where operators are process in risk-control steps that completed in two steps with the present. prevent outer tub surfaces to become following possible combinations. contaminated and protect pre- The Grade C barrier surrounding 1) First de-bag manual under sterilised containers and the filling environment needs monitoring to unidirectional Grade A air supply zone from exposure to understand the extent of bioburden plus second de-bagging using contamination. that is challenging the barrier. With NTT in Grade B zone with measurable cfu in these Depending on whether the barrier protective Grade A air supply at environments, it is possible to be separation technology used in aseptic bag opening and NTT through a proactive if contamination levels process filling is a RABS or isolator, mouse hole to the next Grade A increase or microflora profiles different de-bagging/NTT steps may zone. apply. change and before the Grade A areas 2) First de-bag with semi-automatic are potentially contaminated hence Sterile product filling using open de-bagger/NTT and second de- avoiding very difficult root cause system aseptic processing in RABS bag via fully automated NTT. investigations. Sampling barriers would require a minimum As the de-bagging step is essentially frequencies and when should be background environment of Grade defined in risk-based EM programs B/ISO 7. In open system closed system processing because the tub remains closed (via Tyvek cover) that together form the processing, the sterile containers in handling and transfer, the de- environmental contamination are openly exposed to the Grade A bagging RABS can be specified with control plan. zone where containers are handled a Grade C background environment and filled. hence compatible with the aseptic Perspective on use of Starting with double bagged tubs, a filling isolator. Figure 5 shows the first de-bag step includes a manual final de-bagging step and NTT to RMM in risk-based EM wipe disinfection as single bagged prevent outer sterile tub surfaces Real-time microbiological tubs are transferred from a Grade C becoming contaminated before monitoring technology is environment through a material transfer into the Grade A de-lidding considered the future for transfer hatch into the Grade B filling and filling zones. monitoring systems in isolators, but RISK-BASED ENVIRONMENTAL CONTROL AND PROCESS MONITORING IN ASEPTIC PROCESSING 141
Figure 7. Aseptic filling of syringes: diagrammatic example of syringe filling isolator and EM sample sites. they are still at the development and supply. This support area would be Trend metrics provide a more evaluation stage. considered appropriate for such complete picture on the status of contamination control in the Differentiation between non- RMM-RT technology to take manufacturing environments but biological fluorescing materials and advantage of the intervention-free today we also have to consider cross- actual bio-counts is a current area of operation. By use in production contamination control measures that development to manage the issue of operations without the conflict of are often a combination of equipment ‘over reporting’ contamination with batch record data handling, and facility design that together false counts. Full RMM experience can be gained over a time provide a process solution. implementation will require period of operation and not just in technical developments, but also qualification/application study. EM trend data is only as good as the there will need to be regulatory sampling plans and programs and it is recognition of the two very different essential monitoring locations take a data forms of bio-counts, as Summary risk-based perspective. In the clean electronic data and cfus derived from Risk-based initiatives improve environments of isolators, it is classification growth-based patient safety and product quality, important to consider process flows, methods. but the potential is only realised with operator and machine interactions which have the potential as a RMM real-time (RMM-RT) EM implementation of good process contamination source as a result of a data is currently challenged if design and practical control measures deviation event. associated with batch records as that combine to meet requirements increased bio-count recovery may for processing different product types Separation barrier technology confuse compliance to not to exceed and methods of aseptic processing. It (isolators and RABS) are not a cfu levels. As the RMM-RT EM comes down to a fundamental barrier to all combinations so risk- technology is developing maturity, it understanding of the product and based control and monitoring is a may be worth considering processing type and risk control pre-requisite to provide the necessary applications like the Grade B pre- measures, technical and assurance of sterility that products sterilised container tub de-bagging organisational, applied with sound are not compromised during aseptic zone that is protected by Grade A air science and good practice. process/manufacturing. 142 JAMES L DRINKWATER MARC VAN LAERE
Applying risk control measures that 5. Drinkwater JL, Novak W and Cecchetto References A. Transfer of read-to-use sterilised manage contamination risks to 1. Drinkwater JL. Next generation of product primary packaging containers and prevent contaminating sterile isolator barrier technology for aseptic single-use systems into small batch filling container tubs facilitates use of filling. Presentation at the ISPE 24th systems in isolators. European Journal of Annual Aseptic Processing Technologies Parenteral and Pharmaceutical Sciences material transfer solutions that Conference: Cost Saving Solutions to 2015;20(1):23–31. maintain the sterile tub state (inside Solve Quality Concerns, Baltimore, MD, 6. Pharmaceutical and Healthcare Sciences and outside) without use of a surface USA; 23–24 February 2015. Society Bio-contamination Special Interest 2. Novak W. Developments in aseptic filling Group (reviewed by the MHRA). PHSS bio-contamination step during in- of parenterals. Presentation at the PDA Bio-contamination Technical Monograph process transfers. Alternatively, if Europe Conference on Parenteral 20. Swindon, UK: PHSS; September 2014. outer packaging requires removal Manufacturing, Istanbul, Turkey; 25–26 June 2014. and is exposed to a lower 3. Drinkwater JL. Control strategy. classification clean area then an in- European Pharmaceutical Review process surface decontamination step 2014;19(5). 4. Ljungqvist B and Reinmuller B. The LR is required, e.g. ebeam, before entry method in critical areas – airflow patterns to Grade A zones for aseptic and the design of aseptic interventions. processing. Pharmaceutical Technology 2004;28(7): 46–54.
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A comprehensive review
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 management in controlled / GMP PREPARED BY A PHSS SPECIAL INTEREST GROUP 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
Overview of content PRICE: Members £125 / Non members £175
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 European Journal of Parenteral & Pharmaceutical Sciences 2015; 20(4): 144-151 © 2015 Pharmaceutical and Healthcare Sciences Society
Regulatory Review
Introduction disease • Pharmacovigilance inspection report Several of the changes in USA regulations relate to the ongoing situation of the Food and Drug Administration’s (FDA’s) control over compounding pharmacies. In the USA “Products” section of this edition we report on yet another • Formal Dispute Resolution: Appeals Above the Division instance of lack of sterility assurance of products from one of these pharmacies. We also note the suspension of a drug Level product and a separate facility suspension of a CE certificate • Q3D Elemental Impurities (see “Products” section for both occurrences) for all medical • Nonproprietary Naming of Biological Products devices from that facility. Both suspensions were due to good • Acceptability of Draft Labeling to Support ANDA manufacturing practice (GMP) issues. [abbreviated new drug application] Approval – Guidance Readers will also note that the publication of EU Guidelines for Industry to Good Manufacturing Practice Annex 16 (Certification by a • Maintenance procedures for the guidance for industry Q3C Qualified Person [QP] and Batch Release) has finally been impurities – residual solvents published and comes into force on 15 April 2016. • Integrated Summary of Effectiveness – Guidance for Industry Europe • Adverse Event Reporting for Outsourcing Facilities • Pharmacy Compounding of Human Drug Products Under • European Commission (EC), European Medicines Agency Section 503A of the Federal Food, Drug, and Cosmetic (EMA) and World Health Organization (WHO) step up [FD&C] Act cooperation to better protect global public health • Interim Policy on Compounding Using Bulk Drug • Implementing Act on Principles and Guidelines on GMP for Medicinal Products for Human Use Substances Under Section 503A and 503B of the Federal • Annex 16 – Certification by a Qualified Person and Batch Food, Drug, and Cosmetic Act – Guidance for Industry Release • United Sates Pharmacopeia (USP) visual inspection of • European Directorate for the Quality of Medicines (EDQM) injections (Pharmacopeial Forum 41(6) In-Process webinar on glass containers for pharmaceutical use Revision: <1790>) • Webinar on how to prepare a successful certificate of • <1039> Chemometrics In-Process Revision suitability (CEP) application • Organ-Specific Warnings: Internal Analgesic, Antipyretic, • CEP – content of the dossier for chemical purity and and Antirheumatic Drug Products for Over-the-Counter microbiological quality Human Use – Labeling for Products that Contain • European Pharmacopoeia (Ph. Eur.) Elemental Impurities: Acetaminophen [paracetamol] Clarification for Products Outside the Scope of the ICH • Formal meetings between the FDA and biosimilar [International Conference on Harmonisation) Q3D biological product sponsors or applicants Guideline • Certification Process for Designated Medical Gases • New edition of Technical Guide for the Elaboration of Monographs • Safer use of medicines by preventing medication errors International • New strategy to fight antimicrobial resistance • Replacement of good clinical practice (GCP) non-compliant Pharmaceutical Inspection Cooperation Scheme pivotal studies in centralised marketing authorisation applications not accepted (PIC/S) • GMP Q&A supply chain for active substances • Revision of PIC/S GMP Guide • Quality of medicines Q&A – variations • 2015 PIC/S Seminar, Indonesia • Electronic application forms (eAFs) mandatory for all • Croatia (Agency for Medicinal Products and Medical medicines licensing from the beginning of 2016 Devices of Croatia (HALMED)) joins PIC/S • Medicines and Healthcare Products Regulatory Agency (MHRA) signs Memorandum of Understanding (MOU) WHO with its counterpart body in India • Guidance on Good Data and Record Management Practices • Optimising the presentation of medicines for Alzheimer's – Draft for Comment REGULATORY REVIEW 145
Products 536/2014 and a new implementing directive on principles and guidelines of GMP for medicinal products for human • CE certificate for all medical devices made by Brazilian use with the first paragraph of Article 47 of Directive manufacturer Silimed suspended 2001/83/EC as its legal basis. • Re-scheduling of codeine products (Australia) • EMA fast-tracks antidote to anticoagulant Pradaxa Annex 16 – Certification by a Qualified Person and • New EU guidance to speed up development of Batch Release antibiotics This annex has been revised to reflect the globalisation • Human papilloma virus (HPV) vaccines – EMA review of the pharmaceutical supply chains and the introduction • Inductos to be suspended in the EU of new quality control strategies. The revision has been • First oncolytic immunotherapy medicine recommended carried out in the light of Directive 2011/62/EU for approval amending Directive 2001/83/EC as regards the • Drug Products Intended to be Sterile by Chen Shwezin prevention of the entry into the legal supply chain of Inc. falsified medicinal products. This version also implements ICH Q8, Q9 and Q10 documents, and Europe interpretation documents, such as the manufacturing and importation authorisation (MIA) interpretation document, as applicable. Also, some areas, where the EC interpretation by Member States has not been consistent, EC, EMA and WHO step up cooperation to better have been clarified. The deadline for coming into protect global public health operation is 15 April 2016. The EC and the EMA have agreed with the WHO to share certain non-public information on the safety, quality and EDQM efficacy of medicines already authorised or under review Free webinar on glass containers for pharmaceutical in the European Union (EU), or pre-qualified or under review by the WHO. use Under the confidentiality arrangement, the organisations This EDQM webinar offered an excellent opportunity to involved may share information such as the following. learn more about the revision of the Eur. Ph. General Chapter on Glass Containers for Pharmaceutical Use, • Post-authorisation pharmacovigilance data, particularly published in July 2014. Compared to the previous version, related to adverse drug reactions, as well as safety this text contains a section on how to deal with the concerns arising from periodic safety update reports, delamination phenomenon. In addition, the text has been and post-authorisation obligations and commitments. revised to be in line with International Organization for • Information in applications for scientific advice, orphan Standardization (ISO) 4802-1 and 4802-2, and more details medicine designation, marketing authorisation or post- for the performance of the hydrolytic resistance test have authorisation activities of significant public health been added. Now that experience has been obtained by interest, and applications for agreement of paediatric users, and since the EDQM always aims to improve its investigation plans. texts, the general text on glass containers for • Data related to inspections, manufacturing facilities and pharmaceutical use is under revision again in order to deal clinical research activities and related reports. more explicitly with certain aspects in the hydrolytic resistance test. This strengthened cooperation started on 1 September 2015. How to prepare a successful CEP application On 26 November 2015, the EDQM Division of Implementing Act on Principles and Guidelines on Certification of Substances (DCEP) organised a webinar GMP for Medicinal Products for Human Use for manufacturers, CEP holders and other interested parties The sole purpose of this consultation is to collect views, on the topic of “how to prepare a successful CEP relevant evidence and information from stakeholders to application” for chemical purity. help the EC develop its thinking in this area. The webinar focused on best practices in preparing the Regulation (EU) No 536/2014 of the European documentation (common technical document (CTD) Parliament and of the Council on Clinical Trials on dossier) for a CEP application and how to avoid common Medicinal Products for Human Use, and repealing errors in submission or dossier set up. There were also Directive 2001/20/EC requires that the EC adopt delegated details on how to respond to requests for additional acts to specify the principles and guidelines of GMP and information and how to/where to place the information in the detailed arrangements for inspection for ensuring the the dossier. The webinar focused on different sections of quality of investigational medicinal products. It is, the CTD and provided guidance in the form of examples therefore, necessary that Directive 2003/94/EC is repealed or common misunderstandings, and how to minimise those and replaced by a delegated act on principles and mistakes. The goal of this webinar is to help applicants guidelines of GMP for investigational medicinal products reduce common errors and obtain faster approval in with its legal basis as Article 63(1) of Regulation (EU) No granting of the CEP. 146 REGULATORY REVIEW
CEP – content of the dossier for chemical purity and assessed. The goal is to improve reporting and to learn from microbiological quality medication errors for the benefit of public health. The This document is intended for applicants as a guide for second part of the guide clarifies key principles of risk compiling a dossier that is suitable for evaluation for a management planning in relation to medication errors. It CEP. A new CEP application should contain three modules describes the main sources and types of medication errors (Modules 1–3). Module 1 should contain a cover letter, and proposes options to minimise the risk of medication correctly filled application form including relevant errors throughout the lifespan of a medicine. declarations and information on the expert (i.e. CV). The guide was released for public consultation from 14 Module 2 (Quality Overall Summary (QOS)) should be April 2015 to 14 June 2015. It is one of the key deliverables prepared preferably by using the EDQM template for the of the EMA/Heads of Medicines Agencies (HMA) joint QOS. Module 3 should be structured according to the CTD action plan on medication errors agreed in 2013. as defined by ICH guidance documentation (ICH M4 Organisation of the Common Technical Document for the New strategy to fight antimicrobial resistance Registration of a Pharmaceutical for Human Use). The EMA has released for public consultation a new Note – the new guidance is applicable immediately. It strategy on antimicrobials which has been adopted by its takes account of the increased requirements of newly Committee for Veterinary Medicinal Products (CVMP). published and revised ICH and EU guidelines. CEP The strategy, recognising that antimicrobial resistance is a applicants should ensure compliance with these new global problem affecting both animal and human health, requirements. Failure to do so could result in the sets clear objectives based on a 'One Health' approach to application being considered deficient. help combat the threat of resistance which may arise from the use of antimicrobials in animals. Ph. Eur. Elemental Impurities: Clarification for This draft strategy sets out the CVMP’s course of action Products Outside the Scope of the ICH Q3D Guideline for the next 5 years, with a vision to promote the For products outside the scope of the ICH Q3D guideline, availability of effective antimicrobials for the treatment of such as products for veterinary use, the absence of important infectious diseases of animals while, at the same elemental impurities (including heavy metals) tests from time, minimising risks to animals or humans arising from an individual monograph on a substance used for their their use. production does not release manufacturers from the need to control the level of such elements in their products, Replacement of GCP non-compliant pivotal studies in where relevant. centralised marketing authorisation applications not accepted New edition of the Technical Guide for the Elaboration The EMA will not accept the replacement of a pivotal of Monographs clinical study that has been found to be non-compliant with At its 152nd session, the Ph. Eur. Commission approved GCP by another study during the assessment of a the publication of a new edition of the Technical Guide for centralised marketing authorisation application. This the Elaboration of Monographs. This guide is an essential position aims to reinforce the application of GCP during tool for the drafting of monographs but also for the the conduct of clinical trials by applicants. transposition of analytical techniques and parameters into a pharmacopoeial method. It helps to ensure a high level GMP Q&A supply chain for active substances of harmonisation throughout the texts of the Ph. Eur., The EMA has recently added a Q&A related to written by the experts of the different groups. documentation and verification of the supply chain for active substances that indicates the following. Safer use of medicines by preventing medication errors The EMA has published a good practice guide on • The supply chain for each active substance must be medication errors to improve the reporting, evaluation and established back to the manufacture of the active prevention of medication errors by regulatory authorities substance starting materials. This should be documented and the pharmaceutical industry throughout the EU. In and must be kept current. parallel, the EMA has launched a webpage highlighting • The risks associated with this supply chain should be measures recommended by the agency to prevent formally documented. medication errors for specific medicines. • Control of each incoming consignment of active Medication errors can occur for many reasons at the substance should include verification that it has been time of prescribing, dispensing, storing, preparation or received from the approved supplier and approved administration of a medicine. It is estimated that, among manufacturer. hospitalised patients, 18.7% to 56% of adverse events are • The entire supply chain should be verified for a supplied caused by medication errors. batch periodically to establish a documented trail for the This good practice guide on medication errors batch back to the manufacturer(s) of the active complements the Guideline on Good Pharmacovigilance substance starting materials. The frequency of this Practices (GVP) and other existing guidelines published verification should be based on risk. by the agency. It consists of two parts: the first part details how suspected adverse reactions that are caused by Quality of medicines Q&A – variations medication errors should be recorded, coded, reported and This Q&A relates to medicines manufactured via complex REGULATORY REVIEW 147 processes. In particular, it relates to such manufacture in USA respect of FDA • change in batch size of finished product; • change or addition of a site of manufacture. Formal Dispute Resolution: Appeals Above the Division Level It is noted that, where relevant, if a change is submitted as This draft guidance provides recommendations for industry a type IB variation, it is up to the applicant to provide and review staff on the procedures in the Center for Drug adequate justification for not considering a manufacturing Evaluation and Research (CDER) and the Center for process as a ‘complex’ one. However, under the safeguard Biologics Evaluation and Research (CBER) for resolving clause, it should be noted that if the supplied justification scientific and/or medical disputes that cannot be resolved is not accepted, it is possible for the competent authority at the division level. It revises the draft guidance for to upgrade the submission to a type II variation during the industry and review staff Formal Dispute Resolution: validation phase. Appeals Above the Division Level issued in March 2013. This revision expands the scope of the guidance to include MHRA Formal Dispute Resolution Requests (FDRRs) for human drug applications covered under the Biosimilar User Fee eAFs mandatory for all medicines licensing from the Act of 2012. Additionally, certain areas were revised to beginning of 2016 provide more clarity, such as when a matter is and is not It has been mandatory to submit applications using eAFs appropriate for an FDRR, and information to include in the for marketing authorisations through the centralised supporting background information. Also, this guidance procedure from 1 July 2015. It will become mandatory for clarifies that the CDER and the CBER intend to manage all other procedure types, including national procedures, formal requests for appeals of scientific and/or medical disputes related to an application for a user fee product from the beginning of 2016. All other MHRA submission under any of the available regulatory mechanisms requirements remain unchanged. processes. MOU with MHRA’s counterpart body in India Q3D Elemental Impurities This agreement will increase collaboration between the two There are three parts of this final guidance: countries in the area of medicines and medical devices with the aim of further improving public safety in the two • the evaluation of the toxicity data for potential elemental countries. This is the first MOU agreed with the Central impurities; Drugs Standard Control Organisation (CDSCO), part of the • the establishment of a permitted daily exposure (PDE) Ministry of Health and Family Welfare of Republic of for each element of toxicological concern; India. The central understandings of the agreement include • application of a risk-based approach to control promotion of each other’s regulatory frameworks, elemental impurities in drug products. requirements and processes. Significant outcomes will include the facilitation and exchange of information and An applicant is not expected to tighten the limits based on opportunities for technical cooperation of mutual benefit, process capability, provided that the elemental impurities helping to ensure the regulators are better equipped to in drug products do not exceed the PDEs. The PDEs protect the health of their respective publics. established in this guidance are considered to be protective of public health for all patient populations. In some cases, Optimising the presentation of medicines for lower levels of elemental impurities may be warranted Alzheimer's disease when levels below toxicity thresholds have been shown to The MHRA is working with the pharmaceutical industry have an impact on other quality attributes of the drug to optimise the way medicines for the treatment of product (e.g. element catalysed degradation of drug substances). In addition, for elements with high PDEs, Alzheimer’s disease are presented. All these medicines will other limits may have to be considered from a include the days of the week clearly on the blister packs. pharmaceutical quality perspective and other guidances This small but important change may enable patients to should be consulted (e.g. ICH Q3A). retain independence in taking their medicines. It could have the added effect of aiding compliance with dosage Nonproprietary Naming of Biological Products regimens and ultimately maximising the efficacy of This draft guidance describes the FDA’s current thinking treatment for patients. on the need for biological products licensed under the The MHRA expects that the improved packaging will Public Health Service (PHS) Act to bear a non- be introduced from June 2016. proprietary name that includes an FDA-designated suffix. The FDA’s current thinking is that shared non- Pharmacovigilance inspection report proprietary names are not appropriate for all biological The MHRA has published this report covering the period products. There is a need to clearly identify biological April 2014–March 2015. products to improve pharmacovigilance and, for the 148 REGULATORY REVIEW purposes of safe use, to clearly differentiate among Integrated Summary of Effectiveness – Guidance for biological products that have not been determined to be Industry interchangeable. This procedural guidance describes the recommended Accordingly, for all biological products, the FDA content of the integrated summary of effectiveness (ISE) intends to designate a non-proprietary name that includes for inclusion in a new drug application (NDA) or biologics a suffix composed of four lower case letters. Each suffix license application (BLA). Although there are no will be incorporated in the non-proprietary name of the regulations requiring an ISE for BLA submissions, product. This naming convention is applicable to applicants are encouraged to provide an ISE because it biological products previously licensed and newly represents an opportunity to present a coherent analysis and licensed under Section 351(a) of the PHS Act or 351(k) presentation of the drug’s benefits. of the PHS Act, as added by the Biologics Price The guidance supercedes Section II.G. of the existing Competition and Innovation Act of 2009. The non- Guideline for the Format and Content of the Clinical and proprietary name designated for originator biological Statistical Sections of an Application. It also incorporates products, related biological products, and biosimilar the conceptual framework of Section 2.7.3, Summary of products will include a unique suffix. However, as Clinical Efficacy, from the ICH guidance for industry M4E discussed in Section IV.C of this guidance, the FDA is (The CTD – Efficacy). seeking comment on whether the non-proprietary name for an interchangeable product should include a unique Adverse Event Reporting for Outsourcing Facilities suffix, or should share the same suffix as its reference This final guidance explains the FDA’s current thinking on product. By differentiating among biological products adverse event reporting for outsourcing facilities. It is that have not been determined to be interchangeable, the intended for firms that have registered with the FDA under goal of this naming convention is to help minimise Section 503B of the FD&C Act as human drug inadvertent substitution. compounding outsourcing facilities (outsourcing facilities). Under Section 503B(b)(5) of the FD&C Act, an Inadvertent substitution may lead to unintended outsourcing facility must submit adverse event reports to alternating or switching of biological products that have the FDA “in accordance with the content and format not been determined by the FDA to be interchangeable. requirements established through guidance or regulation This naming convention may also facilitate under Section 310.305 of title 21, Code of Federal pharmacovigilance for multiple biological products Regulations (or any successor regulations)”. containing related drug substances when other means to track a specific dispensed product are not readily Pharmacy Compounding of Human Drug Products accessible, as described in Section III.B.2 of this guidance. Under Section 503A of the FD&C Act – Guidance Application of the naming convention to all biological This final guidance announces the FDA’s intention with products is intended to (1) encourage routine use of regard to enforcement of Section 503A of the FD&C Act designated suffixes in ordering, prescribing, dispensing, (21 U.S.C. 353a) to regulate entities that compound drugs, and record keeping practices, and (2) avoid inaccurate now that Section 503A has been amended by Congress to perceptions of the safety and effectiveness of biological remove the advertising and solicitation provisions that were products based on their licensure pathway, as described in held unconstitutional by the U.S. Supreme Court in 2002. detail in this guidance. Several parts of Section 503A require rulemaking and consultation with a Pharmacy Compounding Advisory Acceptability of Draft Labeling to Support ANDA Committee to implement. This guidance explains how the Approval – Guidance for Industry provisions will be applied pending those consultations and The FDA is implementing this guidance for immediate rulemaking. It also describes some of the possible implementation, without prior public comment because it enforcement actions the FDA can bring against individuals has determined that prior public participation is not feasible or firms that compound drugs in violation of the FD&C or appropriate. The guidance presents a less burdensome Act. policy. This guidance is intended to assist applicants submitting Interim Policy on Compounding Using Bulk Drug ANDAs under Section 505(j) of the Act to the Office of Substances Under Section 503A and 503B of the Generic Drugs (OGD) in the CDER. It explains the FDA’s Federal Food, Drug, and Cosmetic Act – Guidance for interpretation of the regulatory provision related to the Industry submission of copies of applicants’ proposed labelling in Section 503A of the FD&C Act includes certain restrictions ANDAs and clarifies that the OGD will accept draft on the bulk drug substances that can be used in labelling and does not require the submission of final compounding and directs the FDA to develop a list of bulk printed labelling in order to approve an ANDA. drug substances that can be used in compounding under that section. Maintenance procedures for the guidance for industry The FDA is developing this list of bulk drug substances Q3C impurities – residual solvents (the 503A bulks list), and this guidance describes the The FDA notes and draws attention to the fact that the ICH FDA’s interim regulatory policy for licensed pharmacists has developed maintenance procedures for revising the in State-licensed pharmacies and Federal facilities, and also PDE of solvents included in the Q3C guidance. for licensed physicians that compound human drug REGULATORY REVIEW 149 products using bulk drug substances while the list is being products intended to be submitted under 351(k) of the developed. PHS Act. This guidance does not apply to meetings A similar interim policy is proposed for compounding associated with NDAs or ANDAs under Section 505 of using bulk drug substances under Section 503B. the FD&C Act or to BLAs under Section 351(a) of the PHS Act. This guidance discusses the principles of good meeting USP visual inspection of injections (USP management practices and describes standardised Pharmacopoeial Forum 41(6) In-Process Revision: procedures for requesting, preparing, scheduling, <1790>) conducting, and documenting such formal meetings. The General Chapters–Dosage Forms Expert Committee proposes this new chapter to provide guidance Certification process for designated medical gases on the inspection of injectable drug products for visible Title XI, Subtitle B of the FDA Safety and Innovation particles. The methods discussed are also applicable to Act added Sections 575 and 576 to the FD&C Act, detection of other visible defects that may affect container creating a new certification process for approval of integrity or cosmetic appearance of the product. designated medical gases. Section 575 defines “designated medical gas” to include oxygen, nitrogen, USP<1039> Chemometrics In-Process Revision nitrous oxide, carbon dioxide, helium, carbon monoxide, The purpose of this new general chapter is to summarise and medical air, that meet the standards set forth in an and incorporate, into one document, the concepts and official compendium. practices of chemometrics, which are emerging in the Section 576 permits any person to file a request for pharmaceutical industry and the relevant fields. The certification of a medical gas as a designated medical gas concepts of chemometrics span the areas of chemical for certain indications specified in the statute. A designated analysis and physical analysis of drugs, excipients, dietary medical gas for which a certification is granted is deemed supplements, and food ingredients. This chapter is an to have in effect an approved marketing application under above-1000 guidance that describes the best practices for Section 505 of the FD&C Act (human drugs), Section 512 incorporation of chemometric models into the lifecycle of of the FD&C Act (animal drugs), or both, depending on the analytical procedure. Key concepts, such as method the type of certification requested and granted. development, validation, and maintenance of these models, This guidance explains how the FDA administers the are described, and an overview of relevant tools and certification process. Specifically, the draft guidance applications is provided. discusses what products qualify as designated medical Organ-Specific Warnings: Internal Analgesic, gases, who should submit a certification request, what Antipyretic, and Antirheumatic Drug Products for information should be submitted, how the FDA will Over-the-Counter Human Use – Labeling for Products evaluate and act on the request, and how the FDA plans to that Contain Acetaminophen [paracetamol] – Guidance enforce these new medical gas provisions. for Industry This guidance is intended to inform manufacturers of International certain non-prescription (OTC) internal analgesic, antipyretic, and anti-rheumatic drug products that contain acetaminophen of the circumstances in which the FDA PIC/S does not intend to object to the inclusion of a liver warning that differs from that required under § 201.326(a)(1)(iii)(A) Revision of PIC/S GMP Guide and § 201.326(a)(1)(v)(A) (21 CFR 201.326 (a)(1)(iii)(A) The PIC/S Guide to Good Manufacturing Practice for and 21 CFR 201.326(a)(1)(v)(A)), provided the warning Medicinal Products (PE 009-12) has been revised to appears as described in the guidance. incorporate revised Annex 15 and entered into force on 1 The FDA believes that this alternative language should October 2015. eliminate the potential confusion described and help ensure appropriate dosing of OTC acetaminophen-containing 2015 PIC/S Seminar, Indonesia products, while also informing consumers that using more This seminar on “How to inspect biopharmaceuticals”, than the currently proposed maximum daily dose of 4000 which took place on 7–9 October was open to regulators mg of acetaminophen for adults may result in severe liver only. The objectives of the 2.5 day seminar were to discuss damage. and update inspectors on GMP principles and requirements specific to the field of biopharmaceucticals, in particular, Formal meetings between the FDA and biosimilar in order to ensure a better understanding of biotech biological product sponsors or applicants manufacturing processes and relevant current regulatory This final guidance reflects a unified approach to all requirements, including laboratory testing and risk-based formal meetings between sponsors or applicants and the inspections of biopharmaceuticals facilities. The seminar FDA for biosimilar biological products. This guidance is also aimed at providing input for a revision of the current intended to assist sponsors or applicants in generating PIC/S Aide Memoire: Inspection of Biotechnology and submitting a meeting request and the associated Manufactures (PI-024-2), which entered into force on 1 meeting package to the FDA for biosimilar biological January 2006. 150 REGULATORY REVIEW
Croatia (HALMED) joins PIC/S anticoagulant medicine Pradaxa (dabigatran etexilate), HALMED of Croatia will join the Scheme from 1 January when rapid reversal of its effect is required. Praxbind is to 2016. HALMED will become PIC/S’ 48th Participating be used when a patient taking Pradaxa needs to undergo an Authority. The PIC/S assessment of HALMED was part of emergency surgery or when life-threatening or a tripartite assessment carried out jointly with the EU under uncontrolled bleeding occurs. the Joint Audits Programme as well as jointly by Health Pradaxa belongs to a new generation of oral Canada under the EU–Canada Mutual Recognition anticoagulants (medicines that prevent the blood from Agreement. clotting) approved over the past few years, which have given doctors and patients a wider range of options to WHO prevent and treat thromboembolic disorders in adults. Praxbind is the first medicine designed to specifically Guidance on Good Data and Record Management neutralise the anticoagulant effect of Pradaxa. Practices – Draft for Comment This guidance consolidates existing normative principles New EU guidance to speed up development of and gives further detailed illustrative implementation antibiotics guidance to bridge the gaps in current guidance. The EMA has released a draft guideline for public Additionally, it gives guidance as to what these high-level consultation on the use of pharmacokinetics and requirements mean in practice and what should be pharmacodynamics analyses in the development of demonstrably implemented to achieve compliance. antibiotics. The document provides guidance for the These guidelines highlight, and in some instances conduct of robust analyses to facilitate and speed up the clarify, the application of data management procedures. development of new antibiotics, in particular, those The focus is on those principles that are implicit in existing targeting multi-drug resistant bacteria. WHO guidelines and that if not robustly implemented can impact on data reliability and completeness and undermine HPV vaccines – EMA review the robustness of decision making based upon that data. The EMA has completed a detailed scientific review of the Illustrative examples are provided as to how these evidence surrounding reports of two syndromes, complex principles may be applied to current technologies and regional pain syndrome (CRPS) and postural orthostatic business models. These guidelines do not define all tachycardia syndrome (POTS) in young women given HPV expected controls to assure data reliability and this vaccines. These vaccines are given to protect them from guidance should be considered in conjunction with existing cervical cancer and other HPV-related cancers and pre- WHO guidelines on this topic. cancerous conditions. This review concluded that the (Readers should note that this draft has been issued evidence does not support a causal link between the directly to a restricted audience only, i.e. the individuals vaccines (Cervarix, Gardasil/Silgard and Gardasil-9) and and organisations having received this draft directly from development of CRPS or POTS. Therefore, the EMA WHO. It is provided to our readers to raise awareness of considers that there is no reason to change the way the WHO thinking on this topic. WHO have provided vaccines are used or amend the current Product permission for this – MH.) Information.
Inductos to be suspended in the EU Products The EMA has recommended the suspension of Inductos, an implant used to help new bone develop in patients with CE certificate for all medical devices made by Brazilian spinal disc problems and leg fractures. manufacturer Silimed suspended Inductos will remain suspended until issues with the European healthcare product regulators of member states manufacturing site for one of the components of Inductos have been informed of the suspension of the CE certificate (an absorbable sponge) are resolved. for all medical devices made by the Brazilian manufacturer The EMA started a review of Inductos following an Silimed. The German notified body, has recently carried inspection by Dutch and Spanish authorities which found out an inspection of the manufacturing plant in Brazil and the manufacturing site of the absorbable sponge to be non- established that the surfaces of some devices were compliant with manufacturing requirements. The contaminated with particles. inspectors noted that the manufacturer, located in the USA, did not have adequate measures in place to prevent particle Re-scheduling of codeine products (Australia) contamination of the sponges. Australia’s medicines regulator, the Therapeutic Goods Although there is no indication of risk to patients linked Administration, has published an interim decision on a to the inspection findings, EMA’s Committee for proposal to up-schedule codeine. The comment period Medicinal Products for Human Use (CHMP) considered ended on 15 0ctober 2015. that the quality of Inductos cannot be assured with the current manufacturing process. The CHMP, therefore, EMA fast-tracks antidote to anticoagulant Pradaxa concluded that Inductos should be suspended until the The EMA has recommended granting a marketing manufacturing issues are satisfactorily addressed. authorisation, following accelerated assessment, for The recommendation will be sent to the EC for a final Praxbind (idarucizumab) as a specific antidote to the legally binding decision. REGULATORY REVIEW 151
First oncolytic immunotherapy medicine recommended company’s ability to assure the sterility of drug products for approval that it produced. The FDA subsequently recommended that The EMA has recommended authorising Imlygic Park Compounding Pharmacy cease sterile operations until (talimogene laherparepvec) for the treatment of adults with adequate corrections are made at its facility, and recall all melanoma that cannot be removed by surgery and that has of its non-expired sterile drug products. On 30 September spread either to the surrounding area or to other areas of 2015, Park Compounding Pharmacy informed the FDA the body without affecting the bones, brain, lung, or other that it has agreed to cease sterile operations, but the internal organs. company has refused to recall its products. Imlygic is a first-in-class advanced therapy medicinal product derived from a virus, that has been genetically Further information on these and other topics can be found engineered to infect and kill cancer cells. in recent versions of the “Regulatory Update” on the PHSS website and on the websites of the relevant regulatory Drug products intended to be sterile by Chen Shwezin bodies and international organisations Inc. In addition a list of useful websites can be obtained During a recent inspection by the US FDA of Park from: [email protected] Compounding Pharmacy’s facility, FDA investigators Regulatory review is prepared by Malcolm Holmes, an observed insanitary conditions, including poor sterile independent consultant with over 40 years’ experience in production practices, which raise concerns about the senior roles within the pharmaceutical industry European Journal of Parenteral & Pharmaceutical Sciences 2015; 20(4): 152 © 2015 Pharmaceutical and Healthcare Sciences Society
PHSS Activity and Initiatives Report
As we start a new year, 2016, there is a need to reflect on the as with the PHSS Annual Conference, will open with a key challenges ahead in sterile and non-sterile product note speech from a regulatory perspective on challenges in manufacture and all associated activity in product sterile product GMP and QRM followed by a discussion panel development, scale up, clinical trials and transfer, to with senior representatives from the pharmaceutical, bio- production settings with formulation, filling, packaging, pharmaceutical and biotech industries and hospital distribution and compounding preparations – all following compounding/aseptic preparation pharmacies. In addition, principles of good manufacturing practice (GMP) and quality suppliers will provide demonstrations on new technology and risk management (QRM). best practice on some identified challenging areas of GMP. By now, we should all be aware of EU Guidelines to Good The conference will also include presentations on key Manufacturing Practice Annex 1 addressing the manufacture technology areas that are new and offer control measure of sterile medicinal products (including considerations for attributes that consider the need for flexibility, cost saving non-sterile product manufacture) is in revision with the first and speed to market for new products. draft expected mid-2016. Here we have to reflect not just on In 2016, the PHSS will continue to develop special interest what impact this revision will have in GMP for sterile product and focus groups that prepare discussion and guidance manufacturing and compliance, but why this revision is resources to assist all involved in GMP/QRM as we take on needed and the impact of those challenges. board the impact of GMP chapter and Annex revisions The need for EU Guidelines to Good Manufacturing together with the challenges and opportunities offered by new Practice Annex 1 is driven by a more complex profile of technology and changes in working practice. New process product types that have various and broad requirements from designs now more than ever have to consider cross- conventional sterile product manufacturing to unique contamination control and not just risks of sterile product requirements that respect the complex nature of some contamination from the environment and operators. biological products. These PHSS conferences and documented guidance For such a complex product and manufacturing profile, resources will continue to be free PHSS website downloads to there are challenges not just in product manufacturing all PHSS members as a significant member benefit. technologies and process design but in the knowledge levels Through 2016, the PHSS will also reinforce our to manufacture such products, where the basis of manufacture collaborations with other not-for-profit societies and has to be with implementation of QRM. New technologies are associations together with building the neutral platform for developing to meet these new challenges with technical and discussion between the pharmaceutical industry, healthcare organisation control measures now forming different and GMP sectors and the regulatory authorities. specific process designs following quality-by-design principles. In June 2016, the PHSS are planning another major James L Drinkwater conference on challenges in sterile product manufacturing Chairman of the PHSS considering key aspects of GMP and QRM. The conference, • • • • • • • •
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